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A S H A B S T R A C T S

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THE POLE OF PROTEIN KINASE-C AND C M O l l ' IN THE REGULATION OF INJOREPINEPHRITTF RELEASE FROf THE VASCULAR ADRENERGIC NEURONS IN HYPERTENSION K . T s u d a * , S . T s u d a , Y . F a s u y a m a a n d ¥ . G o l d s t e i n D i v i s i o n o f C a r d i o l o g y , Wakayama M e d i c a l C o l l e g e , Wakayama... J a p a n , a n d New Y o r k U n i v e r s i t y M e d i c a l C e n t e r , New Y o r k , N Y , U S A .

T h i s s t u d y w a s d e s i g n e d t o i n v e s t i g a t e t h e r o l e o f p r o t e i n k i n a s e - C a n d c a l c i u m i n t h e v a s c u l a r a d r e n e r g i c t r a n s m i s s i o n i n h y p e r t e n s i o n . I n p e r f u s e d m e s e n t e r i c v a s c u l a t u r e s o f s p o n t a n e o u s l y h y p e r t e n s i v e r a t s (SHR) a n d a g e - m a t c h e d W i s t a r K y o t o r a t s ( W K Y ) , we h a v e e x a m i n e d t h e e f f e c t s o f t h e s p e c i f i c p r o t e i n k i n a s e - C i n h i b i t o r , H-7, o n e n d o g e n o u s n o r e p i n e p h r i n e ( N E ) r e l e a s e a n d v a s c u l a r r e s p o n s i v e n e s s d u r i n g n e r v e s t i m u l a t i o n . (1) NE r e l e a s e a n d p r e s s o r r e s p o n s e s t o e l e c t r i c a l n e r v e s t i m u l a t i o n w e r e s i g n i f i c a n t l y g r e a t e r i n SHR t h a n i n WKY (NE r e ] e a s e a t 5 Hz:;SHR 0.68+0.05 n g / g o f w e t t i s s u e w e i g h t , n = 1 4 , WKY 0.24+0.03 n g / g , n = 1 4 , P < 0.01, 15 H z : S H R 1.87+0.12 n g / g , n = 1 4 , WKY 0.99+0.08 n g / g , n=14 , P<0.01). (2) T h e p r o t e i n k i n a s e - C i n h i b i t o r , H-7, i n h i b i t e d t h e s t i m u l a t i o n - e v o k e d NE r e l e a s e a n d p r e s s o r r e s p o n s e s d o s e - d e p e n d e n t l y . T h e s u p p r e s s i v e m a g n i t u d e s o f t h e s e r e s p o n s e s b y H-7 w e r e s i g n i f i c a n t l y g r e a t e r i n SHR t h a n i n WKY (NE r e l e a s e a t 15 H z : K-7 1.7X10 6 M , SHR 57.2+1.5 % o f t h e c o n t r o l NE r e l e a s e , n = 7 , WKY 94.0+8.3 % ,n=7, P<0.05, H-7 3.3X10~ 6 M, SHR 34.0+1.6 %,n=7 ,WKY 56.0 +3.2 % ,n=7 ,P<0.05). ( 3 ) C a l c i u m - r e m o v a l f r o m e x t r a c e l l u l a r f l u i d a l s o m o r e s t r o n g l y r e d u c e d t h e NE r e l e a s e in SHR t h a n i n WKY. T h e s e r e s u l t s i n d i c a t e t h a t p r o t e i n k i n a s e - C - a n d c a l c i u m - d e p e n d e n t NE r e l e a s e f r o m t h e v a s c u l a r a d r e n e r g i c n e u r o n s m i g h t b e e n h a c e d i.n SHR, w h i c h m i g h t c o n t r i b u t e , a t l e a s t p a r t i a l l y , t o t h e C a - r e l a t e d a b n o r m a l i t i e s i n t h i s m o d e l o f h y p e r t e n s i o n .

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AGE-RELATED CHANGES IN MEMBRANE FLUIDITY OF ERYTHROCYTES IN ESSENTIAL HYPERTENSION K.Tsuda*, S.Tsuda, Y.Masuyama and M.Goldstein Division of Cardiology, Wakayama Medical College, Wakayama, Japan, and New York University Medical Center, New York, NY, USA.

Our previous study showed that the membrane fluidity was decreased in essential hypertension. In the present study, we have examined the age-and calcium-related changes in the membrane fluidity in essential hypertension by use of an electron spin resonance method (ESR). Erythrocytes were obtai.ned from patients with untreated essential hypertension, and the ESR spectra for a fatty acid spi.n label agent(5-nitroxy stearate) incorporated i.nto the erythrocyte membranes were examined. (l)The value of outer hyperfine-splitting and order parameter(S) was significantly higher in essential hypertension than in the normotensive subjects(S value at 30°C:EH 0.742+0.004,n=45, NT 0.695+0.004,n=10,P<0.01). However, the values in secondary hypertension were not changed. This finding indicates that the membrane fluidity of erythrocytes was lower in essential hypertension. (2) Calcium-loading to erythrocytes with Ca-iono-phore A23187 decreased the membrane fluidity (S value was increased) more strongly in essential hypertension than in the normotensive subjects. This Ca-induced change in membrane fluidity was significantly correlated, with age in essential hypertension (r=0.44, P<0.05).

These results demonstrate that lower membrane fluidity of erythrocytes might be a genetically-determined abnormality in essential hypertension. Furthermore, it is suggested that this abnormality might be accelerated by calcium, especially in the aged essential hypertension.

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INHIBITORY ACTIONS OF OPIOID PEPTIDES ON VASCULAR ADRENERGIC TRANSMISSION IN SPONTANEOUSLY HYPERTENSIVE RATS AND DOCA-SALT HYPERTENSIVE RATS K.Tsuda* , S.Tsuda, Y.Masuyama and M.Goldstein Division of Cardiology, Wakayama Medical College, Wakayama, Japan, and New York University Medical Center, New York, NY, USA.

The purpose of this study was to investigate the effects of opioid peptide on the adrenergic transmission in blood vessels of hypertension. In perfused mesenteric vasculatures prepared from spontaneously hypertensive rats(SHR) and DOCA-salt hypertensive rats(DOCA-HT), the effects of an opioid pepti.de (methionine-enkephalin: Met-Enk) on vascular responsiveness and norepinephrine (NE) release from the sympathetic nerve endings were examined. (1) Stimulation-evoked pressor responses and NE release were inhibited by Met-Enk in a dose-dependent manner, and these effects were antagonized by naloxone. Vasoconstrictor responses to exogenous NE were not affected by Met-Enk. (2) In SHR,the pressor responses and NE release evoked by nerve stimulation were enhanced compared with age-matched Wistar Kyoto rats(WKY), alteratively the inhibition of these responses by Met-Enk was less in SHR than in WKY (Met-Enk 5.0X10 _ 7M:15 Hz NE release,SHR 77.4+4.9 % of the control NE value, n=5, WKY 50.3+5.0 %,n=5,P<0.05, Met-Enk 1.0X10~ 6M: SHR 65.4+5.0 %,n=5,WKY 36.7+2.0 %,n=5,P<0.05). (3) Met-Enk inhibited the pressor responses in DOCA-HT, while the suppression was similar to that in the normotensive controls. These results suggest that Met-Enk could affect NE release from the sympathetic nerve endings in blood vessels, and that the regulation of the adrenergic transmission by the opioid peptide might be impaired in SHR, but not in DOCA-salt hypertension.

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NEUROPEPTIDE Y AND GALANIN ENHANCE THE INHIBITORY EFFECTS OF CLONIDINE ON NOREPINEPHRINE RELEASE FROM MEDULLA OBLONGATA K.Tsuda*, S.Tsuda, Y.Masuyama and M.Goldstein Division of Cardiology, Wakayama Medical College, Wakayama, Japan, and New York University Medical Center, New York, NY, USA.

The medulla oblongata is thought to play an important role in the central regulation of blood pressure. Neuropeptide Y(NPY) and galanin(Gal) coexist with norepinephrine(NE) and may have a functional interaction in this region. The aim of this study was to investigate whether NPY and Gal could modulate the presynaptic neuronal mechanisms, especially the 0(2-adrenoceptor function, inhibiting NE release. In slices of medulla oblongata, clonidine, an 0(2-agonist, inhibited the NE release elicited by electrical stimulation in a dose-dependent manner (S2/S1 ratio: control 0.920+0.038,n=5, Clon.lO- 8M 0.515+0.029,n=5, P < 0.05, Clon.lO" 7M 0.173+0.017,n=5 ,P<0.05). A combination of clonidine and a low concentration of NPY(10~9M) resulted in an increase of the inhibitory activity of clonidine on stimulation-evoked NE release (S2/S1 ratio: Clon.lO _ 8M+NPY 0.200+ 0.039,n=5,P<0.05, Clon.l0 - 7M+NPY 0.021+0.017,n=5, P<0.05). Gal(10~ 8M) also potentiated the inhibitory effect of clonidine (S2/S1 ratio:Clon.lO _ 8M+ Gal 0.130+0.043,n=5,P<0.05, Clon.lO" 7M+Gal 0.038+ 0.017,n=5 ,P<0.05). These results indicate the existence of the presynaptic NPY-and Gal-receptors on the noradrenergic nerve terminals, which may enhance the presynaptic (X2-adrenoceptor function to inhibit NE release. This suggests a possible involvement of NPY and Gal in the regulation of the sympathetic nerve activity in the central nervous system.

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1 1 0 0 5 1 I N H I B I T I O N O F N O R E P I N E P H R I N E R E L E A S E FROM T H E VASCULAR ADRENERGIC NEURONS B Y ORAL A D M I N I S T R A T I O N O F β - B L O C K E R I N D O C A - S A L T H Y P E R T E N S I O N K . T s u d a * , S . T s u d a , Y . M a s u y a m a a n d M . G o l d s t e i n D i v i s i o n o f C a r d i o l o g y , W a k a y a m a M e d i c a l C o l l e g e , i W a k a y a m a , J a p a n , a n d New Y o r k U n i v e r s i t y M e d i c a l j C e n t e r , New Y o r k , N Y , U S A .

T h e a b i l i t y o f t h e β - b l o c k e r t o i n h i b i t t h e v a s c u l a r s y m p a t h e t i c n e r v e a c t i v i t y a s s o c i a t e d

; w i t h h y p e r t e n s i o n w a s s t u d i e d i n D O C A - s a l t h y p e r - j t e n s i v e r a t s . S e v e n w e e k t r e a t m e n t o f D O C A - s a l t r e s u l t e d i n a n i n c r e a s e i n t h e s y s t o l i c b l o o d

] p r e s s u r e . A d m i n i s t r a t i o n o f p r o p r a n o l o l ( 4 0 m g / L ; a n d 8 0 m g / L i n d r i n k i n g w a t e r ) s l i g h t l y i n h i b i t e d \ t h e d e v e l o p m e n t o f h y p e r t e n s i o n . A f t e r t h r e e w e e k j

I a d m i n i s t r a t i o n o f p r o p r a n o l o l , p e r f u s e d m e s e n t e r i c ; j v a s c u l a t u r e s w e r e p r e p a r e d i n v i t r o , a n d e n d o g e n o u s n o r e p i n e p h r i n e ( N E ) r e l e a s e a s w e l l a s v a s - | c u l a r r e a c t i v i t y w e r e e x a m i n e d . ( 1 ) P r e s s o r r e - ] s p o n s e s a n d e n d o g e n o u s NE r e l e a s e d u r i n g e l e c t r i c a l n e r v e s t i m u l a t i o n w e r e g r e a t e r i n D O C A - s a l t } h y p e r t e n s i o n t h a n i n t h e n o r m o t e n s i v e c o n t r o l s (NEJ r e l e a s e a t 1 5 H z : DOCA-HT 1 . 6 4 + 0 . 1 4 n g / g o f w e t t i s s u e w e i g h t , n = 5 , NT 0 . 7 2 + 0 . 1 0 n g / g , n = 6 , P O . 0 1 ) .

. ( 2 ) I n t h e p r o p r a n o l o l - t r e a t e d D O C A - s a l t h y p e r t e n s i v e r a t s , t h e s t i m u l a t i o n - e v o k e d NE r e l e a s e a n d p r e s s o r r e s p o n s e s w e r e s i g n i f i c a n t l y a t t e n u -a t e d c o m p a r e d w i t h t h e u n t r e a t e d D O C A - s a l t h y p e r t e n s i o n ( 1 0 Hz NE r e l e a s e : u n t r e a t e d DOCA-HT 1 . 3 6 + 0 . 0 8 n g / g , n = 5 , 4 0 m g p r o p . - t r e a t e d DOCA-HT 0 . 4 5 + 0 . 0 8 n g / g , n = 5 , 8 0 mg p r o p . - t r e a t e d DOCA-HT 0 . 3 1 + 0 . 0 9 n g / g , n = 5 , P < 0 . 0 1 ) . T h e s e r e s u l t s d e m o n s t r a t e t h a t p r o p r a n o l o l i n h i b i t e d t h e v a s c u l a r a d r e n e r g i c n e r v e a c t i v i t y i n D O C A - s a l t h y p e r t e n s i v e r a t s . T h i s s u g g e s t s a p o s s i b l e r o l e o f t h e p r e s y n a p t i c β - a d r e n e r g i c r e c e p t o r s i n t h e d e v e l o p m e n t o f D O C A - s a l t h y p e r t e n s i o n .

11007| THE NEW PEPTIDE URODILATIN (ANP-95-126) IN DOGS WITH AND WITHOUT HEART FAILURE A.3.G. Riegger, D. Eisner, P. Schulz-Knappe, W.G. Forssmann, Ε.Ρ. Kromer, Med. Univ.-Klinik Wurzburg and Dep. of Anatomy Univ. Heidelberg, FRG

In healthy dogs and dogs with congestive heart failure (CHF) (rapid right ventricular pacing 260/min;; 10 days) we investigated hemodynamic, hormonal and renal effects of a new 32 amino acid residue of ΑΝΡ-1- \ 126: urodilatin (ANP-95-126), which is most likely originated from renal tubules and secreted into the tubular lumen. In this experimental setting, iv infusions of alpha-ANP (99-126) covering a whole dose-response curve (0.01, 0.03, 0.1, 0.3 and 0.6 ,ug/kg/min; each for 30 min) had no renal effects in CHF. In control dogs >. urodilatin in equimolar concentrations sign. (p< 0.001) reduced right atrial pressure (RAP), stroke volume (SV), cardiac output (CO) and MAP. Urodilatin increased heart rate and did not change pulmonary arterial pressure (PAP) and peripheral vascular resistence (PVR). In contrast to alpha-ANP, no significant suppression of \ renin and aldosterone was observed. Urine flow and sodium excretion increased 2.4-fold ( p < 0.001). In CHF, unlike alpha-ANP, urodilatin stimulated urine flow 2.6-fold and urinary sodium excretion 3-fold ( p < 0.001). Under both conditions the dose-response curve was shifted to the left. Plasma cGMP was identically stimulated in healthy dogs and animals with CHF. In CHF urodilatin decreased RAP (p < 0.002) and PAP ( p < 0.001); CO, MAP, PVR, renin and aldosterone were unchanged. Urodilatin has similar hemodynamic effects as alpha-; ANP but its renal activity is much more potent, promising a new effective therapeutic approach in CHF.

11006| ENDOTHELIN(ET) STIMULATES PROSTAGLANDIN E 2 (PGE 2 ) PRODUCTION I N A CALCIUM-INDEPENDENT MANNER I N CULTURED RAT MSSANGIAL(M) CELLS. M . F u k u n a g a , Y . F u j i w a r a , S . O c h i , T.Takama, X.Yokoyama, Y . O r i t a ,

jT .Xamada. 1 s t . D e p t . o f M e d i c i n e , Osaka U n i v . sMedical School , Osaka,Japan.

To s t u d y a p o s s i b l e r o l e o f ET , a v a s c u l a r j e n d o t h e l i a l c e l l - d e r i v e d potent v a s o c o n s t r i c t o r , i n t h e r e g u l a t i o n o f g l o m e r u l a r f u n c t i o n , we examined the presence of s p e c i f i c b ind ing s i t e s and the b i o l o g i c a l a c t i o n of ET i n c u l t u r e d r a t Η c e l l s . Μ c e l l s w e r e p r e p a r e d f r o m i s o l a t e d g l o m e r u l i ( G ) of Sprague-Dawley r a t s and f i r s t - ! s u b c u l t u r e d c e l l s were used when t h e y a t t a i n e d subconf luent . ET b i n d i n g assay was performed by using 1 2 5 i _ i a b e i e ( j ET ( 1 2 ^ I - S T ) . PGE 2 was measured by r a d i o i m m u n o a s s a y . The s p e c i f i c b i n d i n g o f 1 2 ^ 1 - E T t o Μ c e l l s was t i m e - and t e m p e r a t u r e - * dependent, and Scatchard a n a l y s i s i n d i c a t e d the; p r e s e n c e o f a s i n g l e c l a s s o f h i g h a f f i n i t y ^binding s i t e s w i t h t h e a p p a r e n t d i s s o c i a t i o n c o n s t a n t ( I d ) o f 1 . 7 nM and t h e max ima l b i n d i n g

[capaci ty of 0 .23 pmol/mg p r o t e i n . E T ( 1 0 " 1 0 M - 1 0 _ 7 M ) s i g n i f i c a n t l y s t i m u l a t e d PGS 2 p r o d u c t i o n i n Μ c e l l s w i t h t h e t i m e c o u r s e and c o n c e n t r a t i o n dependency s i m i l a r to those of ^ ^ Ι - Ε Ί b i n d i n g . However, the i n t r a c e l l u l a r f r e e Ca c o n c e n t r a t i o n i n Μ c e l l s es t imated by Fura -2 was not a f f e c t e d by ET. We concluded t h a t : 1)M c e l l s have the h i g h -a f f i n i t y b i n d i n g s i t e s f o r ET l i n k e d t o t h e p r o d u c t i o n o f P G E 2 , w h i c h h a s b e e n known t o ;

i n h i b i t v a s o c o n s t r i c t o r - i n d u c e d Μ c e l l c o n t r a c t i o n . 2 )PGE 2 p roduct ion by ET i n Μ c e l l s i s t h r o u g h some unknown C a - i n d e p e n d e n t s i g n a l i n g mechanism. Our r e s u l t s suggest t h a t ET p lays an i m p o r t a n t r o l e i n t h e r e g u l a t i o n g l o m e r u l a r f u n c t i o n by modulat ing of mesangial c e l l f u n c t i o n .

110081 PROSTAGLANDINS, RENIN AND ATRIAL NATRIURETIC PEPTIDE IN THE CONTROL OF THE CIRCULATION AND RENAL FUNCTION IN HEART FAILURE IN THE DOG A.J.G. Riegger, D. Eisner, J . Hildebrand, K. Kosch, E.P. Kromer, Medizinische Univ.-Klinik Wurzburg, FRG

We investigated in an experimental model of congestive heart failure (CHF) in the dog (right ventricular pacing 240/min; 10 days) hemodynamic, hormonal and renal changes before and after indomethacin and captopril. We observed (day 0 - 7 , without pharmacological

i intervention) a sign, decrease of cardiac output (CO), mean arterial pressure (MAP) and an increase of right atrial pressure (RAP) (p-^0.001). Plasma norepinephrine j increased ( p < 0.01) and atrial natriuretic peptide (ANP) j from 6 + 1 to 56 + 10 pg/ml (p< 0.001) in correlation to RAP (r=0.67; ρ < 0.001). The stimulated ANP secretion ί led to a sign, suppression of plasma renin concentration \ (PRC) from 2.9 + 0.7 to 1.5 + 0.2 mg AI/ml/h ( p < 0.01). \ Renal blood flow (RBF) was unchanged, but glomerular \ filtration rate (GFR) was sign, reduced (p^O.Ol). Uri- ; nary secretion of PGE 2 increased in CHF, but plasma j

[levels of PGE.- and 6-keto PGF 1 alpha were unchanged. \ j Inhibition of PG-synthesis by indomethacin (day 8 -11) j did not change CO and MAP, but increased RAP and body weight by fluid retention. PGs were sign. i p < 0.001) reduced. Cyclo-oxygenase inhibition resulted ' in a dramatic increase of renal vascular resistance ί (48%) and a decrease of RBF (56%). GFR did not j change. Captopril in addition (day 11) reduced PVR, < RAP and renal vascular resistance and increased CO. Our results suggest a crucial role for vasodilator prostaglandins in maintaining RBF in heart failure and for angiotensin II in preserving GFR. They also show that j ANP may be able to suppress the renin system in the early phase of heart failure, despite a fall of MAP and a stimulation of sympathetic nerve activity.

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110091 E N D O T H E L I N INCREASES C A R D I A C OUTPUT AND P E R I P H E R A L R E S I S T A N C E . A . O t s u k a , H . M i k a m i , K . K a t a h i r a , T . T s u n e t o s h i , K . K o h a r a , K . M i n a m i t a n i , T . O g i h a r a . " * D e p t . o f G e r i a t r i c M e d i c i n e , O s a k a U n i v e r s i t y M e d i c a l S c h o o l . O s a k a 5 5 3 , J a p a n .

T o e v a l u a t e h e m o d y n a m i c e f f e c t s o f e n d o t h e l i n , 4 0 0 p m o l / k g o f e n d o t h e l i n w a s i n j e c t e d i n t r a v e n o u s l y t o n o r m a l a n d c h e m i c a l l y d e n e r v a t e d ( h e x a m e t h o n i u m ) p e n t o b a r b i t a l a n e s t h e t i z e d d o g s . T h e m e a n b l o o d p r e s s u r e ( M B P ) , h e a r t r a t e ( H R ) , c a r d i a c o u t p u t ( C O ) , s t r o k e v o l u m e ( S V ) , t o t a l p e r i p h e r a l r e s i s t a n c e ( T P R ) , r i g h t a t r i a l p r e s s u r e ( R A P ) , p u l m o n a r y a r t e r i a l p r e s s u r e ( P A P ) , p u l m o n a r y c a p i l l a r y w e d g e p r e s s u r e ( P C W P ) w e r e m o n i t o r e d f o r o n e h o u r a f t e r t h e a d m i n i s t r a t i o n . I n b o t h d o g s t h e MBP i n c r e a s e d w i t h t w o p e a k s . T h e f i r s t p e a k o f M B P ( 5 m i n : 1 2 1 % ) i n n o r m a l d o g s ( n = 5 ) r e s u l t e d f r o m i n c r e a s e i n t h e C 0 ( 1 1 9 % ) , a n d t h e s e c o n d p e a k o f M B P ( 3 0 m i n : 1 2 2 % ) w a s d u e t o i n c r e a s e i n t h e T P R ( 1 6 5 % ) a s s o c i a t e d w i t h d e c r e a s e i n t h e C 0 ( 7 8 % ) . T h e HR d e c r e a s e d i n t h e l a t e r p h a s e ( 6 0 m i n : 8 2 % ) . T h e SV i n c r e a s e d i n i t i a l l y ( 5 m i n : 1 1 9 % ) a n d d e c r e a s e d l a t e r ( 6 0 m i n : 8 0 % ) . I n d e n e r v a t e d d o g s ( n = 5 ) t h e f i r s t p e a k o f MBP ( 3 m i n : 1 3 7 % ) w a s d u e t o i n c r e a s e i n t h e C 0 ( 1 2 5 % ) , a s s o c i a t e d w i t h i n c r e a s e i n H R ( 1 0 4 % ) a n d S V ( 1 2 0 % ) . T h e s e c o n d p e a k o f MBP ( 3 0 m i n : 1 5 9 % ) w a s d u e t o i n c r e a s e i n t h e T P R ( 1 6 5 % ) w i t h o u t c h a n g e s i n t h e C O , SV o r H R . T h e R A P , PAP a n d PCWP i n c r e a s e d 3 t o 5 m i n a f t e r i t s i n j e c t i o n i n b o t h d o g s . T h u s e n d o t h e l i n h a s p o s i t i v e i n o t r o p i c a n d p o s i t i v e c h r o n o t r o p i c a c t i o n s a s w e l l a s v a s o c o n s t r i c t i v e a c t i o n . T h e c a r d i o -s u p p r e s s i v e a c t i o n i n l a t e r p h a s e may b e m e d i a t e d b y a n e u r a l m e c h a n i s m .

I ion I T A U R I N E ( T ) T R A N S P O R T I S INCREASED I N SYNAPTOSOMES ISOLATED FROM B R A I N OF SPONTANEOUSLY HYPERTENSIVE R A T S ( S H R ) . Η . T r a c h t m a n * , S . F u t t e r w e i t , R . d e l P i z z o . S U N Y - S t o n y B r o o k , S c h n e i d e r C h i l d r e n ' s H o s p . o f L I J M C , D e p t . P e d i a t r i c s , New H y d e P a r k , N Y .

T , a s u l f u r a m i n o a c i d , l o w e r s b l o o d p r e s s u r e i n m i n e r a l o c o r t i c o i d a n d SHR m o d e l s o f h y p e r t e n s i o n . S i n c e t h i s a c t i o n may b e m e d i a t e d b y t h e c e n t r a l n e r v o u s s y s t e m , w e e v a l u a t e d Τ t r a n s p o r t b y t h e N a + - c o t r a n s p o r t e r , u t i l i z i n g s y n a p t o s o m e s p r e p a r e d f r o m SHR. B r a i n s y n a p t o s o m e s w e r e i s o l a t e d f r o m SHR ( m e a n B P : 1 7 1 mmHg) a n d c o n t r o l W i s t a r - K y o t o (WS) r a t s ( m e a n B P : 1 0 3 mmHg) b y h o m o g e n i z a t i o n a n d p u r i f i c a t i o n o n a d i s c o n t i n u o u s F i c o l l g r a d i e n t a n d t h e i r s t r u c t u r a l i n t e g r i t y c o n f i r m e d b y e l e c t r o n m i c r o s c o p y . Τ u p t a k e was a s s a y e d a t 3 7 ° C i n t h e p r e s e n c e o f a n i n w a r d l y - d i r e c t e d N a + g r a d i e n t u s i n g a r a p i d f i l t r a t i o n t e c h n i q u e . N o n s p e c i f i c b i n d i n g a n d u p t a k e w e r e a s s e s s e d i n t h e p r e s e n c e o f a K + - g r a d i e n t , t h e d i f f e r e n c e ( Δ ) b e t w e e n N a + - a n d K + - g r a d i e n t t r a n s p o r t r e p r e s e n t i n g s p e c i f i c Τ u p t a k e . ( R e s u l t s : m e a n ± S E M ) . I n c u b a t i o n E x t e r n a l T a u r i n e U p t a k e ( u M / m g P r o t e i n )

T i m e M e d i u m ' SHR ( N = 1 0 ) WK ( N = 1 0 ) ~ 1

6 0 Na 4 . 9 4 ± 0 . 1 8 * 4 . 3 6 ± 0 . 2 3 Κ 1 . 1 2 ± 0 . 0 5 1 . 1 7 ± 0 . 0 3 Δ 3 . 8 1 ± 0 . 1 6 * 3 . 1 9 ± 0 . 2 4

1 2 0 Na 5 . 4 5 + 0 . 3 5 * 4 . 7 2 + 0 . 2 6 Κ 1 . 4 9 + 0 . 0 7 1 . 5 0 ± 0 . 3 8 Δ 3 . 9 6 ± 0 . 3 1 * 3 . 2 1 ± 0 . 2 5

* ρ < 0 . 0 5 , SHR v s WK ( p a i r e d t - t e s t ) . T h e s e r e s u l t s i n d i c a t e t h a t c e r e b r a l Τ t r a n s

p o r t i s e n h a n c e d b y 15% i n s y n a p t o s o m e s i s o l a t e d f r o m SHR. T h i s a d a p t i v e i n c r e a s e i n b r a i n Τ u p t a k e may b e i n s t r u m e n t a l i n t h e h y p o t e n s i v e a c t i o n o f t h i s a m i n o a c i d .

1 0 1 0

NEPHRON SITES OF T H E NATRIURETIC E F F E C T OF L O W D O S E I N T R A R E N A L INFUSION OF A T R I A L NATRIURETIC PEPTIDE IN THE RAT. J . -L . Ader * . F. Praddaude, and T. Tran-Van. Med. School and Inserm U133 , Toulouse, France.

The mechanisms by which atrial natriuretic peptide (ANP) induces a natriuresis, i.e. the extent to which alterations in glomerular filtration rate (GFR) and/or in tubular reabsorption participate in this effect, are the subject of controversy. The effects of the infusion of a low dose (0 .03 μ ^ π ύ η ^ body weight) of rANP 1-28 into the right renal artery (via a very thin catheter inserted into the suprarenal artery) were therefore studied in 33 anesthetized male Wistar rats compared with 14 vehicle-infused control rats. Lithium clearance (C Li) was used to monitor proximal tubular function.

Right intrarenal ANP infusion did not cause changes in blood pressure nor in left kidney inulin clearance, handling of sodium and C Li. ANP did not alter right kidney PAH clearance while significantly increasing ( P < 0 . 0 0 1 ) inulin clearance, filtration fraction (by 3.7 ± 1.0 %) and the filtered load of sodium (by 23.4 ± 5.3 μmoVπlin/g kidney weight). Whole right kidney absolute and fractional excretion of sodium increased by 1.5 ± 0.4 umol/min/g and 0.9 ± 0.3 % respectively (P<0.001) . ANP increased C Li by 22 .2 ± 16.7 μΐ/min/g (P<0 .01) and proximal tubule absolute sodium reabsorption by 19.8 ± 4.9 umol/min/g (P<0.001) , but caused no change in proximal tubule fractional reabsorption (78.5 ± 6.6 % ) . The delivery of sodium from the proximal tubule and the absolute reabsorption by the distal parts of the nephron increased by 3.5 ± 2.2 and 2.3 ± 1.9 uxnol/min/g respectively (P<0.01). However, the distal fractional reabsorption of filtered and of distally delivered sodium decreased by 1.7 ± 1.3 and 3.8 ± 1.3 % respectively (P<0.01) .

When ANP has no systemic action, its natriuretic effect on the nephron results from two mechanisms : an increase in the filtered load of sodium and a decrease in reabsorption in the distal parts. Proximal tubule sodium reabsorption is not decreased by ANP and increases in proportion to the filtered load.

1 0 1 2

IMPAIRED RENAL RESPONSE TO A T R I A L N A T R I U R E T I C P E P T I D E ( A N P )

I N ESTABLISHED ACUTE RENAL FA ILURE ( A R F ) OF C R I T I C A L L Y

I L L P A T I E N T S .

E . H e i d b r e d e r ^ R . G O t z ^ K . B a u s e w e i n 1 , H . G e i g e r ^ C h . E i l -

l e s 2 , M . S o l d 3 , G . E r t l 4 , W . H a b s c h e i d 4 , A . H e i d l a n d 1 . ^ e p t .

o f N e p h r o l o g y , ^ D e p t . o f N u c l e a r m e d i c i n e . ^ I n s t i t u t e o f A n a e s -

t h e s i o l o g y , 4 M e d i c a l I n t e n s i v e C a r e U n i t , U n i v e r s i t y o f

W C I r z b u r g , FRG

I n s e v e r e a n i m a l s t u d i e s ANP was a b l e t o a m e l i o r a t e e a r l y

i s c h e m i c ARF o r t o x i c A R F . T h e r e f o r e , we i n v e s t i g a t e d t h e

e f f e c t o f ANP i n c r i t i c a l l y i l l p a t i e n t s w i t h e s t a b l i s h e d

ARF r e s i s t a n t t o d o p a m i n e a n d f u r o s e m i d e a p p l i c a t i o n . 17

p t s . o f i n t e n s i v e c a r e u n i t s ( 1 2 m a l e , 5 f e m a l e ) w e r e s t u d i e d .

1 0 p t s . w e r e a n u r i c , 7 p t s . n o n - o l i g u r i c ( 1 5 0 0 m l / d ) .

ANF ( 1 - 2 8 h - A N a P , B i s s e n d o r f , W . - G e r m a n y , 2 . 5 M g / m i n ) was

i n f u s e d c o n t i n u o u s l y f o r 3 h o u r s . F o l l o w i n g p a r a m e t e r s

w e r e m e a s u r e d b e f o r e a n d d u r i n g ANP i n f u s i o n : u r i n e v o l u m e ,

c r e a t i n i n e , e l e c t r o l y t e s , o s m o l a l i t y i n s e r u m a n d u r i n e ,

p l a s m a c a t e c h o l a m i n e s , p l a s m a r e n i n a c t i v i t y ( P R A ) , p l a s m a

ANP a n d g l o m e r u l a r f i l t r a t i o n r a t e ( G F R , C r - E D T A ) .

I n a n u r i c p t s . ANP was n o t a b l e t o r e v e r s e a n u r i a . I n n o n -

o l i g u r i c p t s . u r i n e v o l u m e i n c r e a s e d ( 5 0 m l / h t o 1 6 0 m l / h ,

NS) o n l y d u r i n g i n f u s i o n p e r i o d . GFR d i d n o t c h a n g e s i g n i f i

c a n t l y b o t h i n t h e a n u r i c g r o u p a n d i n t h e n o n - o l i g u r i c

g r o u p ( 1 2 m l / m i n t o 1 5 m l / m i n , N S ) . S o d i u m e x c r e t i o n ( F E N a )

i n c r e a s e d i n s i g n i f i c a n t l y . A l l p t s . showed a s l i g h t e l e v a t i o n

o f h e m o g l o b i n a n d h e m a t o c r i t . P l a s m a ANP r o s e up f r o m 2 1 1 + 3 3

t o 1 1 7 5 + 3 1 0 p g / m l . A s l i g h t d e c r e a s e o f PRA was o b s e r v e d

i n b o t h g r o u p s , a n e l e v a t i o n o f p l a s m a n o r e p i n e p h r i n e o n l y

i n t h e n o n - o l i g u r i c s t a t e s .

T h e s e d a t a s u g g e s t t h a t ANP was n o t a b l e t o i m p r o v e e s t a b

l i s h e d ARF i n c r i t i c a l l y i l l p t s . We c o n c l u d e t h a t ANP

i s t o i n f u s e e a r l i e r b e f o r e m o r e s e v e r e f u n c t i o n a l a n d

a n a t o m i c a l l e s i o n s d e v e l o p e .

Dow



[10131 REDUCTION OF PROTEINURIA IN "PATIENTS SUFFERING FROM NEPHROTIC SYNDROME BY LONG-TERM ACE-INHIBITON - MORE THAN AN ANTIHYPERTENSIVE EFFECT? R Go'tz, U Drechsler , Ε Heidbreder, A Heidi and. Dept. of Nephrology, Medical U n i v e r s i t y of Wurzburg, FRG In a prospective study over a period of 24 weeks the e f f e c t s of the new ACE- inhib i tor Ramipri l on renal funct ion ^ / c r e a t i n i n e , Cr51-EDTA-Clearance), p r o t e i n u r i a ( b i u r e t ) , t o t a l serum p r o t e i n , albumin and mean a r t e r i a l blood pressure were invest iga ted in pat ien ts su f fe r ing from h i s t o l o g i c a l l y proven glomerulonephr i t is (GN) wi th nephrot ic syndrome (NS) . We examined 23 pa t ien ts wi th s l i g h t l y impaired renal func t ion (mean age 34.5 y e a r s , male n=18.female n=5) wi th GN and NS (membranous GN, n=8, mesang io -pro l i f e ra t i ve GN, n=8, foca l s c l e r o s i s , n = 7 ) . Ramipri l ( 1 . 2 5 mg) was admini stered every second day wi th increasing doses up to 2.5 mg/day f o r 24 weeks. Mean a r t e r i a l pressure (MAP) f e l l from 113 to 102 mmHg i n the f i r s t 10 weeks (p 0 . 0 1 ) . In the f o l l o w i n g 14 weeks MAP remained unchanged. During the whole study period prot e i n u r i a f e l l s i g n i f i c a n t l y from 10.4 to 8 .4 g/day (p 0 . 0 1 ) . Simultaneously there was a s i g n i f i c a n t increase of t o t a l serum prote in from 5 .2 g/d l to 5.9 g/d l and albumin from 3.2 to 3.7 g/d l (p 0 . 0 1 ) . A f t e r a i n s i g n i f i c a n t decrease w i th in the f i r s t 2 weeks the r a t i o ^ / c r e a t i n i n e remained s tab le ( 0 . 78 1/mg% week 0 and week 2 4 ) . The GFR showed no s i g n i f i c a n t change (73 ml/min to 69 ml/min) during the treatment . Side e f f e c t s from the drug therapy were neglec-t a b l e . We conclude, t h a t long term admin is t ra t ion of the ACE- inh ib i t o r e f f e c t i v e l y reduces blood pressure and p r o t e i n u r i a in these p a t i e n t s . The l a t t e r e f f e c t i s presumably not only the r e s u l t of a lower blood pressure, but i s also due to a f a l l i n in t rag lomeru lar c a p i l l a r y pressure without impairment of renal f u n c t i o n . This treatment may be b e n e f i c i a l in pa t ien ts su f fe r ing from GN wi th NS.

[1015 THE EFFECT Or HUMAN A T R I A L N A T R I U R E T I C P E P T I D E ON I N S U L I N LEVELS I N HEALTHY VOLUNTEERS. Τ H a a k , b J u n g m s n n , Β H a n n a p p e l , Κ S c h o f f l i n g . D e p t . o f E n d o c r i n o l o g y , U n i v e r s i t y C l i n i c , F r a n k f u r t , , - o d e r a l R e p u b l i c o f G e r m a n y .

I n p r i o r L i c u d i e s , a p h a r m a c o l o g i c a l d o s e o f human a t r i c l n a t r i u r e t i c p e p t i d e (hANP) ( 1 0 0 pg i . v . ) was round t o i n c r e a s e s e r u m i n s u l i n . T o e x a m i n e w. ' iouher a n d how i n s u l i n r e s p o n s e t o a n o r a l o r i . v . r j l u c o s e l o a d a r e i n f l u e n c e d by e l e v a t e d . h A N P l e v a l s w i t h i n a p h y s i o l o g i c a l r a n g e , 3 h e a l t h y , n o r m a l - w e i g h t e d , m a l e v o l u n t e e r s r e c e i v e d i n r a n d o m o r d e r 0 . 3 p g / m i n hANP ( B i s s e n -d o r f P e p t i d e , FRG) o r p l a c e b o . 3 0 m i n a f t e r t h e i n f u s i o n s w e r e s t a r t e d , an o r a l g l u c o s e l o a d ( 7 5 g ) o r a n i . v . g l u c o s e b o l u s i n j e c t i o n ( G . 5 g / kg bw) w e r e g i v e n .

D u r i n g t h e h A N P - i n f u s i o n s maximum hANP l e v e l s w e r e 7 2 Ζ 1 1 p g / m l . hANP i n c r e a s e d t h e a r e a u n d e r t h e c u r v e o f s e r u m i n s u l i n f r o m 5 6 8 6 ± 1 0 4 7 i n t h e p l a c e b o e x p e r i m e n t t o 6 3 5 3 ± 3 8 0 ( p < 0 . 0 5 ) . i n t h e o r a l g l u c o s e t o l e r a n c e t e s t . I n t h e i . v . g l u c o s e t o l e r a n c e t e s t i n s u l i n l e v e l s i n c r e a s e d f r o m 1 8 9 2 ± 2 6 4 t o 2 1 9 4 ± 5 2 0 - ( p < 0 , 0 5 ) . R e s p o n s e s o f b l o o d g l u c o s e a n d C - p e p t i d e l e v e l s w e r e u n a f f e c t e d by hANP- i n b o t h s t u d i e s . T h u s , e l e v a t e d hANP l e v e l s w i t h i n t h e p h y s i o l o g i c a l r a n g e l e a d t o an i n c r e a s e o f s e r u m i n s u l i n w i t h o u t i n f l u e n c i n g C - p e p t i d e c o n c e n t r a t i o n s . T h e r e f o r e , hANP d o e s n o t i n t e r f e r e w i t h i n s u l i n s e c r e t i o n , b u t a p p e a r s t o i n h i b i t i n s u l i n d e g r a d a t i o n .

I ioi4| BUCCAL N I F E D I P I N E ENHANCES RENAL RESPONSES TO H U MAN A T R I A L N A T R I U R E T I C P E P T I D E I N HEALTHY MAN E . J u n g m a n n , T . H a a k , S . Z e u z e m , K. S e e l , E . H o f -m a n n , E . - H . S c h e u e r m a n n , K. S c h o f f l i n g , C e n t e r o f I n t e r n a l M e d i c i n e , J o h a n n W o l f g a n g G o e t h e - U n i v e r s i t y , F r a n k f u r t am M a i n , FRG T o e x a m i n e p o t e n t i a l i n t e r a c t i o n o f t h e c a l c i u m a n t a g o n i s t n i f e d i p i n e w i t h human a t r i a l n a t r i u r e t i c p e p t i d e ( h A N P ) , t h e e f f e c t s o f n i f e d i p i n e 15 mg g i v e n a s b u c c a l s p r a y ( M u n d i p h a r m a , FRG) o n t h e a c t i o n o f hANP 1 0 0 μ ς i v ( B i s s e n d o r f P e p t i d e , FRG) o n b l o o d p r e s s u r e , h e a r t r a t e a n d r e n a l a n d h o r m o n a l i n d e x e s w e r e s t u d i e d i n 8 m a l e v o l u n t e e r s ( a g e , 2 8 + 1 y e a r s ) a c c o r d i n g t o a d o u b l e - b l i n d , r a n d o m i z e d , p l a c e b o - c o n t r o l l e d t r i a l d e s i g n u s i n g t h e d o u b l e - d u m m y t e c h n i q u e . Max imum n i f e d i p i n e l e v e l s a t t a i n e d d u r i n g t h e s t u d y w e r e 3 5 + 5 n g / m l . I n t h e h A N P - o n l y e x p e r i m e n t , d i u r e s i s a n d n a t r i u r e s i s w e r e i n c r e a s e d ( p < 0 . 0 5 ) , b u t b l o o d p r e s s u r e , h e a r t r a t e a n d p l a s m a r e n i n a c t i v i t y w e r e l e f t u n c h a n g e d . I n t h e n i f e d i p i n e - o n l y e x p e r i m e n t , n a t r i u r e s i s a n d d i u r e s i s w e r e l i k e w i s e s t i m u l a t e d ( p < 0 . 0 5 ) , t o g e t h e r w i t h d e c r e a s e d d i a s t o l i c b l o o d p r e s s u r e a n d i n c r e a s e d p l a s m a r e n i n a c t i v i t y , h e a r t r a t e a n d hANP p l a s m a l e v e l s ( a l l p < 0 . 0 5 ) . N i f e d i p i n e + hANP r e s u l t e d i n f u r t h e r e n h a n c e m e n t o f d i u r e s i s a n d n a t r i u r e s i s ( p ^ 0 . 0 5 ) , o t h e r p a r a m e t e r s d i d n o t d i f f e r f r o m n i f e d i p i n e - o n l y e x p e r i m e n t . C r e a t i n i n e c l e a r a n c e d i d n o t c h a n g e t h r o u g h o u t t h e s t u d y . T h u s , d e s p i t e i t s h y p o t e n s i v e a c t i o n a n d i t s s t i m u l a t i n g e f f e c t o n p l a s m a r e n i n a c t i v i t y , n i f e d i p i n e e n h a n c e d r e n a l e f f i c a c y o f o f hANP i n h e a l t h y m a n , m o s t p r o b a b l y b y t h e s y n e r g i s m o f b o t h s u b s t a n c e s i n t h e r e n a l t u b u l a r s y s t e m .

I1016I HUMAN A T R I A L N A T R I U R E T I C P E P T I D E LEVELS I N P A T I E N T S W I T H ADRENAL F A I L U R E : EFFECT OF GLUCOCORT I C O I D REPLACEMENT THERAPY E . J u n g m a n n , T . N i c k e l s e n , P . - M . S c h u m m - D r a e g e r , E . S c h i f f e r d e c k e r , B . O . Bohm, T . H a a k , K. S c h o f f -l i n g . C e n t e r o f I n t e r n a l M e d i c i n e , J o h a n n W o l f g a n g G o e t h e - U n i v e r s i t y , F r a n k f u r t am M a i n , FRG

T o e x a m i n e p o t e n t i a l e f f e c t o f g l u c o c o r t i c o i d s o n human a t r i a l n a t r i u r e t i c p e p t i d e ( h A N P ) l e v e l s i n p a t i e n t s w i t h a d r e n a l f a i l u r e , hANP a n d C o r t i s o l l e v e l s , p l a s m a r e n i n a c t i v i t y , h e a r t r a t e a n d b l o o d p r e s s u r e w e r e s t u d i e d i n 8 p a t i e n t s w i t h A d d i s o n ' s d i s e a s e a n d 10 p a t i e n t s w i t h s e c o n d a r y a d r e n a l f a i l u r e , a g e d 2 8 - 6 8 y e a r s , b e f o r e a n d a f t e r a 2 4 - h o u r w i t h d r a w a l o f h y d r o c o r t i s o n e / c o r -t i s o n e r e p l a c e m e n t - t h e r a p y . C o m p a r e d t o h e a l t h y s u b j e c t s , hANP l e v e l s w e r e i n c r e a s e d ( 2 2 + 4 v s 13 + 1 p g / m l , p < ^ 0 . 0 5 ) , a l t h o u g h b l o o d p r e s s u r e was n o r m a l i n a l l p a t i e n t s . I n t h e w i t h d r a w a l e x p e r i m e n t , C o r t i s o l l e v e l s f e l l f r o m 2 0 + 2 t o 5 + 1 u g / d l ( p ^ O . 0 1 ) . B l o o d p r e s s u r e , h e a r t r a t e , p l a s m a r e n i n a c t i v i t y a n d hANP l e v e l s r e m a i n e d u n c h a n g e d . H o w e v e r , hANP l e v e l s w e r e f o u n d t o b e i n c r e a s e d f r o m 2 4 + 9 t o 2 8 + 1 0 p g / m l ( p < 0 . 0 5 ) i n p a t i e n t s r e s p o n d i n g t o t h e w i t h d r a w a l e x p e r i m e n t w i t h i n c r e a s e d b l o o d p r e s s u r e , w h i l e hANP l e v e l s f e l l f r o m 1 7 + 3 t o 14 + 4 p g / m l ( p < * 0 . 0 1 ) i n p a t i e n t s e x h i b i t i n g a d e c r e a s e i n o l o o d p r e s s u r e . T h u s , c h a n g e s i n hAiJP l e v e l s i n p a t i e n t s w i t h a d r e n a l f a i l u r e e x c l u s i v e l y c o r r e s p o n d e d w i t h c h a n g e s i n b l o o d p r e s s u r e a n d w e r e i n d e p e n d e n t o f c h a n g e s i n s e r u m C o r t i s o l . T h i s i s i n k e e p i n g w i t h f i n d i n g s i n p a t i e n t s w i t h C u s h i n g ' s d i s e a s e w h e r e hANP l e v e l s w e r e n o t h i g h e r t h a n e x p e c t e d f r o m h y p e r t e n s i v e d i s e a s e .

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AGE IS THE PRIMARY DETERMINANT OF PLASMA ATRIAL NATRIURETIC PEPTIDE (ANP) RESPONSE TO VARIED SODIUM (Na) INTAKE IN HYPERTENSIVE SUBJECTS. E .D. B u r g e s s * , P.M. K e a n e * , R .G. Hawkins, M. W a t a n a b e * , T . Wong. U n i v e r s i t y o f C a l g a r y , C a l g a r y , A l b e r t a , Canada

S i x t y - s i x d r u g - f r e e h y p e r t e n s i v e s u b j e c t s were s t u d i e d on both 10 and 100 mmol Na i n t a k e s . Blood p r e s s u r e s were measured and b lood samples were drawn on day 5 o f each d i e t segment a f t e r o v e r n i g h t recumbency. Plasma ANP i n c r e a s e d (mean±SE) from 9 . 8 ± 0 . 7 t o 1 4 . 5 ± 1 . 0 p m o l / L , p = 0 . 0 0 1 . Mean a r t e r i a l p r e s s u r e (MAP) did not change ( 1 0 6 . 0 ± 1 . 3 t o 1 0 5 . 9 ± 1 . 7 mmHg). D i v i s i o n o f s u b j e c t s i n t o t e r t i l e s a c c o r d i n g t o plasma ANP on 100 mmol Na d j e t r e v e a l e d s i g n i f i c a n t d i f f e r e n c e s a c r o s s groups f o r a g e , plasma ANP r e s p o n s e , and plasma ANP and plasma r e n i n a c t i v i t y (PRA) on both Na i n t a k e s . Plasma ANP l e v e l s on 10 and 100 mmol Na d i e t and plasma ANP r e s p o n s e s c o r r e l a t e d t o age ( r = 0 . 5 3 0 , p = 0 . 0 0 1 ; r = 0 . 6 2 4 , p = 0 . 0 0 1 ; r = 0 . 4 7 7 , p = 0 . 0 0 1 r e s p e c t i v e l y ) . Although plasma ANP l e v e l s appeared t o be c o r r e l a t e d with PRA and plasma a l d o s t e r o n e c o n c e n t r a t i o n , t h i s was not s i g n i f i c a n t when c o n t r o l l e d f o r a g e . MAP r e s p o n s e ranged from - 1 6 . 7 t o 1 9 . 4 mmHg and was r e l a t e d t o age ( r = 0 . 3 1 6 , p = 0 . 0 1 ) but not t o plasma ANP r e s p o n s e . T h e r e f o r e plasma ANP l e v e l s on c o n t r o l l e d d i e t s and plasma ANP r e s p o n s e t o i n c r e a s e d d i e t a r y Na a r e r e l a t e d t o a g e , but not t o MAP, PRA o r plasma a l d o s t e r o n e c o n c e n t r a t i o n .

1 0 1 9

MECHANISMS OF HYPERTENSION INDUCED BY ERYTHROPOIETIN IN PATIENTS ON HEMODIALYSIS. M. Yamakado*', M.Umezu, M.Nagano, T.Takano, H.Tagawa, H.Kiyose. Dept. of Int. Med., Mitsui Memorial Hospital, Tokyo, Japan.

To i n v e s t i g a t e the m e c h a n i s m s of hypertension induced by recombinant human erythropoietin (rHuEPO) in patients on hemodialysis (HD), mean blood pressure (MBP), PRA, PAC, PNE, PE, whole blood viscosity, blood volume (BV), cardiac index (CI) and total peripheral resistance index (TPRI) were measured before and after the treatment of rHuEPO for 3 months in 9 patients on HD. Pressor responsiveness to exogenous NE were also compared before and after the treatment. According to the responses of MBP to rHuEPO, 4 patients were classified as "responder" (R) whose MBP increased by more than 10% and 5 patients as "non-responder" (non-R) whose MBP did not change or increased by less than 10% of the initial MBP. Initial values of PRA and TPRI were significantly higher and BV was significantly less in R than in non-R. After the treatment of rHuEPO, TPRI was increased in both groups, however CI was decreased only in non-R, but not in R. There was a significant correlation between changes in MBP and viscosity to rHuEPO. Pressor responsiveness to NE in R was significantly enhanced after the treatment. These results suggest that inappropriate cardiovascular responses to correction of the anemia with rHuEPO and enhanced pressor responsiveness to pressor substances may participate in the mechanisms of hypertension induced by rHuEPO.

1 0 1 8

RELATIONSHIP OF MEAN ARTERIAL PRESSURE (MAP), SERUM CALCIUM (SCa) AND 1 , 2 5 VITAMIN D ( V i t D ) RESPONSES TO ALTERED SODIUM INTAKE DIFFERS IN LOW-NORMAL VERSUS HIGH RENIN HYPERTENSION. E .D. B u r g e s s * , P.M. K e a n e * , T . Wong, M. W a t a n a b e * , R.G. Hawkins. U n i v e r s i t y o f C a l g a r y , C a l g a r y , A l b e r t a

T w e n t y - s i x d r u g - f r e e h y p e r t e n s i v e s u b j e c t s were s t u d i e d on both 10 and 100 mmol Na d i e t s (K 100 mmol, Ca 25 mmol) . Blood p r e s s u r e s were measured and blood samples were drawn on day 5 o f each d i e t segment a f t e r o v e r n i g h t recumbency. High r e n i n s u b j e c t s ( H R ) ( n = 1 0 ) had plasma r e n i n a c t i v i t y ( P R A ) ^ _ 0 . 4 5 n g / L / s , and low-normal ( L N ) ( n = 1 6 ) had P R A < 0 . 4 5 n g / L / s . With i n c r e a s e d Na i n t a k e , u r i n a r y Ca e x c r e t i o n (mmol/D) i n c r e a s e d (mean±SE)(LN 2 . 6 ± 0 . 2 t o 3 . 2 ± 0 . 3 p = 0 . 0 1 3 ; HR 2 . 5 ± 0 . 5 t o 3 . 4 ± 0 . 6 , p = 0 . 0 1 1 ) . The change in SCa ( c o r r e c t e d f o r changes in serum a lbumin) was - 0 . 0 1 ± 0 . 0 1 mmol/L (p=NS) in both LN and HR. Plasma VitD ( p m o l / L ) i n c r e a s e d 5 1 . 2 ± 5 . 5 t o 6 1 . 0 ± 5 . 4 ( p = 0 . 0 4 5 ) o n l y in HR. In LN, MAP r e s p o n s e was d i r e c t l y c o r r e l a t e d t o c o r r e c t e d changes in SCa ( r = 0 . 6 8 3 , p = 0 . 0 0 4 ) , but in HR was i n v e r s e l y c o r r e l a t e d ( r = - 0 . 7 7 8 , p = 0 . 0 0 8 ) . In HR, MAP r e s p o n s e c o r r e l a t e d i n v e r s e l y t o p e r c e n t change in VitD (%dVitD) ( r = - 0 . 6 5 0 , p = 0 . 0 4 2 ) , but not in LN ( r = 0 . 2 5 7 ) . P e r c e n t change o f PRA and %dVitD were i n v e r s e l y c o r r e l a t e d in HR ( r = - 0 . 7 5 6 , p = 0 . 0 1 ) . I n c r e a s e d Na i n t a k e r e s u l t s i n i n c r e a s e d UCa, but f a l l s in SCa may be a t t e n u a t e d by i n c r e a s e d VitD s e c r e t i o n . The MAP r e s p o n s e c o r r e l a t e s d i f f e r e n t l y t o changes in SCa and VitD in LN v e r s u s HR, p o s s i b l y due t o u n d e r l y i n g p a t h o p h y s i o l o g i c a l d i f f e r e n c e s .

1 0 2 0

ROLE OF ANP IN THE REGULATION OF FLUID VOLUME IN PATIENTS ON HEMODIALYSIS: RESPONSES OF ANP TO CORRECTION OF THE ANEMIA WITH RECOMBINANT HUMAN ERYTHROPOIETIN (rHuEPO). M. Yamakado'*, M.Umezu, M.Nagano, H.Tagawa, M.Ishibashi, T.Yamgaji. Dept. of Int. Med., Mitsui Memorial Hospital, Tokyo, Japan.

To a s s e s s the role of ANP in the regulation of fluid volume in patients on hemodialysis (HD), changes in ANP, hematocrit (Ht), PRA, PAC, PNE, PE, blood volume (BV), left atrial dimension (LAD) and ejection fraction (EF) were measured before and after correction of the anemia with rHuEPO in 9 patients on HD. After the treatment of rHuEPO for 3 months, Ht was significantly increased from 18.5% to 29.5. BV was also increased from 79.5 ml/kg to 82.9. Basal ANP was significantly correlated with blood volume. According to the responses of ANP to rHuEPO, patients were divided into two groups as follows: increasing group (I) whose ANP was significantly increased from 212±69 pg/ml to 316+69 and decreasing group (D) whose ANP was significantly decreased from 480±140 to 228±86. PNE was significantly higher in D than that of I after the treatment and there was a significant correlation between changes in ANP and PNE (r=-0.65, p<0.05). EF was significantly increased to rHuEPO in D but not in I and a significant correlation was observed between changes in ANP and EF (r= -0.67, p<0.05). These results suggest that ANP may play an i m p o r t a n t r o l e in the regulation of body fluid as a protector against volume overload in patients on HD.

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[1021 ALTERED ATRIAL NATRIURETIC PEPTIDE LEVELS IN THE LOCUS COERULEUS FOLLOWING EXPERIMENTAL CHANGES IN THE BODY FLUID AND ELECTROLYTE HOMEOSTASIS. Η Geiger*, U Banner, Μ Palkovits1, A Heidland. Dept. of Nephrology, Medical University of WUrzburg, FRG and -NIH, Bethesda, Maryland, U.S.A. The effect of different models of experimental hypertension and of experimental alterations in the salt and water balance on brain ANP was investigated to elucidate the role of ANP in the locus coeru-leus (LC). Under various conditions ANP concentrations (pg ANP/mg protein) of LC were altered markedly. NaCl elevates ANP in adrenalectomized rats (311 + 36 vs 142 + 21, p<0.05), whereas replacement of aldosterone and dexamethasone did not change ANP levels neither after ADX nor in intact rats. Antidiuretic treatment of diabetes insipidus rats (DDAVP) decreases ANP (63 + 12 vs 102 i 16, ρ < 0.05). Both young SHR and adult SHR showed a reduced ANP concentration compared to WKy (31 + 4 vs 45 + 5, ρ < 0.05 and 54 + 3 vs 73 + 7, ρ 4 0.05). ANP of the LC in DOCA-salt rats was elevated (87 + 4 vs 64 + 4, ρ < 0.05). ANP in lKlC-hyper-tension (low renin) was increased in contrast to 2KlC-hypertension (high renin). Our data demonstrate that ANP of LC plays an important role as a neuropeptide in the maintenance of electrolyte and volume homeostasis.

[1023I CAN A BETA BLOCKER WITH VASODILATING ACTION DECREASE LV MASS IN HYPERTENSIVE PATIENTS? SP Glasser,* JA Strom,* MP Poland, SR Nelson, DK Koehn, Univ. of South Florida Medical Center, Tampa, FL.

This double-blind parallel group study in patients with mild to moderate hypertension compared the antihypertensive efficacy and effect on echocardiographic left ventricular mass regression between dilevalol (D,n=22), a beta blocker with beta£ agonism and metoprolol (M,n=10). After 2-4 weeks of placebo, doses were titrated to achieve normotension (mean dose of D-695mg χ 10 wks, M=211mg χ 9 wks); mean age D=55 yrs. and M=56 yrs. D lowered systolic (-11.4±5 p<.04) and diastolic BP (-19.5±4 p<.0001), while only DBP was significantly decreased with Μ (-18.4±5 p<.002). Echo results were as follows:

Change and Significance from Baseline* ESP EDD EF% IVST PWT LVMI HR

D -.10 +.08 +3.4** -.86 -0.4 -7.6 -6.5 p= NS NS <.004 <.008 <.08 <.03 <.003

Μ +.03 -.02 -0.5** +.01 -.34 -3.5 -7.2 p= NS NS NS NS NS NS ^.08

* Two tailed t-test ** The'fin EF with D vs the φ with Μ p<.05 NS - not statistically significant

Thus, D-BP and4»LV mass without any adverse changes in LV function. The reduction in LV mass was due to changes in wall thickness and not to changes in EDD.

1022 GLUCOCORTICOIDS ACTIVATE VOLTAGE DEPENDENT CALCIUM CHANNEL I N A7R5 VASCULAR SMOOTH MUSCLE CELLS V IA RECEPTOR MEDIATED PATHWAY T . H a y a s h i * , H. Tada, T . Misawa, S. Kim, R. F u j i w a r a , Y . Kutsumi, T . Nakai? S. Miyabo. The T h i r d Department o f I n t e r n a l M e d i c i n e , Fukui Med ica l School , Fukui 9 1 0 - 1 1 , Japan

P r e d e s p o s i t i o n o f h y p e r t e n s i o n i s a w e l l known m a n i f e s t a t i o n o f g l u c o c o r t i c o i d excess d isease as Cushing 's syndrome. To i n v e s t i g a t e whether g l u c o c o r t i c o i d s d i r e c t l y modulate ca lc ium h a n d l i n g i n v a s c u l a r smooth muscle c e l l (VSM2), we s t u d i e d the H 5 C a 2 + uptake and washout i n VSMC l i n e , A7r5 c e l l s . F o r t y e i g h t hour t rea tment w i t h 100 nM dexamethasone (DEX) i n c r e a s e d u n i d i r e c t i o n a l "'Csr*1" uptake upto 2 min and the n e t 30 min Ca2"*" uptakes i n c o n t r o l and DEX t r e a t e d c e l l s were 1 0 . 7 ± 0 . 2 and 2 0 . 0 ± 0 . 9 nmoles/mg p r o t e i n , r e s p e c t i v e l y . However, *5Ca2+ e f f u l x r a t e was n o t changed by DEX t r e a t m e n t . Lag t ime f o r the DEX e f f e c t on 1 4 'Ca 2 ' '" uptake was approx imate ly 8 h . ECsos o f DEX and a ldosterone were 2 . 0 nM and 0 . 5 μΜ, r e s p e c t i v e l y . T h i s e f f e c t o f s t e r o i d s was c o m p l e t e l y a b o l i s h e d by a n t i - g l u c o c o r t i c o i d , RU38486. Concomitant i n c u b a t i o n o f ac t inomycin D and cycloheximide a l s o a b o l i s h e d the e f f e c t o f DEX. Modula t ions o f 30 min n e t l * 5 C a 2 ' h uptake by a n g i o t e n s i n I I , v a s o p r e s s i n , ouaba in , and a m i l o r i d e were a d d i t i v e t o DEX e f f e c t . 55 mM KC1 d e p o l a r i z a t i o n inc reased l* 5Ca 2"'" i n f l u x t o the same l e v e l b o t h i n c o n t r o l and DEX t r e a t e d c e l l s . The e f f e c t o f DEX was b locked by n i f e d i p i n e i n a dose dependent manner. These r e s u l t s i n d i c a t e t h a t g l u c o c o r t i c o i d s inc rease the l * 5 Ca 2 ' t " uptake through a c l a s s i c a l g l u c o c o r t i c o i d r e c e p t o r pathway w i t h new p r o t e i n ( s ) syn thes is and the L type v o l t a g e dependent Ca channels may be i n v o l v e d i n t h i s e f f e c t .

1024 ECHOCARDIOGRAPHIC MEASUREMENT OF LEFT VENTRICULAR MASS AND VOLUME I N NORMAL AND HYPERTENSIVE RATS. (L. de Simone. D.C. W a l l e r s o n , M. Volpe* R.B. Devereux*. C o r n e l l Med ica l Center , New York , NY.

Al though r a t s a re commonly used to study l e f t v e n t r i c u l a r (LV) hyper t rophy , measurement o f LV mass (LVM) and dimensions has r e q u i r e d s a c r i f i c e . To determine the accuracy o f echocardiography i n r a t s , LVM measurement from 2-D t a r g e t e d m-mode echocardiography was compared to necropsy LV weight ( 0 . 2 8 to 1.5 g) i n 41 normotensive (body we igh t : 116 to 763 g) and 17 h y p e r t e n s i v e r a t s (body w e i g h t : 350 to 560 g ) . Anatomic measurements o f chamber volumes i n 28 normotensive r a t s ( 0 . 2 to 1.9 ml) were a lso compared to echocard iographic v o l u m e s . B l i n d e d measurements o f LV d i a s t o l i c dimension ( d ) , septum ( s ) and p o s t e r i o r w a l l (pw) made from s h o r t - a x i s v i e w , a t the t ime o f maximum-d i a s t o l i c d and o f LV s y s t o l i c d were used to (ca lcu la te LVM by e i t h e r the cube f u n c t i o n or an b l l i p t i c a l model (LVMe l ) , c r o s s - s e c t i o n a l a rea (CSA), and LV s y s t o l i c and d i a s t o l i c volumes by the e l l i p t i c a l model. C o r r e l a t i o n w i t h LV weight was r - 0 .87 f o r LVM, 0 .88 f o r LVMel, and 0 .90 f o r CSA ( p < 0 . 0 0 0 0 1 ) . Necropsy LV volume was more c l o s e l y r e l a t e d to s y s t o l i c echo LV volume than d i a s t o l i c echo volume ( r - 0 . 7 8 , p < 0 . 0 0 0 0 1 , vs 0 . 7 1 ) , compat ib le w i t h e f f e c t s o f postmortem c o n t r a c t u r e . Necropsy and echo v a r i a b l e s n o r m a l i z e d f o r body Weight were compared i n h y p e r t e n s i v e and i n 25 normotensive r a t s 3 to 4 month o l d ; d i f f e r e n c e was 27% f o r anatomic we ight ( p < 0 . 0 0 0 1 ) , 21% f o r JLVMel ( p < 0 . 0 0 5 ) , 19% f o r CSA and LVM ( p < 0 . 0 0 2 ) . We conclude t h a t echocard iographic d e t e r m i n a t i o n o f LV mass and volume can be used to e v a l u a t e LV ^structure i n r a t s and can d e t e c t i n v i v o LV anato -jnic d i f f e r e n c e s induced by growth or h y p e r t e n s i o n .

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| 1 0 2 5 1

EVALUATIONS OF A0RT0-DYNAMIC CHARACTERISTICS WITH AORTIC PULSE PRESSURE WAVE. T. Natsume*, T. Noda, H. S e k i g u c h i , M. F u j i i , T . K a t s u k i , Y. Kawada, A. Komaba, H. Komatsu, H. W a t a b i k i , T. Yaginuma. Dept of C a r d i o l o g y , J i c h i Medical School , T o c h i g i , JAPAN

To i n v e s t i g a t e whether aorto-dynamic c h a r a c t e r i s t i c s might be eva lua ted wi th a o r t i c pulse pressure wave (AW), a o r t i c pulse pressure and f l o w - v e l o c i t y contours were obta ined s imul taneously using M i l l a r mul t isensor c a t h e t e r a t the a o r t i c roo t during d iagnost ic c a t h e t e r i z a t i o n in 29 p a t i e n t s wi th chest p a i n , and a n a l y z e d . R e f l e c t i o n wave r a t i o (RWR) was obta ined from P1-P4/P0-P2 ( p o : beginning pressure of AW, Px : pressure a t peak f l o w - v e l o c i t y , P 2 : peak pressure of AW). Phase of r e f l e c t i o n wave (PRW) was obta ined from t /R -R ( t : d i f f e r e n c e between p x and p 2 , R-R: measured on ECG). Before and a f t e r the a d m i n i s t r a t i o n of t r i m ' t r o g l y c e r i n (NG: 0.3mg SL, n = 6 ) , n i t r o p r u s s i d e (NP: 20yg/min D IV , n = 8 ) , n i f e d i p i n e (NF: 20mg SL, n=9) and propranolo l (PR: 6mg I V , n = 6 ) , AW and f l o w -v e l o c i t y were recorded s imul taneous ly . Resul ts were as f o l l o w s :

NG NP NF PR

RWR before a f t e r

. 37± .16

. 1 4 ± . 1 1 * . 4 0 ± . 0 7 . 1 5 ± . 1 3 *

. 40± .09

. 2 6 ± . 0 9 * . 3 U . 1 4 . 2 8 ± . 1 2

PRW before a f t e r

. 13± .01

. 1 0 ± . 0 5 . 1 5 ± . 0 2 . 1 4 ± . 0 2

. 1 6 ± . 0 2

. 1 7 ± . 0 2 . 1 3 ± . 0 2 . 1 5 ± . 0 1 *

MAP before a f t e r

104±13 94±18*

105±11 8 5 ± 1 1 *

108±11 91±13*

103±9 97±12*

I F U I I I I C J U I 1 , 3 ) I I 1 3 I , IM I V~ I U U C U U N A Υ N U , NR

and NF reduced the tonus of small a r t e r i e s whi le PR induced ton ic reduct ion of condui t a r t e r y , and t h a t aorto-dynamic c h a r a c t e r i s t i c s may be poss ib ly eva lua ted wi th AW.

1 0 2 7

DIFFERENCE IN THALLIUM-201 UPTAKE BETWEEN INTERVENTRICULAR SEPTUM AND LEFT VENTRICULAR FREE WALL IN ESSENTIAL HYPERTENSIVES Μ Hamada, Y Fujiwara, Y Shigematsu, Μ Mukai, Τ Tsuruoka, Τ Sumimoto, Μ Sekiya, Κ Hiwada*, Τ Kokubu*. Dept. of Medicine, Ehime Univ., Ehime, Japan. To elucidate whether the difference in develop

ment of myocardial hypertrophy exists between interventricular septum(IVS) and left ventricular free wall(FW) in essential hypertensives(EHT), IVS and FW were evaluated by thallium-201(201T1) myocardial single photon emission computed tomography , and 201T1 uptake of IVS was compared with that of FW[201T1 uptake ratio = IVS/FW χ 100(%)]. The thickness in IVS and left ventricular posterior wall(IVST, PWT) was also measured by echocardiography. EHT were subdivided into two groups(EKT-I: IVST and PWT 10mm, EHT-II:IVST and/or PWT 10mm).

201T1 uptake IVST PWT IVST/FWT ratio(IVS/FW)(%) (mm) (mm)

normotensives 91 6.6 7.2 0.9C (n=24) +22 +1.1 +0.9 +0.14 EHT-I 86 7.2 7.7 0.10 (n=20) +33 +0.9 +0.9 +0.10, EHT-II 62* 1C.1* 13.2* 0.76* (n=18) +24 +1.4 +1.C +0.12

* ρ 0.01(normotensives vs EFT-I or EHT-II) The values are mean+SD.

In advanced stage of EHT, both 201T1 accumulation and wall thickness in left ventricular free wall were greater than those in IVS. These findings suggest that differenced in progress of left ventricular hypertrophy associated with hypertension exist between interventricular septum and left ventricular free wall

1 0 2 6

CHARACTERISTICS OF REGRESSION OF LEFT VENTRICULAR HYPERTROPHY IN SECONDAFY HYPERTENSIVE PATIENTS SUCCESSFULLY TREATED WITH SURGICAL PROCEDURE Μ Hamada, Y Shigematsu> Μ Mukai, Κ Kiwada x, Τ Kokubu':. Dept. o f Medicine, Ehime Univ., Ehime, Japan.

To elucidate the time course of regression of left ventricular(LV) hypertrophy in secondary hypertensives(8 primary aldosteronism, 5 pheochromocytoma, 3 renovascular hypertension) successfully treated with surgical procedures, electrocardiogram (Sokolow-Lyon:SV1+RV5) and echocardiogram (Devereux :LV mass) were obtained before opera-tion(pre-ope), and in "early"(less than 1 0 days) and "late"(more than 3 months) points after operation. Data were expressed as percent changes.

Blood pressure(mmHg) % changes % changes syst. diast. of SV1+RV5 of LV mass

pre-ope 1 8 4 + 7 1 0 9 + 3 — early 1 4 1 + 5 * 9 0 + 5 * - 1 6 + 4 * - 3 + 3 late 1 2 2 + 3 * + 8 1 + 2 * + - 2 9 + 4 * + - 3 4 + 1 0 * + Mean+SE,*p ,01(vs pre-ope),+p . 0 1 (early vs late).

In the early point, a significant reduction in only SVl+PvV5 was seen, and there was a very good correlation between % change of blood pressure and %change of SV1+RV5. In the late point, normalization of both SV1+RV5 and LV mass occurred in all patients.Patients with severer LV hypertrophy need longer time to return to normal hearts in size.

These results suggest that normalization of LV hypertrophy due to secondary hypertension occurrs by normlization of blood pressure. With regard to time course of LV regression, first, electrocardiographic change occurrs early after operation , then % reduction of LV mass as well as further % reduction of electrocardiogram occurrs gradually and finally both return to normal.

1 0 2 8

HEMODYNAMIC CHARACTERISTICS IN PATIENTS WITH PHEOCHROMOCYTOMA - DIAGNOSTIC SIGNIFICANCE OF SYSTOLIC TIME INTERVALS -Μ Hamada, Μ Mukai, Y Shigematsu, Κ Hiwada*, Τ Kokubu*, Ehime Univ., Ehime, Japan, R Takeda*, Kanazawa Univ., Kanazawa, Japan.

Cardiac functions of 8 patients with pheochromocytoma were assessed and the results were compared with data obtained from 12 normal controls and 20 essential hypertensives. The following systolic time intervals were measured;1)electromechanical systole(Q-II),2)left ventricular ejection time(ET) ,3)pre-ejection period(PEP),4)PEP/ET ratio. ET was corrected for heart rate.

Blood pressure showed no difference between patients with pheochromocytoma and essential hypertensives. Heart rate was 64+7 beats/min in normal controls,78+10 in pheochromocytoma and 65 +10 in essential hypertensives.

Q-II ET ETindex PEP PEP/ET (msec) (msec) (msec) (msec)

Normal 407 292 398 116 0.40 controls + 1 9 + 1 6 ± 9 + 4 +0.02 Pheochromo- 331* 213* 332 118 0.56* cytoma Essential hypertensives ± 2 2 + 3 1 + 17 ± 17 +0.15 *p<0.01(normal controls vs pheochromocytoma or essential hypertensives), +p<0.01(pheochromocytoma vs essential hypertensives).All values are mean±SD.

These results suggest that chronic catecholamine exess from pheochromocytoma has deleterious effects on the heart and disparate difference in systolic time intervals between pheochromocytoma and essential hypertensives allows differentiation of the two groups.

± 29 ± 24 420 272

t 29 + 17 ±0.11 378* 149* 0.57*

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[1029 AGE IS NOT A REASON FOR DOSE ADJUSTMENT OF FOSINOPRIL IN HYPERTENSION. B. Levinson*. WF Graney, AR DeVault, Κ Kassler-Taub, The Squibb Institute for Medical Research, Princeton, NJ.

Despite the low renin levels commonly found in the elderly, angiotensin-converting enzyme (ACE) inhibitors have been effective in the treatment of hypertension in this age group. Fosinopril, a novel ACE inhibitor, has been shown to attain similar blood levels when given in the same dose to healthy elderly(E) and young(Y) volunteers. Data from several multicenter, double-blind studies were pooled to compare the efficacy of various doses of fosinopril in elderly 65) and young hypertensive patients (-^65). The studies consisted of a 4 to 6 week placebo lead-in period followed by a 4-week period of once-daily therapy. At a daily dose of 20 mg, the following geometric means (SE) for seated diastolic blood pressure were obtained in elderly (N=18) and young (N=92) patients: AGE PRE POST %Change Y 102.2 (0.5) 94.1 (0.9) 7.9 (0.8) Ε 99.8 (1.1) 91.5 (1.9) 8.2 (1.9) Similar decreases is systolic pressure were seen in young and elderly patients of 5.3% and 7.0%, respectively. No significant differences in efficacy were found between age groups ( p > . 0 5 ) . Elderly and young patients had a similar frequency of drug-related adverse events. These data indicate that fosinopril has a similar efficacy and safety profile in the two age groups. There is no need for dose adjustment based on age.

1031 PLASMA FATTY ACIDS I N HTN P A T I E N T S BEFORE AND A F T E R EPA SUPPLEMENTS E . R . B r a v e r m a n * . M.D. and H . E . R a y n e r , M . P . H . , T o t a l H e a l t h C e n t e r , S k i l l m a n , N J .

Mega d o s e s o f EPA and DHA h a v e been d e m o n s t r a t e d t o l o w e r t r i g l y c e r i d e s , c h o l e s t e r o l , b l o o d p r e s s u r e , f i b r i n o g e n and p l a t e l e t a g g r e g a t i o n . B l e e d i n g t i m e s c a n b e s l i g h t l y p r o l o n g e d , w h i l e HDL and A p o l i p r o t e i n A 1 a r e e l e v a t e d . F i v e HTN p a t i e n t s supplemented (S) w i t h 3 . 5 g o f EPA and 2 . 3 g DHA d a i l y f o r a minimum o f s e v e n months w e r e compared w i t h s i x HTN c o n t r o l (C) p a t i e n t s . S had an EPA o f 4 . 9 3 + 1 . 9 r e l a t i v e % concent r a t i o n while C had 0 . 6 3 + . 1 5 ρ < . 0 0 1 while DHA was S = 5 . 4 5 ± 2 . 1 and C = 3 . 7 + .7 ρ < 0 . 1 NS. Percent changes in m y r i s t i c , p a l m i t i c , s t e a r i c , alpha l i n o l e n i c , gamma l i n o l e n i c , m y r i s t o l e i c , p a l m i t o l e i c , nervonic a c i d s were NS. Yet arachidonic was S - 7 . 1 + 1 . 7 2 C -1 1 . 2 + 2 . 4 ρ < . 0 1 . Dihomogammalinolenic ρ < . 0 1 and o l e i c ρ < . 0 5 were a l s o d e c r e a s e d . These e f f e c t s on o t h e r plasma f a t t y a c i d s probably account f o r t h e ant inf lam-matory a c t i o n s of EPA. Furthermore, t h i s reduct ion may expla in t h e BP lowering e f f e c t o f EPA by reducing t h e s y n t h e s i s o f v a r i o u s prostaglandins and l e u k o t r i e n e s . Some o f t h e EPA e f f e c t s on plasma f a t t y a c i d s may a l s o be due t o t h e f a c t t h a t t h e S group was on a d i e t high i n p o l y u n s a t u r a t e s .

1030 L o n g - T e r m I m p r o v e m e n t o f L i p i d P r o f i l e s w i t h I s r a d i p i n e i n E l d e r l y H y p e r t e n s i v e P a t i e n t s

G . H . S t e i n * , L . L o p e z , G . Q u a y , D . M c C a r l e y a n d K. M a t t h e w s , E v a l u a t i o n C l i n i c , VA M e d i c a l C e n t e r & D e p a r t m e n t o f M e d i c i n e , U n i v . o f F l o r i d a , G a i n e s v i l l e , F L . , & S a n d o z R e s e a r c h I n s t i t u t e , E a s t H a n o v e r , N . J . P o t e n t i a l l y a d v e r s e e f f e c t s f r o m d i u r e t i c s a n d b e t a b l o c k e r s o n l i p i d p r o f i l e s a r e w e l l k n o w n . A p r e l i m i n a r y r e p o r t o f s h o r t - t e r m e f f e c t s o f i s r a d i p i n e ( I S ) a new c a l c i u m a n t a g o n i s t , s h o w e d n e u t r a l l i p i d p r o f i l e s . T h e p u r p o s e o f t h i s s t u d y w a s t o c h a r a c t e r i z e l o n g - t e r m e f f e c t s o f I S o n l i p i d p r o f i l e s o f h y p e r t e n s i v e p a t i e n t s ( N = 3 8 ) > 6 0 y e a r s o l d . D i a b e t i c p a t i e n t s w e r e e x c l u d e d . A f t e r a 2-4 w e e k w a s h o u t p l a c e b o p e r i o d , d o s e o f I S ( 5 - 2 0 mg d a i l y ) w a s t i t r a t e d t o a d i a s t o l i c p r e s s u r e < 9 0 mmHg. L i p i d p r o f i l e s ( t o t a l c h o l e s t e r o l [ C H O ] , h i g h d e n s i t y l i p o p r o t e i n [ H D L ] a n d l o w d e n s i t y l i p o o r o t e i n [ L D L ] ) w e r e o b t a i n e d f r o m p a t i e n t s a f t e r b a s e l i n e a n d 6 a n d 12 m o n t h s o f I S t h e r a p y . L i p i d p r o f i l e s w e r e p e r f o r m e d a t a n a t i o n a l c o m m e r c i a l c l i n i c a l l a b o r a t o r y ( S K B ) . R e s u l t s a s m e a n d i f f e r e n c e f r o m b a s e l i n e , m g / D l a r e a s f o l l o w s :

CHO HDL L D L H D L / L D L CHO/HDL

6 mos - 3 . 5 9 1 . 2 6 4 . 2 7 - 0 . 0 0 - 0 . 1 9 12 mos - 7 . 5 1 3 . 8 9 * - 6 . 2 1 - 0 . 0 6 * - 0 . 5 7 *

* p < 0 . 0 5

U s e o f I S w a s a s s o c i a t e d w i t h s i g n i f i c a n t i m p r o v e m e n t o n HDL a n d r e l a t e d r a t i o s . S u c h i m p r o v e d l i p i d p r o f i l e s s u g g e s t s a n a d v a n t a g e o f I S o v e r o t h e r a n t i h y p e r t e n s i v e a g e n t s i n t h e t r e a t m e n t o f e l d e r l y h y p e r t e n s i v e - p a t i e n t s .

|1032| THE EFFECT OF CILAZAPRIL ON SYSTOLIC AND D I A S T O L I C C A R D I A C F U N C T I O N IN HYPERTENSIVE PATIENTS. Adam Schneeweiss . Tiberio Green, Jessie Krakuer, Ehud Goldhamer, Alon Marmor. The Geriatric Cardiology Research Foundation, Tel-Aviv, Israel, Cardiology Department, Safed Medical Center, Safed, Israel, and Haifa Medical Center, Haifa, Israel.

Diastolic function may be impaired in hypertensives even before alterations in systolic function. We studied the effect of a single dose of cilazapril, 5 mg orally, on systolic and diastolic cardiac function in 20 hypertensive patients using a double-blind crossover placebo controlled design. All patients had mild to moderate concentric left ventricular hypertrophy, preserved systolic function and long standing hypertension (for a period of 11.9±9.0 years) . Radionuclide scintigraphy was performed with cilazapril and placebo, given one week apart . A 2-weeks washout period of all cardioactive drugs preceded the study. Within one hour af ter oral administration of cilazapril blood pressure was significantly lowered. The absolute time to peak filling ra te of the left ventricle, as well as the time to peak filling ra te expressed as % of diastole, were reduced from 176±34 to 158±33 msec (p<0.01) and from 46±10% to 37±8% (p<0.02) (reduction by 9% and 18.4%, respectively). Heart rate , left and right ventricular ejection fraction and peak filling ra te were not significantly altered. Placebo had no significant effect. In conclusion: cilazapril seems to improve diastolic cardiac function in hypertensive patients. Long-term therapy may result in improvement of other, less sensitive, indices of diastolic dysfunction.

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[1033 THE E F F E C T OF TREATMENT WITH β-ADRENORECEPTOR BLOCKERS OVER SEVERAL YEARS ON LEFT VENTRICULAR HYPERTROPHY IN HYPERTENSIVE PATIENTS A. Marmor, T. Green, A. Schneeweiss. The Ziv Medical Center, Safed, Israel

Treatment of hypertension can reverse myocardial hypertrophy. We studied by echocardiography and radionuclide scintigraphy. 16 patients (pts) with moderate hypertension (mean age 59 years) treated for 5.4±0.8 years by β-blockers (atenolol or propranolol), alone or in combination with diuretics (7 cases) or calcium antagonists (5 cases). In all pts diastolic blood pressure was reduced to 90 mm Hg or less and systolic pressure was reduced by at least 10%. Left ventricular ejection fraction was 68.5±11.9% before and 65.4±8.3% after treatment. The pts h a d no o t h e r c a r d i o v a s c u l a r d i s e a s e . Measurements before and after the period of treatment revealed concentric left ventricular hypertrophy with wall thickness of 1.3±0.2 cm before and 1.510.2 cm after the period of treatment. Conclusion: long-term treatment of hypertension, based on β-blockers, alone or in combination with other drugs, does not reduce or prevent lef t ventr icular hypertrophy. The difference between our results and those of previous studies may be due to the very long treatment period in our study (as compared with periods of 3 to 12 months in other studies), from the moderate extent of hypertrophy in our pts, or from the fact that the goal of therapy was not complete normalization of blood pressure.

1035 TISSUE DISTRIBUTION OF ACE IN THE RABBIT FETUS AND PLACENTAL PASSAGE OF AN ICE, PERIND0PRIL(ΡIL) JP Mor in , Ρ T o u t a i n , Η B o r g h i , Β M o u l i n , JP F i l l a s t r e * . INSERM, Rouen, F r a n c e .

Female New Zealand r a b b i t s ( 3 t o 4 . 5 kg) were d i s t r i b u t e d i n t o 3 g r o u p s : G l , p r e g n a n t c o n t r o l s (n= 6 ) ; G2, p r e g n a n t r a b b i t s r e c e i v i n g 1 mg/kg PIL (n = 7 ) ; and G3, p r e g n a n t r a b b i t s r e c e i v i n g 10 mg/kg PIL ( n = 7 ) . PIL was a d m i n i s t e r e d by gavage 3 h r s and 24 h r s b e f o r e s a c r i f i c e . The a n i m a l s were s a c r i f i c e d a t 28 days (3 days b e f o r e t e r m ) , ACE l e v e l was d e t e r m i n e d in t h e serum and homogenates were e v a l u a t e d u s i n g C h i p p u r y l - h i s t i d y l - 1 e u c i -n e . T h e d i s t r i b u t i o n o f ACE in Gl p r e g n a n t r a b b i t s was s i m i l a r t o t h a t found in a p r e v i o u s s tudy in nonpregnant r a b b i t s . In t h e f e t u s e s ( n = 4 0 ) ACE a c t i v i t y was h i g h e s t in t h e lungs (m±SD, 1 9 1 9 1 5 9 2 nmol/mn/g o f t i s s u e ) and lower in the p l a c e n t a ( 1 6 2 1 6 ) , t h e u t e r u s ( 9 8 1 3 4 ) , t h e k idney ( 2 9 . 6 1 1 6 ) and in t h e serum ( 1 5 . 7 + 3 . 4 ) , where ACE a c t i v i t y was not d i f f e r e n t from t h a t o f m a t e r n a l serum. ACE a c t i v i t y d e c r e a s e d wi th i n c r e a s e d d o s e s o f P I L . A f t e r a d m i n i s t r a t i o n o f 1 and 10 mg/ kg o f P I L , t h e p e r c e n t a g e o f i n h i b i t i o n compared t o c o n t r o l s was r e s p e c t i v e l y 7 7 . 4 % and 9 9 . 4 % in t h e serum, 3 6 . 6 % and 53% in t h e l u n g s , 21% and 88% in t h e k i d n e y , and 7 0 . 5 % and 9 2 . 9 % in t h e p l a c e n t a .

In c o n c l u s i o n , ACE d i s t r i b u t i o n in t h e k idney o f t h e p r e g n a n t r a b b i t i s s i m i l a r t o t h a t found in nonpregnant c o n t r o l a n i m a l s . ACE a c t i v i t y in t h e 2 8 - d a y r a b b i t f e t u s o c c u r s m a i n l y in t h e lungs and t o a l e s s e r d e g r e e in t h e k i d n e y s . ACE a c t i v i t y i s a l m o s t e n t i r e l y i n h i b i t e d in t h e f e t u s a f t e r h i g h - d o s e PIL a d m i n i s t r a t i o n t o t h e mot h e r , s u g g e s t i n g t h a t t h i s i n h i b i t o r c r o s s e s t h e p i a c e n t a .

1034 EFFECT OF ANTIHYPERTENSIVE TREATMENT OVER SEVERAL YEARS ON LEFT VENTRICULAR SYSTOLIC AND DIASTOLIC FUNCTION AND WALL THICKNESS. Alon Marmor, Tiberio Green, Adam Schneeweiss. The Cardiology Department, Zive Medical Center, Safed, Israel and the Geriatric Cardiology Research Foundation, Tel-Aviv, Israel.

We studied by echocardiography and radio-nuclide s c i n t i g r a p h y the e f f e c t of antihypertensive treatment on left ventricular systolic and diastolic wall thickness in 20 hypertensive patients (mean age 59 years) treated for 6 to 7 years by β-blockers, alone or with diuretics, calcium antagonists, clonidine or prazosin. The goal of therapy was to lower diastolic pressure to 90 mm Hg or less. Ejection fraction was 67.319.8% before and 64.7+8.4% a f t e r treatment . The patients had no other cardiovascular disease. Measurements before and after the period of treatment revealed concentric left ventricular hypertrophy with wall thickness of 1.310.2 cm before and 1.510.2 cm after treatment (p<0.05). Time to peak filling ra te of the left ventricle, expressed as percentage of diastole, was prolonged from 37.119.9% to 45.919.8%. Other indices of diastole function were not altered. In conclusion: Long-term treatment of hypertension, based on β-blockers, alone or in combination with other drugs: 1. Does not reduce left ventricular hypertrophy and does not prevent i ts progression; 2. Slightly impairs diastolic left ventricular function. 3. Does not impair normal systolic function. It is possible, however, that without antihypertensive therapy the progression of hypertrophy would have been even faster , and the impairment in diastolic function-greater. A greater lowering of blood pressure could have altered our findings.

1036 DIURETICS (D) :A RATIONAL PHARMACOLOGICAL APPROACH FOR THE TREATMENT OF OBESE HYPERTENSIVES (OH): Ε R e i s i n * , SG Weed* . S e c t i o n of N e p h r o l o g y , L o u i s i a n a S t a t e U n i v e r s i t y , New O r l e a n s , LA.

We c o m p a r e d t h e e f f i c a c y & s a f e t y o f C h l o r t h a l i d o n e (CT) up t o 5 0 m g / d a y w i t h t h a t of C l o n i d i n e (C) up t o 0 . 4 m g / d a y in 32 OH p a t i e n t s ( p t s ) randomly d i s t r i b u t e d in a d o u b l e b l i n d f a s h i o n . Al l u n r e s p o n s i v e pts(DBP>90mmHg) e n t e r e d o p e n - l a b e l t r e a t m e n t wi th a c o m b i n a t i o n CT+C (up t o p r e v i o u s d o s e s ) . S a m p l e s of b l o o d s p e c i mens were o b t a i n e d b e f o r e and a f t e r t r e a t m e n t f o r b i o c h e m i s t r a l s t u d i e s . BP c h a n g e s were as f o l l o w s :

Mean s e a t e d BP change # p t s c o n t r o l l e d CT - 2 5 / - 1 5 p < 0 . 0 0 1 / 0 . 0 0 1 1 7 / 1 9 C - 1 0 / - 6 p < 0 . 0 1 / 0 . 0 0 1 5 / 1 6 C T + C - 2 8 / - 1 7 p < 0 . 0 0 1 / 0 . 0 0 1 1 1 / 1 3 Serurn a l d o s t e r o n e , c h o l e s t e r o l , t r i g l y c e -r i d e s and l i p o p r o t e i n s remained unchanged in a l l 3 s t u d y g r o u p s . S e r u m K + l e v e l s were s i g n i f i c a n t l y d e c r e a s e d in p t s t r e a t e d with CT or C+CT but o n l y one r e q u i r e d K+ s u p p l e m e n t . C a t e c h o l a m i n e l e v e l s were s l i g h t l y but not s i g n i f i c a n t l y d e c r e a s e d in p t s t r e a t e d w i t h C. We c o n c l u d e t h a t u s i n g D as a f i r s t t r e a t m e n t c h o i c e i s a r a t i o n a l & s a f e a p p r o a c h in OH.The n a t r i u r e s i s & d e c r e a s e d h y p e r v o l e m i a i n duced by D was r e i n f o r c e d in t h e u n r e s p o n s i v e p t s by C,which i n h i b i t e d t h e i n c r e a s e d r e l e a s e of e p i n e p h r i n e ( d e s c r i b e d in OH) and c a r d i a c r e s p o n s e s t o p o s t g a n g l i o n i c a d r e n e r g i c n e r v e s t i m u l a t i o n .

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1037 ALPHA-2 ADRENOCEPTORS ARE INCREASED IN THE PROXIMAL TUBULE (PT) OF THE SPONTANEOUSLY HYPERTENSIVE (SH) RAT. CK Stanko. DD Smyth, (Spon: J K McKenzie*). Depts. of Pharmacology and Internal Medicine, U. of Manitoba, Winnipeg, Manitoba, Canada.

Alpha-2 adrenoceptors (A2R) are increased in renal membranes of SH rats compared to their normotensive controls, and may represent a response to elevated blood pressure. We compared A2R density in the PT of 12 week old SH rats and Wistar Kyoto (WKY) rats using 3H-rauwolscine (3H-Rau) (0.6-20 «M). The PT were isolated with a percoll gradient technique. SH rats had a significantly greater number of A2R sites (BMax) than did WKY rats (146 + 13 vs 58 + 7 fmol/mg) (p<0.001). The dissociation constants (Kd's) were similar (2.1 + 0.7 and 1.4 + 0.6 nM respectively). A2R in the SH rats were characterized with 3H-Rau and varying concentrations of cold alpha adrenoceptor agonists and antagonists (Ki=binding affinity constant).

Ki(/iM) Pseudo-Hill slope Agonists

Clonidine (CI) 28 .62 UK 14,304 (UK) 240 .73 Epinephrine 2997 .42

Antagonists Rauwolscine 1.6 1.1 Yohimbine 3.9 .91 Phentolamine 11.5 .8 Prazosin 32.5 1.1

The rank order of potency was compatible with an alpha-2B adrenoceptor. However, the rank order of CI and UK was reversed, compared to other non-renal tissues. The agonist curves were shallow and displayed a pseudo-Hill slope of <1, indicating more than one receptor site. In conclusion, A2R number is increased in the PT of the SH rat, compared to the WKY rat. The reversed rank order of potency of CI and UK suggests that another A2R subtype may be involved. Agonists bind to more than one affinity site of the A2R in the SH rat. Supported by the Medical Research Council of Canada and Sandoz of Canada.

11039| COMPARATIVE TRIAL O F KETANSERIN AND METHYLDOPA IN THE TREATMENT OF ARTERIAL HYPERTENSION. E F F E C T ON LIPID PROFILE. L . A l c o c e r * , C.Cobo, B. Calderon. Hospital General de Mexico, Mexico , D.F . , Mexico.

Ketanserin (ktn) a selective antagonist of S2 receptors was compared with methyldopa (mtd) in the t r e a t m e n t of essential hypertension and its e f fec t on the lipid profile. 30 patients were included in a comparat ive , double blind, placebo-control led randomized trial in hypertensives with initial blood pressure (BP) of 1 4 0 / 9 5 or more . All patients received placebo for 1 month (Period A) and then enter in a double blind period of 3 months t o receive 20 mg of ktn or 2 5 0 mtd BID for 2 weeks and af terwards if not normalized the BP 4 0 mg of ktn or 500 mg of mtd BID (Period B ) . Every patient were clinical evaluated every 2 weeks and by routine laboratory and lipid profile at the end of periods A and B. Changes from p r e t r e a t m e n t wi thin t r e a t m e n t group were evaluated using a Wilcoxon signed-rank t e s t , intergroup comparison was carr ied out by Mann Whitney U t e s t , all s ta t i s t i ca l test were t w o - t a i l e d and significance was defined as ρ J_ 0 . 0 5 . At the end of period A ktn and mtd groups were similar related to sex , a g e , body weight, systolic and diastolic pressure, hypertension severity and previous t r e a t m e n t with antihypertensive drugs. Not significant differences were o b served between both groups in heart r a t e . Ktn and mtd e f f e c t s on BP: 14 patients on ktn and 12 of mtd completed period B. A significant lowering in systolic BP (p / 0 . 0 1 ) and diastolic BP (p / 0 . 0 0 1 ) for ktn comparing with mtd. It was observed in kts group a significant increase of 27.3% in HDL (p £ 0 . 0 1 ) and a decrease of 9 .09 (p J_ 0 . 0 3 ) in L D L .

11038| SUPPRESSION AND IIASKING OF RENAL VEIN RENIN PROFILES INDUCED BY MANNITOL PROPHYLAXIS. RL Benz*, BP Teehan, GS Gilgore, MH Sigler and CR Schleifer, Lankenau Hospital, Philadelphia, PA.

Renal vein renin (RVR) profiling is the physiologic and diagnostic standard for evaluating significant renal artery stenosis. False negative RVR profiles with failure of lateralization in anatomically apparent high grade stenosis complicates the dx of renovascular hypertension (RVH). Mannitol prophylaxis (MP) is a regimen utilized for preventing contrast dye nephropathy.

Five pts. with RVH were studied prospectively to determine whether MP induces false negative RVR profiles. RVR samples were obtained pre and post infusion of 12 .5 gms MP. RVR sampling preceded angiography. Pts. received oral ACE inhibitor stimulation prior to testing. In each study renin secretion from the ischemic kidney was suppressed. Mean ischemic side renin values fell from 21 .9 to 1 1 . 1 ng/ml/hr (p=0 .01 ) . Lateralization was lost in 3 of 5 pts. Mean suppression of the non--involved side and IVC renin was not significant (p=0.55 and 0 . 2 1 , respectively). To evaluate MP induced volume expansion or dilutional effects pre and post Hct, serum Na+ and osmolality were obtained. No significant changes were found (p= 0 . 7 3 , 1 . 0 0 and 0 . 7 6 ) . Mean U ^ V increased from 0 .04 pre MP to 0 .15 mEq/ min. post MP.

In conclusion, ID? results in significant suppression of renin release by the ischemic kidney in RVH despite ACE inhibitor stimulation. This suppression can alter the RVR profile producing a false negative ratio. The mechanism of MP suppression may relate to increased distal sodium delivery or improved renal blood flow at the arteriolar level.

CAPTOPRIL AtJD CARDIOVASCULAR ^JEACTIVrTY. I I I DIABETES-ASSOCIATED HYPERTENSION. C ^ B e r e t t a -P i c c o l i * , W . H . Z i e g l e r . Dep t . o f M e d i c i n e , Ospedale I t a l i a n o , V i g a n e l l o , S w i t z e r l a n d .

Non-azotemic d i a b e t e s m e l l i t u s i s accompanied by h igh exchangeable sodium (NaE) and exagger a t e d pressor r e a c t i v i t y t o n o r e p i n e p h r i n e ( N E ) . The response o f these v a r i a b l e s t o an 8 weeks t rea tment w i t h c a p t o p r i l (50-100 rag/day) was e v a l u a t e d i n 11 d i a b e t i c s ( type I or I I ) w i t h h y p e r t e n s i o n . A t t h e end o f a 3 weeks p lacebo phase, t h e p a t i e n t s had an increase (P < 0 . 0 5 ) o f NaE (+9.4%) and a decrease of NE pressor dose ( -60%) , w h i l e plasma NE, a n g i o t e n s i n I I ( A l l ) , a ldosterone and t h e pressor r e a c t i v i t y t o A l l were normal . Acute v a g a l i n h i b i t i o n w i t h a t r o p i n e suppressed plasma i E by 20% i n c r e a s i n g t h e NE pressor dose by 35% ( ? < 0 . 0 5 ) . C a p t o p r i l decreased b lood pressure ( f rom 156/100 + 21 /10 (SD) t o 138 /86 + 18 /12 mm Hg; Ρ 0 . 0 1 ) , w i t h o u t changes o f w e i g h t , NaE, plasma NS, t h e pressor response t o NE, i n the absence or presence o f a t r o p i n e . The r e n i n - a n g i o t e n s i n - a ldos te rone system responded w i t h an inc rease o f plasma r e n i n a c t i v i t y (+88%; Ρ < 0 . 0 1 ) , w h i l e t h e plasma A l l and a ldosterone l e v e l s , t h e pressor and a ldos te rone response t o A l l d i d not change.

I n hyper tens ive p a t i e n t s w i t h d i a b e t e s m e l l i tus c a p t o p r i l e x e r t s a marked a n t i h y p e r t e n s i v e e f f e c t , w i t h o u t m o d i f i c a t i o n o f NaE. I n t h e s t a b l e phase o f c o n v e r t i n g enzyme i n h i b i t i o n , t h e r e l a t i o n s h i p s between' endogenous n o r a d r e n e r g i c or ang io tens inogenic a c t i v i t y and t h e pressor r e a c t i v i t y t o NE or A l l a re not m o d i f i e d .

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EFFECT OF ACUTE AND CHRONIC HEMATOCRIT CHANGES IN SPONTANEOUSLY HYPERTENSIVE RAT. Susie, D, Mandal AK* Jovoric DJ and Kentera D, Inst for Med Res, Beograd, Yugoslavia and Dept Med, VA Med Center and Wright State Univ, Dayton, OH 45428

We have shown that reduction in blood pressure (BP) is consistently accompanied by a significant decrease in hematocrit (Hct) in heparin (H) treated spontaneously hypertensive rat (SHR). (J Lab Clin Med 111:63, 1988). This report describes the effect of acute and chronic Hct changes on BP, cardiac output (CO) and total peripheral resistance (TPR) in SHR and normotensive Wistar rat (NWR). Eight rats in either group were utilized in each acute and chronic study. Acute Hct decrease upto 50% of baseline by blood removal with replacement of equivalent volume of rat's plasma did not affect BP in SHR or NWR. This was accompanied by a significant increase in CO and decrease in TPR in both SHR and NWR. Whereas, chronic Hct decrease from 48 to 37% induced by Η or phenylhydrazine (hemolytic agent) treatment for 4 wks resulted in a significant decrease in BP (201 + 3.2 vs 167 ± 4.3 mmHg; P<.05) only in SHR. A significant direct correlation between Hct and BP (r=0.86; P<.01) was also found only in SHR. An inverse relationship between Hct and CO and a direct one between Hct and TPR was found in both SHR and NWR. No difference was found in plasma or blood volume between the groups. In conclusion, the observed difference in BP response to chronic Hct change between SHR and NWR is consistent with the idea that hematocrit is a major determinant of blood viscosity which may contribute to BP regulation in hypertensive animals.

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REGULATION OF THE SECRETION OF A N F - ( 9 9 - 1 2 6 ) FROM PRIMARY NEONATAL R A T CARDIOCYTES. C.C. Glembotski* and P.P. Shields*. Dept. of Biology, San Diego State University, San Diego CA 92182

Primary cultures of atrial and ventricular cardiocytes were maintained for up to 60 days in serum-free medium. Both atrial and ventricular cultures were capable of co-secretionally processing A N F - ( 1-126) to A N F - ( l - 9 8 ) and (99-126) in a glucocorticoid-dependent fashion. Phorbol esters, calcium channel agonists, and KC1 depolarization stimulated mature ANF release from the atrial cultures by up to five-fold over basal values, however secretion from the ventricular cultures were uneffected by these compounds. Forskolin and cAMP analogues decreased both basal and phorbol ester stimulated ANF secretion in atrial cultures, but did alter peptide release from ventricular cultures. The a -adrenergic agonist phenylephrine stimulated ANF release from atrial cultures with an EC&p of 1 μΜ; this stimulation was blocked by the aj-adrenergic antagonist prazosin with an I C 5 Q of on 1 nM. Phenylephrine-stimulated ANF release from atrial cultures was inhibited by forskolin ( I C 5 0

= 10 μΜ) and the ^-adrenergic agonist isoproterenol. Atrial cultures maintained in the absence of glucocorticoids were not consistently responsive to any secretion stimulus. These results indicate that when primary atrial cultures are maintained in glucocorticoid-containing serum-free medium they are responsive to several ANF secretagogues. Activators of the protein kinase C pathway enhance ANF secretion from the cultures, while activators of the protein kinase A pathway inhibit secretion. Thus, it appears that the activation of α-adrenergic receptors on the cultured atrial cardiocytes stimulates ANF secretion, while activation of ^-adrenergic receptors inhibits secretion.

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THE CHANGING CLINICAL SYMPTOMS OF PRIMARY ALDOSTERONISM^ PA ) -THE ANALYSIS OF 120 CASES. Y.Kasai*, K.Abe,M.Seino,M.Yasuj ina* Y.Imai,M.Sato,K.Tsunoda, K.Takeuchi ,T.Hagino & K.Yoshinaga. 2nd Dept of Int Med.,Tohoku Univ.,Sendai, JAPAN. The purpose of this study is to examine if the re

cent progress in the diagnostic Instruments such as CT make the inprovement in early diagnosis and treatment of PA Oatients. The 120 patients with PA (10U with adenoma and l 6 with hyperplasia) who admitted and treated in TOHOKU Univ hospital are studied retrospectively. We analysed the duration of hypertension,main complaint,severity of hypertension,family history,laboratory datum and post-opera tive prognosis. The 120 cases are divided into 3 groups according to the year of admission.1st deca de ( l 9 5 8 - 1 9 6 7 ) , 2 n d decade(1968-1977) ,3rd decade ( l9 7 8 - 1 9 8 7 ) .The duration of HT before PA diagnosis are as follows.(years)0-1 1-5 5-10 lOmore 1st decade ( n = l h ) 0% 6h% 1% 20% 2nd decade(n=li8) 20$ k0% 2h% 15$ 3rd decade(n=58) 2h% 28% 26% 22% The incidence of muscle symptoms are as follows.

muscle cramps lassitude total 1st decade(n=lU) 50$ 21% 11% 2nd decade(n=U8) 33% 31% 6k% 3rd decade(n=58) lh% hQ% 62% The results show the improvement in the diagnosis of PA along with the decades but one fifth of the patients in the recent decade were still diagnosed more than 10 years after their first visit.The incidence of muscle symptoms did not decrease prominently. So we conclude that it is still important to re-check the labo datum and clinical symptoms of HT patients to differentiate PA from essential hypertension.

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EFFECT OF DIETARY CALCIUM ON AORTIC TISSUE RESPONSIVENESS TO A HYPERTENSIVE FACTOR. E.I. Mangiarua. G.L. Wright*, W.D. McCumbee*. Marshall University, School of Medicine, Huntington, WV.

It has been proposed that Ca supplementation in the diet is associated with a reduction in blood pressure (BP). We studied vascular tissue sensitivity to a Hypertensive Factor (HF) in spontaneously hypertensive (SHR) and Wistar Kyoto rats (WKY) fed a high-Ca diet. HF, which has been isolated from erythrocytes, is thought to be a peptide. It increases BP when injected into normotensive rats and stimulates Ca uptake by aortic rings in vitro. Five-week-old rats were divided into four groups: SHR and WKY fed a regular diet (1 % Ca) , and SHR and WKY fed a high-Ca diet (4% Ca). They were sacrificed after 8 weeks. Tissue responsiveness was determined by incubating aortic rings from the rats in the different groups with HF and measuring lanthanum-resistant Ca uptake. Results are expressed as the % increase above Ca uptake by unstimulated tissue from rats in the same treatment group.

WKY WKY 4%-Ca SHR SHR 4%-Ca BP (mm Hg) 124+2 125+2 163+3* 140+3+ Tis.Res.(%) 78±11 56+12 173±11* 61±17 *p<0.01 vs WKY, WKY 4%-Ca and SHR 4%-Ca; +p<0.01 vs WKY and WKY 4%-Ca.

A 4-fold increase in dietary Ca reduced BP and tissue responsiveness to HF in the SHR. Neither parameter was affected by the high Ca diet in the WKY. The results suggest that the increased tissue responsiveness to HF in the SHR may be associated with high BP. (NIH HL 37661-02).

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110451 COMPARISON OF HEMODYNAMIC RESPONSE TO POSTURE IN HYPERTENSIVE L E F T VENTRICULAR H Y P E R T R O P H Y AND DILATED CARDIOMYOPATHY J S Gottdiener, A Notargiacomo, J Pasquini, Μ Wish, R F l e t c h e r . VA Medical Center , Washington, D.C. , and University of Maryland Hospital, Bal t imore , Maryland

Clinical expression of C H F depends on the relation between myocardial diastolic properties and loading. We measured lef t (L) and right (R) a t r ia l (A) pressures, LV diastolic dimension (DD), and stroke volume (SV) by thermodilution while supine (SU), with upright tilt (UP), and with leg elevation (ELEV) in 9 hypertensive men (BP 163 ± 2 1 / 1 0 5 ± 11 mmHg, av age 56 + 4 yrs) with concentr i c (c) LVH (relative wall thickness .64 ± .07) and in 9 men (58 ± 9 yrs) with e c c e n t r i c (e) LVH (relative wall thickness .30 ± . 04 ) , matched for LV mass (LV mass index C-LVH 197 ± 56 g m / m 2 ; E-LVH 208 ± 44 g m / m 2 , pNS). In C-LVH pts, P C W - U P of 7 ± 4 mmHg increased to 12 ± 3 SU, and to 14 ± 3 ELEV (p < .05 SU and ELEV vs UP) , while in E-LVH pts P C W - U P of 14 ± 11 mmHg increased to 22 ± 9 SU, and to 27 + 6 ELEV. RA pressures showed smaller changes. In C-LVH pts, SV-UP of 77 ± 12 ml increased to 100 ± 21 SUP, and to

102 + 14 ml ELEV, while in E-LVH pts, SV-UP of 44 ± 23 ml increased to 53 ± 24 ml SU, and to 58 ± 28 ml ELEV (p < . 0 5 , SU and ELEV vs UP for both C - and E-LVH). In C-LVH, LVDD of 45 ± 5 mm UP, increased to 48 + 7 mm SU, and to 49 ± 5 mm ELEV (p < .05 , ELEV vs UP) , while in E-LVH, LVDD-UP of 66 ± 8 mm showed no significant increase with SU or ELEV position. LV fract ional shortening (43 ± 7% C-LVH, 14 ± 6% E-LVH) did not change with position. We conclude: 1) Despite equivalent magnitude of LVH, pts with C-LVH differ importantly from E-LVH in the response to postural a l terat ions in preload; 2) Passive tilt is an excel lent technique for studying e f f e c t s of preload on hemodynamics in hypertensive LVH.

1047 ATRIAL NATRIURETIC PEPTIDE DOES NOT CHRONICALLY ATTENUATE PRESSURE DEPENDENT RENIN RELEASE IN THE CONSCIOUS DOG. SD Kivlighn. TE Lohmeier*, HM Yang. Dept. Physiology, Univ. Miss. Med. Ctr . , Jackson, MS

To ascertain whether a t r i a l na t r iure t i c peptide (ANP) chronically inhibits renin release, we examined the relationship between steady-state plasma renin a c t i v i t y (PRA) and renal a t e r i a l pressure (RAP) during control conditions and during 5 days of intravenous infusion of alpha-human ANP (5ng/kg/min). In 4 dogs maintained on a normal Na intake, ANP infusion produced almost a three-fold increase in plasma ANP concentration (control -= 35±8 pg/ml) and a transient increase in urinary Na excretion on day 1 (from 35±1 to 64±5 mEq/day) ; however, there were no significant chronic changes in either mean a r t e r i a l pressure or basal levels of PRA. RAP was servo-controlled at reduced levels (71±2 and 61±2 mmHg) with an inflatable occluder placed around the abdominal aorta r o s t r a l to the renal a r t e r i e s . Values (X±SEM) for PRA (ng AI/ml/hr) prior to occlusion and at the end of each 45 min period of reduced RAP were as follows:

Control ANP RAP DAY 1 DAY 3 DAY 1 DAY 3 DAY 5

100±2 .76±.14 .97±.19 .98±.30 .88±.17 1.2±.37 71±2 5.2±.43 4.7±.32 5.9±.99 6.9±1.34 6.5±.66 61±2 10.4±1.8 9.9±1.5 12.4±2.4 16.9±2.2 13.0±3.0

We conclude that in conscious resting dogs, moderate elevations in plasma ANP concentration do not have appreciable long-term effec ts on either basal PRA or the PRA response to reduced RAP. (Supported by HL11678)

1046 CLINICAL CHARACTERISTICS ASSOCIATED WITH RENOVASCULAR DISEASE. L.P. Svetkev*. M J . Helms, P.E. Klotman*. Duke University Medical Center, Durham, NC

Clinical characteristics, such as the presence of arxiorninal bruit, are generally used to select hypertensive patients likely to have renal artery stenosis (RAS). We evaluated the ability of commonly used clinical features to predict the presence of RAS. Hypertensive adults were selected with one or more of the clinical features listed in the Table. All subjects underwent conventional renal arteriography. RAS was diagnosed if there was 50% or greater stenosis of a main renal artery. Eighteen of 100 subjects had RAS. The association between each clinical feature and the presence of RAS is summarized in the table, along with a test of the significance of the association. Since the presence of bruit was so strongly associated with RAS, and most patients with bruit also had other clinical features, the other features were analyzed only in patients who did not also have bruit.

Clinical feature Ν Ν with RAS p-value (Fisher's exact test)

Bruit 18 10 <.0005 Refractory HTN 32 6 .051 Progressively severe HTN 32 5 .25 Severe HTN 48 3 .27 Recent onset of HTN 15 2 .63 Early onset (age < 25 yr) of HTN 20 1 .67 Late onset (age > 45 yr) of HTN 14 1 1.0 Abnormal I VP 6 0 1.0

These data suggest that bruit and refractory hypertension are associated with RAS, but that other clinical features thought to be associated with RAS may not be, and suggest that other means of screening for renovascular disease are needed.

110481 REGULATION OF BIOLOGICALLY ACTIVE (B-) AND CLEARANCE (C-) ANP RECEPTORS IN RAT GLOMERULI AND VASCULAR SMOOTH MUSCLE HOMOGENATES (VSMH) IN RESPONSE TO CHRONIC SALT LOADING. H. Michel. H. Meyer-Lehnert*, and H.J. Kramer*. Med. Pol1kl1n1k, Univ. of Bonn, West Germany.

We investigated the e f f e c t s of chronic s a l t loading (NaCl) for 35 days on ANP receptor subtype regulation in freshly isolated rat glomeruli and in VSMH. Tissues were acid-washed (pH 5) in order to unmask potentially preoccupied ANP receptors. B-receptor c h r a c t e r i s t i e s were evaluated a f t e r C-receptor blocking with 4-23 cANP (5x10 _ 7 M). Receptor studies were performed as competitive binding inhibition and binding saturation studies.

B»ax (fmol/mg prot) Receptors Controls NaCl

Kd (PM) Controls NaCl

Glomeruli Total 492133 320+28** 162116 188138 Β 101118 88115 372117 478123** VSMH Total 188121 191119 462143 421133 Β 103114 69116* 421138 193156** n=5,meaniSEM, * .05<p<0.1 , **p<.02 NaCl vs Control Plasma ANP concentration was s l ight ly Increased in NaCl rats (681168 in NaCl vs 501154 1n C, .05<p< 0 . 1 ) . ANP stimulated cGMP synthesis 1n both glomeruli and VSMH was unchanged af ter NaCl. In glomeruli, the decrease 1n to ta l receptor number a f t e r NaCl 1s due t o a decrease in C-receptor number. In VSMH, the moderate decrease 1n B-receptor number was associated with significant Increase 1n B-receptor a f f i n i t y . Thus, our results suggest different regulation of ANP receptor subtypes 1n rat glomeruli and vascular smooth muscle 1n r e sponse to chronic s a l t loading.

Dow



1 0 4 9

TRANSIENT AND SUSTAINED INCREASE BY ENDOTHELIN OF INTRACELLULAR CALCIUM [ C a 2 + ] i IN VASCULAR SMOOTH MUSCLE CELLS (VSMC): RELATION TO INHIBITION OF Na-K-ATPase? H .Meyer -Lehner t * , C. Wanning, A. Backer, H. S t e l k e n s , H . J . Kramer*. Med. P o l i k l i n i k , Univ . of Bonn, West Germany.

The c e l l u l a r mechanisms o f a c t i o n o f t he endogenous v a s o c o n s t r i c t o r e n d o t h e l i n s t i l l remain t o be e l u c i d a t e d . We examined the e f f e c t s o f endot h e l i n ( 1 0 " 8 M ) on [ C a 2 + ] i i n c u l t u r e d r a t VSMC. Wi th in seconds, e n d o t h e l i n induced a rap id t r a n s i e n t increase o f [ C a 2 + ] i (77±3 vs 10415 nM, p< . 0 5 ) . Increased [ C a 2 + ] i decreased t o basal va lues w i t h i n appr . 5 min . P re incuba t ion w i t h e n d o t h e l i n f o r 60 min r e s u l t e d in a susta ined increase o f ba sa l [ C a 2 + ] i (77± 3 vs 105± 8 nM, p< . 0 5 ) . P r e i n c u b a t i o n w i t h e n d o t h e l i n a lso enhanced vasopressin ( 1 0 - 7 M ) - s t i m u l a t e d peak l e v e l s o f [ C a 2 + ] i (528120 vs 969121 , p < . 0 1 ) . The e f f e c t o f e n d o t h e l i n on Na-K-ATPase a c t i v i t y was a lso examined. 1 0 _ 5 M endot h e l i n i n h i b i t e d Na-K-ATPase by 30.5%. For compari s o n , ouabain ( 1 . 5 x 1 0 " e M ) i n h i b i t e d Na-K-ATPase by 50%. Ouabain d id not e x h i b i t a f a s t t r a n s i e n t e f f e c t on [ C a 2 + ] i ; however, p r e i n c u b a t i o n w i t h ouabain r e s u l t e d in a susta ined increase o f [ C a 2 + ] i (7713 vs 15817 nM, p < . 0 1 ) . Thus, e n d o t h e l i n may e x e r t i t s v a s o c o n s t r i c t o r e f f e c t s a t l e a s t in p a r t v i a a l t e r a t i o n s of c e l l u l a r C a 2 + m o b i l i z a t i o n i n VSMC. The susta ined increase o f [ C a 2 + ] i and t h e enhancement o f vasopressor- induced C a 2 + m o b i l i z a t i o n may be r e l a t e d t o i n h i b i t i o n o f Na-K-ATPase. V i a i n d i r e c t i n h i b i t i o n o f Na-Ca-exchange, t h i s may r e s u l t i n an increase o f C a 2 + content o f i n t r a c e l l u l a r s t o r e s , s e n s i t i v e t o m o b i l i z a t i o n by vasopressor hormones. The f a s t t r a n s i e n t e f f e c t o f e n d o t h e l i n may i n d i c a t e ca lc ium a g o n 1 s t - l i k e p r o p e r t i e s o f t h i s endogenous v a s o c o n s t r i c t o r .

110511

FIACE AND GENDER INFLUENCE THE DIURNAL PATTERN OF BLOOD PRESSURE IN ADOLESCENTS. GA Harshfield*. BS Alpert, ES Willey, GW Somes, JK Murphy,L Dupaul,B Cobb. Dept. of Pediatrics, Univ. of Tennessee, Memphis and CRC, LBCMC, Memphis, TN.

Previous research in adults has demonstrated 1) a diurnal pattern of blood pressure (BP) and 2) racial differences in the pattern, with blacks showing less of a decrease in BP during sleep. The present study examined the diurnal pattern of BP in normotensive adolescents, determining the influence of gender and race. Ambulatory BP recordings were performed on 199 adolescents, including 42 black males (BM), 55 white males (WM), 65 black females (BF) and 37 white females (WF). The mean age was 13 ± 2 years with a mean casual BP of 105 / 61 ±12 /11 mm Hg. The means (± SD) for awake and sleep systolic (SBP) and diastolic (DBP) BP were: Awake

BM WM BF WF SBP 118 ± 6 117 ± 6 113 ± 6 114 ± 6 DBP 70 ± 4 69 ± 4 69 ± 4 69 ± 4

Sleep SBP 112 ± 6 105 ± 6 104 ± 6 105 ± 6 DBP 65 ± 6 61 ± 4 63 ± 4 61 ± 4 The interaction between race and gender was significant for both SBP (p<.001) and DBP (p<.04). BM's had the highest SBP, followed by WM's, WF's and BPs. BM's also had the highest DBP, followed by BPs, WF's and WM's. The interaction between race and condition was also significant for SBP (p<.01) and DBP (p<.001). SBP and DBP were highest in blacks while awake, followed by whites while awake, blacks during sleep and whites during sleep. These results indicate that both race and gender are important determinants of the diurnal pattern of BP in adolescents. Increased BP in blacks, particularly males, during sleep may help to explain race and gender differences in the development of hypertension, and aid in the detection and definition of the prehypertensive state.

1 0 5 0

DISTINCT EFFECTS OF AN ENDOGENOUS Na-K-ATPase INHIBITOR AND OF OUABAIN ON CYTOSOLIC CALCIUM [ C a 2 + ] i IN VASCULAR SMOOTH MUSCLE CELLS (VSMC). H .Meyer -Lehner t * , C.Wanning, A.Backer , H . M i c h e l , and H.J .Kramer* . Med. U n i v . - P o l i k l i n i k Bonn, FRG.

An endogenous I n h i b i t o r of Na-K-ATPase, a oua-b a i n - l i k e f a c t o r (OLF) , may p lay a r o l e in volume-dependent hyper tens ion . We c o l l e c t e d 24 h u r i n e from s a l t - l o a d e d hea l thy s u b j e c t s . Ur ine a l i q u o t s corresponding t o 1 h u r i n e c o l l e c t i o n were pooled and chromatographed on Sephadex G-25 a f t e r lyophy-l i z a t i o n . The e l u t e d p o s t - s a l t f r a c t i o n (F I V ) c o n t a i n i n g OLF was re-chromatographed on Sephadex G-10. I n v i t r o i n h i b i t i o n o f Na-K-ATPase was e x a mined using a p u r i f i e d enzyme from hog c e r e b r a l c o r t e x . St rongest ATPase i n h i b i t i o n was observed in the l a t e f r a c t i o n (F I V / 7 ) which showed a dose-r e l a t e d enzyme i n h i b i t i o n from 10% ( 0 . 1 3 mg/ml) t o 58% ( 0 . 5 2 mg/ml ) . Th is f r a c t i o n was subjected t o reverse-phase HPLC; OLF was again e l u t e d i n a l a t e f r a c t i o n (F I V / 7 g ) . E f f e c t s o f OLF (10 mg/ml) on [ C a 2 + ] i were s tud ied in c u l t u r e d r a t VSMC using f u r a 2 . OLF r a p i d l y increased [ C a 2 + ] i (8219 vs 253 123 nM, p < . 0 1 ) . OLF-st imulated [ C a 2 + ] i was a t t e n u ated by verapami l (12615 nM, p< .01 ) and was a l s o reduced in C a - f r e e medium (10419 nM, p < . 0 1 ) . As opposed t o OLF, ouabain d i d not e x h i b i t t h i s f a s t e f f e c t on [ C a 2 + ] i . P re incubat ion (45 min) w i t h OLF increased basal [ C a 2 + ] i from 8219 nM t o 15517 nM ( p < . 0 0 1 ) . T h i s e f f e c t was not a f f e c t e d by verapa mi l (15517 vs 161110 nM, NS). OLF increased vasopress in ( 1 0 _ 8 M ) - s t i m u l a t e d maximum [ C a 2 + ] i (31018 vs 3771 10 nM, p < . 0 5 ) . P re incubat ion w i t h ouabain ( 1 0 " 5 M ) increased basal [ C a 2 + ] i t o 14518 nM (p< 0 . 0 1 ) . Thus, OLF may a f f e c t vascu la r r e s i s t a n c e v i a a dual e f f e c t on [ C a 2 + ] i . These e f f e c t s a re a t l e a s t in p a r t d i f f e r e n t from those o f ouabain .

|1052|

E F F E C T S O F D I E T A R Y C A L C I U M O N T H E E X P R E S S I O N O F A

C I R C U L A T I N G H Y P E R T E N S I V E F A C T O R I N S P O N T A N E O U S L Y

H Y P E R T E N S I V E R A T S ( S H R ) . R . Z . L e w a n c z u k * , Ρ . Κ . Τ .

P a n g * . D e p a r t m e n t o f P h y s i o l o g y , U n i v e r s i t y o f

A l b e r t a , E d m o n t o n , A l b e r t a , C a n a d a .

I n r e c e n t y e a r s i t h a s b e e n s h o w n t h a t d i e t a r y

c a l c i u m c a n a f f e c t b l o o d p r e s s u r e i n s e l e c t e d

c a s e s o f h u m a n a n d e x p e r i m e n t a l h y p e r t e n s i o n . T h e

m e c h a n i s m o f s u c h a n e f f e c t i s u n k n o w n . R e c e n t l y ,

w e d e s c r i b e d t h e p r e s e n c e o f a c i r c u l a t i n g h y p e r

t e n s i v e f a c t o r i n t h e p l a s m a o f S H R r a t s a n d s o m e

h u m a n h y p e r t e n s i v e s . T h i s f a c t o r i n c r e a s e s c a l

c i u m u p t a k e i n v a s c u l a r s m o o t h m u s c l e w i t h a t i m e

c o u r s e i d e n t i c a l t o t h a t o f i t s h y p e r t e n s i v e e f f e c t .

I t w a s , t h e r e f o r e , c o n s i d e r e d i m p o r t a n t t o d e t e r

m i n e w h e t h e r t h i s f a c t o r m i g h t b e i n v o l v e d i n t h e

b l o o d p r e s s u r e r e s p o n s e t o d i e t a r y c a l c i u m m a n i

p u l a t i o n . F i v e w e e k o l d S H R r a t s w e r e p l a c e d o n

h i g h ( 2 % ) , n o r m a l ( 0 . 5 % ) o r l o w ( 0 . 0 2 % ) c a l c i u m

d i e t s . A f t e r 8 w e e k s o f d i e t a r y t r e a t m e n t , a n i m a l s

i n t h e l o w c a l c i u m g r o u p w e r e f o u n d t o h a v e s i g

n i f i c a n t l y h i g h e r b l o o d p r e s s u r e s t h a n r a t s i n t h e

o t h e r t w o g r o u p s . C o n v e r s e l y , r a t s i n t h e h i g h

c a l c i u m g r o u p h a d t h e l o w e s t b l o o d p r e s s u r e s . O v e r

a l l , m e a n a r t e r i a l p r e s s u r e w a s f o u n d t o c o r r e l a t e

s i g n i f i c a n t l y ( r = . 7 8 , ρ = . 0 0 0 1 ) w i t h r e l a t i v e

l e v e l s o f t h e c i r c u l a t i n g h y p e r t e n s i v e f a c t o r , a s

d e t e r m i n e d b y a n i n v i v o b i o a s s a y . T h e s e r e s u l t s

s u g g e s t t h a t d i e t a r y c a l c i u m m a y a f f e c t b l o o d

p r e s s u r e b y i n f l u e n c i n g t h e e x p r e s s i o n o f t h i s

c i r c u l a t i n g h y p e r t e n s i v e f a c t o r . S p e c i f i c a l l y , a

h i g h c a l c i u m d i e t s u p p r e s s e s e x p r e s s i o n o f t h i s

f a c t o r , w h e r e a s a l o w c a l c i u m d i e t i n d u c e s i t s

e x p r e s s i o n .

Dow



[10531 RACIAL DIFFERENCE IN PREVALENCE AND SEVERITY OF LVH IN MEN WITH MILD-MODERATE HYPERTENSION: ECHOCARDIOGRAPHIC ASSESSMENT OF A MULTICENTER POPULATION JS Gottdiener, DJ Reda, A Notargiacomo, Β Materson, Veterans Adminsitration Cooperative Hypertension Study Group and University of Maryland Hospital, Baltimore, Maryland.

Differences in the clinical expression of hypertension (HTN) may be in part related to race. To determine the relationship between race and the cardiac response to HTN, we analyzed centrally-read, 2D-targeted M-Mode echocardiograms done prospectively in 256 (163 black, 93 white) male HTN pts (av age 59 ± 10 yrs, av BP 151 ± 15/ 98 ± 6 mmHg). Blacks had higher LV mass index (LVMI) than whites (av 137 ± 44 vs. 126 ± 4 0 gm/m 2 , ρ = .058), greater prevalence (blacks 49%, whites 31%, ρ = .008) of LVH (LVMI > 134 gm/m 2 Cornell criteria), greater severity of LVH; moderate - severe LVH (LVMI 152-316 gm/m 2 ) found in 30% of blacks vs 19% of whites (p = .06). Although relative wall thickness was greater in blacks (.52 ± 13) than whites (.48 ± .11, ρ < .01) distribution of "concentric," or "eccentric-dilated" LVH, and disproportionate septal thickening did not differ by race. Average age, weight, "obese" weight, blood pressure (BP), end-systolic stress and cardiac output [ did not differ by race. Physical activity index and plasma renin activity were lower ( ρ < .05) in blacks. On multiple logistic regression analysis, variables best related to LVMI were systolic BP, age, plasma renin, 24 hour urine sodium, race, and serum cholesterol. Separate analysis stratified by race showed plasma renin activity and urinary sodium excretion to be significant only in blacks. We conclude: 1) Despite equivalent severity of HTN, black men have greater LV mass, as well as higher prevalence and severity of LVH than white men. 2) These differences are associated with renin activity and sodium excretion.

110551 CHLORIDE ION PLAY AN IMPORTANT ROLE FOR SODIUM INDUCED VOLUME EXPANSION IN NORMAL HUMAN. Y Tomita, Μ Ueno, Τ Tsuchihashi, Η Muratani, Κ Kobayashi, S Takishita, Μ Fujishima. 2nd Dept. Intern. Med., Kyushu University, Fukuoka, Japan.

We examined whether anion component of sodium (Na) salt would have an influence on blood volume and humoral factors. After control diet containing 135mEq Na chloride(Cl), 8 normal females, aged 18-20 years, took 120mg furosemide and were maintained with low salt diet(30mEq NaCl). Then they were administered 105 mEq NaCl supplement Sup) for 3 days or equi-molar Na citrate(Cit) Sup. Each subject received both Sup experiments in crossover design. Body weight (BW), plasma norepinephrine(NE), renin activity (PRA), aldosterone concentration(PAC) and urinary excretion of Na(UNa), potassium(UK) were determined.

n=8 NaCl Sup NaCit Sup UNa (mEq/3days) 107 ± 19 ** 197 ± 10 A:vs low salt UK (mEq/3days) 9 6 ± 6 ** 130±7 mean±SEM ABW (Kg) 1 .610.1 ** 0 .6±0 .1 * :p<0.05 ΔΡΝΕ (%) -44 ± 6 * -28 ± 8 **:p<0.01 Δ PRA (%) -93 ± 1 ** -73 ± 1 (paired t - test ) APAC (%) -69 ± 2 • -54 ± 5

NaCit Sup induced greater UNa and UK than NaCl Sup. BW increased with both salt Sup, although degree of gain was significantly smaller with NaCit Sup. This difference in UNa (UNa with NaCl Sup - UNa with NaCit Sup) was negatively correlated with the difference in BW gain (with NaCl Sup - with NaCit Sup), r= -0.78 p< 0.05. Thus smaller UNa during NaCl Sup means greater Na retention and concomitant volume expansion. And this greater volume expansion with NaCl Sup caused greater suppression of PNE, PRA and PAC. In conclusion, CI ion do play an important role for Na handling in normal subjects, which influence blood volume and humoral factors.

1054 THE BLOOD PRESSURE AND HEART RATE RESPONSE OF THE P H Y SICIAN PERFORMING BALLOON ANGIOPLASTY/VALVULOPLASTY. Ifi DiSessa, B S A l p e r t , L D u p a u l . Ε W i l l e y . D e p a r t m e n t of P e d i a t r i c C a r d i o l o g y , U n i v e r s i t y o f Tennessee, M e m p h i s , TN.

To d e t e r m i n e t h e hemodynamic response of t h e p h y s i c i a n t o t h e s t r e s s of an i n t e r v e n t i o n a l c a t h e t e r i z a t i o n , w e e m p l o y e d an a m b u l a t o r y b lood p r e s s u r e ( B P ) m o n i t o r t o m e a s u r e s y s t o l i c ( S ) , d i a s t o l i c ( D ) , mean ( M ) BP and h e a r t r a t e ( H R ) e v e r y 1 5 m i n u t e s d u r i n g a r o u t i n e w o r k d a y ( n = 4 ) , d iagnos t i c ca rd i ac c a t h e t e r i z a t i o n ( n = 5 ) and ba l l oon a n g i o p l a s t y / v a l v u l o p l a s t y ( n = 4 ) i n one p h y s i c i an . The s u b j e c t ' s average d a i l y BP and HR d u r i n g a n o r m a l w o r k i n g day was 1 2 0 ± 6 m m H g ( S ) , 8 2 ± 5 m m H g ( D ) and 9 1 ± 7 m m H g ( M ) . Hea r t r a t e d u r i n g a r o u t i n e day was 7 5 ± 9 b e a t s / m i n ( b p m ) . Compared t o t h e m e a s u r e m e n t s ob ta ined d u r i n g r o u t i n e d a i l y a c t i v i t i e s , t h e r e was a s i g n i f i c a n t i nc rease i n S , D , and Μ BP and HR d u r i n g a r o u t i n e d iagnos t i c c a t h e t e r i z a t i o n ( S = 1 3 1 ± 11 m m H g , D * 8 6 ± 6 m m H g , M = 9 9 ± 7 m m H g , H R = 8 9 ± 1 2 b p m ) ( p = 0 0 0 1 f o r a l l ) . The BP and HR d u r i n g an a n g i o p l a s t y / v a l v u l o p l a s t y ( S = 1 5 1 ± 11 m m H g , D = 9 5 ± 8 m m H g , M = 1 0 6 ± 8 m m H g , HR= 1 0 4 ± 1 3 b p m ) w e r e s i g n i f i c a n t l y g r e a t e r t h a n t h e va l ues o b s e r v e d d u r i n g bo th a r o u t i n e day and a d iagnos t i c c a t h e t e r i z a t i o n ( p = 0 0 0 1 f o r a l l ) . I n a d d i t i o n , w e c o m p a r e d v a l u e s obse rved d u r i n g t h e a n g i o p l a s t y / v a l v u l o p l a s t y t o r e s t i n g va l ues reco rded p r i o r t o t h e p r o c e d u r e and r e c o v e r y v a l u e s measu red 1 hou r a f t e r t h e p r o c e d u r e . Base l i ne v a l u e s ob ta ined p r i o r t o i n t e r v e n t i o n a l p r o cedu re w e r e s i m i l a r t o those obse rved on a r o u t i n e day. T h e r e was a s i g n i f i c a n t i nc rease i n S , D and Μ BP and HR d u r i n g t h e i n t e r v e n t i o n . One h o u r post i n t e r v e n t i o n , a l l v a l u e s r e t u r n e d to p r e p r o c e d -u r a l l eve l s . A n g i o p l a s t y / v a l v u l o p l a s t y p roduces s i g n i f i c a n t i n c reases i n BP and HR i n t h e p h y s i c i a n p e r f o r m i n g t h e p r o c e d u r e s i g n i f i c a n t l y above those measured d u r i n g r o u t i n e d iagnos t ic c a t h e t e r i z a t i o n . F u r t h e r s tud ies a r e needed t o eva lua te bo th i n t e r p h y s -i c i a n v a r i a b i l i t y and poss i b l e use o f BP c o n t r o l d u r i n g t h e p r o c e d u r e f o r those w h o a r e h y p e r r e a c t o r s to t h i s s t r e s s o r .

11056| E L E C T R O P H Y S I O L O G I C A L I N V E S T I G A T I O N O N P R E S Y N A P T I C

a- A N D 3 - A D R E N O C E P T O R S I N S P O N T A N E O U S L Y H Y P E R T E N

S I V E R A T S ( S H R ) . Κ F u j i i , Η K u r i y a m a § , Κ K o b a y a s h i ,

Μ F u j i s h i m a , 2 n d D e p t . o f I n t e r n . M e d . a n d D e p t .

o f P h a r m a c o l o g y § , K y u s h u U n i v . , F u k u o k a , J a p a n .

W e e v a l u a t e d p r e s y n a p t i c α - a d r e n o c e p t o r ( α - R ) -

a n d 3 - a d r e n o c e p t o r ( 3 - R ) - m e d i a t e d m o d u l a t i o n o f

t r a n s m i t t e r r e l e a s e i n S H R w i t h a n e w a p p r o a c h i n

t h i s f i e l d , e l e c t r o p h y s i o l o g i c a l m e t h o d . E x c i t a

t o r y j u n c t i o n p o t e n t i a l s ( E J P ) w e r e e l i c i t e d b y

n e r v e s t i m u l a t i o n a n d r e c o r d e d w i t h m i c r o e l e c -

t r o d e s i n i s o l a t e d m e s e n t e r i c a r t e r i e s f r o m y o u n g

( 6 - 8 w ) a n d a d u l t ( 1 8 - 2 2 w ) S H R a n d W i s t a r K y o t o r a t s

( W K Y ) . T h e a m p l i t u d e o f E J P w a s e n h a n c e d e i t h e r b y

b l o c k a d e o f i n h i b i t o r y α - R w i t h p h e n t o l a m i n e ( P ) o r

b y s t i m u l a t i o n o f f a c i l i t a t o r y 3 - R w i t h i s o p r o

t e r e n o l ( I ) . T h e d e g r e e o f i n c r e a s e i n a m p l i t u d e o f

E J P b y Ρ o r I , i n d i c a t i n g t h e r e s p o n s i b i l i t y o f

α - R o r 3 - R , r e s p e c t i v e l y , d i d n o t d i f f e r b e t w e e n

S H R a n d W K Y a t e i t h e r a g e ( t a b l e 1 ) . M e m b r a n e p o

t e n t i a l s ( M P ) , M P w i t h n o r e p i n e p h r i n e ( N E ) 1 0 _ 5 M a n d

s p a c e c o n s t a n t s ( λ ) w e r e m e a s u r e d i n a d u l t s r a t s ,

a n d w e r e s i m i l a r b e t w e e n S H R a n d W K Y ( t a b l e 2 ) .

t a b l e 1 % i n c r e a s e i n a m p l i t u d e o f E J P m e a n t S D

Ρ 1 0 - 6 M I 1 0 - 9 M I 1 0 - 8 M I 1 0 - 7 M

S H R ( Y ) 3 8 + 1 3 1 3 ± 3 5 4 ± 1 2 1 0 4 ± 1 5

W K Y ( Y ) 3 5 ± 1 2 1 1 ± 3 5 5 ± 1 1 9 2 ± 1 9

S H R ( A ) 5 5 ± 1 7 1 5 ± 5 4 9 ± 1 8 5 4 ± 6

W K Y ( A ) 4 4 ± 9 2 1 ± 4 3 8 ± 1 6 5 8 ± 1 3

t a b l e 2 M P ( m V ) M P w i t h N E λ ( m m )

S H R - 6 8 . 4 ± 2 . 4 - 6 0 1 ± 3 . 2 0 . 9 0 1 0 . 1 7

W K Y - 6 8 . 9 ± 3 . 2 - 5 9 5 ± 3 . 0 0 . 8 5 ± 0 . 1 6

I n c o n c l u s i o n , n e i t h e r p r e s y n a p t i c m o d u l a t i o n

o f t r a n s m i t t e r r e l e a s e n o r t h e m e m b r a n e p r o p e r t y

i s a l t e r e d i n S H R , s u g g e s t i n g t h a t t h e s e f a c t o r s

m a y n o t p l a y a m a j o r r o l e i n e i t h e r d e v e l o p m e n t o r

m a i n t e n a n c e o f h y p e r t e n s i o n i n S H R .

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[10571 EFFECTS OF MEALS AND PHYSICAL ACTIVITY ON BLOOD PRESSURE VARIABILITY IN THE ELDERLY PATIENTS. Τ Tsuchihashi, Γ Abe, A Tsukashima, Κ Kobayashi, Μ Fujishima. 2nd Dept. Intern. Med., Kyushu Univ., Fukuoka, Japan.

We investigated blood pressure (BP) variability in the elderly patients focusing on the effects of meals and physical activity. Twenty-two elderly patients were divided into two groups. Active group consists of 11 patients (67-90, mean 78y.o.) who had no restriction in physical activity. Another 11 patients (Passive group;68-87,mean 79y.o.) were passively recumbent in bed whole day due to bone fracture or cerebrovascular disease. Each subject was alert and had normal "sleep-awake" rhythm. 24-hour ambulatory BP was determined at intervals of 20 minutes using non-invasive device. In both groups, postprandial reductions in systolic and diastolic BPs were around 20 and 10 mmHg, respectively. As a result, postprandial BP levels were comparable to those seen during nighttime. In active group, BP variability was significantly greater during daytime than nighttime and day-night difference in BP was not detected. On the other hand, daytime diastolic BP was significantly higher than nighttime in passive group, while BP variabilities were similar. When postprandial BPs were excluded, day-night changes in BP became prominent. The pulse rate was significantly higher during daytime in each group.

We conclude: 1) Postprandial reduction in BP is evident in the elderly patients, which contributes largely to the variation of BP during daytime. 2) Day and night rhythms of BP and pulse rate do exist in passively recumbent patients. 3)The greater variability in daytime BP obscures the difference in BP between day and night in active patients.

[10591 BIPHASIC CHANGES I N TOTAL PERIPHERAL RESISTANCE (TPR) AND REGIONAL VASCULAR RESISTANCE BY ENDOTHELIN (ET) I N RATS. Y Nakao, Y Takata*, Κ Fujii, Τ Koga, Κ Kobayashi, Μ Fujishima. 2nd Dept. of Intern. Med., Kyushu Univ., Fukuoka, Japan.

We evaluated the hemodynamic response to ET in normotensive rats. ET(0.1-lnmol/kg) was intravenously given in conscious rats for recording of mean arterial pressure(MAP) and also in anesthetized rats for measuring blood flows of ascending aorta(cardiac output;CO) , carotid (CBF) , femoral (FBF) and mesenteric(MBF) arteries by pulsed doppler flowmeters. ET led to a transient and dose-related hypotension in conscious rats, followed by a gradual and sustained increase in MAP. Similarly, in anesthetized animals, ET decreased MAP initially and increased subsequently without alteration of CO. Hence, TPR was lowered initially (p<0.01) and raised at the following phase. Although MBF was slightly decreased immediately after ET injection, CBF and FBF were clearly increased (p<0 . 01 ) . At the following phase, all regional blood flows were reduced. Carotid(CVR) and femoral(FVR) vascular resistances were markedly decreased at the early phase(p<0.01) but slightly increased at the late phase. In a similar way, in mesenteric vascular resistance(MVR), the biphasic change in vascular resistance was induced by ET, although the degree of the initial decrease in MVR was less than in the other regions. In conclusion, the initial fall in MAP in rats was induced by decreases in TPR, which may.be attributed to decreases in CVR and FVR, and partially to decreases in MVR. On the other hand, a rise in TPR related to elevation of CVR, FVR and MVR was responsible for the following increases in MAP.

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COMPARISON OF ENALAPRIL AND CAPTOPRIL ON RENAL FUNCTION AND SERUM POTASSIUM IN THE TREATMENT OF MALIGNANT HYPERTENSION. Τ Tsuchihashi, A Tsukashi-ma, I Abe, Μ Ueno, Κ Kobayashi, Μ Fujishima. 2nd Dept. Intern. Med., Kyushu Univ., Fukuoka, Japan.

We compared the effects of enalapril(E) and captopril(C) on serum creatinine (S-Cr) and potassium (S-K) concentrations in the treatment of malignant hypertension. 26 patients with malignant hypertension were divided into 3 groups;8 patients (mean age 45.3y.o.) were treated with 5-10 (mean 8.1)mg of Ε (Group Ε ) , another 8 (42.4y.o.) with 75-400 (mean 213)mg of C (Group C ) , and the remaining 10 (40.0y.o.) without converting enzyme inhibitors (Group N ) . Loop or thiazide diuretics were combined in 5 patients in both Group Ε and C, and 4 in Group N. The average blood pressures on admission in Group E,C and Ν were 214/138, 240/145,and 219/141 mmHg, respectively,, which decreased to 132 /89, 147/95 and 156/95 after two weeks' treatment.

Enalapril Captopril Non-CEI S-Cr Owk 2.8±0.6 2.6+0.8 2.610.6 (mg/dl) lwk 3.310.8 2.7±0.9 2.910.8

2wks 3.2±0.8 3.0±0.9 2.810.7 S-K Owk 3.9±0.2 3.6±0.2 3.710.2 (mEq/L) lwk 4.7±0.2** 4.110.2** 4.3+0.2**

2wks 5.2±0.2**#$ 4.210.1* 4.410.2** Results are mean 1 SEM. *p<0.05,**p<0.01 vs Owk, #p<0.01 vs Captopril, $p<0.05 vs Non-CEI. As shown in Table, S-Cr did not change significantly. S-K, however, increased significantly in each group. S-K at second week was significantly higher in Group Ε than those in Group C and N.

We conclude: 1) Both Ε and C led to sufficient reduction in blood pressure without the deterioration of renal function. 2) Ε produced greater increase in S-K than C.

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ARTERIAL BAROREFLEXES ARE NOT IMPAIRED IN GLUCOCORTICOID-INDUCED HYPERTENSION. Κ Szemeredi, G Bagdy, IJ Kopin and DS Goldstein; Clinical Neuroscience Branch, NINDS, NIH, Bethesda, MD

Baroreflex-cardiac sensitivity often is decreased in patients with hypertension and in laboratory hypertensive models, but baroreflex function has not been examined in glucocorticoid-induced hypertension. Effects of chronic glucocorticoid treatment on arterial baroreflex function and on cardiac 8- and vascular oc-adrenoceptor-mediated responses therefore were assessed in conscious, unrestrained Wistar-Kyoto rats. Cortisol (25 mg/kg/day) was administered for seven days using a subcutaneous reservoir pump. Arterial baroreflex-vagal sensitivity was calculated from the relationship between the cardiac interbeat interval and the mean arterial blood pressure during phenylephrine a n d nitroprusside challenge; and baroreflex-sympathoneural sensitivity was calculated from the ratio of the increase in the arterial norepinephrine concentration to the decrease in mean arterial pressure at 15 min during intravenous infusion of nitroprusside. Cardiac β-adrenoceptor-mediated responsiveness was estimated from heart rate responses to bolus-injected isoproterenol, and vascular α-adrenoceptor-mediated responsiveness was estimated from peak mean arterial pressure responses to bolus-injected phenylephrine. Cortisol treatment increased mean a r t e r i a l pressure, decreased heart r a t e , a n d i n c r e a s e d heart rate responses to isoproterenol, whereas baroreflex-vagal sensitivity, baroreflex-sympathoneural sensitivity, a n d pressor responses to phenylephrine were unaffected. The results indicate that hypertension due to chronic C o r t i s o l administration is not associated with decreased sensitivity of the baroreceptor-vagal reflex. The sympathetic component of the baroreflex and a1-adrenoceptor responsiveness also are normal, whereas β-adrenoceptor responsiveness is increased.

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|1061 NOREPINEPHRINE (NE) AND VASOPRESSIN (AVP) DO NOT INCREASE 1,2-DIACYLGLYCER0L (DAG) IN RESISTANCE VESSELS. J Ohanian, Ρ Collins, JD Ollerenshaw, AM Heagerty. Dept. of Medicine, University of Leicester, Leicester, UK.

DAG is liberated during membrane phosphoinositide hydrolysis, and activates protein kinase C (PKC), which is involved in smooth muscle contraction and growth; as such it may be important in the genesis of hypertension. Different sub-species of PKC may be activated by structurally different DAG. We have studied inositol trisphosphate (IP 3) levels, the mass levels, and arachidonic acid containing subspecies (AA-) of DAG in rat resistance arterioles stimulated for 20 sec by NE or AVP. Arterioles of 150-200 ui.d. were incubated at 37 ^ for one houig, then exposed to either NE 10" Μ or AV,P 10 Μ, DAG was extracted, converted to ^phosphatidic acid (PA), by DAG-kinase and Ρ-γ-ΑΤΡ. The PA was derivatized and separated by degree of saturation using TLC and HPLC. IP 3 was increased by AVP, DAG was not changed by NE or AVP. AA-DAG was reduced by AVP. These data are contrary to findings in cultured myocytes and suggest that DAG levels are tightly controlled in intact arterioles and the response is different with NE compared to AVP. When analysing the biochemical events surrounding contraction, experiments using cultured cells should be interpreted with caution.

ΪΡ~3 DAG 16:0/20:4 18:0/20:4 fmol/mgP nmol/mgP pmol/mgP pmol/mgP

CONTROL 26+6 2.2+0.2 40+5 265+15 NE(10 _M) 41 + 11 2.2+0.2 37 + 7 255±32 AVP(10 8M) *85+_l8 2 .1+0.2 *24+2 **180 + 15 * p < 0 . 0 3 , ** p<0 . 0 0 3 (P=Protein)

|1063| THE TAIM STUDY: EFFECTS OF DRUG, DIET AND BLOOD PRESSURE ON QUALITY OF LIFE SW Smoller*. Albert Einstein College of Medicine, Bronx, NY, MD Blaufox*, Β Davis, Η Langford, A Oberman, Μ Knerr, C Swencionis for TAIM Group

Change in Quality of Life (QOL) was assessed af ter 6 mos. of drug and diet therapy for 720 participants in the collaborative, c l i n i c a l Trial of Antihypertensive Interventions and Management (TAIM), using placebo or chlorthalidone (25 mg) or atenolol (50 mg), combined with either usual diet or weight reduction (WtU/) or sodium r e s t r i c t i o n (Na^). Overall, neither drug had significant negative impact on QOL. Among males, however, chlorthalidone increased sexually related physical complaints, spec i f i ca l ly problems with erection, with 28% of those on chlorthalidone alone reporting worsening in problems with erection, vs . 3% of placebo group (P< .01 ) . Wt^combined with chlorthalidone attenuated this e f f e c t , with only 13% worsening. Wt b was beneficial while Na U produced unfavorable effects on sleep disturbances, sexual complaints in men, and significantly greater (P<.025) increase in fatigue (33%) than either usual diet (17.3%) or Wt^(16 .3%) .

Blood pressure reduction, independently of drug or diet assignment, resulted in improvement in sleep disturbances (P< .05 ) , physical complaints (P< .05) , and sa t i s fac t ion with health (P<.05) and with sex (P< .01 ) .

We conclude that 1)while these drugs at low doses generally show few side e f f e c t s , Wt^ added to active drug minimizes them; 2) Na4fhas some adverse e f f e c t s ; and 3) blood pressure reduction, per se, impacts favorably on quality of l i f e .

|1062| EFFECTS OF HYPERTENSION ON MURINE MYOCARDIAL PHOSPHOLIPID METABOLISM DH Maclver, JD Ollerenshaw, AM Heagerty. Dept. of Medicine, University of Leicester, Leicester, UK.

Left ventricular hypertrophy occurs in response to an increase in pressure load. However the biochemical regulation of this is incompletely understood. Recently it has been reported that hydrolysis of phosphoinositol lipids is implicated in cellular growth in some tissues. Accordingly it was decided to investigate the effects of hypertension on this signalling system during the development of cardiac hypertrophy. Female Wistar rats (approximately 200 g) were rendered hypertensive by banding the aorta between the origins of the renal arteries. At 9 days, slices (200 urn thick) of left ventricular myocardium were incubated for 2 hours in H-myoinositol. The tissue was then homogenized in trichloro-acetic acid and inositol phosphates separated using high performance liquid chromatography. Results expressed as mean + SEM. Mean arterial pressure was significantly higher in animals with coarctation compared to sham operated animals (166+3 vs 129+4 mmHg, p < 0 . 0 0 1 ) . Inositol 1,4,5 trisphosphate (71+14 vs 36+5 fmol/mg, p < 0 . 0 5 ) and inositol 1,4 bisphosph.ate (25+5 vs 65+16 fmol/mg, p < 0 . 0 5 ) were both significantly higher in the animals with coarctation hypertension than sham operated animals. It is concluded that there is increased hydrolysis of phosphoinositol lipids in the left ventricle in this model of hypertension and this process may be implicated in the cellular mechanism necessary for the development of cardiac hypertrophy.

1064 ALPHA 2 ADRENOCEPTORS IN HYPERTENSION DUE TO SINOAORTIC BARORECEPTOR DENERVATION IN HUMANS. B. Chamontin 0, J.M. Senard 0 0, J.Guittard 0, J.L. Montastruc 0 0and M. Salvador 0

Departments of Internal Medicine 0 and Clinical Pharmacology 0 0 CHU Purpan,Toulouse,FRANCE.

The purpose of the study was to investigate baroreflex activity in three patients (pts),mean age 60.6±2 years with both arterial hypertension (AH) (paroxysms recorded at 250/130 mmHg) and orthostatic hypotension (OH).They received radiation therapy to the entire cervical area for neoplasm 9.6 ± 2.8 years ago. Every pt had a severe and symptomatic OH: blood pressure (BP) and heart rate- (HR) were respectively 163.3 ± 16.9/105 ± 7 mmHg 82 ± 5 b/min recumbent and 81.6 ± 15.4 /53.3 v ± 9.4 mmHg 99.3 ± 0.9 b/min upright.The standing-induced increase in HR was lower (AHR =+17.3 b/min) than expected ;atropine infusion (0.02 mg/kg) and Valsalva's maneuver were ineffective ;the massage of sinocarotid receptors induced a slight decrease in HR ( AHR= - 8 b/min).Infusion of norepinephrine (0.016 mg/ min) increased BP without effect on HR.Platelet alpha2 adrenoceptors (alpha2-AR) evaluated by (3H) Yohimbine binding showed a significant increase in Bmax (fmoles/mg protein) without any significant change in affinity (KD) when compared with normotensive and essential hypertensive patients :

pts NT EH p*<0.05 Bmax 242±34*° 162±22* 128±12° p°<0.001 KD 31±0.2 2.7±0.3 2.5±0.3 This study described an unusual etiology of paroxysmal AH and suggested the potential interest of platelet alpha2-AR measurement to evaluate sympathetic tone.

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1065 TACHYCARDIA DURING REVERSAL OF ONE-KIDNEY, ONE CLIP HYPERTENSION IN CONSCIOUS RATS. BH Machado and HC Salgado*. Department of Physiology, School of Med icine of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, SP, Brazil.

The objective of the present study was to evaluate the efferent sympathetic activity to the heart during reversal of one-kidney, one clip (1K1C) hypertension using as an index the changes in heart rate (HR) of conscious freely moving rats. 1K1C rats (n=9) presented a marked tachycardia (366+15 vs 300±12 before declipping) during the first 8 h after declipping but 24 h later the HR (321±4 bpm) was back to control values. The direct recording of mean arterial pressure (MAP) indicated a fall from 188±15 to 135±10 mm Hg .3 h after declipping, whereas after 8 h MAP was 120±6 mm Hg. The integrity of the baroreflex was tested in sham operated (SO) and 1K1C rats by means of a short-term (15 min) infusion of sodium nitroprusside. Sodium nitroprusside produced a fall in MAP from 174±9 to 108±7 mm Hg (-37±3%) in 1K1C rats (n=5) and of 112±5 to 78±7 mm Hg (-31±4%) in SO rats (n=5). Moreover, sodium nitroprusside produced a similar reflex tachycardia in 1K1C rats {482±28 vs 374±29 bpm before sodium nitroprusside infusion (+30±7%)} and in SO rats {498±9 vs 354±15 bpm before sodium nitroprusside infusion (+41±5%)}. These results show that the baroreceptor reflex to the heart was operating normally during the fall in MAP due to the infusion of sodium nitroprusside in 1K1C rats as well as during the prompt reversal of hypertension after unclipping.

Supported by FINEP, CN^q and FAPESP.

1067 DIFFERENTIAL EFFECTS OF CHRONIC FOSINOPRIL AND PROPRANOLOL THERAPY ON HUMAN LYMPHOCYTE BETA2 AND PLATELET ALPHA2 ADRENOCEPTORS IN HYPERTENSION. KK Hui*, JL Yu and ML Lovett, Dept. of Medicine, UCLA School of Med, Los Angeles, CA.

The aim of the study is to compare the effects of propranolol (Pr) with an once daily ACEI, fosinopril (Fo),on the adrenegic system in 24 subjects with moderate to severe hypertension in a randomized, double blind clinical study. After 4 weeks of chlorthalidone (25 mg qd), either Fo (20-40 mg qd) or Pr (40-80 mg bid) was added to control DBP under 90 mm Hg. The patients on Fo (M 5, F 7, age 57+11) were well matched to those on Pr (M 5, F 7, age 54+11). Their supine BP before Fo or Pr was 169+20/104+4 and 160+24/105+7 respectively. Two supine bloods were obtained before and after 8 weeks of Fo or Pr. Measurements included plasma epi (E) and norepi (NE) by HFLC-EC, lymphocyte beta 2 adrenoceptor B m a x , I ^ ) by 3H-CGP-12177, isop-roterenol-stimulated cAM£ ( V m x ) ; platelet a l p h a 2 adrenoceptor B m ,Κρ by %-yohimbine, PGEi-stimulated cAMP ( V m x ) and I C 5 0 of Ε for inhibiting 10 uM PGEi-induced cAMP. NE and Ε did not change in both groups. Pr increased lymphocyte B m x , Kp and vmax (930+256 vs 1153+281 sites/cell, 0.45+ 0.29 vs 2.39+1.09 nM, 12,9+9.6 vs 18.9+ 10.4 pmol/10 6 cells/10 min respectively, p<0.01). However, Pr decreased alpha 2 Β^χ (351+ 165 vs 282 +100 sites/cell, P=0.1) and increased IC50 of Ε (0.75+ 0.56 vs 1.37+1.68 uM, P<0.05). There was no effect of Pr on ΡΟΕ^-ν^χ. In contrast to the significant effect of Pr on adrenoceptor and function, Fo did not affect lymphocyte and platelet adrenergic receptor density, affinity and function to any appreciable degree.

1066 THE EFFECTS OF FOSINOPRIL VS PROPRANOLOL ON MEMORY IN HYPERTENSION. ML Lovett, DW Zaidel C Rossen, D Chan, J Mitchell and KK Hui*, Department of Medicine and Psychology, UCLA Medical Center, Los Angeles,CA.

The aim of this study was to compare an ACE inhibitor with a beta blocking agent to determine whether or not they differ in their effect on memory and cognitive performance. We studied 24 adults, 10 males and 14 females, mean age 55 + 11 with moderate or severe hypertension using a double dummy design. All patients received Chlorthalidone 25 mg qd. Either propranolol (PR), (80-160 mg per day) or fosinopril (FO), (20-40 mg qd.) was added to control the diastolic B/P < 90mmHg. There were 12 subjects in each drug group. Subjects underwent an extensive battery of standardized tests(verbal vs nonverbal and short vs longterm memory) after 4 weeks of Chlorthalidone monotherapy, and 8 weeks after combination treatment with either FO or PR. The battery included the following tests: immediate story recall,immediate paired associates, memory for digits, delayed paired associates, delayed story recall, memory for faces, benton visual retention test, immediate recall of complex figure, and delayed recall of complex figure. Statistical analyses of age adjusted scaled scores using a one-way ANOVA revealed no significant group difference in memory either initially or at the end of 8 weeks. The results suggest that neither drug has detrimental effects on memory.

[10681 EFFECTS OF BRAIN NATRIURETIC PEPTIDE (BNP) IN CONSCIOUS RATS WITH CONGESTIVE HEART FAILURE A Ho f fman . H R Keiser. N H L B I , N IH , Be thesda , M D

A n e w natr iuret ic 2 6 a m i n o - a c i d po l ypep t i de ex t rac ted f rom porc ine bra in w a s desc r i bed recent ly . Repo r ted l y it has simi lar h e m o d y n a m i c a n d rena l e f fec ts as the atr ia l na t r iu re t ic factor (ANF) e v e n though 8 res idues are rep laced . W e have prev ious ly s h o w n h igh leve ls of p l a s m a A N F t o g e t h e r w i th a m a r k e d l y b l u n t e d r e s p o n s e to e x o g e n o u s A N F in rats w i t h c o n g e s t i v e hear t fa i lu re ( C H F ) , so it w a s of in teres t to s tudy the ef fec ts of B N P in this mode l .

In W i s t a r - K y o t o ra ts w e p l a c e d a s u t u r e l e s s i n f ra rena l a o r t o c a v a l f i s tu la , 1.2±0.2 m m l o n g , to p r o d u c e h igh ou tpu t C H F . S e v e n to ten d a y s later, under ha lo thane anes thes ia , the rats a n d n o r m a l c o n t r o l s w e r e c a n n u l a t e d a n d p r e p a r e d for ur ine c o l l e c t i o n s . A f te r 4 h o u r s of r e c o v e r y , b a s e l i n e m e a n a r t e r i a l p r e s s u r e ( M A P ) a n d r e n a l p a r a m e t e r s w e r e d e t e r m i n e d and a bo lus of 20 ug /Kg syn the t i c B N P w a s g iven i n t ravenous l y . V a l u e s ( M e a n ± S E M ) for 1 hr and an add i t iona l recovery per iod of 1 hr w e r e :

Basel ine B N P Recove ry M A P ( m m Hg) 140±5 121 ±4* 135±8

C o n t r o l V (ul /min) 28±5 40±4* 14±5* (n=6) U N a V ( u e q / m i n ) 1.4±0.2 3 .710 .6* 2.1 ±0 .1 *

M A P ( m m Hg) 115±7** 115±8 115±7 C H F V (ul /min) 7 . 1 + 3 . 1 * * 8 . 5 1 3 . 4 * * 10.5±7.7

(n=6) U N a V ( u e q / m i n ) 0 . 2 6 + 0 . 1 4 * * 0 . 2 3 + 0 . 1 3 * * 0 . 1 7 + 0 . 0 9 " (V -u r i ne v o l u m e , U N a V - u r i n a r y s o d i u m e x c r e t i o n , * = p < 0 . 0 5 v s . B a s e l i n e , * * = p < 0 . 0 5 v s . Con t ro l )

W h e r e a s B N P el ic i ted c o n s i d e r a b l e d iu re t i c , na t r iu re t ic and h y p o t e n s i v e r e s p o n s e s in c o n t r o l ra ts , t h e s e e f f ec t s w e r e m a r k e d l y d i m i n i s h e d in ra ts w i t h C H F . T h i s s u g g e s t s tha t ne i ther A N F nor B N P are e f fec t ive in C H F . T h e res i s tance to both pep t ides in th is mode l may be d u e to " d o w n regu la t ion" of recep to rs and /o r a n t a g o n i s m by the r e n i n - a n g i o t e n s i n s y s t e m and may cont r ibu te to s o d i u m re tent ion in C H F .

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T H E I N I T I A L V A S O D I L A T I O N A N D T H E L A T E VASOCONSTRICTION OF ENDOTHELIN (ET) ARE SELECTIVE FOR SPECIFIC VASCULAR BEDS A H o f f m a n . Ε G r o s s m a n , KP O h m a n , Ε M a r k s , HR Keiser . N H L B I , N IH , Be thesda , M D T h e new e n d o t h e l i u m de r i ved vasocons t r i c to r pep t ide ET w a s r e p o r t e d to c a u s e p o t e n t a n d p r o l o n g e d c o n t r a c t i o n s in a r t e r i a l s t r i p s f r o m v a r i o u s o r i g i n s in vitro. T h i s w a s a s s o c i a t e d w i t h a rap id i n c r e a s e of i n t r ace l l u l a r c a l c i u m . H o w e v e r , in vivo ET c a u s e s an ini t ial d r o p in b lood p ressure (BP) w h i c h is d u e to p r o f o u n d v a s o d i l a t i o n , f o l l o w e d by a g radua l p r o l o n g e d inc rease in BP. T h e ini t ial vasod i l a t i on w a s not r e p o r t e d to o c c u r in vitro a n d is st i l l u n e x p l a i n e d . To assess the m e c h a n i s m of the init ial d ip in BP w e tr ied to block it by p r e t r e a t i n g W i s t a r - K y o t o ra t s w i t h v a r i o u s d r u g s be fo re adm in i s te r i ng 1nmo l / Kg ET. V e r a p a m i l , i ndome thac in , ke tanse r i n , o u a b a i n , a t rop ine , m e t h y l e n e b lue and e thano l , all fa i l ed to a b o l i s h it. T o a s s e s s r e g i o n a l h e m o d y n a m i c s w e m e a s u r e d b l o o d f l ow in s e v e r a l a r te r ia l b e d s s imu l t anous l y w i th BP. At 3 0 s e c o n d s the f lows inc reased in the caro t id and the f e m o r a l b e d s f r o m 4 .2±0.3 m l / m i n to 5.6±0.4, and f rom 1.2±0.1 to 2 . 1 1 0 . 3 r e s p e c t i v e l y ( p < 0 . 0 5 ) w h i l e M A P d e c r e a s e d s ign i f i can t l y . A c c o r d i n g l y , t he c a l c u l a t e d reg iona l r es i s tance d e c r e a s e d f r om 26±4 m m H g / m l / m i n to 12±2 and f r o m 81 ±11 to 27±3 r e s p e c t i v e l y ( p < 0 . 0 0 5 ) . In con t ras t , in the rena l a n d m e s e n t e r i c v a s c u l a r b e d s f l o w s i m m e d i a t e l y d e c r e a s e d f r o m 4 . 4 1 0 . 4 m l / m i n t o 2 . 0 1 0 . 7 a n d f r o m 1 0 . 6 1 1 . 2 to 6 .011 ( p < 0 . 0 5 ) a n d r e s i s t a n c e i n c r e a s e d f r om 2 3 . 8 1 2 . 6 to 4 8 . 1 1 1 0 . 4 a n d f r o m 1 0 . 8 1 1 . 3 to 1 3 . 3 1 3 . 0 , r e s p e c t i v e l y ( p < 0 . 0 5 ) . A l l b e d s e x h i b i t e d l a t e vasocons t r i c t i on to va r i ous d e g r e e s w i t h a m a x i m a l r esponse (at 10 minu tes ) in the renal bed ( + 1 5 6 % ) . T h e m e c h a n i s m of the se lec t i ve ini t ial vasod i l a t i on in the m u s c u l o c u t a n e o u s bed is u n k n o w n but may be d u e to the s e c o n d a r y re lease of a v a s o d i l a t o r l ike E D R F . T h e e x q u i s i t e sens i t i v i t y of the renal b e d t o E T m a y h a v e a s i g n i f i c a n t r o l e in s o m e p a t h o p h y s i o l o g i c a l cond i t i ons .

110711

ENDOTHELIN IS A POTENT REGULATOR OF ARTERIAL PRESSURE W I T H E F F E C T S O N T H E K IDNEY A N D O N A T R I A L NATRIURET IC PEPTIDE LEVELS. KP O h m a n . A Ho f fman , H R Keiser . N H L B I , N IH , Be thesda , M D E n d o t h e l i n (ETL ) w a s g i v e n in i.v. b o l u s i n jec t i ons to male S p r a g u e - D a w l e y ra ts . E f f ec t s on s y s t e m i c ( M A P ) a n d r ight a t r i a l p r e s s u r e ( R A P ) , h e a r t r a te ( H R ) , c i r c u l a t i n g a t r ia l n a t r i u r e t i c p e p t i d e ( A N P ) a n d u r i n a r y v o l u m e ( U V ) , a n d e x c r e t i o n of e lec t ro l y tes ( U N a , UK) w e r e s t u d i e d . E T L 0.3, 1.0 a n d 3 .0 nmo l / kg bw g i ven to a w a k e rats p r o d u c e d s imi la r t rans ien t fal ls in M A P and inc reases in HR, fo l l owed by a dose d e p e n d e n t i n c r e a s e in M A P , w i t h m a x i m u m a f t e r 5 - 1 0 m i n u t e s . M A P r e t u r n e d to b a s a l v a l u e s w i t h i n 3 0 m i n u t e s f o l l o w i n g 0.3 n m o l / k g bw , w h i l e a f te r 3 .0 n m o l / k g b w M A P rema ined h igh at 10 minu tes and 2 hours . T h e inc rease in M A P w a s comp le te l y abo l i shed by ve rapam i l and n i t rop russ ide (NP) , s l ight ly inh ib i ted by At r iopep t in III and una f fec ted by Sara las in . T h e ini t ial fal l in M A P w a s not a l te red by any of the agen ts . E T L 1.0 nmo l /kg b w reduced marked l y U N a . E T L 3.0 nmol /kg b w c a u s e d tota l renal shu t d o w n . E T L 1.0 nmo l / kg bw g iven to a n a e s t h e t i z e d ra ts c a u s e d a r e l e a s e of A N P tha t w a s a p p a r e n t a f te r 2 m i n u t e s , m a x i m a l a f te r 5 m i n u t e s , a n d r e m a i n e d e l e v a t e d du r ing the o b s e r v a t i o n t ime of 20 minu tes . R A P s h o w e d a sma l l t rans ien t i nc rease du r ing the f irst m inu te and t hen fel l to leve ls be low con t ro l v a l u e . M A P w a s e leva ted for on ly 10 m inu tes in t h e s e ra ts . W h i l e the i nc rease in M A P w a s b locked w i th NP, E T L stil l re leased A N P for 2 0 minu tes . In c o n c l u s i o n w e f ind tha t E T L m a y c a u s e the re lease of a poten t vasod i la to r s u b s t a n c e ini t ia l ly, a n d t hen act as a potent v a s o c o n s t r i c t o r w i t h a long d u r a t i o n . I n t e r m e d i a t e d o s e s of E T L dec rease U N a exc re t i on , e v e n wh i le A N P is inc reased , and in h igher d o s e s ser ious ly impa i r rena l f unc t i on . E T L s e e m s to act d i rec t ly on the a t r ia to re lease A N P , i n d e p e n d e n t of r ight a t r ia l or s y s t e m i c p r e s s u r e .

1 0 7 0

C O N S C I O U S A T R I A L A P P E N D E C T O M I Z E D R A T S H A V E A B L U N T E D A T R I A L N A T R I U R E T I C F A C T O R (ANF) R E L E A S E T O V O L U M E E X P A N S I O N B U T N O R M A L R E S P O N S E S T O O T H E R A C U T E STIMULI A Ho f fman . H R Keiser . N H L B I , N I H , Be thesda , M D

R e c e n t repor t s i nd i ca te tha t a t r ia l a p p e n d e c t o m y (AP) in anes the t i zed rats c a u s e s a b lun ted r e s p o n s e to acu te v o l u m e e x p a n s i o n bo th in t he re lease of A N F and in nat r iu res is . Th is w a s a t t r i b u t e d to d e f i c i e n t s t o r e s of A N F a v a i l a b l e fo r r e l e a s e . H o w e v e r , o t h e r s r e p o r t e d n o r m a l r e s p o n s e s in c o n s c i o u s ra ts or in d i f f e ren t s p e c i e s . In o the r s t u d i e s a d i s s o c i a t i o n b e t w e e n A N F a n d n a t r i u r e t i c r e s p o n s e s w a s o b s e r v e d .

T o c l a r i f y t h i s c o n t r o v e r s y w e s t u d i e d c o n s c i o u s , un res t r a i ned ra ts , 3 w e e k s af ter b i la te ra l A P or s h a m (SH) ope ra t i on . A ser ies of acu te s t imu l i (1 m in ) , e i ther assoc ia ted or u n a s s o c i a t e d w i t h v o l u m e c h a n g e s , w a s a p p l i e d ; sal t load ( S A L ) N a C l 2 .8 m e q / K g , n o r e p i n e p h r i n e (NE) 6.0 n m o l / K g , a n d v o l u m e e x p a n s i o n ( V O L ) 2 0 m l / K g of 5 % d e x t r o s e . Base l i ne and s t imu la ted p l a s m a A N F leve ls (af ter 1-2 min , in p g / m l ) w e r e ( M e a n l S E M , * = p < 0 . 0 5 ) :

Basel ine S A L N E V O L S H (n=5) 6 6 1 1 8 185129 2 0 6 1 1 5 3 0 2 1 5 9 A P (n=6) 7 3 1 1 2 181123 151+23* 122115*

A P rats have a no rma l i nc rease of p l a s m a A N F to S A L ( + 1 4 8 % ) , an i n t e r m e d i a t e r e s p o n s e t o N E ( + 1 0 7 % ) , a n d a b l u n t e d r e s p o n s e to V O L ( + 6 7 % ) . T h e f a c t t ha t a t r i a l a p p e n d e c t o m y d o e s not abo l i sh the re lease of A N F to s o m e a c u t e s t i m u l i i n d i c a t e s t ha t s t o r e s of A N F a v a i l a b l e for re lease are not dep le ted . T h e b lun ted response to V O L may be d u e to i n t e r f e r e n c e w i t h t he ro le of t h e a t r i a in v o l u m e r e g u l a t i o n . T h e i n c r e a s e in p l a s m a A N F a f t e r s t i m u l i u n a s s o c i a t e d w i t h v o l u m e c h a n g e s m a y re f l ec t d i f f e ren t re lease m e c h a n i s m s and /o r d i f fe rent s o u r c e s of A N F .

1 0 7 2

NIFEDIPINE GASTROINTESTINAL THERAPEUTIC SYSTEM (NGITS) IN PATIENTS WITH MILD ESSENTIAL HYPERTENSION: THtfAPEUTIC EFFECTS CF A NOVEL DELIVERY SYSTEM. G.P. Lewis, R.P. Ares*, A.K. Halperin, R.L. Reeves, R.W. Rosenheim, R.M. Zusman*, Lemuel Shattuck Hospital, Tufts University School of Medicine, Boston, MA. In a 10 week multicenter double blind placebo (P) controlled dose response tr ia l , 174 patients with mild essential hypertension (sitting diastolic BP 95-105 imflg) were randomized to P, NGITS 30 mg, 90 mg or 120 mg/day. Efficacy was assessed by comparing A BP and HR 24 hr post dose from baseline to end treatment. Results: NGITS 30, 90 or 120 mg significantly reduced both sitting and standing BP at the final treatment visit (endpoint analysis) compared to placebo.

ADJUSTED NEAN Δ BP AND HR FROM BASELINE TO FINAL VISIT N-GITS N-GITS N-GITS 30 mg 90 mg 120 mg Ρ

SITTING 30 mg

Systolic BP (nm Hg) -11.8* -14.2*** -19.9*** -3.1 Diastolic BP (nm Hg) -9.9** -11.0*** -12.7*** -3.9 Heart Rate (bpm) +1.4 +1.4 +0.8 -1.1

STANDING Systolic BP (nm Hg) -12.0** —14.4*** -21.2*** -3.2 Diastolic BP (nm Hg) -9.0** -ιι!δ*** -12.7*** -3.2 Heart Rate (bpm) +0.8 +2.4 +1.3 -0.8

* (**)(***) Significantly different from placebo mean at 0.01, (0.001) and (0.0001) level, respectively. NGITS 120 mg reduced sitting systolic BP more than either 30 mg (p=.003) or 90 mg (p=.035). In the standing position, the 120 mg dose of NGITS produced greater reductions than either 30 mg (p=.0006) or 90 mg (p=.01) in systolic BP and was more effective than the 30 mg dose in reducing the diastolic BP (p=.027). No significant changes were observed in hR in any treatment group. Conclusions: NGITS 30 mg to 120 mg is an effective once daily antihypertensive agent; efficacy increases with increasing dose.

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11073

FIRST STEP THERAPY IN HORMONALLY-PROFILED OLDER WHITE PATIENTS WITH HYPERTENSION (HT) : A COMPARISON OF A CALCIUM CHANNEL BLOCKER (CCB) AND AN ANGIOTENSIN CONVERTING ENZYME INHIBITOR (ACEI) P.Cargo, Hypertension Research Associates, Nashville, TN; J.Heusner*; M.DesChamps*; J.Gray, (Houston, TX); J.Hollifield*, (Nashville, TN).

CCBs and ACEIs are both effective monotherapies for initial treatment (tx) of mild to moderate (m-m) essential HT. We compared their efficacy and safety in a group of Caucasian patients with m-m HT over age 55. 41 m-m HT patients (24male/17 female) profiled as to renin status, participated in this randomized, open-label, cross-over study comparing a CCB (VerapamilSR-VSR) with an ACEI (Enalapril-E). Washout periods pre-study and between tx segments were followed by active therapy of VSR-240, 360, 480mg/day or E-5, 10, 20mg/day. Doses were increased incrementally at two-week intervals until supine diastolic blood pressure (SDBP) fell to 90mmHg or less OR to end of dose titration. RESULTS: Overall, mean reduction of SDBP with VSR-240mg, was 14mmHg, and with E-5mg, was 10 mmHg (p=.0318). In 29/41 (71%) patients, SDBP was reduced by 15mmHg with VSR and/or E. Of the 29 reductions, 16 were with VSR only, 6 with Ε only, and 7 were with both. Increasing VSR dose increased both mean SDBP reduction and number of patients normalizing, while no additive effect was seen with E. No clinically significant adverse experiences occurred with either drug. CONCLUSIONS: CCB, as first step therapy, appears more efficacious than ACEI in the tx of older white, especially low .renin, HT.

1 0 7 5

ANGIOTENSINOGHi GENE REGULATION IN THE FETAL RAT. A.p. Everett. N. Wilfong, R.L. Chevalier*, R.A. Gomez*. Department of Pediatrics, University of Virginia Medical Center, Charlottesville, VA

We have recently demonstrated that angiotensinogen (Ao) gene expression is developi^tally regulated in a tissue specific manner. Hepatic Ao mRNA levels are markedly lower in the fetal than the newborn and adult rat. However, the hormonal regulation of the Ao gene in the fetus and pregnant rat are not known. To evaluate if the Ao gene is regulated by glucocorticoids in the pregnant rat and fetus, five pregnant Wistar-Kyoto rats at 15 days gestation (term = 21 days) were given daily injections of vehicle (saline) or dexamethasone (Dex) (0.04mg-12.8mg) intraperitoneally for five days. The mothers were sacrificed on the sixth day and maternal and fetal brains, kidneys and livers were removed. RNA was extracted and subjected to Northern and Dot blotting, and hybridization to a full length 1.6 Kb -^P Ao cDNA. Comparison of relative concentrations of Ao mRNA by densitometric analysis of dot blots demonstrated a five-fold (p<0.05) increase in the maternal and a two-fold increase in fetal hepatic gene expression with Dex administration. Furthermore, the slope of the maternal hepatic response to Dex was two-fold higher than the fet u s ( p < 0 . 0 5 ) , suggesting increased responsiveness of the maternal Ao gene relative to the fetus. In addition, Ao mRNA was present in the fetal kidney, and brain. Thus, 1) Ao gene expression is regulated by Dex in the term fetal and maternal liver, p o s s i b l y via a glucocorticoid receptor; 2) Ao mRNA is demonstrated in multiple fetal organs supporting the notion of local renin-angiotensin systems in fetal organs.

1 0 7 4 [

BLOOD PRESSURE CHANGES FOLLOWING EXTRACORPOREAL SHOCK WAVE LITHOTRIPSY (ESWL) FOR NEPHROLITHIASIS. PD Toth*, JR Woods, JE Lingeman, DM Newman. Methodist Hospital Inst i tute for Kidney Stone Disease, Methodist Hospital of Indiana, I n c . , Indianapolis, IN.

Preliminary observation have suggested a possible relationship between ESWL and hypertension (HT). The present study examined the effects of ESWL and non-ESWL treatments on BP in a total of 956 patients with nephrolithiasis (ESWL;n=765) (non-ESWL;n=191) which consisted of 72.9% of subj e c t s contacted. BP was measured by a trained observer using a random zero device on two dif ferent occasions at least one week apart (3 measurements/visit). HT was defined as mean BP > 140/90 on both v i s i t s . Annualized incidence of new onset HT was 2.4% ESWL group vs . 3.8% non-ESWL group ( N . S . ) . Annualized mean DBP changes compared to baseline values are as follows:

mmHg p-value ESWL 0.78±5.33 0.0001

non-ESWL -0 .88±11 .86 N.S.

ESWL Kidney 0.67±5.32 0.0007

ESWL Ureter 3.35+4.86 0.0004

Comparison between the ESWL and non-ESWL groups was also significant (p<0 .01 ) . A multiple linear regression analysis also demonstrated that the r ise in BP was significant even after controlling for other variables. Although the incidence of HT was not increased in the ESWL group, there was a small but significant r ise in DBP (ureter > kidney). The long-term s ignificance of such changes are unknown and requires further study.

1 0 7 6

THE TRANSIENT INCREASE OF URINARY DIGOXIN-LIKE SUBSTANCE (U-DLS) EXCRETED DURING EXCESS SODIUM INTAKE IN REDUCED RENAL MASS RATS (RRM). Μ Nakaaawa r Κ Shimamoto, Κ Matsuda, S Saitoh,Η Nakagawa,N Ura and 0 Iimura* Second Department of Internal Medicine, Sapporo Medical College, Sapporo, JAPAN

The dynamics of U-DLS was studied to clarify the relationship between DLS and sodium excretion (UNaV).

Nine S-D rats were heminephrectomized (1/2RRM). In 5 of them, an additional 1/3 kidney was removed ( 2 / 3 R R M ) . Five rats were sham operated ( C ) . All were given 1% NaCl solution to drink. U-DLS was measured by using digoxin RIA.

UNaV increased rapidly after 1% NaCl drinking in the 3 groups. U-DLS did not differ in any of the 3 groups(2.8±0 . 9 : C, 3.1±0.8:1/2RMM, 3.5±1.3ng digoxin/kg/day: 2/3RRM)before drinking,and significantly increased immediately after 1% NaCl drinking in the 3 groups. It returned to the basal level 2 weeks later. The peaks of U-DLS appeared in 2 or 4 days after 1% NaCl (6.5±1.5:C,10.6±1.5:1/2RRM,12.1 ±5.4ng digoxin/kg/day:2/3RRM) . Both UNaV and U-DLS was significantly higher in both 1/2 and 2/3 RRM than in C. However, there was no difference in blood pressure among them. A significant positive correlation was found between U-DLS and UNaV (r=0.49, p < 0 . 0 0 1 , n = 3 2 0 ) .

From these data, it was concluded that DLS may play an important role in maintaining Na and water h o m e o s t a s i s .

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11077

ENDOTHELIUM-DERIVED CONTRACTING FACTOR RELEASED BY SEROTONIN IN THE SHR AORTA. Wolfgang Auch-Schwelk and Paul M. Vanhoutte. Mayo Clinic, Department of Physiology, Rochester, MN 55905.

Contractions to serotonin are augmented in aortas with endothelium from spontaneously hypertensive rats (SHR) compared to normotensive controls (WKY). The present study was designed to determine, whether this increase is due to the release from the endothelium of a vasoconstrictor prostanoid. Rings of aortas with and without endothelium were taken from SHR and WKY and suspended in organ chambers for isometric tension recording. The maximal response to norepinephrine and a cumulative concentration-response curve to serotonin were obtained. Contractions to serotonin were similar in rings without endothelium from both strains. The presence of the endothelium reduced the contractions to all concentrations of serotonin in the WKY; in the SHR the endothelium inhibited only the response to lower concentrations of serotonin. Indomethacin (or meclofenamate) reduced the contractions to high concentrations of serotonin only in rings from SHR with endothelium; it did not affect the response in SHR rings without endothelium or in rings from WKY (with and without endothelium). The endothelium inhibited contractions to norepinephrine only in the presence of indomethacin in both strains. These experiments suggest, that serotonin stimulates the release of vasoconstrictor prostanoids from the endothelium of the SHR but not from the WKY aorta. Norepinephrine may release the endothelium-derived contracting factor in both strains.

[10791 RELATION OF AMBULATORY BLOOD PRESSURE AND TREATMENT OUTCOMES. DJ Glunk, AP Shapiro* Dept. of Medicine, Shadyside Hospital, Pittsburgh, PA.

In 36 patients with essential hypertension, casual office blood pressures (BPs) were compared to a 24-hour ambulatory BP recording (ABPR). Casual BPs were obtained by the patient's physician and the BPs used as data points were from the clinic visit immediately prior to the 24-hr ABPR (Orig) and from the most recent clinic visit (Last). The mean duration of follow-up was 6.2 months (range 1-22 months); the patients were on various medications which were adjusted by their primary physician. ABPR (24-hr x) were obtained using a non-invasive monitor (SpaceLabs) which recorded BP every 30 minutes while awake anrl every 60 min during sleep. Means of Systolic BPs (SBP) at these 3 points were Orig 165±27 mmHg, 24-hr χ 142±8, and Last 142+20. One-way ANOVA indicated no significant difference between the 24-hr χ SBP and the Last whereas the mean of the Orig was significantly higher than the 24-hr χ and the Last (p <.001 for both). Diastolic BPs (DBP) were Orig 100+14, 24-hr χ 87±12 and Last DBP 86±9. Again, no significant difference was observed between the 24-hr χ and the Last, but the mean of the Orig was higher than the 24-hr x and the Last, (p=<.001 for both). Thus, the 24-hr χ SBP and DBP reflected the clinic pressure obtained after follow-up. From this retrospective study it appears that 24 hr χ obtained during ABPR may be a predictor of future casual BP. The implications of this "regression to the mean" need further study, but the data suggest that ABPR is an important guide in the management of hypertensive patients.

1 0 7 8

ATRIAL NATRIURETIC PEPTIDE IS SYNTHESIZED IN THE RAT THYMUS

A.M. Vollmar1TR.E. Lang 2 , J. Hanze 2 R. Schulz 1. 11nstitute of Pharmacology, Toxicology and Pharmacy, University of Munich and ^Department of Pharmacology, University of Heidelberg, FRG.

The ANP has been considered in the past to be a major regulator of fluid and electrolyte homeostasis. Our data presented here draw attention to a new field of action for ANP, the immune system. We suggest that the thymus is a site of synthesis for ANP-like material. The data are based on the following evidence. Firstly, immunoreactive ANP-material (IRAN P) was detected in acidic extracts of thymus after immunoaffinity chromatography. This IR-ANP material is likely to be the precursor ANP (1-126) molecule based on RP-HPLC analysis in combination with the use of two antisera recognizing either the N-terminal or C-terminal sequences of ANP (1-126). The actively growing thymus of 1 day old rats was found to contain more IR-ANP (7-fold) than adults . Secondly, mRNA to ANP could be detected in the rat thymus, using a 580 bases Pst l-restricted ANP cDNA fragment as a probe. Furthermore, newborn rats exhibit considerably more mRNA to ANP in the thymus as adults. Thirdly, immunohistochemical analysis of thymus sections locate the IR-ANP-material to the cortex. Predominately large sized thymocytes concentrated in the outer cortex appear to be ANP positive. Immunostaining of isolated thymocytes of either 1 day old or 75 day old rats showed a significantly higher degree of positive cells in the very young as compared to adult amimals (30% versus 10%).

1 0 8 0

SALT-INDUCED ACCELERATION OP MALIGNANT HYPERTENSION IN SETOK^HOtE SHR (SHRSP) IS RELATED TO A PARADOXICAL RISE IN RENIN. M.Volpe, MJ GamargD, WG Campbell, JE Sealey, JH Laragh. Cornell Univ Ffed Coll, New York, NY.

The effects of higi NaCl (4*Cl/O.75$0 (NA) (n=36) or high IfeCl/high Κ (4Λθΐ/2.11$0 (K) (n=36) 12-week diet on blood pressure (BP), plasma renin activity (ERA, ng/ml/h), renal and cerebrovascular morbidity were assessed in 6-week old male SHRsp. After 4 weeks of diet PRA was 3·5+.8 in NA and 4 .1+.9 in Κ rats (n.s.) with urinary sodium excretion (UNaV, mBi/24 h) of 9·4+.7 and 7.6+1, respectively. PRA was not different (5.2+1.6) in SHRsp on regular diet (0.35feCl/l.1$0 (R) despite UNaV was · 96κ1 · No renal lesions were detected in the 3 groups at this time. At 8 weeks, PRA was sigiificantly increased only in high. NaCl group (13-7+3-9)· At 12 weeks, PRA was sigiificantly higher in NA (22.>+4)than in Κ (11.1+3) or R (7.8t2) SHRsp. At this time, the histological renal vascular damage index was 79+14 in NA, 40+11 in Κ and 7.8+4-6 in R SHRsp, and incidence of stroke was 81.1$ in NA, 24-5$ in Κ and 1.1% in R SHRsp. The progressive rise in BP was comparable in the 3 groups. PRA values were highly correlated with renal lesions and incidence of stroke. Our data demonstrate that: 1) The high NaCl diet-induced acceleration of vascular injury in SHRsp is related with a paradoxical rise in PRA; 2) In the SHRsp protected by Κ PRA does not rise. They also suggest that high sodium intake does not cause the physiological suppression of IRA in SHRsp. Non-suppressible PRA may contribute to the acceleration of malignant hypertension in SHRsp.

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1 0 8 1

A MULTIFACTORIAL EVALUATION OF THE ANTIHYPERTENSIVE EFFICACY OF THE COMBINATION OF DILTIAZEM AND HYDROCHLOROTHIAZIDE. M R W e i r , * J F B u r r i s , * S O p a r i l , * M A W e b e r , * W J C a d y . C a r d i z i d e M u l t i f a c t o r i a l T r i a l G r o u p , K a n s a s C i t y , M O .

T h i s s t u d y w a s a m u l t i c e n t e r , r a n d o m i z e d , d o u b l e -b l i n d , m u l t i f a c t o r i a l , p l a c e b o - c o n t r o l l e d , p a r a l l e l g r o u p e v a l u a t i o n o f t h e d o s e - r e s p o n s e o f s l o w - r e l e a s e d i l t i a z e m ( D S R ) a l o n e a n d i n c o m b i n a t i o n ( C ) w i t h v a r i o u s d o s e s o f h y d r o c h l o r o t h i a z i d e ( H C T Z ) i n p a t i e n t s ( P ) ( m e a n a g e 5 2 . 1 y e a r s ) w i t h s u p i n e d i a s t o l i c b l o o d p r e s s u r e ( D B P ) b e t w e e n 9 5 a n d I 10 m m H g . A f t e r p l a c e b o r u n - i n , Ρ w e r e r a n d o m i z e d t o t h e r a p y w i t h p l a c e b o , I o f 4 d o s e s o f D S R ( 6 0 , 9 0 , 1 2 0 , 1 8 0 m g ) , I o f 3 d o s e s o f H C T Z ( 6 . 2 5 , 1 2 . 5 , o r 2 5 m g ) , o r I o f t h e 12 p o s s i b l e C ; e a c h a d m i n i s

t e r e d t w i c e d a i l y ( b i d ) f o r 6 w e e k s . 13 t o 17 Ρ w e r e i n e a c h t r e a t m e n t g r o u p ( c e l l ) f o r a t o t a l o f 2 9 7 ( 2 6 4 Ρ c o m p l e t e d t h e 6 w e e k s ) . A d o s e r e l a t e d r e d u c t i o n i n b o t h s y s t o l i c ( S ) a n d D B P w a s d e m o n s t r a t e d w i t h e a c h d r u g . T h e m a x i m u m e f f e c t i v e d o s e o f D S R w a s n o t r e a c h e d , a n d w a s b e t w e e n 2 5 a n d 5 0 m g f o r H C T Z . R e d u c t i o n f r o m b a s e l i n e D B P o f 9 9 . 4 m m H g i s s h o w n b e l o w .

D S R ( m g b i d ) 0 6 0 9 0 1 2 0 1 8 0

0 - 4 . 2 T.Q -Γ .2 3 0 T j T . 8 H C T Z 6 . 2 5 - 6 . 9 - 8 . 5 - 9 . 6 - 1 0 . 8 - 1 3 . 7 ImTbid) 1 2 . 5 - 8 . 7 - 1 0 . 1 - I 1.0 - 1 2 . 1 - 1 4 . 7

2 5 - 9 . 6 - 1 0 . 4 - I I . I - 1 1 . 9 - 1 4 . 0 T h e C d o s e s w e r e m o r e e f f e c t i v e c o m p a r e d t o e i t h e r o f c o r r e s p o n d i n g m o n o t h e r a p y d o s e s f o r e a c h o f t h e 12 c e l l s w h e r e a C o f t h e 2 d r u g s w e r e g i v e n ( p < . 0 5 ) . S i m i l a r a d d i t i v e e f f e c t s o f t h e 2 d r u g s w e r e n o t e d f o r l o w e r i n g s u p i n e S B P . T h e r e s u l t s w e r e a n a l y z e d b y s u r f a c e r e s p o n s e t e c h n i q u e s a n d a n a l y s i s o f v a r i a n c e . T h u s , t h e C o f D S R a n d H C T Z l o w e r s D B P a n d S B P m o r e e f f e c t i v e l y t h a n e i t h e r d r u g a l o n e .

1 0 8 3

SUPPRESSED END0THEL IUM-DEPENDENT V A S O D I L A T I O N , I N V I V O , I N SPONTANEOUSLY H Y P E R T E N S I V E R A T S ( S H R ) Y T a k a t a * , Τ K o g a , Κ K o b a y a s h i , S T a k i s h i t a , Μ F u j i s h i m a . 2 n d D e p t o f I n t e r n a l M e d i c i n e , K y u s h u U n i v e r s i t y , F u k u o k a , J a p a n .

We e v a l u a t e d w h e t h e r c h a n g e s i n e n d o t h e l i u m -d e p e n d e n t v a s c u l a r r e l a x a t i o n w o u l d r e l a t e t o h y p e r t e n s i o n i n SHR. I n c o n s c i o u s SHR a n d WKY, a d e n o s i n e t r i p h o s p h a t e ( A T P ) , a c e t y l c h o l i n e ( A C h ) a n d n i t r o p r u s s i d e ( S N P ) w e r e i n t r a v e n o u s l y i n j e c t e d . U n d e r a n e s t h e s i a , d o p p l e r f l o w p r o b e s w e r e p l a c e d t o r e c o r d m e s e n t e r i c ( M B F ) , r e n a l ( R B F ) a n d f e m o r a l ( F B F ) b l o o d f l o w s . M e s e n t e r i c a r t e r y ( M A ) a n d a o r t a ( A o ) w e r e t a k e n t o m e a s u r e i s o m e t r i c t e n s i o n . R e s p o n s e s t o A T P , ACh a n d SNP w e r e r e c o r d e d i n p r e c o n t r a c t e d r i n g s b y n o r e p i n e p h r i n e . T h e p e r c e n t f a l l i n b l o o d p r e s s u r e b y ATP a n d ACh w a s c l e a r l y d i m i n i s h e d i n SHR c o m p a r e d t o t h a t i n WKY. H y p o t e n s i o n b y SNP d i d n o t d i f f e r b e t w e e n g r o u p s . D e c r e a s e s i n RBF i n r e s p o n s e t o ATP w e r e g r e a t e r i n SHR t h a n i n WKY, i n d i c a t i n g a s u p p r e s s e d d i l a t i o n o f r e n a l a r t e r i o l e s i n i n t a c t SHR. MBF a n d FBF r e s p o n s e s t o ATP a s w e l l a s M B F , RBF a n d FBF r e s p o n s e s t o ACh a n d SNP w e r e s i m i l a r i n t h e t w o g r o u p s . ATP c a u s e d a d o s e - r e l a t e d Ao r e l a x a t i o n i n SHR a n d WKY w h i c h w a s a b o l i s h e d b y r u b b i n g e n d o t h e l i u m . D o s e - d e p e n d e n t r e l a x a t i o n t o ACh i n b o t h g r o u p s o c c u r r e d i n MA a n d A o w i t h e n d o t h e l i u m , b u t n o t w i t h o u t e n d o t h e l i u m . I n c o n t r a s t , r e l a x a t i o n s o f MA a n d A o w e r e i n d u c e d b y S N P , i r r e s p e c t i v e o f t h e p r e s e n c e o f e n d o t h e l i u m . I n c o n c l u s i o n , d i m i n i s h e d h y p o t e n s i v e r e s p o n s e s t o ATP a n d A C h , a n d i m p a i r e d d i l a t i o n r e s p o n s e s o f r e n a l a r t e r i o l e t o ATP i n SHR s u g g e s t t h a t s u p p r e s s i o n o f e n d o -t h e l i u m - d e p e n d e n t h y p o t e n s i o n may b e r e s p o n s i b l e f o r t h e m a i n t e n a n c e o f h y p e r t e n s i o n .

1 0 8 2

A COMPARISON OF THE EFFICACY OF ATENOLOL, CAPTOPRIL AND VERAPAMIL SR IN HYPERTENSIVE BLACKS. M R W e i r * , Ε S a u n d e r s * , B W K o n g * a n d t h e B l a c k H y p e r t e n s i o n S t u d y G r o u p . U n i v . o f M a r y l a n d H o s p . a n d U r b a n C a r d i o l o g y R e s . C t r . , B a l t i m o r e , M D .

A d o u b l e - b l i n d , p o s i t i v e l y c o n t r o l l e d , f o r c e d d o s e t i t r a t i o n s t u d y c o m p a r i n g t h e e f f i c a c y a n d s a f e t y o f a t e n o l o l ( A ) , c a p t o p r i l ( C ) , a n d v e r a p a m i l S R ( V ) , a s s i n g l e a g e n t s i n t h e t r e a t m e n t o f b l a c k p a t i e n t s ( P ) w i t h h y p e r -t e n s i o n ( H ) ( d i a s t o l i c ( D ) b l o o d p r e s s u r e ( B P ) 9 5 m m H g b u t < I l 4 m m H g ) w a s c o n d u c t e d . 3 9 4 Ρ w e r e r a n d o m i z e d t o o n e o f t h e 3 t h e r a p i e s . A l l Ρ w e r e t r e a t e d w i t h p l a c e b o f o r 2 - 4 w e e k s t o e s t a b l i s h b a s e l i n e B P , w h i c h r a n g e d f r o m 9 9 . 9 - 1 0 0 . 3 D a n d 1 5 0 . 4 - 1 5 2 . 1 s y s t o l i c ( S ) f o r t h e 3 g r o u p s . 3 3 7 Ρ s u c c e s s f u l l y c o m p l e t e d t h e f i r s t t r e a t m e n t p e r i o d ( T P ) w h i c h c o n s i s t e d o f t h e r a p y w i t h e i t h e r 5 0 m g q d A ( l 1 6 ) , 2 5 m g q l 2 h C ( l 10 ) , o r 2 4 0 m g q d V ( I I I ) . D u r i n g t h e s e c o n d 4 - w e e k T P w h i c h 3 0 4 Ρ s u c c e s s f u l l y c o m p l e t e d , h a l f o f t h e Ρ h a d t h e i r m e d i c a t i o n i n c r e a s e d : l O O m g q d A ( I 0 5 ) , 5 0 m g q l 2 h C ( 9 8 ) , 2 4 0 m g q A M , l 2 0 m g q P M V ( 1 0 1 ) . G o a l B P w a s d e f i n e d a s t h e s u p i n e D B P < 9 0 m m H g o r > I 0 m m d r o p o f s u p i n e D B P f r o m p r e t r e a t m e n t l e v e l s . A , C , o r V t h e r a p y w a s a s s o c i a t e d w i t h g o a l B P a c h i e v e m e n t d u r i n g t h e f i r s t T P : 5 5 . 7 % , 4 4 . 0 % , a n d 6 8 . 8 % o f t h e t i m e , r e s p e c t i v e l y ( R ) , a n d d u r i n g t h e s e c o n d T P 6 0 . 4 % , 5 7 . 7 % , a n d 7 3 . 0 % o f t h e t i m e , R . M e a n c h a n g e s i n s u p i n e D B P f o r A , C , a n d V t h e r a p y a t t h e e n d o f t h e f i r s t T P w e r e : - I 0 . 0 ± 7 . 7 , - 8 . 6 ± 8 . l , - l l . 6 ± 8 . 2 , R , a n d f o r t h e s e c o n d T P w e r e : - I 0 . 2 ± 8 . 0 , - 9 . 6 ± 9 . l , - I 2 . 9 ± 7 . 7 , R . M e a n c h a n g e s i n s u p i n e S B P f o r A , C , a n d V t h e r a p y a t t h e e n d o f t h e f i r s t T P w e r e : - 8 . 5 ± I 2 . 7 , - 8 . 2 ± I 3 . 0 , - I I . 2 ± I 2 . I , R , a n d f o r t h e s e c o n d T P : - 9 . 6 ± I 3 . 5 , - 8 . 5 ± 1 4 . 2 , - I 3 . 8 ± I 2 . 3 , R . S i d e e f f e c t s w e r e m i n i m a l a n d c o m p a r a b l e f o r a l l 3 d r u g s . T h u s , V a p p e a r s m o r e e f f e c t i v e a s a m o n o t h e r a p y a g e n t t h a n A o r C i n t r e a t i n g b l a c k Ρ w i t h H .

[1084I EFFECTS OF HOSPITALIZATION ON SYMPATHETIC ACTIVITY AND BLOOD PRESSURE IN ESSENTIAL HYPERTENSIVES(EHT) Y Takata*/ Y Nakao, Μ Tominaga, Y Yamashita, Τ Tsuchihashi, Τ Koga, S Takishita, Κ Kobayashi, Μ Fujishima. 2nd Dept of Internal Medicine, Kyushu University, Fukuoka, Japan.

We evaluated whether a reduction in sympathetic reactivity would play a major role in spontaneous fall in blood pressure(BP) during the hospitalization of EHT. In 12 untreated EHT, BP, pulse rate (PR) as well as plasma catecholamines(PCA) and renin activity(PRA) responses to both isometric handgrip and tilting were determined on the 1st, 2nd and 7th admission days. Hypotensive effects of phentolamine were also examined on the 1st, 2nd and 7th days. BP fell significantly during hospitalization for 1 day. The BP levels on the 2nd day were similar to those on the following days. The responses of PCA, PRA, BP and PR to handgrip and tilting and also the resting level of PCA were not altered during 24 hours of hospitalization. The effects of phentolamine on BP and PR did not differ between the 1st and 2nd days. Similarly, on the 7th day of admission, hospitalization did not alter the responsiveness of BP, PR and PCA to handgrip and tilting. The hypotensive action of phentolamine was similar on the 1st and 7th days of admission. However, the resting levels of plasma norepinephrine before handgrip, tilting and phentolamine were significantly diminished on the 7th day. Body weight and urinary sodium excretion were also reduced by the 7th day. In conclusion, the withdrawal of sympathetic activity may be partially responsible for the hospitalization-induced fall in BP. Reductions of body weight and sodium intake may also relate in part to the spontaneous fall in BP by hospitalization.

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[10851 DOCA-SALT TREATMENT ENHANCES HYPOTENSIVE EFFECTS OF NIFEDIPINE WITHOUT LOWERING SERUM CALCIUM ION. Y Takata*, Y Yamashita, S Takishita, Κ Kobayashi, Μ Fujishima. 2nd Dept of Internal Medicine, Kyushu University, Fukuoka, Japan.

We examined whether or not DOCA-salt treatment to rats would decrease serum ionized calcium concentrations in relation to the enhanced hypotensive response to the calcium blocker nifedipine. Male Wistar strain rats were divided into 2 groups of DOCA+uninephrectomy+saline drinking(DOCA group, n=13) and vehicle+uninephrectomy(C group, n=14). Following 5 weeks of treatment, mean arterial pressure(MAP) was recorded in conscious and unrestrained rats. Thereafter, blood was drawn to measure serum calcium with ionized fractions and albumin. In another set of experiments, nifedipine (10,100yg/kg) was administered intravenously to rats of DOCA and C groups in conscious state. DOCA and salt treatment increased MAP, and enhanced the hypotensive effects of nifedipine(absolute fall; 99±4mmHg for DOCA and 38±3 for C, p<0.001: percent fall; 49±2% for DOCA and 19±2 for C, p<0.001). Serum total calcium(p<0.005) and albumin(p<0.001) levels were clearly reduced, but the ionized fraction of calcium was not altered by DOCA-salt. The total serum calcium concentration, but not the ionized calcium, significantly correlated with serum albumin in DOCA-salt rats(r=0.66, p<0.02). There was no difference in serum creatinine levels between the groups. In conclusion, DOCA-salt treatment did not decrease serum calcium ion concentrations while inducing an enhancement of hypotensive responses to nifedipine, thereby suggesting no relationships between changes in serum ionized calcium and enhanced depressor responses to nifedipine.

1087 A H R - 1 6 3 0 3 : A N O V E L A N T I H Y P E R T E N S I V E A G E N T W I T H C O M B I N E D A N T A G O N I S T I C A C T I V I T Y A T C A + + C H A N N E L S A N D 5-HT2-RECEPTORS. RJ . B a r r e t t * , K C . A p p e l l , J C . N o l a n , and B.K. Ki lpatr ick, A . H . Robins Research Labs., R ichmond , V A .

A H R - 1 6 3 0 3 (AHR, 1 - [4 - [3 - [4 - [B is (4 - f luoropheny l )hydrox -m e t h y l ] - 1 - p i p e r i d i n y l ] p r o p o x y ] p h e n y l ] - 2 - m e t h y l - 1 - p r o p a n o n e e t h a n e d i o a t e ( 1 : 1 ) ) is t h e successful resul t o f a p r o j e c t t o discover an ant ihyper tens ive C a + + channel b locker w i t h 5 - H T 2

recep tor a n t a g o n i s t a c t i v i t y . C a + + c h a n n e l a n t a g o n i s t i c activity was d e t e r m i n e d in e x p e r i m e n t s w h i c h s h o w e d t h a t : A H R inh ib i ted C a + + - i n d u c e d contract ions of K + - d e p o l a r i z e d rabbi t aort ic strips, y ie ld ing a p A 2 = 8 .3; n i fed ip ine (NIFED = 9 .8) , verapami l (VERAP = 8.0) . A H R displaced 5 H - n i m o d i p i n e b ind ing to v o l t a g e sensit ive Ca + + channe ls w i t h a n I C 5 u = 15 n M ; c o m p a r e d t o 26 n M for NIFED, 2 0 0 μ Μ for VERAP, a n d 1.0 μ Μ for RITAN. A H R also inh ib i ted C a + + f lux (Fura 2) in to c u l t u r e d P C 1 2 ce l l s w i t h a s i m i l a r o r d e r o f p o t e n c y (NIFED = A H R > VERAP). 5 - H T 2 r e c e p t o r a n t a g o n i s t i c a c t i v i t y was d e t e r m i n e d in studies w h i c h s h o w e d t h a t : A H R displaced 3 H - k e t a n s e r i n b ind ing f r o m rat ce rebra l cor t ica l m e m b r a n e s w i t h an I C 5 0 = 184 n M , c o m p a r e d t o IC 5o's o f > 1,000 n M for NIFED and VERAP a n d 1 0 n M for RITANS. In a n e s t h e t i z e d , g a n g l i o n - b l o c k e d , spontaneously hypertensive rats (SHR), A H R inhib i ted t h e pressor responses t o IV 5-HT w i t h an I D 5 0 = 184 pg /kg ( IV) ; I D 5 0 ' s for NIFED, VERAP, and RITANS in t h e same test w e r e > 3 0 0 , 94 , a n d 4 p g / k g . 5 -HT- induced p a w e d e m a in rats was inh ib i ted 6 3 % by A H R and 8 0 % by RITANS at 1 m g / k g PO. NIFED and VERAP w e r e inactive a t 30 m g / k g . In conscious SHR, A H R (10 , 20 , 30 , 100, 3 0 0 m g / k g , PO) d o s e - d e p e n d e n t l y reduced m e a n b lood pressure (MBP) by 9, 13, 2 1 , 3 2 , a n d 4 0 % f r o m control a f te r 4 hr, w i t h o u t causing any changes in hear t ra te nor over t toxici ty . In conscious SHR subjected t o g a n g l i o n i c b lockade 3 hr a f te r 30 m g / k g , PO, A H R , pressor responses t o IV 5-HT (1 -600 pg /kg) w e r e comple te ly a n t a g o n i z e d . A H R - 1 6 3 0 3 a n t a g o n i z e s 5 - H T 2 r e c e p t o r s a n d r e d u c e s M B P v ia Ca + +

channel a n t a g o n i s m , yet has no e f fec t on hear t ra te .

1086 SUPPRESSED RENIN-ANGIOTENSIN SYSTEM(RAS) IN SPONTANEOUSLY HYPERTENSIVE RATS(SHR) WITH TYPE-2 DIABETES MELLITUS(DM). Y Takata*, Y Yamashita, Y Tomita, Y Nakao, Τ Tsuchihashi, Μ Iwase, S Takishita, Κ Kobayashi, Μ Fujishima. 2nd Dept of Intern Med, Kyushu University, Fukuoka, Japan.

We evaluated whether neonatal streptozotocin (STZ)-induced DM would alter blood pressure, RAS, sympathetic function and vasopressin(AVP) in SHR. Two-day-old SHR neonates were injected with STZ(DM group) or its vehicle(C). Three months after STZ, the following experiments were performed in conscious rats with a continuous recording of mean arterial pressure(MAP) and heart rate(HR). (i)Three doses of each norepinephrine(NE), AVP and angiotensin II(All) were intravenously(iv) administered, (ii)Enalapril(MK,10mg/kg), d(CH 2) 5Tyr(Me) AVP(AVPA,lOyg/kg) and hexamethonium(C &,30mg/kg) were sequentially injected iv. (iii)C , captopril (SQ,lmg/kg) and AVPA. (iv)AVPA, C & , and SQ. Body weight of DM was decreased compared to that of C. Plasma glucose was .higher in DM than in C. MAP and HR were decreased in DM group. MAP correlated directly with body weight, and inversely with plasma glucose. The hypotensive effects of MK and SQ were much smaller, regardless of preceding AVPA or C^, in DM than in C group. The depressor actions of SQ following AVPA and C^ inversely correlated with plasma glucose in DM. The effects of either C or AVPA were similar between the groups. Combinea inhibitions by either MK+AVPA+C or AVPA+C 6+SQ abolished the differences in MAP between groups. Pressor and bradycardic responses to NE, AVP and All did not differ. In conclusion, a decrease in MAP in SHR with neonatal STZ may be induced by reduced activity of RAS.

1088 THE EFFECT OF ANF ON ION TRANSPORT IN RAT COLON IN VIVO AND IN VITRO. Ν Β Vakil. G J Barros, J Gutkowska, G D Potter. Div. of Gastroenterology, University of Texas, Houston, Texas. Studies of the effects of ANF on mammalian intestine have yielded conflicting results and the role of ANF receptors in the colon is uncertain. As ANF could affect both vascular and gut receptors, we studied the effects of ANF in vivo and in vitro. Methods: Sprague Dawley rats were fasted overnight and anesthetized with methoxyflurane for in vivo perfusion of the colon with 3H-PEG saline at 0.4 ml/min. ANF was infused into the jugular vein at 0.5 or 1.0 μg/kg/min. After 50 min equilibriation, 2 basal 20 minute collections were made, followed by collections during perfusion of ANF. 3H-PEG activity and ion concentrations were measured and water and ion movements were then calculated. For experiments in vitro, rat distal colon was excised, stripped of muscle layers and mounted in Ussing chambers.The short circuit current ( l s c ) was recorded and 2 2 Na and 3 6 CI were used to measure ion fluxes. Rat ANF was determined after infusion by radioimmunoassay after extraction on Vycor glass. Results: mean +SEM

Water Na CI Κ Control 67.5+10.9 19.6+2.6 16.8+3 -1.2+0.2 ANF 72.4+11.2 19.5+2.2 20±3.4 -1.3+0.1 μΙ/min/g (water) & μβς/ιτιιηΛ} (ion flux) Electrolyte transport in vitro ι n=7)

Na .CI G t

J n e t J n e t lsc G t

Control 2.7±1.0 1.7+0.5 0.9±.0.2 13.9+0.8 ANF10" 6 M 2.3+1.0 2.5+1.1 1.1+Ό.2 13.7+Ό.7

No significant differences were observed in vitro or in vivo. Basal plasma ANF was 139±55 and increased to 1385+396 pg/ml during ANF infusion (p=0.01). Biological activity of the infused ANF was demonstrated by an increase in urine output from 12.6+0.5 to 37.4+2.9 μΙ/min (p<0.05). Conclusions: 1) Despite a 10 fold increase in plasma ANF and a marked diuresis, ANF had no effects on colonic water and electrolyte transport in vivo. 2) ANF had no effect on electrolyte transport in strips of colonic tissue in vitro either 3) We postulate that these colonic receptors may have a role in liberating cyclic GMP into the circulation with secondary effects on other organs.

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1089 CHRONIC INFUSION OF ENDOPEPTIDASE 24.11 INHIBITOR AND NON-GUANYLATE CYCLASE-LINKED ATRIOPEPTIN (AP) RECEPTOR LIGAND ON MEAN ARTERIAL PRESSURE (MAP) IN SPONTANEOUSLY HYPERTENSIVE RATS (SHR). JP Koepke* LD Tyler & EH Blaine*- Searle Research & Development, Department of Pharmacology, Washington Univ Sch Med, St Louis, MO 63110

Acute coadministration of thiorphan (an inhibitor of endopeptidase 24.11) and SC-46542 (a ligand selective for non-guanylate cyclase-linked AP binding sites) increases urinary sodium excretion to a greater degree in conscious SHR than normotensive Wistar-Kyoto rats (unpublished). In addition, urinary cGMP excretion is increased in both SHR and Wistar-Kyoto rats without changes in filtered load or plasma concentration of cGMP, indicating that the urinary cGMP excretion response is nephrogenous. In the present study, we examined the effects of chronic 10 day infusion of SC-46542 (des[Phel06,Glyl07 Alall5,Glnll6]AP-(103-126)) alone (n = 6), thiorphan alone (n = 7), or coinfusion of SC-46542 and thiorphan (n = 8) on MAP in SHR. Thiorphan (1.5 mg/kg/hr) or SC-46542 (100 μg/kg/hr) was infused continuously intravenously via an external pump; MAP was measured daily from 10:00 AM to 2:00 PM via a femoral artery catheter and pressure transducer. Data are means ± SE; C = preinfusion control day; SC = SC-46542; TH = thiorphan; *p<0.05 compared to C.

days of infusion Q L2 Μ 5z6 Μ 9d0

SC 152±4 155+3 144±5 157+7 156+8 162±9 TH 147±4 151+5 143±4 146±6 153±6 159+5 SC+TH 156±6 126±7* 126±4* 132+4* 140±4* 145±6

In a vehicle time-control group, MAP remained stable. SC-46542 alone or thiorphan alone did not lower MAP. The coinfusion of SC-46542 and thiorphan lowered MAP, but failed to maintain MAP in a normotensive range. Heart rates were similar among groups during infusions. Conclusion: Coinfusion of a ligand selective for the non-guanylate cyclase-linked AP binding site (SC-46542) and an inhibitor of endopeptidase 24.11 (thiorphan) is not an effective long-term treatment for hypertrension in SHR.

11091 ENHANCED P H O S P H O I N O S I T I D E H Y D R O L Y S I S IN THE PINEAL GLAND OF SPONTANEOUSLY HYPERTENSIVE RATS ( S H R ) . J T Laitinen, Τ Torda, JM Saavedra*. Unit Preclin N e u r o p h a r m a -col . Lab Clin Sci, NIMH, Bethesda, M D .

Decreased c a t e c h o l a m i n e levels, as well as increased number of (^-adrenoceptors are found in the h y p o t h a l a m u s of SHR. Moreover, SHR h a v e increased p e r i p h eral sympathetic activity. The pineal gland responds to adrenergic stimulation, originating from the peri p h e r a l sympathetic ganglia, w i t h a cAMP-mediated increase in the activity of N - a c e t y l t r a n s -ferase ( N A T ) . (^-adrenoceptor stimulation potentiates the β-receptor me d i a t e d increase in pineal cAMP. A 4-fold increase in basal N A T - a c t i v i t y h a s been found in SH rats. To clarify the role of (^-adrenoceptors in the pineal of SHR, we studied the t r a n s m i t t e r - s t i m u l a t e d p h o s p h o inositide h y d r o l y s i s (measured as the accumulation of inositol m o n o p h o s p h a t e s , IP.,) . Both basal and n o r e p i n e p h r i n e - s t i m -ulated IP 1 accumulation w e r e significantly higher in SHR than in normotensive W i s t a r Kyoto r a t s . This increase seems to be specific for adrenergic stimulation, as the pineal ΙΡ,,-response to carbachol w a s similar in both g r o u p s . The enhanced basal and n o r e p i n e p h r i n e - i n d u c e d second m e s s e n g e r response probably reflects the increase in peripheral sympathetic activity and u p r e g u l a t i o n of the pineal ay-adrenoceptors in this m o d e l of h y p e r t e n sion.

1090 EFFECTS OF MAGNESIUM ON CHANGES IN BLOOD PRESSURE AND PLASMA ALDOSTERONE INDUCED BY ANGIOTENSIN II K.Atarashi, M.Takagi, H.Matsuoka, T.Sugimoto, The Second Department of Internal Medicine, University of Tokyo, Tokyo, Japan.

Biological activities of angiotensin II (All) are mediated through an increse in intracellular calcium (Ca). Magnesium (Mg) is known to antagonize the action of Ca. Vie therefore investigated the effects of Mg on changes in blood pressure and plasma aldosterone concentration (PAC) induced by All or captopril, ACE inhibitor, administration. Catheterized rats were treated with dexaraethazone 2hrs before experiment. Rats were infused All (0.1 nmol/ kg/min, i.v.) with or without MgS04 (5nraol/kg/ min) for 30 min (n=5, each). The other rats were given captopril (20mg/kg,p.o.) 1 hr before experiment and infused the same dose of MgS04 (n=5). The rats were conscious and unrestrained during the experiment. Mean arterial pressure (MAP) was recorded directly through the carotid catheter. PAC was determined before and after the Mg infusion. MgS04 attenuated an elevation of MAP (ΔΜΑΡ; All 25.5±2.2(SE)mmHg vs All with Mg 13.3±1.3, p<0.01) and an increase in PAC (181±19 pg/ml vs 80±19, p<0.01) induced by All infusion. In captopril-treated rats MAP was decreased by 18mraHg, and MgS04 showed no significant effects on MAP and PA. We conclude: 1) Mg decreases blood pressure and PAC only when All is administered. 2) The results suggest that Mg may counteract the increase in intracellular Ca by All.

1092 MORPHOMETRIC ANALYSIS OF EFFECTS OF NOREPINEPHRINE AND ATRIAL NATRIURETIC PEPTIDE ON THE RENAL ARTERIOLES. Kenjiro Kimura,Yasunobu Hirata* Shinichiro Nanba, Akihiro Tojo, Hiroaki Matsuoka, Tsuneaki Sugimoto. University of Tokyo, Tokyo, Japan

The ef fec ts of norepinephrine(NE) and a t r i a l n a t r i u r e t i c peptide(ANP) on renal a r t e r i o l e s were evaluated by using vascular c a s t s . Acryl compound were infused into kidneys during the administration of NE(200 ng/kg/min. ; NE group) ,a-rANP (0.33 g/kg/min.; ANP group) or NE+a-rANP (ΝΞ+ΑΝΡ group) to anesthetized Wistar r a t s . Vascular casts were examined on the scanning electron microscope. The diameters of a r t e r i o l e s in the superficial cortex as mean±SEM(um):

control NE ANP NE+ANP afferent 17.2±0.6 14.G±1 . 2 * 16-1±1 .1 17 .5+1.2 efferent 14.4±0.4 14.3±1 .1 11.9+1 . 0 * 12 .1+1 .0* * ρ<0.05 vs control In the deep cortex , any significant changes in a r t e r i o l a r diameters were not observed. ANP seemed to antagonize the renal e f f e c t s of NE mainly by dilat ing afferent a r t e r i o l e s . Furthermore, ANP-induced natriuresis may be augmented through the efferent constr ic t ion. In different groups of r a t s , NE decreased both GFR(-7%) and UNaV(-16%). However, simultaneous administration of ANP with NE recovered GFR(+15%) and markedly increased UNaV(+11,000%). In conclusion, NE decreases GFR and natr iuresis by constrict ing the afferent a r t e r i o l e , while ANP increases them by constrict ing the efferent a r t e r i o l e . Dilating e f f e c t s of ANP on the afferent a r t e r i o l e became apparent when administered with ΝΞ.

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[10931 MORPHQMETRIC ANALYSIS OF RENAL ARTERIOLES IN SPONTANEOUSLY HYPERTENSIVE RATS. Kenjiro Kimura, Shinichiro Nanba, Akihiro Tojo, Yasunobu Hirata*, Hiroaki Matsuoka, Tsuneaki Sugimoto University of Tokyo, Tokyo, Japan

Recent studies have shown that intraglomerular hypertension plays an important role in the progression of glomerular diseases. Intraglomerular pressure depends on the systemic arterial pressure as well as on the arteriolar resistance. We therefore morphometrically evaluated the state of the arterioles in hypertension. Four-week-old and twenty-week-old male spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY) were used. After the perfusion fixation with 2.5% glutaraldehyde, the acryl compound was infused into the left kidney. Vascular casts were examined on the scanning electron microscope. The results as mean±SEM:

BP(mmHg) diameters(urn) afferent efferent

4-week-old SHR 124+1 10.3±0.6* 10.U0.7 WKY 116±7 12.3±0.7 10.U0.9

20-week-old SHR 1 92±5** 14.3±0.5* 15.4±1.2* WKY 140±4 17.U0.6 12.9±0.4

* p<0.05 vs WKY, ** p<0.01 The results indicate that the afferent arterioles constrict and the efferent arterioles dilatate in a hypertensive state. The net effects may contribute to the maintenance of intraglomerular pressure within the normal range in spite of the systemic high blood pressure.

1 0 9 4

EFFECTS OF ATRIAL NATRIURETIC PEPTIDE (ANP) ON URINARY PROTEIN EXCRETION IN MESANGIAL PROLIFERATIVE GLOMERULONEPHRITIS

Hi r a t a Y'x", Fukui K, Hayakawa H, Sugimoto T, Kimura K, Matsuoka H, Sugimoto T, I s h i i M*. U n i v e r s i t y o f Tokyo, Tokyo, JAPAN

We have p r e v i o u s l y r e p o r t e d t h a t ANP i n f u s i o n i n c r e a s e s p r o t e i n u r i a in pr imary g l o m e r u l a r d i s e a s e . To s tudy whether or not mesangia l p r o l i f e r a t i o n i n f l u e n c e s t h i s e f f e c t , we i n f u s e d ot-hANP ( 2 5 ng/kg/min , 40 min) i n t o 6 p a t i e n t s with minor g l o m e r u l a r a b n o r m a l i t i e s (MGA), 10 with f o c a l g l o m e r u l o n e p h r i t i s (FGN) and 8 with d i f f u s e GN (DGN), and determined t h e r e n a l e f f e c t s . Basa l g l o m e r u l a r f i l t r a t i o n r a t e did not d i f f e r among t h e s e g r o u p s . Although ANP s i g n i f i c a n t l y i n c r e a s e d u r i n a r y Na e x c r e t i o n in a l l g r o u p s , t h e d e g r e e s o f t h e i n c r e a s e s were not d i f f e r e n t among t h e groups ( a b o u t +200%, p < 0 . 0 1 ) . ANP i n f u s i o n brought about s i g n i f i c a n t i n c r e a s e s in u r i n a r y p r o t e i n e x c r e t i o n (MGA + 6 5 , FGN + 6 9 , DGN + 1 4 4 u g / m i n ) . T h i s i n c r e a s e was g r e a t e r in DGN than in t h e o t h e r two groups ( p < 0 . 0 5 f o r b o t h ) , but was not r e l a t e d t o t h e p r e i n f u s i o n l e v e l o f p r o t e i n u r i a . E l e c t r o p h o r e t i c c h a r a c t e r i s t i c s o f u r i n a r y p r o t e i n were not changed by ANP i n f u s i o n . Although ANP i n c r e a s e d u r i n a r y c r e a t i n i n e e x c r e t i o n , t h e r a t i o o f u r i n a r y p r o t e i n t o c r e a t i n i n e was s i g n i f i c a n t l y e l e v a t e d in t h e 3 groups (MGA 0 . 4 vs 1 . 3 , FGN 1 . 2 vs 2 . 2 , DGN 1 . 0 vs 2 . 5 ) . Thus, ANP seems t o i n c r e a s e p e r m e a b i l i t y o f t h e g l o m e r u l a r basement membrane t o p r o t e i n . T h i s e f f e c t may be r e l a t e d t o mesangia l p r o l i f e r a t i o n and t h e a s s o c i a t e d changes in a d j a c e n t t i s s u e s in which abundant ANP r e c e p t o r s a r e known t o e x i s t .

11095

NEPHROGENOUS c y c l i c GMP PRODUCTION DURING NaCl LOADING AND ANP INFUSION

H i r a t a Y * f Fukui K, Hayakawa H, Namba S , I s h i m i t s u T, Sugimoto T, Kimura Kt Matsuoka H, Sugimoto T. U n i v e r s i t y o f Tokyo, Tokyo, JAPAN

To f u r t h e r s t u d y t h e m e c h a n i s m s o f r e n a l e f f e c t s o f ANP, we e x a m i n e d t h e e f f e c t s o f NaCl l o a d i n g and ANP i n f u s i o n on nephrogenous cGMP (N-cGMP) p r o d u c t i o n . S i x n o r m o t e n s i v e s (NTs) and 7 h y p e r t e n s i v e s (HTs) were p l a c e d on 7-day low ( 3 g / d a y ) and then 7-day high NaCl d i e t s ( 2 0 g / d a y ) . On t h e l a s t day o f e a c h p e r i o d , n a t r i u r e t i c and N-cGMP ( u r i n a r y cGMP -f i l t e r e d cGMP) r e s p o n s e s t o ANP i n f u s i o n a t 25 n g / k g / m i n f o r 4 0 min w e r e d e t e r m i n e d . ANP i n f u s i o n m a r k e d l y i n c r e a s e d p l a s m a c o n c e n t r a t i o n s o f ANP and cGMP and u r i n a r y e x c r e t i o n o f Na and cGMP. These changes were accompanied by a r i s e in N-cGMP ( 5 5 vs 1300 pmol/min, p < 0 . 0 0 1 ) . I n c r e a s e s in N-cGMP d u r i n g ANP i n f u s i o n were not d i f f e r e n t between HTs and NTs d e s p i t e g r e a t e r n a t r i u r e t i c r e s p o n s e in HTs (HTs + 2 2 8 vs NTs + 2 9 UEq/min d u r i n g low NaCl p e r i o d , p < 0 . 0 5 ) . NaCl l o a d i n g s i g n i f i c a n t l y i n c r e a s e d plasma c o n c e n t r a i o n s o f ANP (+50%, p < 0 . 0 1 ) and cGMP (+40%, p < 0 . 0 5 ) and n a t r i u r e t i c r e s p o n s e t o ANP i n f u s i o n in both groups (+250%, p < 0 . 0 5 ) . However, N-cGMP p r o d u c t i o n i n d u c e d by ANP i n f u s i o n was n o t a f f e c t e d by c h a n g e s in NaCl i n t a k e . T h u s , a l t h o u g h ANP-induced n a t r i u r e s i s i s a s s o c i a t e d wi th an i n c r e a s e in N-cGMP, t h e n a t r i u r e t i c e f f e c t o f ANP s e e m s t o be d e t e r m i n e d t o a g r e a t e r e x t e n t by i n d i r e c t mechanisms such as r e n a l p e r f u s i o n p r e s s u r e and body f l u i d volume s t a t u s .

1 0 9 6

RENAL EFFECTS OF ATRIAL NATRIURETIC PEPTIDE (ANP) DURING DOPAMINE INFUSION H i r a t a Y * t Fukui K, Hayakawa H, Suzuki F_, Sugimoto T, Kimura K, Matsuoka H, Sugimoto T. U n i v e r s i t y o f Tokyo, Tokyo, JAPAN

To s tudy whether t h e r e n a l e f f e c t s o f ANP a r e mediated by dopaminerg ic mechanisms, we examined t h e i n t e r a c t i o n between dopamine and ANP on r e n a l c i r c u l a t i o n . Dopamine was i n f u s e d a t 1 ug/kg/min f o r 80 min i n t o 6 n o r m o t e n s i v e s u b j e c t s . A f t e r 40 min o f dopamine i n f u s i o n , ANP i n f u s i o n was added t o dopamine. B e f o r e , d u r i n g and a f t e r t h e i n f u s i o n , r e n a l f u n c t i o n and nephrogenous cGMP (N-cGMP; u r i n a r y e x c r e t i o n o f cGMP - f i l t e r e d cGMP) were d e t e r m i n e d . Dopamine did not i n f l u e n c e blood p r e s s u r e , but i n c r e a s e d u r i n a r y Na e x c r e t i o n (UNaV) by 108%. A d d i t i o n o f ANP f u r t h e r i n c r e a s e d UNaV by 63% ( b o t h p < 0 . 0 1 ) . Although r e n a l b lood f l o w was i n c r e a s e d o n l y by dopamine ( + 1 9 % ) , g l o m e r u l a r f i l t r a t i o n r a t e (GFR) was i n c r e a s e d by both dopamine (+13%) and ANP (+9%, each p < 0 . 0 5 ) . Reduced r e n a l v a s c u l a r r e s i s t a n c e by dopamine i n f u s i o n was somewhat r a i s e d by t h e a d d i t i o n o f ANP. These r e n a l hemodynamic changes were m a i n l y caused by c a l c u l a t e d g l o m e r u l a r a f f e r e n t r e s i s t a n c e d u r i n g dopamine i n f u s i o n ( - 2 1 % , p < 0 . 0 2 ) and a r i s e in e f f e r e n t r e s i s t a n c e d u r i n g ANP i n f u s i o n (+29%, p < 0 . 0 5 ) . Plasma and u r i n a r y cGMP and N-cGMP ( 6 0 vs 550 pmol/min/m , p < 0 . 0 1 ) were e l e v a t e d o n l y dur ing ANP i n f u s i o n . T h e s e r e s u l t s s u g g e s t t h a t t h e e f f e c t s o f ANP and dopamine on both GFR and UNaV were a d d i t i v e . F u r t h e r m o r e , in c o n t r a s t wi th dopamine, ANP i n c r e a s e d e f f e r e n t r e s i s t a n c e and N-cGMP, s u g g e s t i n g t h a t t h e r e n a l e f f e c t s o f ANP a r e independent o f d o p a m i n e r g i c r e g u l a t i o n .

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1099 DETERMINANTS OF RENAL RESPONSE TO ATRIAL NATRIURETIC PEPTIDE (ANF): DISPARATE EFFECTS DURING MYOGENIC- AND NOREPINEPHRINE-INDUCED AFFERENT ARTERIOLAR VASOCONSTRICTION. K. Havashl. R.Loutzenhiser*, M. Epstein*. Nephrol. Sec t . , V.A. Med. Ctr . , and Univ. Miami, Miami, Florida

ANF is a potent vasodilator of the afferent a r ter io le (AA). However, recent studies suggest that ANF has no effect on renal autoregulation, a phenomenon involving pressure-induced (myogenic) AA-vasoconstriction. We therefore examined the effects of ANP on myogenic activation of the AA. Chronic unilateral hydronephrosis was induced in r a t s to f a c i l i t a t e direct visualization of renal microvessels. Hydronephrotic kidneys were excised, perfused in v i t r o , and AA diameter was measured by videomicroscopy. We previously demonstrated that ANF completely reverses norepinephrine-induced AA vasoconstriction (0 .3 μΜ NE, diameters in μπι) :

NE + ANP [concentration, nM] pre-NE NE Γ0.1Ί ΓΙ.01 Γ101 ΓΙ00Ί

20±1 14±1 16±1 17±1 19±1 21±1 (mean ± SEM, n = l l , JPET 246:522-528, 1988)

In contrast , ANF and the c-GMP-dependent vasodilator nitroprusside (1 μΜ, NP) had no effect when AA vasoconstriction was induced by elevating renal a r t e r i a l pressure (RAP). Conversely, the calcium antagonist nifedipine ( 1 . 0 μΜ, NIF) completely prevented this response (RAP, mm Hg):

RAP (n) 80 100 120 140 160 180 AA-Cont (17) 19±1 18±1 16±1 15±1 15±1 14±1 AA-ANF (6) 18±1 17±1 16±1 15±1 15±1 14±1 AA-NP (5) 20±1 19±1 18±1 17±1 16±1 15±1 AA-NIF (6) 20±1 20±1 20±1 20±1 21±1 22±1

These findings indicate that the renal microvascular effects of ANF vary depending on the type of vasoconstrictor stimuli setting basal renal vascular tone. I t is suggested that c-GMP-induced vasodilation involves an uncoupling of r e c e p t o r - s t i m u l a t e d p h o s p h a t i d y l i n o s i t o l hydrolysis (Circ Res 58:407-410, 1986) . This formulation could explain the divergent effects of ANF on NE- and myogenic-induced act ivation of the renal afferent a r t e r i o l e .

|1098| MODULATION OF PRESSOR RESPONSES BY FITNESS; RACIAL DIFFERENCES AMONG CHILDREN. JK Murphy, BS A l p e r t , ES Wi l l ey , JV Chr i s tman , JE Sexton, GA H a r s h f i e l d . * Un i ve rs i t y of Tennessee, Memphis.

In t h i s s tudy, 143 black (B; 8 4 boys and 59 g i r l s ) and 113 w h i t e (W; 66 boys and 47 g i r l s ) heal thy ch i l d ren be tween 6 - 1 8 years of age underwent max ima l exerc ise t e s t i n g on a cyc le ergometer and psychologic s t r e s s t e s t i n g w i t h a t e l e v i s i o n v ideo game (V6). Based upon measured max ima l oxygen consumpt ion dur ing exerc ise , ch i l d ren were grouped in to t e r t i l e s of f i t ness . Blood pressure (BP) and hear t r a te (HR) responses of f i t (F; h ighest t e r t i l e ) and u n f i t (U; l owes t t e r t i l e ) ch i ld ren dur ing the VG were compared. Ana lys i s of VG-HR ind ica ted F<U dur ing basel ine (BL; p<.01), VG (p<.02), and recov ery (REC; p<.01); B<W dur ing BL (p<.01) and REC (p<.01) only. For s y s t o l i c BP ( tab le ; mean + SD, in mmHg). race and f i t n e s s i n te rac ted s i a n i f i c a n t l u GrouD BL VG REC

BF 104±17 116+17 107+14 BU 101+10 111+11 103+11 WF 102+12 110+14 104+12 WU 103+14 113+15 105+14

dur ing VG (p<.05), i.e., WF<WU but BF> BU. D ias to l i c BP was not s i g n i f i c a n t l y a f f ec ted by race or f i t ness. Resul ts suggest tha t the sa lu ta ry e f f e c t s of f i t n e s s may be less cons is ten t among Β than W.

Iiiool R E I N T E R P R E T I N G C L I N I C A L DRUG T R I A L RESULTS W I T H AN ELECTRONIC M O N I T O R . P . R u d c K * S . A h m e d , V . Z a c h a r y , C . B a r t o n . D e p t . o f M e d . ; S t a n f o r d U n i v . M e d . C t r . ; S t a n f o r d , C A .

We c o m p a r e d c l i n i c a l t r i a l r e s u l t s o b t a i n e d f r o m a l t e r n a t i v e m e a s u r e s o f m e d i c a t i o n - t a k i n g a m o n g a m b u l a t o r y p a t i e n t s . O v e r 13 w e e k s , we p r o s p e c t i v e l y a s s e s s e d 21 h y p e r t e n s i v e s ( m e a n a g e 57 y r s . , 67'/. m a l e ) , r a n d o m i z e d t o i s r a d i p i n e ( I S R ) o r e n a l a p r i l (ΕΝΑ) a t I E h r . i n t e r v a l s . A l l s u b j e c t s r e c e i v e d s t u d y m e d i c a t i o n i n s p e c i a l l y m o d i f i e d v i a l s w i t h e l e c t r o n i c m o n i t o r i n g (MEMS; A p r e x C o r p . ; F r e m o n t , C A ) , w h i c h r e c o r d e d e x a c t o p e n i n g t i m e s , a n d t r a d i t i o n a l , s u r r e p t i t i o u s p i l l c o u n t s a t 1-2 w e e k i n t e r v a l s . V A R I A B L E I S R [ n = 1 0 3 Ε Ν Α [ n = 1 1 ] p_

B a s e l i n e S i t t i n g B P ( m e a n , Μ H g ) 1 4 9 / 1 0 0 1 5 0 / 9 9 n s

C h a n g e f r e e D B F B a s e l i n e ( m e a n , m H g ) - 1 4 . 3 - 1 5 . 5 n s

C o i p l i a n c e b y P i l l C o u n t ( m e a n + s d , X ) 96 + 3 1 95 + 8 n s

C o a p l i a n c e b y M o n i t o r ( a e a n + s d , X ) 8 7 + 1 1 9 7 + 6 ( 0 . 0 5

D a y s i n w h i c h d a i l y d o s e s = 2 ( X ) 5 8 + 1 8 68 + 1 7 n s

D o s e s t a k e n a t 1 0 - 1 4 h r . i n t e r v a l s ( X ) 33 + 1 4 4 1 + 1 2 < 0 . 0 5

T h e r e w a s p o o r c o n c o r d a n c e b e t w e e n d o s i n g a d h e r e n c e j u s t b e f o r e s c h e d u l e d v i s i t s a n d t h a t t h r o u g h o u t i n t e r v i s i t i n t e r v a l s . T h o s e s u b j e c t s w i t h " e x t r a " d o s e s j u s t b e f o r e s c h e d u l e d v i s i t s t e n d e d t o h a v e h i g h e r b l o o d p r e s s u r e s t h a n d i d m o r e c o n s i s t e n t l y c o m p l i a n t p a t i e n t s . A n a l y s i s b y m o n i t o r - b a s e d c o m p l i a n c e l e v e l r e d u c e d b l o o d p r e s s u r e v a r i a n c e , s u g g e s t i n g a s m a l l e r s a m p l e c o u l d s u f f i c e . We c o n c l u d e t h a t ( a ) e l e c t r o n i c m o n i t o r s a r e s u p e r i o r t o p i l l c o u n t s , ( b ) d r u g s ' r e l a t i v e e f f i c a c y a n d s a f e t y may b e d i s t o r e d b y i n a c c u r a t e c o m p l i a n c e m o n i t o r i n g , a n d ( c ) b e t t e r m o n i t o r i n g may i m p r o v e b o t h i n t e r p r e t a t i o n a n d c o s t s o f c l i n i c a l d r u g t r i a l s .

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1 lioiI THE RELATIONSHIP OF BLOOD LEAD TO BLOOD PRESSURE IS CONTINUOUS AND GRADED. CD Morris*. WM Bennett*, DA McCarron*, Div. of Neph., Oregon Hlth. Sci . Univ., Portland, OR.

Population studies have demonstrated a posit ive association between blood lead (Pb) and blood pressure (BP), which has depended upon the presence of Pb levels > 20 /ig/dl. As i t is unclear i f this relationship is present for Pb <20 μg/dl, we analyzed Pb levels in a population screened for non-pharmacologic therapy of BP. All subjects had BP measured on no medication during 4 consecutive weeks using a random-zero sphygmomanometer. Blood Pb and erythrocyte protoporphyrin (EPP) were measured. Results were analyzed using multiple linear regression.

BP and Pb were collected in 145 males and 108 females. Pb averaged 8 .0±4 .3 /ig/dl (range 4-39) in males and 6.9±3.7 /ig/dl (range 4-21) in females; a l l but 2 patients had Pb levels < 20 jug/dl. EPP was signif icantly higher (p= 0 .02) in females (20. 0±11.1/ig/dl) than in males (16.4± 8.9 / ig/dl) . In males only, Pb was significantly and positively related to both supine systol ic and standing dias tol ic BP ( r=0 .16 , p<0 .05 ) ; supine dias tol ic and standing sys tol ic BP were also positively related to Pb, though not significantly ( r = 0 . 1 1 ) . A 10 μg/dl increase in Pb was associated with a 5 mmHg increase in supine diast o l i c BP and a 2.9 mmHg increase in standing diastol ic BP. The relationships did not change with adjustment for age and body mass index. There was no relationship between Pb and BP in females, and EPP was not related to BP in males or females. In conclusion, the relationship between Pb and BP in men is continuous and graded at re la t ively low Pb levels , <20 /ig/dl.

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EFFECT OF MEDIUM Na+ CONCENTRATION ON IN VITRO INTESTINAL Ca2+ TRANSPORT IN SPONTANEOUSLY HYPERTENSIVE (SHR) AND WKY CONTROL RATS. Τ Driieke*. Ch Roullet, Ρ Duchambon, L Comte, Β Lacour, DA McCarron*. INSERM U 90, Necker Hospital & Dept. of Nephrology, OHSU, Portland, OR.

We have previously shown that the deletion of Na+ from the incubation medium (replacement of NaCl by choline CI) led to a decrease in enterocyte Ca 2 + efflux rate constant in the WKY, but not the SHR. In order to further explore such difference, we investigated in either rat strain Ca2+ uptake using the isolated enterocyte (cellular Ca 2 + flux and pool: Jcell and P C ell . nmol/mg.min and nmol/mg, resp.), and duodenal Ca2+ transport in Ussing chambers for mucosa-serosa and net Ca 2 + flux : J m . s and Jnet. nmol/cm2.hr. Na+ concentration of incubation medium was either high (145 mM) or low (25 or 0 mM). Results as meantSEM (n>6):

SHR+hiNa SHR+loNa WKY+hiNa WKY+loNa ( 1 ) ( 2 ) ( 3 ) ( 4 )

Jcell . 5 5 ± . 0 5 * . 5 3 ± . 0 9 . 7 9 ± . 0 6 ,90±.09c

Pcell 8 .9± .83a 1 3 ± 3 13±1 .5 1 7 ± 2 . 8

Jm-s 3 7 ± 5 . i a 20±1 .8b 6 6 ± 2 . 9 5 7 ± 6 . 9 C

Jnet 1 4 ± 3 . 4 * 1.6±2b 4 3 ± 2 . 5 37±8c

Ρ < .05 for a, (1) vs (3); b, (2) vs (1); c, (4) vs (2). Thus, cell Ca 2 + flux and pool were lower in SHR than in WKY. A decrease of Na+ in the incubation medium did not modify enterocyte Ca 2 + uptake in either strain. However, in the Ussing chamber it was associated with a decrease in transcellular absorptive Ca 2 + fluxes in the SHR, but not the WKY. In conclusion, in intact duodenal epithelium of the SHR a decrease in luminal and serosal Na+ concentration appears to interfere with active Ca 2 + extrusion at the baso-lateral side whereas luminal Ca 2 + uptake by the isolated enterocyte was not modified.

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TOTAL BODY MINERAL DENSITY IN HYPERTENSIVE AND NORMOTENSIVE HUMANS. JA Metz. L Roberts, Μ McClung, CD Morris*. Div. of Neph., Or. Hlth. Sci . Univ. & Providence Med. C t r . , Portland, OR.

Alterations in calcium metabolism and nutri tion are associated with osteoporosis and hypertension. In the spontaneously hypertensive r a t , bone density and bone calcium content are signif icant ly lower than in normotensive Wistar-Kyoto r a t s . This led us to question i f bone density differs s ignif icantly with BP in humans. We assessed bone density in 17 normotensive (NL) and 26 hypertensive (HTN) males with dual photon absorptiometry using a Lunar DP4 dichromatic bone densitometer with a 153-Gd source. Total body bone mineral density and bone density of the femoral neck and lumbar spine were measured. BP was determined for 4 consecutive weeks in subj e c t s on no medication. HTN males had mean a r t e r i a l pressure (MAP)>105 mmHg and NLs had MAP<105 mmHg. No subject had received thiazide diuretics nor had a history of disease or medication known to af fec t calcium balance.

There was no significant difference between NL and HTN males in age (HTN 52.6±11.9 yrs vs NL 47.4±13.2 yrs) nor body mass index. Total body bone mineral density (TBBMD) did not differ between HTN and NL males nor did density at specif ic s i t e s .

Site ( a l l in g/oA HTN NL TBBMD 1.26±0.12 1.27±0.07 L2-L4 1.36±0.22 1.32±0.13 Femoral neck 1.01±0.15 1.03±0.14 Trochanter 0 .86±0.12 0 .90±0.10 Ward's tr iangle 0 .82±0.16 0 .86±0.18

There appears to be no relationship between bone density and blood pressure in humans.

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METABOLIC AND BLOOD PRESSURE EFFECTS OF CALCITRIOL IN NORMOTENSIVE HUMANS. EW Young*. DA McCarron*, CD Morris*. Oregon Health Sciences University, Portland, OR.

Calc i t r io l [l,25(OH)2D] has been proposed as a potential mediator of the blood pressure changes associated with s a l t r e s t r i c t i o n and calcium supplementation. At least two studies have reported that c a l c i t r i o l given with supplemental calcium raises blood pressure in human subjects. We performed a pi lo t study to determine whether c a l c i t r i o l alone raises blood pressure in normotensive human subjects . Calc i t r io l was given to 11 healthy volunteers at a dose of 0.25 /ig/d for 2 weeks followed by 0.5 /ig/d for one week. Both doses caused significant metabolic changes. After three weeks of c a l c i t r i o l treatment, serum c a l c i t r i o l increased from 31+5 to 35+8 pg/ml (p= .04) , serum phosphorus increased from 3.0+3 to 3 .3+ .5 mg/dl (p- .004) and urinary calcium increased from 105+66 (x+SD) to 182+97 mg/d (p= .001) . Significant decreases were found in serum ionized calcium (1 .31+0 .4 to 1.25+.03 mmd/L, p= .001) , serum t o t a l calcium ( 8 . 9 ± . 4 to 8.5 + .3 mg/dl, p<.001) and serum bicarbonate (27 .5+2.7 to 21 .5+2 .5 mEq/L, p< .001) , while serum intact PTH did not change (3 .75+ .99 to 3.55+1.11 pmol/1, p = . 5 6 ) . There were no significant changes in dias tol ic blood pressure (supine 70+5 to 72+7, p«=.52; standing 78+5 to 77+7, p=.43) but systol ic blood pressure f e l l (supine 116+8 to 109+8, p- .Ol; standing 112+9 to 105+8, p= .003) . Thus, oral c a l c i t r i o l given alone for three weeks in a dose suff ic ient to cause increased serum c a l c i t r i o l , phosphorus, and urinary calcium excretion did not resul t in an increase in blood pressure.

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11105 IN-VITRO ACTIVE INTESTINAL C a 2 + TRANSPORT OF WISTAR-KYOTO SPONTANEOUSLY HYPERTENSIVE RATS (SHR) AND NORMOTENSIVE CONTROLS IS NOT INFLUENCED BY LEVEL OF ORAL NaCl INTAKE. Τ Drueke*. Ch Roullet, L Comte, Β Lacour, DA McCarron*. INSERM U 90, Necker Hospital, Paris , France & Div. of Nephrology, OHSU, Portland, OR.

The height of blood pressure (BP) is regulated by many factors including nutrients . Whereas the role of dietary Na+ is unclear, an inverse relat ion exis ts between dietary C a 2 + intake and BP. In the present study, we investigated in SHR and control WKY rats the e f fec t of three differ ent amounts of dietary NaCl intakes (low, medium, and high) on active C a 2 + transport in intact duodenal segments. The experimental model was the Us sing chamber (mucosa-to-serosa, serosa-to-mucosa, and net C a 2 + f lux: J m _ s , J s -m a n c * ^net» nmol/cm2.hr). Results as mean+SD: Rats Diet η Jm-s Js-m Jnet SHR +lowNaCl 9 109±36 52±21 57±33 WKY +lowNaCl 8 151+26 60+16 91±21 SHR +medNaCl 8 116+24 50±20 66±41 WKY +medNaCl 9 169+57 52±13 117±56 SHR +highNaCl 9 101±43 39+12 63±39 WKY +highNaCl 9 173+52 58+9 115±55 Analysis of data by ANOVA showed a s t ra in , but not a diet , e f fec t in that duodenal J m _ s and J n e t of C a 2 + was constantly lower in SHR than in WKY, independent of diet . Therefore, changes of intest inal C a 2 + absorption in vivo, which may occur with chronic dietary Na+ manipulation, are probably not due to an interaction with the active C a 2 + transport step but due to effects exerted by the t ranscel lular Na+ drive.

I nozl ULTRASTRUCTURAL AND FUNCTIONAL ABNORMALITIES OF INTESTINAL AND RENAL EPITHELIUM IN THE SPONTANEOUSLY HYPERTENSIVE RAT (SHR). Τ Drueke*. Β Nabarra, L Ben Nasr, Μ Thomasset, Β Lacour, DA McCarron*. INSERM U 90, U 25 and U 120, Paris , France and Div. of Neph., OHSU, Portland, Oregon.

Intest inal and renal Ca handling are disturbed in the SHR compared with i t s control (WKY) . In the present study, duodenal and renal tubular epithelia of 12- to 14-week-old male SHR and WKY were examined by electron microscopy to determine whether such disturbances could be related to s tructural abnormalities. Patchy loss of microvill i in both duodenal and proximal tubular epithelia was observed in the SHR, whereas brush border membrane was entirely normal in the WKY. In addition, the average height of duodenal and renal microvil l i was reduced in the SHR. Two specific markers of the brush border, alkaline phosphatase and v i l l i n , as well as the cytoplasmic vitamin-D dependent calcium-binding proteins CaBPgK and CaBP~gK were determined in the intest ine . Duodenal alkaline phosphatase a c t i v i t y was reduced in the SHR compared with the WKY: 0.145±0.002 vs 0.186±0.002 IE/min. /xm3 χ 1 0 3 brush border, mean ± SEM, η = 10 pairs , ρ < 0 .001 . However, duodenal v i l l i n expression was not different form that of the WKY. Duodenal CaBPq and renal CaBP _ content was diminished in the SHR: 21.0±0.80 vs 29.9±2.19 and 4 .5±0 .4 vs 7 .7±0.5 /ig/mg protein, η = 6 pairs , respect ively , ρ < 0 .01 . These data showing structural and functional abnormalities of intest inal and kidney c e l l s in the SHR appear to r e f l e c t a disorder of transporting epithelia which may be either an int r insic ce l lular abnormality or related to reduced circulat ing c a l c i t r i o l .

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ETHANOL-INDUCED HYPOTENSION IN RATS. DC Hatton*. S Edgar, DA McCarron*. Dept. of Med. Psych, and Div. of Nephrol. & Hypertension, Oregon Health Sciences Univ., Portland, OR.

Epidemiologists have identified alcohol as a r isk factor in hypertension. Attempts to increase blood pressure in ra ts with chronic alcohol ingestion have met with mixed resul t s . Some investigators have reported increases in blood pressure while others have reported decreases. Most investigators have given alcohol in the drinking water which produces differences in food intake across groups. To control for food intake, Wistar ra ts were simultaneously pair fed a liquid diet with either ethanol as 36% of calories or a control diet using ARF/Israel pair-feeding devices. Within 3 weeks of exposure, animals on ethanol diets had significantly lower systol ic blood pressures than control animals (146 (n-24) vs 130 (n-24) mmHg, P< .001) . This significant difference in blood pressure was maintained through 13 weeks of feeding. Acute withdrawal eliminated the difference in blood pressure (149 (n-13) vs 144 (n-13) mmHg, p > . 0 5 ) . However, a f ter 1 week of abstinence the ethanol group s t i l l had significantly lower blood pressure (158 vs 150 mmHg, p<.05) but the difference in blood pressure between groups had diminished. The data suggest that ethanol produces hypotension in rats when food intake is controlled. (Supported by NDPRB).

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DIFFERENTIAL GROWTH RESPONSE OF MESENTERIC ARTERY MYOCYTES OF SHR AND WKY TO EGF AND l,25(OH) 2

VITAMIN D3. RD Bukoski*. Ρ Dewan. Div. Neph., Oregon Hlth. Sciences Univ., Portland, OR.

Arterial wall thickening is a common feature during hypertension and has been proposed to contribute to increased peripheral vascular r e s i s tance. I t has been previously demonstrated that aor t i c myocytes of the spontaneously hypertensive ra t (SHR) grow faster in culture than those of the normotensive Wistar Kyoto (WKY) r a t . I t has been suggested that this difference may underlie the s tructural changes in vivo. We have found that myocytes derived from the mesenteric artery of the SHR prol i ferate fas ter than those of the WKY in medium containing 10% f e t a l c a l f serum. We tested the hypothesis that the elevated growth pattern of SHR myocytes was the result of enhanced sensi t iv i ty to growth stimuli. Myocytes from both strains were grown to passage 6 then plated in 35 mm dishes at 40 ,000 /pla te . Ten ng/ml epidermal growth factor (EGF), 5xlO-10M 1,25 (OH)2 vitamin D3 or vehicle was added to c e l l s in DMEM/Hams F-12 ( 1 : 1 ) + 2% f e t a l c a l f serum (FCS). After 48 hr were removed with versene/trypsin and counted using a hemocytometer chamber. In the presence of 2% FCS, no differ ence in the rate of growth was detected between SHR and WKY. Both EGF (154%, p<0.05) and 1,25 (OH)2 vitamin D3 (127%, p<0.05) stimulated growth of SHR myocytes. When addd together, their e f fec t was additive. These agents had no e f f e c t on growth of WKY myocytes. These resul ts indicate that different ia l responsiveness to growth factors and/or 1,25 (OH)2 vitamin D3 may underlie the different prol iferat ion rates that have been described for myocytes of the SHR and WKY.

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11109| THE A N T I H Y P E R T E N S I V E EFFECTS OF N I F E D I P I N E ( G I T S ) I N M I L D TO MODERATE H Y P E R T E N S I O N . C. J u r p h y * , C M c N a m a r a * , P . K . M o h a n t y * . V . A . M e d i c a l C e n t e r , M e d i c a l C o l l e g e o f V i r g i n i a , R i c h m o n d , VA

T h e e f f e c t s o f 12 w e e k s o f t r e a t m e n t w i t h e n c i " c n c e - r e i l y n i f e d i p i n e w a s e v a l u a t e d i n a p r o s p e c t i v e , 2 w e e k s p l a c e b o r u n i n , o p e n l a b e l s t u d y i n p a t i e n t s w i t h e s t a b l i s h e d m i l e t o m o d e r a t e h y p e r t e n s i o n . O f 1 3 p a t i e n t s e n r o l l e d , c ( a g e E 4 ± 1 0 ; m e a n ± S D ) h a v e c o t r . p l e t e d t h e s t u d y e n d w e r e v a l i d f o r e f f i c a c y a n a l y s e s . S i n g l e c o s e m o n o t h e r a p y w i t h n i f e d i p i n e s i g n i f i c a n t l y ( p < 0 . 0 G l ) d e c r e a s e d ( m e a n ± S E M ) s i t t i n g s y s t o l i c a n d d i a s t o l i c b l o o d p r e s s u r e ( C P ) f r o m 1 7 0 ± £ mmHg t o 1 3 £ ± 3 mmHr e n d f r o m 1 0 1 ± 2 mmHg t o 7 9 ± 2 mmHg r e s p e c t i v e l y . H e a r t r a t e d u r i n g p l a t e a u p e r i o d w a s n o t s i g n i f i c a n t l y d i f f e r e n t ( 7 4 ± 3 v s . 7 3 + 3 b p m ) f r o m p l a c e b o p h a s e . T h e m e a n d o s e o f n i f e d i p i n e w a s 1 1 2 mg o n c e d a i l y . T h e p e a k a n t i h y p e r t e n s i v e e f f e c t v /as o b s e r v e d d u r i n g 4 t h w e e k ( t i t r a t i o n p h a s e ) a n d w e s s u s t a i n e d t h r o u g h o u t t h e 1 2 w e e k t r i a l . M i n o r s i c e e f f e c t s i n c l u d e i n i t i a l h e a d a c h e s i n 2 , l e t h a r g y i n 1 , t r a n s i e n t c h e s t p a i n i n 1 , a n d a s y m p t o m a t i c b r a d y c a r d i a i n 1 . No p a t i e n t w a s d i s c o n t i n u e d f r o m s t u d y d u e t o s i d e e f f e c t s c r l a c k o f a n t i h y p e r t e n s i v e r e s p o n s e . T h e s e r e s u l t s i n d i c a t e t h a t n i f e d i p i n e ( G I T S ) i n d e s e s 6 0 mg t c 1 8 0 n g ( m e a n d o s e 1 1 2 m g ) i s h i g h l y e f f e c t i v e a s a s i n g l e d e s e m o n o t h e r a p y i n t h e t r e a t m e n t o f m i l d t o m o d e r a t e h y p e r t e n s i o n .

1111

.0001

.01

IN SHR RATS, DIETARY Κ DETERMINES NaCl SENSITIVITY IN NaCl-INDUCED RISES OF BP. Μ Ganguli*& L Tobian* Univ of Minnesota Hospital, Minneapolis, Mn.

I t has been reported that SHR r a t s from Charles River Lab are re la t ively resistant to NaCl-induced r ises in BP, when fed a diet containing about 1.2% K. We sought to determine the effect of different levels of dietary Κ on the NaCl resistance of this s t ra in . Seven-week-old male SHR r a t s were placed on 4 different d i e t s : 8%NaCl+.5%K(HS-NK); .24%NaCl +.5%K(NS-NK); 8%NaCl+2.1%K(HS-HK); .24%NaCl+2.1%K (NS-HK). Direct i n t r a a r t e r i a l ether pressures at 4 weeks were: n= BP(mmHg)

HS-NK(33) i — 182—1 NS-NK(20) p<.000W 1 4 6 = i P " HS-HK(18) *==rl46 Ip<. NS-HKU8) P < - 0 0 1 C Z 1 3 7 J

HS-NK fed ra ts not only had increased BP, but also had a high mortal i ty . At 13 weeks there were 95% stroke deaths in the HS-NK fed r a t s , while none had died on the other three d i e t s . In contrast to this , in Dahl *Rf r a t s eating NS-NK and HS-NK diets for 8 weeks, the i n t r a a r t e r i a l BPs averaged, 122 and 125 respectively. And there were no stroke deaths. These results show that Charles River SHR ra ts are f a i r l y NaCl-resistant on a 2.1% high Κ die t , whereas they are quite susceptible to NaCl hypertension on a .5% normal Κ die t . Thus the high Κ diet strongly protects against an NaCl-induced r i s e of BP as well as stroke deaths in these SHR r a t s . The NS-NK r a t s and the HS-HK both showed equal small r i ses in BP, compared to NS-HK r a t s . Even with a normal NaCl die t , high Κ ra ts have lower BP than normal Κ r a t s . In contrast the Dahl R ra ts are extremely NaCl-resistant even on a HS-NK d i e t . In the SHR r a t s , the level of dietary Κ determines the degree of NaCl s e n s i t i v i t y .

1110 HIGH Κ DIETS MARKEDLY REDUCE ATHEROSCLEROTIC CHOLESTEROL ESTER DEPOSITION IN AORTAS OF RATS WITH HYPERCHOLESTEROLEMIA & HYPERTENSION. L Tobian* Τ Jahner & Μ A Johnson, Univ of Minnesota, Mpls, Mn.

High Κ diets prevent hypertensive endothelial injury & intimal thickening. Cholesterol esters often deposit during hypercholesterolemia. Would a high Κ diet influence cholesterol ester deposits? In a normal ra t on a normal die t , no cholesterol esters are detected in the aorta . Stroke-prone SHR r a t s were fed for 3 months a basic diet containing 4% cholesterol , 14% coconut o i l & 7% NaCl. One group of 13 r a t s had normal (.5%) Κ in the d i e t . Another group of 10 r a t s had high (2.1%) K. Mean i n t r a a r t e r i a l BPs averaged 165 mmHg in the normal Κ group & 161 mmHg in the high Κ group (NS). The serum cholesterol averaged 22 9 mg/dl in the normal Κ group & 214 in the high Κ group (NS). Total aor t i c cholesterol esters per rat involving 16 & IS carbon chain f a t t y acids averaged 187 yg in normal Κ vs 68 \ig in high K, measured by gas chromatography. These were the main es ters ; other esters were negligible . Thus high Κ reduced cholesterol ester deposits by 63% (p<.0003) , even though BPs & cholesterol levels were quite similar in the 2 groups. Both high cholesterol & high BP injure endothelial c e l l s & increase invasion of macrophages & vascular smooth muscle ce l l s into the intima & increase endothelial permeability to proteins. With high plasma cholesterol , these processes lead to atherosclerosis with cholesterol ester deposition. The high Κ diet , by protecting endothelial c e l l s , can greatly decrease this cholesterol ester deposition. This effect could possibly be useful for preventing heart attacks in human hypertension.

1112 ROLE OF HYPERTENSION IN INCREASING INCIDENCE OF END STAGE RENAL DISEASE (ESRD) IN NORTHWEST NORTH CAROLINA. Β Hylander, J Burkart, G Tell , VM Buckalew J r . * Bowman Gray School of Medicine, Winston-Salem, NC

To assess the role of primary hypertension in the increasing incidence of end stage renal disease (ESRD) in North Carolina, we examined the causes of ESRD for new patients entering our dialysis program for the years 1 9 8 1 - 1 9 8 6 . 4 6 9 patients were included representing the entire dialysis population age 15 or above in a large unit in northwest North Carolina. Diagnosis of "hypertensive renal disease" (HRD) or "nephrosc leros is " (Ns) was made according to previously published c r i t e r i a from our center (Arch Int Med 1 4 1 : 4 6 2 , 1981X. For purposes of analysis , data for the years 1 9 8 1 - 1 9 8 3 ( 1 8 5 patients) were compared with data for the years 1 9 8 4 - 1 9 8 6 ( 2 8 4 p a t i e n t s ) . Incidence rates for our population were calculated from incidence rates for the s ta te of North Carolina obtained from ESRD Network 2 1 .

The incidence of ESRD in North Carolina rose from 9 5 . 3 cases per million (cpm) in 1 9 8 1 - 1 9 8 3 to 130 cpm in 1 9 8 4 - 8 6 , an increase of 36%. Over the same period, the incidence of HRD + Ns in our population rose from 2 5 . 6 cpm to 3 1 . 1 cpm, an increase of 2 1 . 5 % . Mean age of our population was 5 0 . 9 years in 1 9 8 1 - 8 3 and rose s l ight ly to 5 2 . 0 in 1 9 8 4 - 8 6 . In 1 9 8 1 - 8 3 , 67 .4% or our populat ion were blacks compared to 58 .6% in 1 9 8 4 - 8 6 . These data indicate that HRD and Ns are increasing as a cause of ESRD in North Carolina despite improved antihypertensive therapy. This increasing incidence is apparently not due to increasing age or black race of the population studied.

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SALT INDUCED HYPERTENSION I N INBRED DAHL RATS I S NOT A S S O C I A T E D WITH INCREASED CSF S O D I U M . CP M c C o r m i c k * , MF C a l l a h a n , KA G r u b e r , A L R a u c h , VM B u c k a l e w J r * . D e p t . M e d . / N e p h r o l o g y , Wake F o r e s t U n i v . M e d i c a l C e n t e r , W i n s t o n - S a l e m , N C .

I n c r e a s e s i n CSF s o d i u m a r e a s s o c i a t e d w i t h b a r o r e c e p t o r i m p a i r m e n t p r e c e d i n g h y p e r t e n s i o n . S i n c e D a h l s a l t s e n s i t i v e r a t s s h o w b a r o r e c e p t o r i m p a i r m e n t p r i o r t o h y p e r t e n s i o n , we d e t e r m i n e d CSF s o d i u m i n s a l t s e n s i t i v e ( S S / J r ) a n d r e s i s t a n t ( S R / J r ) r a t s a f t e r h i g h a n d l o w s o d i u m d i e t .

S y s t o l i c p r e s s u r e w a s d e t e r m i n e d o n f o r t y 5 -w e e k o l d m a l e S S / J r a n d S R / J r r a t s . H a l f o f e a c h g r o u p w a s p l a c e d o n a d l i b i t u m h i g h s o d i u m ( 8 . 0 % ) d i e t w i t h t h e r e s t m a i n t a i n e d o n l o w s o d i u m ( 0 . 4 % ) d i e t f o r 10 d a y s . S y s t o l i c p r e s s u r e s w e r e t a k e n a n d t h e f o l l o w i n g d a y , t h e r a t s w e r e a n e s t h e t i z e d , m o u n t e d i n a s t e r e o t a x i c a p p a r a t u s a n d a 5 0 - 1 0 0 u l s a m p l e o f CSF w a s r e m o v e d f r o m t h e c i s t e r n a magma f o r f l a m e p h o t o m e t r y d e t e r m i n a t i o n o f s o d i u m a n d p o t a s s i u m . T h e r a t s w e r e t h e n s a c r i f i c e d a n d h e a r t a n d a o r t a r e m o v e d f o r d e t e r m i n a t i o n o f o r g a n w t / b o d y w t i n d e x .

We f o u n d t h a t S S / J r r a t s h a v e h i g h e r s y s t o l i c p r e s s u r e p r i o r t o t h e i n i t i a t i o n o f t h e HS d i e t ( 1 0 8 ± 2 v s 1 1 8 ± 1 ) c o m p a r e d t o t h e i r S R / J r c o n t r o l s . H i g h s a l t d i e t i n c r e a s e d p r e s s u r e w i t h i n t h e S r / J r s t r a i n ( 1 6 ± 4 v s 8 ± 4 ) , b u t t h i s e f f e c t w a s g r e a t e r i n t h e S S / J r s t r a i n ( 3 0 ± 3 v s 8 ± 2 ) . B o t h s t r a i n a n d d i e t h a d a n e f f e c t o n h e a r t i n d e x w i t h h i g h s a l t S S / J r s h o w i n g t h e h i g h e s t v a l u e . T h e r e w a s n o e f f e c t o f s t r a i n , d i e t o r s t r a i n χ d i e t i n t e r a c t i o n s o n CSF s o d i u m o r p o t a s s i u m . T h i s s t u d y d e m o n s t r a t e s t h a t i n c o n t r a s t t o s a l t s e n s i t i v e h u m a n s , t h e R a p p i n b r e d s a l t s e n s i t i v e r a t s d o n o t s h o w e l e v a t i o n s o f CSF s o d i u m a s s o c i a t e d w i t h t h e d e v e l o p m e n t o f h y p e r t e n s i o n .

1 1 1 5

P H Y S I O L O G I C ROLE OF A T R I A L N A T R I U R E T I C HORMONE I N ALDOSTERONE R E G U L A T I O N . Y S h e n k e r , * C S e s s i o n s , D L a w r e n c e , C C I i n k i n g b e a r d . M i d d l e t o n V e t e r a n s H o s p i t a l a n d U n i v . W i s c o n s i n , M a d i s o n , W I .

T o e v a l u a t e t h e r o l e o f a t r i a l n a t r i u r e t i c h o r m o n e ( A N H ) i n r e g u l a t i n g a l d o s t e r o n e , v e r y l o w - d o s e ANH ( 0 . 6 p m o l / k g / m i n ) o r p l a c e b o ( P ) w a s i n f u s e d o v e r 2 h i n t o 7 h e a l t h y 1 8 - t o 2 8 - y e a r -o l d m a l e v o l u n t e e r s o n l o w - s a l t ( L S ) d i e t ( u r i n a r y s o d i u m e x c r e t i o n 2 1 ± 6 m E q / 2 4 h ) . I n f u s i o n w a s t h e n c o n t i n u e d w i t h a d d i t i o n o f a n g i o t e n s i n I I ( A l l ) 4 p m o l / k g / m i η f o r 3 0 m i n , f o l l o w e d b y 1 h o f r e c o v e r y . B l o o d p r e s s u r e ( B P ) a n d h e a r t r a t e ( H R ) w e r e m e a s u r e d e v e r y 5 m i n a n d 3 0 - m i n m e a n s w e r e c a l c u l a t e d . U r i n e , u r i n a r y s o d i u m , a n d u r i n a r y p o t a s s i u m e x c r e t i o n w e r e m e a s u r e d a n d p l a s m a a l d o s t e r o n e , A l l , a n d ANH l e v e l s w e r e e s t a b l i s h e d b y R I A . No s i g n i f i c a n t c h a n g e s i n BP o r HR o c c u r r e d . S o d i u m e x c r e t i o n i n c r e a s e d f r o m 2 2 t o 3 5 p E q / m i n d u r i n g ANH i n f u s i o n ( p < . 0 5 ) .

B a s a l 2 h A l l R e c o v e r y

A l d o Ρ 4 4 ± 5 4 8 ± 6 7 8 ± 8 a 4 3 ± 5 ( n g / d l ) ANH 4 1 ± 6 2 6 ± 5 a b 6 6 ± 1 4 * 3 8 ± 6 A l l Ρ 1 9 ± 4 2 0 ± 5 1 1 2 ± 2 5 a 2 8 ± 6 ( p g / m i ) ANH 1 7 ± 3 9 ± 3 a b 8 2 ± l i a 2 3 ± 6 ANH Ρ 2 . 7 ± 0 . 5 2 . 5 ± 0 . 4 2 . 5 ± 0 . 3 2 . 2 ± 0 . 4 ( p m o l / l ) ANH 3 . 5 ± 0 . 3 5 . 4 ± 1 . 0 b 6 . 8 ± 0 . 9 a b 3 . 3 ± 0 . 7 a p < . 0 5 c o m p a r e d t o b a s a l ; b p < . 0 5 c o m p a r e d t o L S V e r y l o w - d o s e ANH i n f u s i o n , p r o d u c i n g p l a s m a ANH c h a n g e s w i t h i n n o r m a l r a n g e , s u p p r e s s e d p l a s m a a l d o s t e r o n e a n d A l l l e v e l s i n L S s u b j e c t s b y > 4 0 % b u t d i d n o t d e c r e a s e s t i m u l a t i o n o f a l d o s t e r o n e s e c r e t i o n b y A l l . We c o n c l u d e t h a t ANH h a s a p h y s i o l o g i c r o l e i n r e g u l a t i n g a l d o s t e r o n e t h a t w i t h s m a l l c h a n g e s i n ANH p l a s m a l e v e l s i s m o s t l y m e d i a t e d b y r e n i n - a n g i o t e n s i n s y s t e m s u p p r e s s i o n .

1 1 1 4

DIFFERENTIAL HEMODYNAMIC EFFECTS OF A CARDIO-SELECTIVE BETA-BLOCKER AND ONE THAT POSSESSES VASODILATING ACTION JA Strom*, Κ Carlson, EH Sonnenblick, WH Frishman, Μ Poland, Albert Einstein College of Medicine, Bronx, NY This double-blind study in 16 hypertensive pts (age: 49 yrs) compared upright rest and exercise hemodynamic effects of acute and chronic doses(s) of dilevalol (D, n=8), a beta-blocker with beta-2 agonism, to those of metoprolol (M, n=8). Pts were studied both before and 2 hours after the first dose of D (400 mg) or Μ (100 mg), and 2 hours after the last chronic dose of D (mean: 1133 mg) or Μ (mean: 340 mg). Measurements of mean arterial pressure (MAP), systemic vascular resistance index (SVRI), cardiac index (CI), HR, stroke index (SI) and arterial compliance (AC) were measured before, at 50 watts, and at peak exercise. Mean exercise duration was reduced with Μ (acute: -4.0 min, ρ 001, chronic: -4.2 min, p=NS), while it was unchanged with D (acute: -1.4 min, chronic +0.4 min). The results are:

% Change from Placebo Baseline after Acute Doses Rest MAP SVRI CI HR SI AC D=400 mg -10% + 1% -11% -15% + 1% +43% M=100 mg - 8% +25% -29% -19% -13% + 5% Ρ value* NS 41.001 <\01 NS NS <.07

50 Watts <\01 <.07

D=400 mg -14% - 3% -12% -19% + 6% +56% M=100 mg - 9% +19% -26% -24% - 4% 0% ρ value* NS <\001 <.03 NS NS ^.04

;tchange in D vs change in M: NS=not significant The beneficial effect of D on SVRI per sisted at peak exercise. The hemodynamic differences were maintained with chronic dosing . D pres erves exer-cise tolerance by its favorable effects on cardiovascular performance.

1 1 1 6

HEMODYNAMIC E F F E C T S OF LISINOPRIL IN THE E L D E R L Y ESSENTIAL HYPERTENSIVE. A. Lindner and A J . Meacham, Department of Medicine, VA Medical C e n t e r , and the University of Washington, S e a t t l e , WA.

Non-invasive Doppler-ultrasound was used to measure cardiac output (CO) and vascular resis tance (SVRI) during t r e a t m e n t with LISINOPRIL in 20 patients (avg. age 71 .5 yrs, 15 Μ and 5 F ) with mild to moderate hypertension. Measurements were made when untreated (4 weeks off medication) and af ter 2 months on LISINOPRIL at 5 , 10, or 20 m g / 2 4 hr, or placebo.

Mean BP fell by 9% (119 to 109 mm Hg) with the 5 mg dose (p < 0 .05) , mostly due to a fall in diastolic B P , and the magnitude of the change did not differ between doses. The primary e f f e c t of LISINOPRIL was vasodilatation, and SVRI fell by 7, 10, or 14% (p < 0 .05) in each group, respectively (NS between groups). CO was maintained or tended to increase (NS) in all t r e a t e d groups. Aor t i c diameter fell by 5 and 3 % , respect ively , with the 5 and 10 mg doses, in c o n c e r t with the BP changes .

LISINOPRIL effec t ively lowers BP in the elderly, primarily by decreasing vascular res is tance , while maintaining C O . Heart r a t e and weight were generally unaffec ted . The stable c a r d i a c output, while dampening the BP fall , may contribute to the exerc ise t o l e r a n c e .

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INCREASED VASCULAR REACTIVITY AND BLOOD PRESSURE ASSOCIATED WITH DELAYED CALCIUM EFFLUX IN ZUCKER OBESE RATS. MB Zemel*, S Shehin, S Reddy. W Lockette, JR Sowers. Wayne Siate Univ. Detroit,MI.

Previous data from this laboratory demonstrate that Zucker obese r a t s , a model of insulin r e s i s t ance, exhibit significant blood pressure elevations compared to their lean controls (FASEB J 2: A503,1988). To determine whether this hypertension is associated with impaired Ca efflux and increased vascular r e a c t i v i t y , i n t r a - a r t e r i a l blood pressure was measured in unanaesthetized, unrestrained 10-week old Zucker obese ra ts and their lean controls (n=12) 48 hours af ter cannula-tion. Thoracic aortae were, then removed and segments of each were loaded with ^ C a f o r study of 4^Ca efflux while contrac t i le responses to phenylephrine, KC1 and serotonin were determined in the remaining segments. Blood pressure was markedly elevated in the obese animals (1C4±6 vs 120±6 ma Hg s y s t o l i c , p<0.005; I05±3 vs 88±5 mm Hg d i a s t o l i c , p<0 .05) , while 45r> efflux was significantly delayed and there was a -significant correlation between 45ς α efflux and mean a r t e r i a l pressure r = - 0 . 9 3 , p<0 .01) . Vascular r e a c t i v i t y to a l l three agonists was increased in the obese animals-as indicated by decreases in the ED5Q for each (phenylephrine, p<0.02; KC1, p<0.03; serotonin. p<0.0001) . Furthers there were significant corr elations between aor t i c ^ C a efflux and vascular r e a c t i v i t y to both phenylephrine and serotonin ( r — 0 . 8 7 , p<0 .01) . These data indicate that hypertension in the Zucker obese ra t is assoc ia t ed with an increase in vascular reac t iv i ty which appears to be related to a Ca transport delect characterized by delayed Ci efflux from vascular smooth muscle.

1119 ERYTHROCYTE SODIUM TRANSPORT IN NORMAL PREGNANCY AND PREGNANCY-INDUCED HYPERTENSION. J Kraniak, MB Zemel,* S Berry, Ρ Zemel,* Μ Walsh, R Sokol, JR Sowers.* Wayne State University, Detroi t , MI.

The relationships between erythrocyte intracel lular Na [Na ] i , N a / r ATPase and plasma endoxin was determined in 15 normal black pregnant women and 17 pre-eclamptic blacks of similar gestational age (>35wks) as well as age matched nonpregnant controls. Results were as follows (*denotes p<0.05):

nonpregnant normal pregnant preeclamptic Na^(mM)7.2+0.4 6.0+0.5* 6.δ+υ.6 Na/K -ATPase 34.9+2.1 55.6+6.9* 40.6+4.0 (pmoles/ul/RBC/min) Endoxin ( p g / m p 70+6 352+34* 298+38* Na K -ATPase act iv i ty was elevated and [Na ] i was decreased in the normal pregnant women compared to the non-pregnant controls possibly due to an adaptive response to elevated endoxin. However, these pregnancy-induced alterations were not observed in tlje pre-eclamptic group. Further, [Na ] i was signif icantly correlated with Na/K-ATPase in both non-pregnant (r=-0.85) and pre-eclamptic (r=-0.78) while no correlation was observed in the normal pregnant group. This suggest that other transport systems play an important role in the maintenance of low intracel lu lar Na levels in normal pregnancy, while pre-eclamptics do not appear to exhibit this phenomenon^ This fa i lure to maintain low intracel lular Na levels in pre-eclamptics may contribute to increased vascular react iv i ty .

[1118| PLATELET CALCIUM DOES NOT REFLECT ALTERATIONS IN VASCULAR RESISTANCE IN PREGNANCY. MB Zemel*, S Gangasani, PR Standley, C Kowalczyk, PC Zemel*, MF Walsh, JR Sowers. Wayne State Univ., Detroit,MI

Pla te le t free calcium (Ca + i-) has been reported to r e f l e c t blood pressure elevations in hypertensive individuals, presumably due to a gross similari ty between pla te le ts and vascular smooth muscle c e l l s . However, there are also marked morphological and functional differences that lead to discrepancies in Ca+^handling between the two c e l l types. Consequently, we conducted the present study to determine whether plate le t Ca +^ r e f l e c t s the reduced vascular resistance c h a r a c t e r i s t i c of pregnancy in non-hypertensive individuals by comparing 20 normal black pregnant women (37 .5±0 .6 weeks gestational age) with 10 normal matched non-pregnant black women. Pla te le t Ca+2 w a s measured fluorometrically in fura-2 loaded pla te le ts and forearm blood flow (fbf) anc vascular resistance (fvr) were determined by e l e c t r i c a l impedance plethysmography. Mean a r t e r i a l pressure was comparable between the two groups (84+3 vs 79±3 in the non-pregnant and pregnant women), but fbf was significantly increased in the pregnant group (8 .8±2 .7 vs . 4 .5±0 .4 cc/100 cc/min. p<0 .01 ) , resulting i:i .1 significant decrease in fvr in the pregnant grou^ (10 .1±3 .2 vs 21.0±2.1 mm Hg/[cc/100 cc/min], p<0 .01 ) . In contrast , pla te le t C a + 2 levels were identical between the two proups (59 .9±4.1 vs 61 .3 ±7.0 nM in the pregnant and non-pregnant groups) and there was no correlation between vascular resistance and platele t C a + 2 . Thus, plate le t Ca+2 failed to r e f l e c t the marked decrease in vascular resistance which accompanies r .omal pregnancy.

1120 EFFECTS OF PHORBOL ESTER AND PROTEIN KINASE C (PKC) MODULATION ON ARGININE VASOPRESSIN (AVP)-INDUCED INCREASES IN PLATELET [CA* ] i . PR Standley, R Prakash, MB Zemel*and JR Sowers5; Wayne State University, Detroi t , MI.

The platelet is widely considered to be a good surrogate for vascular?smooth muscle cells (VSMC) for studies of cel l Ca homeostasis in the hypertensive state. Protein kinase C activation has been^reported to inhibi t AVP-induced rises in VSMC [Ca ] i . Accordingly, we have investigated the effects of the phorbol esters TPA and 4 a-TPA and the PKC modulators H-7 ( inhibitor) 2 ajid SC-9 (activator) on AVP-induced platelet Ca transients. Fur-a-2 loaded platelets from healthy donors were treated with 9μΜ AVP after 20 minutes incubation with the above agents in the presence of 1.5 mM [Ca* jo . Mean+S.D. [Ca* ] i responses'are reported as % of pre-AVP baseline: AVP ONLY T P A — — 4 a-TPA SC-9 TTA+H7 275+37 TT7+20* 273+28 T35+9* 110+6* *p <0.0001 compared to 7CVP only (controls)

These data suggest 1) In the p la te le t , phoj^ol ester inhibit ion of AVP-induced rises in [Ca ] i appears to be largely independent of PKC activation as phorbol esters inhibi t these rises considerably more than the specific PKC activator SC-9 and the phorbol ester inhibit ion is not affected by the specific PKC inhibitor H-7. 2) Since phorbol estg£ inhibit ion of AVP-induced rises in VSMC [Ca ] i have been reported to depend on PKC activat ion, the phorbol esters appear to display different mechanisms2jn the inhibit ion of AVP-induced rises in [Ca ] i in the two cell types. Thus there λγρ H m - ? +

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111211 COMPARISON OF SELECTED QUALITY OF LIFE MEASURES IN BLACK AND WHITE UNTREATED HYPERTENSIVES. Zemel PC*-Greene J, Zemel MB*, and Sowers JR' Wayne State Univ., Detroit MI and VA Med. Ctr., Allen Park,MI.

Thirty seven black hypertensives (hpt) completed quality of life interviews, including evaluation of general well being (gwb), physical symptoms (ps) and sexual and sleep dysfunction (dys), 4 weeks after having antihypertensive medications discontinued and receiving single-blind placebo. Data were compared with 162 white hpt who completed the same instruments after a similar placebo period (Croog, NEJM, 1986). Black hpt were older than whites (58±1 vs 47±1 yrs; p^O.001, had less education (12 vs 14 yrs) and were less likely to be employed (43 vs 100%) or married (51 vs 79%). Black hpt had a longer ^duration of disease (11±1 vs 7±0.5 yrs';p<0.001) and had higher mean arterial pressure (118 vs 113 mm Hg;

but were not more obese (91 vs 93 kg). black white

gwb 87.9 ± 1.9* 104 ± 1.1** ps 7.1 ± 1.1 4.9+ 0.4*** sexual dys 8.1 ± 0.6 1.9± 0.3** sleep dys 7.9 ± 0.7 7.5± 0.3 *mean ± sem; ** ρ < 0.001; ***p < 0.05. Data indicate that black untrea selves as having a lower level ported more physical symptoms a of sexual dysfunction than untr with no differences in reported in the two groups. Demographic associated with gwb, suggesting tion of quality of life measure other cohorts may be attenuated and/or cultural variables.

ted hpt rated them-of well being, rend greater levels eated white hpt, sleep dysfunction variables were not that interpreta-

s in blacks and by socioeconomic

1 1 2 3

INCREASED ERYTHROCYTE MAGNESIUM IN UNTREATED ESSENTIAL HYPERTENSION. SE Kjeldsen*, OM Sejersted, Ρ Leren, IK Eide. Dept. of Internal Medicine, Division of Hypertension, University of Michigan Medical Center, Ann Arbor, MI.

Magnesium deficiency in hypertension may be caused by diuret ics . In addition, reduced i n t r a cel lular free-magnesium has been suggested as a primary factor in essential hypertension. In the present study we aimed at evaluating the magnesium balance in a group of particularly well-characterized 50-year old white men with established, never-treated essential hypertension (HT) without signs of organ damage. The normotensive (NT) cont r o l men were a l l recruited from the same populat ion . Atomic absorption was used to measure intra-erythrocyte (i-RBC) magnesium, potassium and sodium.

Weight (kg) Supine BP (mmHg) i-RBC Mg_++ (mmol/1) i-RBC K*/Na + -ratio Serum Mg + + (mmol/1) Urine Mg++ Cmmol/24h)

HT ' (h«12) NT tri=T2T 90±2 87±1

155±4/109±2 128±2/88±1 ## 2.266±0.063 1.903±0.069 ////

3 .67±0.23 4 .45±0.39 # 0.80±0.02 0 .83±0.02 5.19±0.24 5 .ul±0.41

## p<0.001, # ρ<().05' For a l l the subjects, there was a significant positive correlation between i-RBC magnesium and sys to l i c ( r - 0 . 5 7 , p<0.01) and dias to l ic ( r - 0 . 5 1 , p-0.01) blood pressure. In conclusion, the present data support increased rather than decreased i n t r a - c e l l u l a r magnesium in never-treated, essential hypertension, and lend no evidence for a magnesium deficiency to be r a t e -limiting for the a c t i v i t y of the magnesium dependent Na +-K + ATPase in hypertension.

1 1 2 2

INCREASED SODIUM-LITHIUM COUNTERTRANSPORT IN BLACK NON-INSULIN DEPENDENT DIABETICS. BA Bedford Johnson, JR Sowers*, PC Zemel*, FC Luft*, MB Zemel.* Div. of Endocrinology, Wayne State University and VA Medical Center, Detroit, MI.

We have recently reported that black hypertensive diabetics exhibit increased intracellular Ca compared to either non-diabetic hypertensives or normotensives. Because this increase may stimulate Na/H-antiport, and Na/Li countertransport is thought to represent an alternate operational mode of Na/H-antiport, we sought to determine whether black diabetics exhibit elevations in Na/Li countertransport compared to non-diabetics. Erythrocyte Na/Li countertransport was measured in 18 non-diabetic blacks, 13 non-diabetic C a u c a s i a n s and 13 diabetic blacks. Na/Li countertransport was significantly lower in the blacks than in the C a u c a s i a n s

(0.0170+0.018 vs 0.234+0.019 mmol/l/hr, p < 0 . 0 2 ) , but there was no significant difference between black hypertensives (n=10) and normotensives (n=8) (0.173+0.029 vs 0.167+0.022). In contrast, black hypertensive diabetics exhibited a significant increase in Na/Li countertransport compared to non-diabetic blacks regardless of the presence or absence of hypertension in the non-diabetic group (0.246+0.031 vs 0.170+0.018, p<0.02). Thus, to the extent that Na/Li countertransport represents Na/H antiport, these data indicate that the activity of this antiporter is elevated in black diabetics, possibly due to increased intracellular Ca. This elevation may further contribute to the development of hypertension in this population.

1 1 2 4

INCREASED Na -H E X C H A N G E DOES NOT A L T E R pHj IN P L A T E L E T S OF ESSENTIAL HYPERTENSIVES, AB Weder*, Dept. of Internal Medicine, University of Michigan Hospital, Ann Arbor, ML

Sodium-proton ( N a ^ H 4 ) exchange is increased in platelets of human essential hypertensives c o m p a r e d to normotensives. The N a + - H antiporter is an important determinant of intracellular pH (pH:) and of r e sponsiveness to proton loads; increased N a + - H +

exchange could result in al tered basal pHj or sensitivity t o acid loading in pla te le ts of hypertensives. P l a t e l e t pHj (by B C E C F f luorescence) and ac t iv i ty of the N a + - H + ant iporter (as amiloride-sensitive plate le t volume change) were measured in 10 normotensives (NORMO) and 9 u n t r e a t e d hypertensives ( H Y P E R ) .

RESULTS: P l a t e l e t N a + - H + exchange during graded propionic acid loading ( 0 - 1 4 0 m m N a propionate a t p H Q 6.7) showed a c lear threshold for ac t iva t ion ; further increases in Q?r op ion a te ] resulted in progressive act ivat ion of N a + - H + exchange up to the maximum [propionate] t e s t e d (140mM).

N a + - H + exchange Threshold (%)

3 1 . 0 + 2 . 4 4 1 . 5 + 2 . 5

(mM) 2 6 . 5 + 5 . 6 7 . 1 7 8 + . 0 1 3 3 8 . 4 + 5 . 0 7 . 1 9 6 + . 0 3 5

NORMO H Y P E R _ _

ρ .01 .07 .53 M e a n + _ S E

CONCLUSIONS: In pla te le ts of human essential hypertensives compared to normotensives : 1) Na -H exchange is increased, 2) the threshold for propionate act ivat ion of the N a + - H + ant iporter is increased, 3) pHj is not a l tered. These findings demonstra te that increased c a p a c i t y and responsiveness of the Na -H antiporter in p l a t e l e t s of hypertensives does not a l ter basal pHj.

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11126 THE EFFECT OF CHRONIC CHANGES OF DIETARY PROTEIN AND SALT INTAKE ON ATRIAL NATRIURETIC PEPTIDE AND GLOMERULAR FILTRATION RATE IN HEALTHY SUBJECTS CJ D o o r e n b o s * . JA I e s t r a , S P a p a p o u l o s , J O d i n k l and Ρ van B r u m m e l e n * . U n i v e r s i t y H o s p i t a l L e i d e n and 1 TNO CIVO Z e i s t , The N e t h e r l a n d s . We i n v e s t i g a t e d t h e r o l e o f A t r i a l N a t r i u r e t i c P e p t i d e (ANP) and o t h e r hormones i n t h e r e n a l r e s p o n s e t o c h r o n i c changes o f d i e t a r y p r o t e i n and s a l t i n t a k e i n h e a l t h y s u b j e c t s . Us ing a L a t i n Square d e s i g n , 8 s u b j e c t s each consumed 4 i s o c a l o r i c d i e t s f o r 1 week, c o n t a i n i n g 140 mmol NaCl and 1 g p r o t e i n ( B A S ) , 140 mmol NaCl and 2 g p r o t e i n (PROT), 310 mmol NaCl and 1 g p r o t e i n (SALT) o r 310 mmol NaCl and 2 g p r o t e i n p e r kg body w e i g h t pe r day (COMB). Each day 24 h u r i n e was c o l l e c t e d and b l o o d p r e s s u r e and body w e i g h t were m e a s u r e d . On day 6 and 7 o f each d i e t , b l o o d was s a m p l e d . The 24 h sod ium and u rea e x c r e t i o n c o n f i r m e d c o m p l i a n c e w i t h t h e p r o t o c o l . B l o o d p r e s s u r e and body w e i g h t were n o t s i g n i f i c a n t l y a f f e c t e d . Compared w i t h BAS, s i g n i f i c a n t i n c r e a s e s were f o u n d o f t h e GFR measured as c r e a t i n i n e c l e a r a n c e and o f t h e d a y t i m e dopamine e x c r e t i o n on PROT and COMB, and o f p lasma ANP on SALT and COMB. D i e t BAS PROT SALT COMB B l o o d p r e s s u r e 118 /63 1 1 9 / 6 3 119 /62 119 /62 mm Hg Body w e i g h t 7 9 . 3 7 9 . 4 7 9 . 6 7 9 . 9 kg Urea e x c r e t i o n 411 8 6 4 * 388 8 7 2 * mmol /24 h Sodium e x c r e t i o n 139 103 309* 279* mmol /24 h C r e a t C l e a r a n c e 119 1 3 1 * 127 139* m l / m i n Plasma ANP 11 .7 9 . 4 1 7 . 4 * 1 8 . 2 * p g / m l Plasma g l u c a g o n 81 91 76 94 p g / m l Dopamine e x c r e t i o n 64 8 9 * 75 8 6 * n m o l / h Mean o f day 6 and 7, * = ρ < 0 0 5 , compared t o BAS I n h e a l t h y s u b j e c t s t h e e f f e c t o f p r o t e i n may n o t , b u t t h a t o f s a l t on GFR may be m e d i a t e d by ANP. Dopamine and g l u c a g o n may p l a y a r o l e i n t h e r e n a l e f f e c t o f p r o t e i n .

11128 THE T A I M STUDY: CHANGES I N CARDIOVASCULAR R I S K SCORE W I T H TREATMENT OF M I L D H Y P E R T E N S I O N . A . O b e r m a n , B . R . D a v i s , M . D . B l a u f o x * , H . G . L a n g f o r d * , S . S m o l l e r , N . Z i m b a l d i , T . P . B l a s z k o w s k i , J . R o s s e t . U n i v e r s i t y o f A l a b a m a a t B i r m i n g h a m , B i r m i n g h a m , A L

T h e T r i a l o f A n t i h y p e r t e n s i v e I n t e r v e n t i o n s a n d M a n a g e m e n t ( T A I M ) a l l o w e d u s t o a s s e s s 6 m o . c h a n g e s f o r 8 7 8 m i l d h y p e r t e n s i v e s i n c a r d i o v a s c u l a r r i s k s c o r e ( C R S ) u s i n g e i t h e r p l a c e b o o r 25mg C h l o r t h a l i d o n e ( C ) o r 50mg A t e n o l o l ( A ) c o m b i n e d w i t h u s u a l d i e t o r w t . l o s s o r l o w s o d i u m + h i g h p o t a s s i u m d i e t . B a s e l i n e t r a i t s w e r e 56% m a l e s ; 1 4 . 4 % c i g . s m o k e r s ; m e a n b l . p r e s s . 1 4 2 . 1 / 9 3 . 0 mmHg; a n d s e r u m c h o l e s t e r o l 2 3 3 m g / d l . A CRS w a s c o m p i l e d o n 6 2 7 p a t i e n t s u s i n g m u l t i v a r i a t e l o g i s t i c c o e f f i c i e n t s ( F r a m i n g h a m S t u d y ) . O v e r a l l , t h e CRS w a s s i g n i f i c a n t l y h i g h e r f o r t h o s e o n C a l o n e a s o p p o s e d t o t r e a t m e n t g r o u p s i n w h i c h e i t h e r d i e t a r y t r e a t m e n t w a s a d d e d : A n o d d s r a t i o o f < 1 . 0 0 i n d i c a t e s a r e d u c e d r i s k a n d a n o d d s r a t i o > 1 . 0 0 i n d i c a t e s a n i n c r e a s e d r i s k o f c a r d i o v a s c u l a r d i s e a s e . A f t e r 6 m o . , t h e CRS o d d s r a t i o v a r i e d f r o m . 8 5 f o r t h o s e o n w t . l o s s a n d A t o 1 . 0 4 f o r t h o s e o n C a n d u s u a l d i e t . A d d i t i o n o f w t . l o s s t o C r e d u c e d t h e o d d s r a t i o t o . 8 6 . M u l t i p l e r e g r e s s i o n a n a l y s e s r e v e a l e d a g e ( p = . 0 0 0 5 ) ; r a c e ( p = . 0 0 0 7 ) ; w t . l o s s ( p = . 0 0 3 ) a n d A ( p = . 0 0 1 ) i n d e p e n d e n t l y p r e d i c t e d t h e c h a n g e i n CRS a t 6 m o . f o l l o w - u p . I n m a n a g i n g m i l d h y p e r t e n s i o n , t h e c h o i c e o f i n i t i a l t r e a t m e n t ( d i e t a n d d r u g ) s u b s t a n t i a l l y i n f l u e n c e s CRS f o r a 6 m o . p e r i o d o f f o l l o w - u p .

|1127|

ABSENCE OF PROCESSING OF THE ANF PROPEPTIDE AS REVEALED BY AN ANTISERUM AGAINST ANF ( 9 4 - 1 0 3 ) . G T h i b a u l t * , Μ C a n t i n * . L a b o r a t o r y o f P a t h o b i o l o g y , C l i n i c a l R e s e a r c h I n s t i t u t e o f M o n t r e a l , M o n t r e a l , Quebec , Canada.

In o r d e r t o d e t e c t i f t h e pro-ANF was p r o c e s sed i n a t r i a l g r a n u l e s , an a n t i b o d y was deve loped a g a i n s t t h e p u t a t i v e r e g i o n o f m a t u r a t i o n o f pro-ANF. The f r a g m e n t , ANF ( 9 4 - 1 0 3 ) , was c o u p l e d t o b o v i n e serum albumin and i n j e c t e d i n t r a m u s c u l a r l y i n t o a l b i n o r a b b i t s . An a n t i s e r u m was o b t a i n e d which can bind i o d i n a t e d pro-ANF. The t r a c e r c o u l d be d i s p l a c e d with pro-ANF, ANF ( 9 4 - 1 0 3 ) , ANF ( 9 2 - 1 2 6 ) and ANF ( 9 5 - 1 2 6 ) . ANF ( 9 9 - 1 2 6 ) , ANF ( 1 - 9 8 ) and human ANF ( 7 9 - 9 8 ) d e m o n s t r a t e d l e s s than 0.01?ό c r o s s r e a c t i v i t y . T h i s a n t i b o d y was t h e r e f o r e s p e c i f i c t o t h e p u t a t i v e p r o c e s s i n g s i t e o f pro-ANF r e s i d u e s 98 and 9 9 . Western b l o t s o f r a t a t r i a l e x t r a c t s , p r e v i o u s l y s e p a r a t e d by SDS-PAGE, u s i n g t h i s a n t i s e rum g i v e i d e n t i c a l r e s u l t s a s with a n t i s e r a a g a i n s t ANF ( 1 0 1 - 1 2 6 ) or ANF ( 1 1 - 3 7 ) : only two bands o f 17 kDa and 35 kDa were s t a i n e d c o r r e s ponding t o pro-ANF and i t s d i m e r . Immunohis to -c h e m i c a l e x a m i n a t i o n of. t h e a t r i a l c a r d i o c y t e s r e v e a l e d p o s i t i v e r e a c t i o n wi th t h e t h r e e d i f f e r e n t a n t i s e r a . Immunocryoultramicrotomy with t h e a n t i s e r u m a g a i n s t the h i n g e r e g i o n i n d i c a t e s t h a t t h e p r o p e p t i d e t r a v e l s , u n c l e a v e d , from t h e G o l g i complex t o p r o t o g r a n u l e s t o mature s e c r e t o r y g r a n u l e s . These r e s u l t s s t r o n g l y i n d i c a t e t h a t p r o c e s s i n g o f pro-ANF does not o c c u r i n t r a c e l l u l a r l y a t t h e s e s i t e s . F u r t h e r m o r e t h i s a n t i b o d y can bt used t o assay d i r e c t l y pro-ANF i n e x t r a c t s .

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HYPERINSULINEMIA, CATECHOLAMINES, AND LONG-TERM BLOOD PRESSURE REGULATION. JE Hall*. MW Brands, SD Kivlighn, DA Hildebrandt, HL Mizelle, and CA Gaillard. Dept. of Physiology & Biophysics, Univ. Mississippi Medical Ctr . , Jackson, MS

Although hyperinsulinemia and increased adrenergic tone have been postulated to be important e t io logical factors in obesity-associated hypertension, a cause and effec t relationship between insulin (INS), catecholamines, and hypertension has not been established. The aim of this study was to determine whether chronic hyperinsulinemia, comparable to that found in obese hypertensives, increases plasma catecholamines or potentiates the blood pressure effects of norepinephrine (NE). In 6 normal dogs on a 65 meq/day Na intake, INS infusion (1 .0 mU/kg/min) for 7 days (d) , with euglycemia maintained, increased fasting INS 4-6 fold. However, mean a r t e f i a l pressure (MAP) did not increase, averaging 99±2 mmHg during control and 91±3 mmHg during 7 d of INS infusion. INS did not elevate plasma NE or epinephrine, which averaged 171±27 and 71±14 pg/ml, respectively, during control and 188±29 and 45±12 pg/ml during 7 d of INS. In 6 dogs, NE was infused (0 .2 Mg /kg/min) for 7 d to raise plasma NE to 2940±126 pg/ml. However, INS infusion for 7 d did not further increase MAP, which averaged 101±3 during NE and 98±2 mmHg during INS + NE for 7 d. Thus, chronic hyperinsulinemia did not increase MAP or plasma catecholamines and did not potentiate the blood pressure actions of NE. These observations provide no evidence that hyperinsulinemia, or interactions between INS and plasma catecholamines, can account for obesity-associated hypertension.

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1113Q| C H R O N I C L O W D O S E A N F I N F U S I O N C A U S E S H Y P O T E N SION IN S O D I U M D E P L E T E D D O G S . C A Gaillard*. J E Hall*, H L Mizelle, D A Hildebrandt and J P Montani* . Dept . of Physiology and Biophysics, Univ. Mississippi Med. Ctr., Jackson, M S

The aim of the study was to investigate whether A N F , at physiological levels, has long-term effects on control of renal function and mean arterial pressure ( M A P ) in sodium depleted dogs. M A P , sodium excretion ( U N a V ) , glomerular filtration rate ( G F R ) and effective renal plasma flow ( E R P F ) were measured in 4 chronically instrumented conscious dogs on low sodium intake (7 mmol N a / d a y ) . After a 5 day control period ( C ) , A N F was infused iv at a rate of 10 n g / k g / m i n ( A N F 10) for 7 days, followed by 7 days of 20 n g / k g / m i n ( A N F 20 ) , and 7 days of postcontrol ( P C ) measurements .

Although A N F infusion caused no immediate changes in M A P , by the second day of infusion M A P decreased consistently from 91 ± 3 to 84 ± 4 m m H g . No further decrease in M A P was observed during the higher A N F dose. After termination of the A N F infusion M A P gradually returned toward control levels, although full recovery was observed only after 7 days. Sodium excretion increased slightly on the first day of A N F infusion but then fell below control on the following days. No changes in G F R or E R P F were observed throughout the A N F administration.

C ( 5 d ) A N F 1 0 ( 7 d ) A N F 2 0 ( 7 d ) P C (7d) M A P 91±3 85±3 83±2 89±2 U N a V 8.6±3.2 4.6±2.1 4.7±2.7 2.3±1.0 G F R 95±6 90±4 88±7 83±4 E R P F 238±12 238±5 234+15 248±7 Values are means ± sem of each period; d denotes days.

Thus, in sodium restricted dogs, chronic infusion of low doses of A N F , calculated to produce physiological increases in plasma A N F levels, caused sustained reductions in M A P without changes in G F R and E R P F . The data support the notion that A N F may be involved in long-term blood pressure control to a greater extent than predicted from acute experiments.

|1132| EFFICACY OF A SPECIFIC RENIN INHIBITOR IN MILD HYPERTENSION. JM Neutel, I Essinger, RR Luther*, MA Weber*. Hypertension Center, VA Medical Center & Univ. of California, Long Beach, CA.

Seven patients (6 white, 1 black, average age 53yr) with "normal renin" (mean baseline: 2.6 ng/ml/h) hypertension were treated with a specific inhibitor of renin's enzymatic action (Abbott 64662). Patients were f i r s t studied on a moderately r e s t r i c t e d sodium diet , and la ter during thiazide treatment. In this in-hospital study, the drug was given in 4 sequential i . v . doses (at 45 min intervals) a f ter an i n i t i a l stable placebo control . Values shown are decreases in supine dias to l ic BP derived from the averages of a l l 9 readings (each 5 min with a Dinamap monitor) following each dose.

Diet Diuretic

Placebo Baseline

90. 90.

Dose(mg/kg) 0.03 0.1 0.3 3.9 4 .4

6.5 8.7

3.1 10. 12.

The decreases produced by the 3 higher doses were a l l s ignificant (P<0.05 or g r e a t e r ) . Systolic BP decreases also were s ignif icant . The antihypertensive ef fec t persisted for 6 to 8 hr a f ter final dosing. In 3 patients also treated i . v . with the ACE inhibitor enalapril (1 .25 mg), the renin inhibitor was at least as efficacious and i t s effects were more prolonged. There were no adverse events. This early experience suggests that the renin inhibitor (A64662) displays c l i n i c a l l y meaningful antihypertensive efficacy and duration of action.

1 1 3 1

STIMULATION OF RENIN RELEASE AT CONTROLLED LEVELS OF RENAL PERFUSION PRESSURE BY VERAPAMIL IN THE DOG. Η Lin, DB Young*. Dept. of Physiology, Univ. Miss. Med. C t r . , Jackson, Miss.

A reduction in the [Ca] in the juxtaglomerular c e l l s has been proposed by others to be a prominent signal for the secretion of renin. I f this hypothesis is correct then Ca entry blockers should stimulate the release of renin in vivo. In this experiment the effec t of the Ca entry blocker verapamil on renin release was studied in anesthetized dogs in which the level of renal perfusion pressure was controlled by a suprarenal aor t ic constr ic tor . An index of the renin release rate was determined from the difference in PRA measured in the renal venous and a r t e r i a l plasma multiplied by the renal plasma flow. Renal perfusion pressure was reduced in steps of 10 mmHg from 120 to 60 mmHg, ten minutes at each step. Two groups of dogs were studied, a control group (N=7) and a verapamil treated group (N=6). The treated group received verapamil i n i t i a l l y 150 /ig/Kg i . v . followed by continuous infusion at 4 /ig/Kg/min. Renin release from the two gruops was not different at the higher levels of perfusion pressure, although as pressure was reduced renin release rose to significantly higher levels in the verapamil treated group; at the 70 mmHg pressure level the release rate from the treated group was 61±6 U/min/g Kw, approximately two times greater than that of the control group 32.5±8 U/min/g Kw, p<.020. These results demonstrate that calcium entry blockade augments renin release stimulated by reduction of renal perfusion pressure, but does not stimulate release in the absence of other stimuli.(Supported by HL21435 and HL11678).

[11331 NORADRENERGIC HYPERACTIVITY - A CONCOMITANT OF SILENT ISCHEMIA IN HYPERTENSIVES WITH STABLE ANGINA: EFFICACY OF METOPROLOL THERAPY. DP Lee*, V DeQuattro, S Kimura. USC School of Medicine, Los Angeles, CA.

To evaluate the role of the sympathetic nervous system and the efficacy of metoprolol (M) in s i lent ischemia (SI) during daily l i f e , we studied 30 patients , 10 normotensive (N) and 20 hypertensive (H) with stable angina in a double-blind, placebo (P) controlled crossover t r i a l . At the end of each phase, ambulatory blood pressure (ABP), Holter and Q-Med monitoring with an a c t i v i t y diary were performed and blood for norepinephrine (NE) were taken at supine (Su), standing (St) and the f i r s t SI event (E) using a Conned withdrawing pump. SIE were found in 4 and 8 Ν in Ρ and M, respectively. Eleven of 19 Η had SIE in P; of those 11 Η SIE were absent in 7 Η in M. Comparing Ρ, Μ reduced the frequency 13.2 + 7.0 vs . 0 .9 + 0.6/24-hours (p<0.01) and duration 64.7 + 35.9 vs . 13.8 + 9.6 min/24-hour (p<0.02) of SIE in Η. Μ lowered average ABP in both Ν and Η ( p < 0 . 0 1 ) . Average Ε BP was not different from average ABP. Average Ε heart rate (HR) exceeded average HR ( p < 0 . 0 1 ) . NE while St was increased compared to Su. Μ did not reduce NE either Su or St . NE obtained at the time of SIE while patients were lying down or resting without chest pain was higher than their Su NE 417 + 7 5 vs . 301 + 49 ng/L ( p < 0 . 0 5 ) . In conclusion, noradrenergic hyperactivity may play an important role in SI of daily l i f e . Μ is e f fec t ive on reducing SI in H.

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SUBSTAN CE-P (SP) IN R A T R E N A L TISSUE AND E F F E C T S OF SQ 14 ,225 ON T U B U L A R DEGRADATION. H . J . K r a m e r * , C. Walz, A. Backer , H. M e y e r - L e h n e r t * , H.G. Predel* . Med. Poliklinik, University of Bonn, F R G .

SP is a potent diuretic , natr iuret ic , vasodilatory and renin-suppressing undecapeptide which is extensively metabolized in liver and kidney. In the present study we investigated renal distribution and metabolism of SP. In 2 0 Sprague-Dawley ra ts concentrat ions of endogenous SP in renal c o r t e x , medulla and papilla determined by a specif ic RIA were 0 . 5 1 + 0 . 0 3 , 1 . 2 3 + 0 . 1 9 and 3 . 3 3 + Ό . 2 0 pmol/gm wet weight, resp. A similar distribution per gm t i s ^ e was observed a f t e r i.a. adrnjnistration of I-SP. From the total renal I-SP content 8 3 . 2 + 2 . 5 , 11 .2+1 .7 and 5.6+_l.l % were present in c o r t e x , medulla and papilla, resp. Urinary e x c r e t i o n r a t e and renal c l e a r a n c e of SP in 8 control r a t s averaged 11 .6+2 .2 fmol/min/kg and 0 . 3 7 + 0 . 1 7 ml/min/kg, resp. In 8 ra ts p r e t r e a t e d with oral SQ 14 ,225 ( 5 0 mg/kg BW) 3 0 min before the experiments urinary excre t ion and c l e a r a n c e of SP were significantly increased to 2 6 . 6 + 3 . 9 fmol/min/kg and 1 . 2 2 + 0 . 3 6 ml/min/kg, resp. (p < 0 . 0 2 and 0 . 0 5 ) in the absence of significant changes in inulin c l e a r a n c e and urine volume. SQ 14 ,225 had no e f f e c t on plasma SP ( 5 1 . 0 + 1 5 . 4 vs 6 8 . 6 + 1 8 . 3 pmol/1). Although the mechanisms of action of SP in the kidney are not well understood, the high concentra t ion of this vasoac t ive peptide in renal papilla and medulla suggests an e f f e c t on intrarenal blood flow distribution which may contribute to the rise in sodium and f r e e - w a t e r c l e a r a n c e s . Degradation of SP by peptidases c a n be largely inhibited by ACE-inhibitors .

1 1 3 5

R E N A L AND SYSTEMIC E F F E C T S O F INTRANASAL ADMINISTRATION OF HUMAN ATRIAL NATRIURETIC P E P T I D E (a-hANP). INTERACTION WITH 1-deamino-D-Arg-VASOPRESSIN (d-DAVP). Hans-Georg Predel* , P e t e r Kuklinski*, and Herbert J . K r a m e r . * Med. Poliklinik, Univ. of Bonn, W. Germany

The diuretic , nat r iure t ic and vasodilatory properties of i.v. infused a-hANP are well documented. In the present study we investigated the e f f e c t s of an intranasal (i.n.) administration of 25 μg a -hANP on renal e x c r e t o r y function, blood pressure (BP), heart r a t e (HR) and its interact ion with the renal e f f e c t s of 20 μξ d-DAVP in 10 healthy volunteers. The renal and hemodynamic e f f e c t s o c c u r r e d during the initial 30 min and returned to basal values at 6 0 min. Plasma cGMP significantly rose from 5.9+Ό.3 to 6 . 6 + 0 . 4 a f t e r 3 0 min and returned to 5 . 6 + 0 . 3 pmol/ml 60 min a f t e r a-hANP administration. Urine volume increased from 41 + 11 to 384^51 ml and Na and Κ e x c r e t i o n from 5 .1+2 .7 to 1 4 . 8 + 1 . 4 and 3 . 2 + 1 . 3 to 1 5 . 3 + J . 3 mmol per 3 0 min, resp. (p< 0 .05 ) . Systolic and diastolic BP declined by 8% and 7%, resp. , while HR remained unaltered. A f t e r 4 8 h the protocol was repeated with 20 /*g d-DAVP administered i.n. 120 min before 25 /ig a-hANP i.n. A f t e r 120 min d-DAVP alone had reduced diuresis by approx. 7 5 % , while sodium and potassium excre t ion remained unaffec ted . Subsequent administration of a-hANP almost fully res tored diuresis to control values. The data demonst ra te that i.n. administration of a-hANP produces a significant diuresis, natriuresis and kaliuresis. The antidiuretic e f f e c t of d-DAVP is complete ly reversed by a-hANP which suggests that the diuretic e f f e c t of a-hANP is mainly re la ted to an act ion of this peptide at the col lect ing duct.

[11371 ACUTE HYPERINSULINEMIA IS ASSOCIATED WITH DECREASED SODIUM EXCRETION IN OBESE HYPERTENSIVE SUBJECTS. AL Trujillo*, ML Tuck*. Dept. of Endocrinology, Sepulveda VA Medical Center, Sepulveda, CA.

Insulin has been shown to stimulate sodium reabsorption by the kidney which may contribute to increased total body sodium and expanded extracellular fluid volume. By this mechanism, hyperinsulinemia may contribute to the development of hypertension in obese subjects. We studied 21 obese (>20%IBW) subjects: 6 nondiabetic normotensive (NDNT), 5 nondiabetic hypertensive (NDHT), 4 diabetic hypertensive (DMHT) and 6 diabetic normotensive (DMNT). All diabetics were Type II non-insulin requiring. All medications were discontinued two weeks j>rior to study. After water loading (20 ml/kp,) , 75 grams standard oral glucose load was given. Urine was collected every 2 hours during study. The following results were obtained at 120 minutes after glucose ingestion:

T120 Glucose Insulin %Λ 2

mg/dl uU/L UNA MAP NDNT 172112 167134 18±17 -2±2 NDHT 151+9 158133 -46±10** -2±2 DMNT 309±45* 58125* -18±24 -5±2 DMHT 254+23 49±10* -32±10* -1+4 **p<0.01 and *p<0.05 compared to NDNT ±SEM

A comparable decline in MAP occurred in all groups. Compared to NDNT controls, hypertensive obese subjects had a significant decrease in UNa. Both ND groups had insulin levels higher than observed in the diabetic groups. This data suggests that acute hyperinsulinemia increases sodium reabsorption but does not elevate MAP in obese patients .

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[1138 MOLECULAR EVIDENCE OF GENETIC HETEROGENEITY IN WISTAR-KYOTO RATS (WKY): IMPLICATIONS FOR RESEARCH WITH SPONTANEOUSLY HYPERTENSIVE RATS (SHR). TW Kurtz*, Μ Montano, L Chan, L Simonet, Ρ Kabra. Univ. of California, San Francisco, CA.

"WKY" rats, the most commonly employed controls for SHR, have been presumed to constitute an inbred strain. However, recent studies have revealed important biological variability in "WKY" from different commercial sources. To test the hypothesis that commercially available "WKY" rats are genetically heterogeneous, we performed DNA fingerprint analysis on genomic DNA of "WKY" rats from two of the largest vendors in the United States, Taconic Farms (TF) and Charles River Laboratories (CRL). Hinf I or Alu I digested genomic DNA was probed with a 22 base-pair oligonucleotide that detects tandem repetitive "minisatellite" seauences in mammalian DNA. Restriction fragment natterns ("DNA fingerprints") were found to be variable not only between "WKY" rats from the two different breeding facilities, but also between "WKY" rats within one of the facilities (TF). Although some studies have suggested the possibility of biologic variability in SHR from different sources, DNA fingerprint analysis did not reveal molecular evidence of genetic heterogeneity in SHR from these vendors. In demonstrating genetic variability in "WKY" from different sources, the current study provides compelling evidence that rats designated "WKY" do not constitute an inbred strain. Thus, attempts to reproduce studies that comnare SHR to "WKY" might be compromised by genetic heterogeneity in the so-called "WKY" strain.

111401 DISCREPANCY BETWEEN OFFICE BLOOD PRESSURE AND 24-HOUR AMBULATORY BLOOD PRESSURE LEVELS DURING ΑΝΤΙ-HYPERTENSIVE THERAPY. CVS Ram*, W Featherston, RV1 Boldrick, Μ Simmons, NM Kaplan*. UT Southwestern Medical Center, Dallas, TX.

Previous studies revealed that ambulatorv blood pressure (ABP) levels in uncomplicated hypertension tend to be lower than office blood pressure (BP) readings. Therefore, it has been suggested that ABP readings reflect native BP levels. In the present double-blind placebo (P) controlled study, we evaluated the therapeutic response to a new calcium antagonist, nicardipine (N) (60-90 mg/ day) in patients with chronic essential hypertension. Besides office clinical evaluation, patients ' 24 hour ΆΓ,™ vras monitored with autoratic Spacelabs device. The changes between baseline and 6 weeks of TI therapv are shovn·

OFFICE AVERAGE 24 HR BP (N=ll) (P=9) ~ (N=ll) (P=9)

Δ in systolic BP -18±2 -3±6 -9±3 -1±5 Δ in diastolic BP -9±3 -3±4 -4±1 -2±3

N, in contrast to P, produced significant therapeutic response in the office (P<0.01) as well as ABP readings (P<0.01). Although the averaae 24-hour BP levels were less than the office BP readings, these observations suggest that Ν is an effective antihypertensive agent, as estimated from either ABP or office BP readinas.

1141 ANIPAMIL (A) IN THE TREATMENT OF HYPERTENSION: EFFECTS ON BLOOD PRESSURE (BP), LEFT VENTRICULAR (LV) MASS, EJECTION FRACTION (EF), AND INFLUENCE ON THE RACIAL FACTOR. CVS Ram*, RW Boldrick, HI Tjoa, JA Heller, Ρ Sunderajan, NM Kaplan*. UT Southwestern Medical Center, Dallas, TX.

A is a new calcium antagonist belonging to the phenyI-a IkyI amine family. In comparison to verapamil, i t has been noted that A causes less cardio-depression. In the present study, we evaluated the effec ts of A (20-80 mg/day) on BP, LV mass, EF, in 19 blacks and 17 non-blacks with uncomplicated hypertension. The changes between baseline and treatment (8 weeks) are shown: Δ in systol ic BP, mm Hg = -5±1 .6 (P = 0 . 0 0 3 ) , S Δ in diastol ic BP, mm Ηα - -4±1 (P = 0 .0001) , S Δ in LV mass (gms) + SEM = -4±15 (P = 0 . 3 ) , NS Δ in EF {%) = -3 .5±2 (P = 0 . 1 4 ) , NS

Sub-analysis of the results revealed that A exerted similar quantitative antihypertensive effec ts in blacks and non-blacks. Conclusions: 1) A is an effect ive antihypertensive agent with eguipotent ef fec ts in blacks and non-blacks, 2) EF is unchanged by A in patients with normal cardiac function, and 3) A had no effec t on LV mass in our patients without preexisting LV hypertrophy. Regressive changes in LV mass probably occur only in the hypertrophied but not in the normal myocardium.

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SERIAL ASSESSMENT OF LEFT VENTRICULAR (LV) MASS WITH A NEW MYOCARDI0SCI NT I GRAPHIC TECHNIQUE: INFLUENCE OF ANTIHYPERTENSIVE THERAPY UTILIZING AN ALPHA ANTAGONIST. CVS Ram*, DG Gonzalez, Ρ Kulkarni, J Corbett, NM Kaplan*. Univ. of Texas Southwestern Medical Center, Dallas, TX.

Although echocardiography is widely used to measure the LV dimensions, i t may not delineate the true cardiac anatomy. In the present study, we utilized an entirely new technique - | 1 2 3

phenyIpentadecanoic acid (IPPA) myocardioscinti-graphy - to estimate the LV mass in 20 patients with severe hypertension receiving prazosin (P) , an alpha-antagonist. Ρ was given in incremental doses as needed to lower the dias tol ic blood pressure (DBP) to <90 mm Hg. The therapy was maintained for 16 weeks. In addition to routine cl inical parameters, LV mass was estimated at weeks 4 and 16 by single photon tomographic scintigraphy with IPPA. After the injection of IPPA, the cardiac imaging was performed with a Technicare Omega 500S tomographic camera. The results are shown:

BASELINE WEEK 4 WEEK 16 BP, mm Hg 174±5 166±4 162±5

104±6 99±2 97±2 Septal Thick- 1.35±0.5 1 . 3 U 0 . 5 1.28±0.5

ness, cm Poster Wall Thick- 1.27±0.5 1.27±0.4 1.25±0.5

ness, cm Relative LV mass, 1339±76 1312172 1260±66

voxe I s We conclude that LV mass can be estimated with

IPPA myocardioscintigraphy and that Ρ causes significant regression of LV mass in patients with severe hypertension.

1144 CAPTOPRIL-STIMULATED RENOGRAPHY VS RENAL VEIN RENINS (RVR's) IN TWO-KIDNEY, TWO-CLIP (2K,2C) HYPERTENSION. LA Bedoya. JV Nally*, C Park, NT Stowe. Cleveland Clinic, Cleveland, OH

Debate exists over the renin-dependency of individual kidney function and the concomitant hypertension in bilateral renal artery stenosis (bRAS). Prior studies suggest captopril (C) lowers mean arterial pressure (MAP), reduces kidney function and alters the renogram of the stenotic kidney in a 2K.1C model. We examined MAP, C I N , C p A H , RVR's and renography with Tc-99-DTPA and I-131-Hippuran of each kidney in a canine model of 2K,2C hypertension (n=9) before and after C (1.5 mg/kg bolus and 1.5 mg/min infusion).

Two days after the creation of bRAS (40-60% and 50-80% reduction), the elevation of MAP was significantly lowered (148+7 vs 119+10 mmHg, p<.002) after C. C also reduced total GFR (p<.005) with reductions in both the more stenotic (MS) kidney (13.9+4.1 vs 5.4+2.2 ml/min, p=.01) and less stenotic (LS) (24.6+3.8 vs 18.6+3.1 ml/min, p<.06). Baseline and stimulated RVR's correlated inversely with ipsilateral C I N , C p A H , Hippuran uptake and cross-sectional area of the arterial lumen. C enhanced the RVR ratio (MS/LS) from 3.4 to 4.7 and the diagnostic sensitivity for both the Tc-DTPA and 1-131 Hippuran renograms in all dogs studied. The changes in Tc-DTPA uptake of each kidney after C correlated with the reductions in C I N «.005).

Captopril renography may be a suitable noninvasive tool to complement, or supplant, invasive RVR's as an index of renal perfusion and function in 2K,2C hypertension.

UI43J

ATRIAL NATRIURETIC FACTOR (ANF) PROTECTS THE LUNG FROM ALBUMIN ESCAPE AT PHARMACOLOGIC BUT NOT PATHOPHYSIOLOGIC DOSES. R.S. Zimmerman, A . J . M a r t i n e z , A.A. MacPhee, R.W. Barbee and RTC. Tr ippodo. D i v i s i o n of Research, Al ton Ochsner Med. Found., New Or leans , LA 7 0 1 2 1 .

I t i s wel l es tab l i shed t h a t exogenous administ r a t i o n of ANF causes ex t ravasa t ion of plasma and albumin. The present study determined t o t a l body and organ s p e c i f i c albumin escape ra tes a f t e r ve h i c l e , 25 , 100 and 500 ng/kg/min ANF in fus ion f o r 2 hrs by measurement of ^-^5j_a-j bumi η and 5 1 -chromium l a b e l l e d e ry throcy tes in splenectomized, nephrectomized, anes the t i zed r a t s . A f t e r ANF i n f u s i o n , r a t s (n=32) were f rozen in l i q u i d n i t r o gen. Organs were d issected whi le s t i l l f rozen and r a d i o a c t i v i t i e s measured. Tota l albumin escape (TAE) , hear t ( H T ) , lung (LG) , l i v e r ( L R ) , sp lanchnic ( G l ) , muscle (ML) and skin (SN) albumin e s cape ra tes were determined. ( *p<0.05 vs . c o n t r o l ) ANF ng/kg/min VEH 25 100 500 TAE %/hr 8 . 1 + 0 . 6 9 .2+0 .4 1 2 . 6 + 0 . 5 * 1 8 . 3 + 0 . 7 * HT %/hr 0 . 4 + 0 . 1 0 . 3 + 0 . 1 0 . 6 + 0 . 1 0 .48+0 .02 LG %/hr 1 .0+0 .1 1 .0+0 .1 1 . 8 + 0 . 2 * 1 . 0+0 .1 LR %/hr 1 .5+0 .3 2 . 2 + 0 . 8 2 . 6 + 0 . 3 * 2 . 4 + 0 . 2 * Gl %/hr 6 . 6 + 0 . 5 6 . 1 + 0 . 1 9 . 1 + 0 . 6 * 1 0 . 4 + 0 . 3 * ML %/hr 1 .2+0 .1 1 .5+0 .1 1 . 6 + 0 . 1 * 1 . 9 + 0 . 2 * SN %/hr 0 .4+0 .03 0 .4+0 .05 0 . 5 + 0 . 0 5 * 0 . 8 + 0 . 1 * ANF pg/ml 114+38 287+102 628+168* 7687+508*

This study demonstrates t h a t ANF increases TAE a t pathophysiologic and pharmacologic doses and t h e r e f o r e may c o n t r i b u t e to edema in high ANF s t a t e s such as congest ive hear t f a i l u r e (CHF). At pharmacologic doses ANF pro tec ts the lung from albumin escape, suggesting a possib le r o l e f o r ANF in the t reatment of pulmonary edema s t a t e s such as CHF.

1145 WORKSITE CHARACTERISTICS PREDICT BLOOD PRESSURE DIFFERENCES IN LARGE SCREENED WORKING POPULATIONS YR Schlussel? Ρ Schnall, Μ Zimbler, Κ Warren, TG Pickering*. Cardiovascular Center, Cornell Medical Center, NY, NY,

We analyzed the prevalence of hypertension (HBP) (average diastolic blood pressure>DBP 90mm Hg) at 7 worksites as a precursor to identifying subjects for a case-control study. The average of the 2nd and 3rd readings were evaluated af ter screening 4221 employees (2568 men, 1653 women) including newspaper typographers (n=277), federal health (n=648), 'stock brokerage (n=1005), beverage d i s t i l l i n g (n=1131), hospital (n=285), sanitation department (n=625) and warehouse (n=259) workers. The prevalence of HBP across worksites was highest among male typographers (29%;p<.0001) Sex and age adjusted rates were highest among male brokerage workers over 50 (34%;n=59). Using ANOVA models to simultaneously control for physical and demographic variables, 34% of the variation in systolic pressure (SP) was predicted significantly by 7 variables. After adjusting for upper arm circumference, age and BMI, dif fer ences between brokerage vs beverage companies (8.7mm), males and females (7.5mm), grade school vs college (3.6mm), and single vs married (2.2mm) joint ly increased SP by 22 mmHg. Similar results for DBP suggest that researchers should consider previously underexplored charac ter is t i cs ( e . g . worksite and occupation) as additional components in predicting blood pressure differences in working populations.

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SOURCES OF I N T E R I N D I V I D U A L V A R I A T I O N I N RED CELL N a - L i COUNTERTRANSPORT ( C N T ) I N THE GENERAL P O P U L A T I O N . S . T . T u r n e r * , B . A . K o t t k e , W . H . W e i d m a n , V . V . M i c h e l s , C F . S i n g . M a y o F o u n d a t i o n , R o c h e s t e r , M N , U n i v e r s i t y o f M i c h i g a n , A n n A r b o r .

I n c a s e - c o n t r o l s t u d i e s , C a u c a s i a n s w i t h e s s e n t i a l h y p e r t e n s i o n ( H T ) h a v e h i g h e r CNT t h a n n o r m o t e n s i v e s ( N T ) , b u t p r e d i c t o r s o f CNT h a v e n o t b e e n e s t a b l i s h e d i n t h e g e n e r a l p o p u l a t i o n . We s t u d i e d s o u r c e s o f CNT v a r i a t i o n i n 1 2 8 0 C a u c a s i a n s ( 5 9 7 m a l e s ; 6 8 3 f e m a l e s ) , 2 0 - 9 0 y e a r s o l d , i d e n t i f i e d t h r o u g h h o u s e h o l d s w i t h c h i l d r e n i n R o c h e s t e r , M N , s c h o o l s . M e a n ( ± S D ) CNT ( m m o l / L R B C / h ) w a s g r e a t e r i n m a l e s t h a n f e m a l e s ( 3 2 7 ± 1 1 9 v s . 2 8 6 + 1 0 8 , ρ < . 0 0 1 ) . V a r i a t i o n i n b o d y w e i g h t , p l a s m a t r i g l y c e r i d e ( T G ) , H D L - c h o l e s t e r o l ( H D L - C ) , a n d a p o l i p o p r o t e i n Α Ι ( Α Ρ 0 Α Ι ) a c c o u n t e d f o r 1 0 . 4 % o f CNT v a r i a t i o n i n m a l e s l ( p < . 0 0 1 ) a n d 1 8 . 8 % i n f e m a l e s ( p < . 0 0 1 ) . A f t e r a d j u s t i n g f o r v a r i a t i o n i n w e i g h t , H D L - C , a n d ΑΡ0 A l , s i g n i f i c a n t e f f e c t s o f TG t e r t i l e ( p < . 0 0 1 ) a s w e l l a s b l o o d p r e s s u r e ( B P ) d i a g n o s i s ( p < . 0 0 1 ) w e r e o b s e r v e d o n CNT ( m e a n / ± S D / n ) :

TG M a l e s F e m a l e s T e r t i l e NT HT NT HT

1 s t 2 8 8 3 3 8 2 5 4 2 9 5 + 9 1 + 8 0 + 7 5 + 1 0 5 1 7 2 19 1 6 5 2 5

3 r d 3 4 4 4 0 0 3 0 9 3 4 9 + 1 1 4 + 1 6 0 + 1 2 4 + 1 0 7

1 2 2 1 0 0 1 5 0 4 3 I n c r e a s e i n CNT b e t w e e n 1 s t a n d 3 r d t e r t i l e s o f

TG d i s t r i b u t i o n w a s c o m p a r a b l e t o t h a t b e t w e e n NT a n d HT g r o u p s . T h u s , i n t h e g e n e r a l p o p u l a t i o n TG l e v e l a s w e l l a s BP d i a g n o s i s a n d g e n d e r c o n t r i b u t e t o p r e d i c t i o n o f CNT d i f f e r e n c e s .

1 1 4 8

A T R I A L N A T R I U R E T I C FACTOR ATTENUATES ADENOSINE M E D I A T E D REDUCTIONS I N RENAL HEMODYNAMICS. J . P. L o f t u s , M. R e d f i e l d , W. M i l l e r , a n d J . C . B u r n e t t , J r . , M a y o C l i n i c , R o c h e s t e r , M i n n e s o t a .

T u b u l o g l o m e r u l a r f e e d b a c k ( T G F ) i s a n i n t r a r e n a l a u t o r e g u l a t o r y p h e n o m e n o n w h i c h may b e a c t i v a t e d b y i n c r e a s e d s o l u t e d e l i v e r y t o t h e m a c u l a d e n s a . T h e i n t r a r e n a l p r o d u c t i o n o f a d e n o s i n e ( A D ) d u r i n g TGF a c t i v a t i o n h a s b e e n i m p l i c a t e d a s a m e d i a t o r o f TGF t o d e c r e a s e r e n a l b l o o d f l o w ( R B F ) , t h u s r e g u l a t i n g GFR. We h a v e p r e v i o u s l y r e p o r t e d t h a t a t r i a l n a t r i u r e t i c f a c t o r ( A N F ) may a t t e n u a t e TGF m e d i a t e d d e c r e a s e s i n r e n a l b l o o d f l o w a n d g l o m e r u l a r f i l t r a t i o n r a t e . We t h e r e f o r e h y p o t h e s i z e d t h a t ANF may a t t e n u a t e r e d u c t i o n s i n r e n a l b l o o d f l o w a n d GFR i n r e s p o n s e t o i n t r a r e n a l A D . AD ( 0 . 1 μπ ιο ΐ /m in , i r ) w a s i n f u s e d i n t h e p r e s e n c e o r a b s e n c e o f i n t r a r e n a l ANF ( 0 . 1 ^ g / k g / m i n ) i n 12 a n e s t h e t i z e d d o g s . T h e a b s o l u t e r e s p o n s e s i n RBF a n d GFR a r e a s f o l l o w s :

AD AD+ANF A R B F , m l / m i n - 5 4 . 5 ± 3 . 6 - 3 . 7 ± 3 . 1 A G F R , m l / m i n - 9 . 0 ± 3 . 0 - 0 . 4 ± 2 . 0 *

* p < . 0 5 AD v s AD+ANF

T h e p r e s e n t s t u d i e s d e m o n s t r a t e t h a t ANF b l o c k s i n t r a r e n a l a d e n o s i n e - m e d i a t e d r e d u c t i o n i n r e n a l b l o o d f l o w a n d g l o m e r u l a r f i l t r a t i o n r a t e . T h e s e s t u d i e s may e x p l a i n t h e m e c h a n i s m b y w h i c h ANF a t t e n u a t e s T G F - m e d i a t e d d e c r e a s e s i n r e n a l h e m o d y n a m i c f u n c t i o n .

1 1 4 7

E N D O T H E L I N - I N D U C E D V A S O C O N S T R I C T I O N AND CATECHOLAMINE RELEASE ARE ATTENUATED BY ^ N I T R O G L Y C E R I N ( N T G ) I N V I V O . W. L . M i l l e r , P . G . C a v e r o , L . A a r h u s , D . M. H e u b l e i n , a n d J . C . B u r n e t t , J r . , M a y o C l i n i c , R o c h e s t e r , MN

E n d o t h e l i n ( E T ) , m a y f u n c t i o n p a t h o l o g i c a l l y b y a n t a g o n i z i n g t h e v a s o d i l a t i n g a c t i o n s o f e n d o t h e l i u m - d e r i v e d r e l a x i n g f a c t o r s ( E D R F ) a n d a c t i v a t i n g o t h e r v a s o c o n s t r i c t o r s . A s NTG i n h i b i t s v a s c u l a r s m o o t h m u s c l e b y i n c r e a s i n g cGMP a s d o e s E D R F , we t e s t e d t h e h y p o t h e s i s t h a t NTG ( 5 μ g / k g / m i n , i v ) w o u l d a n t a g o n i z e v a s c u l a r a c t i o n s b y ET ( 5 n g / k g / m i n , i v ) i n t h e a n e s t h e t i z e d d o g . ( M e a n + S E M , p < . 0 5 c o m p a r e d t o c o n t r o l , n = 6 )

C o n t r o l NTG E n d o t h e l i n l h p o s t -i n f u s i o n

M A P , 1 2 0 ± 1 0 1 3 6 ± 1 J 1 2 1 ± 8 mmHg 1 1 6 ± 4 1 0 5 ± 5 1 0 5 + 6 1 1 6 + 7

CO, 2 . 5 ± . 2 1 . 6 + . 1 * 1 . 8 ± . 2 * 1 / m i n 3 . 4 ± . 4 2 . 8 ± . 2 2 . 5 ± . £ 2 . 4 ± . 2

C B F , 5 1 ± 5 3 9 ± 5 4 3 ± 8 m l / m i n 6 3 ± 9 5 6 ± 7 6 4 ± 1 2 5 7 ± 1 0

R B F , 2 2 8 ± 2 0 1 1 3 + 1 1 1 6 7 + 1 8 m l / m i n 2 0 9 ± 1 7 1 9 2 ± 2 0 1 1 8 + 1 7 * 1 2 9 ± 2 4 \

N o r e p i , 9 4 ± 2 4 1 5 0 ± 5 4 2 9 7 + 1 2 1 p g / m l 9 5 ± 2 4 2 0 5 ± 2 4 1 5 7 ± 3 7 1 4 6 ± 3 4 Λ

E p i , 4 9 ± 2 1 1 0 9 ± 5 8 3 2 1 ± 2 0 4 p g / m l 3 8 ± 2 4 2 2 6 ± 1 8 1 7 5 ± 4 1 4 4 ± 2 6

We c o n c l u d e t h a t ET h a s p o t e n t s y s t e m i c , c o r o n a r y , a n d r e n a l v a s o c o n s t r i c t o r a c t i v i t y a n d s t i m u l a t e s c a t e c h o l a m i n e r e l e a s e i n v i v o . T h e s e s t u d i e s a l s o d e m o n s t r a t e t h a t NTG w a s m o s t e f f e c t i v e i n a n t a g o n i z i n g E T - m e d i a t e d c o r o n a r y a s c o m p a r e d t o r e n a l v a s o c o n s t r i c t i o n a n d a l s o a t t e n u a t e s p o s t - i n f u s i o n i n c r e a s e s i n p l a s m a c a t h e c h o l a m i n e s .

1 1 4 9

R E L A T I O N S H I P BETWEEN PLASMA E N D O T H E L I N AND A T R I A L N A T R I U R E T I C FACTOR I N HUMANS W I T H CONGESTIVE HEART F A I L U R E . D . M . H e u b l e i n , R. J . R o d e h e f f e r , P. G . C a v e r o , W. L . M i l l e r , Β. ξ . E d w a r d s , Μ. M. R e d f i e l d , a n d J . C . B u r n e t t , J r . , M a y o C l i n i c , R o c h e s t e r , MN

T h e p r e s e n t s t u d y w a s d e s i g n e d t o d e t e r m i n e i f t h e p o t e n t v a s o c o n s t r i c t o r p e p t i d e , e n d o t h e l i n ( E T ) , i s d e t e c t a b l e i n h u m a n p l a s m a a n d i s i n c r e a s e d i n c h r o n i c c o n g e s t i v e h e a r t f a i l u r e ( C H F ) , a s y n d r o m e c h a r a c t e r i z e d b y a c t i v a t i o n o f v a s o c o n s t r i c t o r s y s t e m s w i t h i n c r e a s e d s y s t e m i c v a s c u l a r r e s i s t a n c e . A s e c o n d o b j e c t i v e w a s t o d e t e r m i n e t h e r e l a t i o n s h i p b e t w e e n p l a s m a ET a n d a t r i a l n a t r i u r e t i c f a c t o r ( A N F ) i n t h e p r e s e n c e a n d a b s e n c e o f c h r o n i c C H F , r e c o g n i z i n g t h a t ET i n v i t r o may b e a p o t e n t s t i m u l u s f o r ANF r e l e a s e . P l a s m a ET w a s d e t e r m i n e d b y a s e n s i t i v e r a d i o i m m u n o a s s a y e m p l o y i n g a p o l y c l o n a l a n t i b o d y t o p o r c i n e ET ( P e n i n s u l a L a b s ) . P l a s m a w a s e x t r a c t e d w i t h C8 B o n d - E l u t c a r t r i d g e s . S e n s i t i v i t y w a s 0 . 5 p g / m l . I n t e r a s s a y v a r i a b i l i t y w a s 9% a n d i n t r a a s s a y v a r i a b i l i t y 2 . 5 % . P l a s m a ANF w a s m e a s u r e d f r o m e x t r a c t e d p l a s m a a s p r e v i o u s l y d e s c r i b e d .

p < 0 . 0 5 c o m p a r e d t o n o r m a l s .

P l a s m a E T , p g / m l P l a s m a A N F , p g / m l

N o r m a l s CHF

2 . 4 ± 0 . 3 1 . 2 + 0 . 2

( n = 7 5 ) ( n = 3 0 )

2 6 . 3 ± 1 . 3 1 8 0 . 5 + 3 0 . 2

( n = 6 7 ) ( n = 3 0 )

T h e p r e s e n t s t u d y d e m o n s t r a t e s t h a t p l a s m a ET i s d e t e c t a b l e i n p l a s m a o f n o r m a l h u m a n s a n d i n C H F . I n c o n t r a s t t o A N F , w h i c h i s i n c r e a s e d i n C H F , p l a s m a ET i s n o t i n c r e a s e d .

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INCREASES I N PLASMA A T R I A L N A T R I U R E T I C FACTOR BY ENDOTHEL IN I N V I V O MAY BE HEMODYNAMICALLY M E D I A T E D . L . L . A a r h u s . W. L . M i l l e r , P . G . C a v e r o , D . M. H e u b l e i n , a n d J . C . B u r n e t t , J r . * , M a y o C l i n i c , R o c h e s t e r , MN

R e c e n t i n v e s t i g a t i o n s i n v i t r o h a v e r e p o r t e d t h a t e n d o t h e l i n ( E T ) may s t i m u l a t e r e l e a s e o f a t r i a l n a t r i u r e t i c f a c t o r ( A N F ) f r o m i s o l a t e d a t r i a l m y o c y t e s . T h e p r e s e n t s t u d y w a s d e s i g n e d t o d e t e r m i n e t h e r e l a t i o n s h i p b e t w e e n p l a s m a ET a n d p l a s m a ANF d u r i n g a d m i n i s t r a t i o n o f ET i n a n e s t h e t i z e d d o g s . A t r i a l p r e s s u r e s w e r e s i m u l t a n e o u l s y m e a s u r e d .

D o s e o f ET ( n g / k g / m i n ) C o n t r o l 5 0

( R ) A P , mmHg 3 . 0 ± 1 . 0 2 . 0 ± 1 . 0 3 . 5 + 1 . 2 ( L ) A P , mmHg 3 . 4 ± 0 . 7 4 . 1 + 1 . 1 9 . 1 + 3 . 5 * P l a s m a E T , p g / m l 1 . 9 + 0 . 6 9 . 8 ± 2 . 3 * 3 0 6 . 7 ± 2 2 . 9 * P l a s m a A N F , p g / m l 7 0 + 1 9 6 6 ± 1 9 1 8 1 + 5 3 *

p < . 0 5 t o c o n t r o l

T h e s e s t u d i e s d e m o n s t r a t e t h a t i n c r e m e n t s i n p l a s m a ET p r o d u c e d b y a d m i n i s t r a t i o n o f s y n t h e t i c ET d o e s n o t r e s u l t i n p a r a l l e l i n c r e a s e s i n p l a s m a A N F . R a t h e r , p l a s m a ANF m o r e c l o s e l y p a r a l l e l s E T - m e d i a t e d i n c r e a s e s i n a t r i a l p r e s s u r e s u p p o r t i n g t h e i n t e r p r e t a t i o n t h a t E T -m e d i a t e d i n c r e a s e s i n ANF i n v i v o m a y b e h e m o d y n a m i c a l l y m e d i a t e d .

111521 ACUTE CONGESTIVE HEART F A I L U R E RESULTS I N A S E L E C T I V E A T T E N U A T I O N OF E N D O T H E L I N - M E D I A T E D VASOCONSTRICT ION I N THE K I D N E Y . P . G . C a v e r o , W. L . M i l l e r , L . \.. A a r h u s , D . M. H e u b l e i n , a n d J . C . B u r n e t t , J r . , M a y o C l i n i c , R o c h e s t e r , MN

R e c e n t s t u d i e s h a v e r e p o r t e d a l t e r e d v a s c u l a r r e a c t i v i t y i n c o n g e s t i v e h e a r t f a i l u r e , a s y n d r o m e c h a r a c t e r i z e d b y e l e v a t e d a t r i a l n a t r i u r e t i c f a c t o r ( A N F ) a n d v a s o c o n s t r i c t o r h o r m o n e s . We h a v e r e p o r t e d t h a t e n d o t h e l i n ( E T ) p r e f e r e n t i a l l y v a s o c o n s t r i c t s t h e r e n a l c i r c u l a t i o n . T h e p r e s e n t s t u d y w a s d e s i g n e d t o d e t e r m i n e i n a n e s t h e t i z e d d o g s ( c o n t r o l n = 7 a n d CHF n = 5 ) i f a c u t e CHF p r o d u c e d b y r a p i d r i g h t v e n t r i c u l a r p a c i n g r e s u l t s i n 1 ) i n c r e a s e s i n e n d o g e n o u s ET l e v e l s a n d / o r 2 ) a l t e r e d r e n a l v a s c u l a r r e s p o n s i v e n e s s t o i n f u s e d ET ( 5 n g / k g / m i n ) . D u r i n g ET i n f u s i o n , r e s p o n s e s i n m e a n a r t e r i a l p r e s s u r e ( + 1 1 . 4 + 4 . 7 v s + 5 . 0 + 0 . 6 % ) , s y s t e m i c v a s c u l a r r e s i s t a n c e ( + 6 3 . 2 + 1 3 . 7 v s + 5 1 . 4 + 5 . 6 % ) a n d c a r d i a c o u t p u t ( - 3 3 . 8 + 1 4 . 5 v s 2 9 . 8 + 3 . 3 % ) w e r e s i m i l a r i n c o n t r o l a n d a c u t e CHF g r o u p s . I n c o n t r a s t , E T - m e d i a t e d d e c r e a s e s i n r e n a l b l o o d f l o w ( - 4 4 . 2 + 4 . 6 v s - 2 4 . 6 ± 5 . 1 % , p < . 0 5 ) a n d i n c r e a s e s i n r e n a l v a s c u l a r r e s i s t a n c e ( + 1 4 2 + 2 0 . 0 v s + 4 2 . 4 + 9 . 8 % , p < . 0 5 ) w e r e m a r k e d l y a t t e n u a t e d i n C H F . D e s p i t e t h i s d i f f e r e n t i a l r e n a l v a s c u l a r r e s p o n s e , e n d o g e n o u s ET w a s n o t i n c r e a s e d i n CHF ( 3 . 3 6 ± 1 . 4 t o 2 . 9 + 1 . 5 5 p g / m l ) i n c o n t r a s t t o p l a s m a ANF ( 2 8 + 5 t o 2 8 8 + 4 9 p g / m l , p < . 0 5 ) . T h e p r e s e n t s t u d y d e m o n s t r a t e s t h a t a c u t e CHF d o e s n o t s t i m u l a t e i n c r e a s e s i n p l a s m a ET b u t r e s u l t s i n a s e l e c t i v e a t t e n u a t i o n o f t h e r e n a l v a s o c o n s t r i c t o r r e s p o n s e t o e x o g e n o u s e n d o t h e l i n .

111511 F A I L U R E OF A T R I A L N A T R I U R E T I C FACTOR TO INCREASE WITH VOLUME EXPANSION I N ACUTE AND CHRONIC CONGESTIVE HEART F A I L U R f I N THE DOG. Μ. M . R e d f i e l d , B . ^ S . E d w a r d s , M. D . M c G o o n , a n d J . C . B u r n e t t , J r . , M a y o C l i n i c , R o c h e s t e r , MN

T h e p r e s e n t s t u d y w a s d e s i g n e d t o t e s t t h e h y p o t h e s i s t h a t c h r o n i c c o n g e s t i v e h e a r t f a i l u r e ( C H F ) i s c h a r a c t e r i z e d b y a n a t t e n u a t e d a b i l i t y t o i n c r e a s e c i r c u l a t i n g a t r i a l n a t r i u r e t i c f a c t o r ( A N F ) i n r e s p o n s e t o f u r t h e r i n c r e a s e s i n a t r i a l p r e s s u r e ( A t P ) . C a r d i a c h e m o d y n a m i c s a n d p l a s m a ANF w e r e m e a s u r e d a t b a s e l i n e a n d d u r i n g a c u t e a n d c h r o n i c C H F . A c u t e s a l i n e v o l u m e e x p a n s i o n ( V E ) w a s p e r f o r m e d t o d e t e r m i n e ANF d u r i n g f u r t h e r i n c r e a s e s i n A t P . R a p i d r i g h t v e n t r i c u l a r p a c i n g ( R R V P ) w a s u s e d t o p r o d u c e a c u t e ( n = 1 0 , 2 5 m i n s RRVP) a n d c h r o n i c ( n = 7 , 1 4 -16 d a y s RRVP) C H F . * = p < . 0 5 CHF v s b a s e l i n e , ϊ = ρ < . 0 5 VE i n CHF v s CHF

B a s e l i n e CHF VE i n CHF RAP ACUTE 0 . 1 ± . 4 3 . 4 ± 1 . J * 1 2 . 1 ± . 7 f

(mmHg) CHRONIC 1 . 3 + . 4 8 . 5 ± . 9 1 3 . 3 ± 1 . 0 !

PCWP ACUTE 2 . 4 ± . 8 1 5 . 8 ± 1 . 8 2 5 . 9 ± 1 . 6 t

(mmHg) CHRONIC 3 . 9 + . 7 1 7 . 6 ± 1 . § * 2 2 . 2 ± 1 . 3 f

ANF ACUTE 3 5 ± 5 5 0 0 ± 8 9 4 5 3 ± 7 9 ( p g / m l ) C H R 0 N I C 3 7 ± 8 3 8 5 ± 7 3 * 3 7 9 ± 9 5

I n c h r o n i c CHF c i r c u l a t i n g ANF w a s n o t i n c r e a s e d c o m p a r e d t o a c u t e CHF d e s p i t e h i g h e r R A P . I n a c u t e a n d c h r o n i c C H F , a c u t e i n c r e a s e s i n A t P d u e t o VE p r o d u c e d n o f u r t h e r i n c r e a s e i n A N F . T h e p r e s e n t s t u d y d e m o n s t r a t e s t h e f o l l o w i n g : 1 ) m a x i m a l r e l e a s e o f ANF i n a c u t e a n d c h r o n i c CHF w i t h n o f u r t h e r i n c r e a s e i n ANF i n r e s p o n s e t o a c u t e i n c r e a s e s i n A t P a n d 2 ) a n a t t e n u a t e d s t i m u l u s - r e l e a s e r e l a t i o n s h i p i n c h r o n i c CHF b e t w e e n A t P a n d A N F .

U l 5 3 |

S Y N E R G I S T I C A C T I O N OF A T R I A L N A T R I U R E T I C FACTOR AND FUROSEMIDE I N ACUTE CONGESTIVE HEART F A I L U R E . D . L . F e t t , P . G . C a v e r o , L . L . A a r h u s , D . M. H e u b l e i n , a n d J . C . B u r n e t t , J r . , M a y o C l i n i c , R o c h e s t e r , MN

F u r o s e m i d e ( F U R ) i s a p o t e n t n a t r i u r e t i c a g e n t e m p l o y e d i n c o n g e s t i v e h e a r t f a i l u r e ( C H F ) . FUR m a y , h o w e v e r , i n c r e a s e p l a s m a r e n i n a c t i v i t y ( P R A ) a n d a l d o s t e r o n e ( A L D O ) , a n d r e c e n t s t u d i e s h a v e r e p o r t e d t h a t FUR may d e c r e a s e e n d o g e n o u s a t r i a l n a t r i u r e t i c f a c t o r ( A N F ) . T h e p r e s e n t s t u d y w a s d e s i g n e d t o d e t e r m i n e t h e a c t i o n o f FUR o n r e n a l a n d e n d o c r i n e f u n c t i o n i n a m o d e l o f a c u t e CHF p r o d u c e d b y 3 h r s o f r a p i d r i g h t v e n t r i c u l a r p a c i n g i n t h e a n e s t h e t i z e d d o g . FUR ( 1 . 7 m g / k g , i . v . b o l u s ) w a s a d m i n i s t e r e d 1 h r a f t e r t h e o n s e t o f a c u t e CHF w i t h ( n = 6 ) o r w i t h o u t ( n = 6 ) c o n t i n u o u s i n f u s i o n o f ANF i n i t i a t e d w i t h FUR. I n a c u t e CHF a t 2 h r s a f t e r FUR, p l a s m a ANF d e c r e a s e d ( 3 7 6 ± 3 6 t o 2 1 1 ± 4 4 p g / m l , p < . 0 5 ) , GFR d e c r e a s e d ( 3 6 . 1 + 4 . 7 t o 2 1 . 1 + 1 . 5 m l / m i n , p < . 0 5 ) , ALDO i n c r e a s e d ( 1 6 . 2 + 2 . 4 t o 3 3 . 1 + 6 . 5 n g / d l , p < . 0 5 ) , a n d PRA w a s u n c h a n g e d . W i t h ANF ( 2 0 n g / k g / m i n , i . v . ) , p l a s m a ANF i n c r e a s e d ( 3 2 1 + 5 5 t o 4 7 3 ± 5 3 p g / m l , p < . 0 5 ) . RBF d e c r e a s e d ( 2 5 0 + 2 8 t o 1 5 1 ± 2 3 m l / m i n , p < . 0 5 ) , b u t GFR w a s u n c h a n g e d ( 2 8 . 9 + 6 . 8 t o 3 3 . 2 ± 4 . 8 m l / m i n , p < . 0 5 ) ; n o s i g n i f i c a n t i n c r e a s e i n ALDO o r PRA o c c u r r e d . U r i n a r y s o d i u m e x c r e t i o n w i t h FUR w a s m a r k e d l y p o t e n t i a t e d b y ANF a t 1 h r ( 1 8 2 + 5 4 v s 4 4 0 + 8 8 / x E q / m i n , p < . 0 5 ) , a n d a t 2 h r s ( 7 2 ± 1 3 v s 1 8 0 + 5 3 / i E q / m i n , p < . 0 5 ) . T h e s e s t u d i e s d e m o n s t r a t e t h a t i n a c u t e CHF w i t h F U R , p l a s m a ANF d e c r e a s e s a s GFR a n d RBF d e c r e a s e a n d ALDO i s a c t i v a t e d . I n t h e p r e s e n c e o f F U R , a d m i n i s t r a t i o n o f ANF i n a c u t e CHF m a i n t a i n s G F R , p r e v e n t s a c t i v a t i o n o f ALDO a n d p o t e n t i a t e s n a t r i u r e s i s .

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IN VIVO EVIDENCE THAT HUMAN ANF STIMULATES PARASYMPATHETIC ACTIVITY IN HUMANS. S Zeuzem, HG O l b r i c h , J A l t , Ε Jungmann. D e p t . o f M e d i c i n e , J W - G o e t h e - U n i v e r s i t y , F r a n k f u r t am Main, West-Germany.

P r e v i o u s s t u d i e s i n r a t s s u g g e s t e d t h a t a t r i a l n a t r i u r e t i c f a c t o r (ANF) has s t i m u l a t i n g e f f e c t s on c a r d i a c - s e n s o r y r e c e p t o r s wi th v a g a l a f f e r e n t s . A r e l i a b l e and n o n - i n v a s i v e method t o a s s e s s p a r a s y m p a t h e t i c i n n e r v a t i o n o f t h e h e a r t i n humans i s t h e measurement o f t h e b e a t -t o - b e a t v a r i a t i o n i n h e a r t r a t e . I n t h i s s tudy e i g h t h e a l t h y male s u b j e c t s (age 2 4 . 9 +_ 0 . 5 y e a r s ) were s t u d i e d t w i c e on d i f f e r e n t d a y s , r e c e i v i n g 100 ug human A N F - ( 9 9 - 1 2 6 ) ( B i s s e n d o r f P e p t i d e , FRG) and NaCl (0 .9%) i n t r a v e n o u s l y i n random o r d e r . Blood p r e s s u r e , h e a r t r a t e and t h e b e a t - t o - b e a t v a r i a t i o n were a s s e s s e d . hANF d e c r e a s e d d i a s t o l i c b lood p r e s s u r e ( 6 9 . 4 +_ 2 . 3 mmHg v s . 7 5 . 6 +_ 3 . 3 mmHg) i n t h e f i r s t minute a f t e r b o l u s i n j e c t i o n , w h i l e no d i f f e r e n c e was o b s e r v e d i n s y s t o l i c b lood p r e s s u r e . Hear t r a t e was i n c r e a s e d by hANF from 6 1 . 9 +_ 3 . 9 t o 7 0 . 9 _+ 3 . 8 min ( p < 0 . 0 1 ) . F o l l o w i n g hANF i n j e c t i o n , an i n c r e a s e i n t h e b e a t - t o - b e a t v a r i a t i o n was o b s e r v e d , d e s p i t e t h e f a c t t h a t p h y s i o l o g i c a l l y t h e b e a t - t o - b e a t v a r i a t i o n d e c r e a s e s w i t h i n c r e a s i n g h e a r t r a t e . The maximum e f f e c t was noted i n t h e f i r s t minute a f t e r i n j e c t i o n ( 4 . 6 5 _+ 0 . 4 9 v s . 5 . 9 5 +_ 0 . 7 8 , p < 0 . 0 1 ) . In c o n c l u s i o n , we o b t a i n e d i n v i v o e v i d e n c e t h a t hANF s t i m u l a t e s p a r a s y m p a t h e t i c a c t i v i t y i n humans.

[11561 THE ROLE OF ATRIAL NATRIURETIC PEPTIDE (ANP) IN THE ABNORMAL DIURNAL SODIUM RHYTHM IN ESSENTIAL HYPERTENSION (EH). WMT janssen . D de Zeeuw, GK van der Hera, PE de Jong. Univ. Hosp. Groningen, The Netherlands.

In EH urinary sodium excretion (UNaV) has a diurnal rhythm with a maximum 3 hours ear l ie r than in normotensives, whereas rhythms of mean a r t e r i a l pressure (MAP) and potassium excretion (UKV) are normal. ANP may play a role in the abnormal renal sodium handling in EH. We therefore studied the effect of a 5-day 0.2 /ig/min ANP infusion on these rhythms as well as on the rhythms of chloride and calcium excretion and plasma ANP (pANP) using the cosinor-method in 6 patients with EH. They were 6 weeks without medication, kept bedrest during 3 equilibration, 3 control , 5 ANP-infusion, and 3 recovery days, and adhered to a rhythm diet with equal amounts of fluid, sodium,and potassium every 4 hours. During control a l l parameters, except pANP, had significant rhythms: the rhythms of UNaV and UChlV were abnormal, and the rhythms of UKV and MAP were normal, as expected. However, during ANP a time-shift towards normal was found in UNaV and UChlV rhythms in a l l EH. In contrast , UKV and MAP rhythms were not affected by ANP. Table shows hours of maximum values (*=p<0.05 vs. control ) . Maximum ± s .d. (h) control ANP recovery Sodium 11.9+2.8 14 .6±1 .4* 10.9±2.7 Potassium 12.1±1 .5 12 .4±1.4 11.4+1.7 Chloride 11 .5±2 .4 13 .311 .7* 11 .0±2 .3 Calcium 8.8±1,5 10 .5±1 .6* 10 .2±2 .4 MAP 16.3±1.2 16 .4±1.8 15 .8±1 .1 Individual shif ts in UNaV correlated (p<0.05) with pANP during ANP infusion.Since diurnal rhythms are complex, these data suggest a fundamental role for ANP in the abnormal renal sodium handling in EH.

1 1 5 5

CHRONIC (5 DAY) INFUSION OF ATRIAL NATRIURETIC PEPTIDE (AgP) IN ESSENTIAL HYPERTENSION (EH). WMT janssen . D de Zeeuw, GK van der Hem, PE de Jong . Univ. Hosp. Groningen, The Netherlands.

To date only relat ive short-term ANP infusions have been studied in man, showing at high dose nat r iure t ic as well as depressor e f f e c t s , and at low dose only natr iuret ic e f f e c t s . We therefore studied the effects of a 5 day very low dose (0.2/ig/min) ANP infusion on mean a r t e r i a l pressure (MAP), sodium balance (NaB), GFR and ERPF in 6 patients with EH in metabolic ward conditions. They were without medication for 6 weeks, in balance on a 150 mmol/day sodium intake, and kept bedrest during 3 equilibration, 3 control, 5 ANP-infusion, and 3 recovery days. MAP and pulse were measured every 15 min; ANP, NaB, GFR, and ERPF every 4 hours (h) . Table shows the 24h mean ± sem.

control ANP 1st 5th-day recovery ANP (pg/ml) 35±6 81111 73+3 3518 MAP (mmHg) 104±3 101+3 92+2 9814 Pulse (bpm) 64±4 6914 7214 6714 NaB (mmol) 0±10 -70+11 -72+15 -3152 GFR (ml/min) 90±3 - 89+2 87+2 ERPF(ml/min) 335116 - 321+7 345115 ANP caused an immediate r ise in sodium excretion,

levelling af ter 24h (range NaB: -32 to -139 mmol). MAP only started to f a l l af ter 12h to level off af ter 40h. The f a l l in MAP was 10.911.0% ( 7 . 7 - 1 3 . 8 %). Plasma ANP levels and NaB recovered to baseline within 24h, whereas MAP slowly returned towards baseline values over 3 days. The data show that in EH chronic low dose ANP infusion causes a negative sodium balance followed by a slower decrease in blood pressure with a new equilibrium af ter about 2 days. Thus, ANP-like substances may become usefull antihypertensive drugs.

1 1 5 7

LABETALOL VS. HYDROCHLOROTHIAZIDE IN HYPERTENSIVE BLACK PATIENTS, C. Lucas.* P. Jenkins, J . Mendels, D.Due,* B. Forbes, M. Sirgo,* Detroit,MI

The safety and efficacy of labetalol (L) and Hydrochlorothiazide (H) were compared in a group of 61 black mild to moderate hypertensives. After a 4 wk placebo run in, patients (pts) entered a 12 week active phase and were t i t r a t e d to either H(25-50mg BID) or L (100-400mg BID) biweekly to a standing dias tol ic blood pressure (SDBP) <90mmHg. The standing systol ic blood pressure (SSBP), SDBP, and heart rate (HR) mean +_ sem results are :

BASELINE TREATMENT Η (N-31) L (N-30) Η (N-28) L (N-25)

SSBP 156+2.8 150+.3.8 135+.2.6* 139+5.1* SDBP 105+.1.1 103+.1.1 95+1.3* 94+.2. 1* HR(BPM) 79+2.1 81+.2.0 79+_2.8 80+.2.2 *(p < .05 from baseline; no significant differences between active treatments)

A to ta l of 18/31 pts (58%) were controlled on a mean daily dose of 70± 12.2 mg of Η vs . 19/30 pts (63%) on 575 ± 88.1 mg of L.

Drug related adverse events consisted of impotence (2pts) decreased libido, edema and dizziness on H; dizziness, nausea and fatigue on L.

Η caused significant (p < .05 ) increases from baseline in cholesterol , t r ig lycer ides , BUN, creatinine, uric acid, and a s ignificant decrease in potassium. There were no significant laboratory abnormalities with L.

These results indicate that L and Η were equally effect ive in reducing BP in hypertensive blacks. L was better tolerated vs . H; with no reports of impotence or abnormal biochemical changes.

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S T U D I E S ON THE MECHANISM OF NEUROPEPTIDE Y I N DUCED P O T E N T I A T I O N OF NEUROGENIC V A S O C O N S T R I C T I O N . JG D u e s l e r , J r 1 , J P H i e b l e 2 a n d RN D a l y 1 * 2 . i D r e x e l U n i v . D e p t . o f B i o s c i e n c e , 2 S m i t h K l i n e & F r e n c h L a b s , D e p t . o f P h a r m a c o l o g y , P h i l a d e l p h i a , P A .

N e u r o p e p t i d e Y ( N P Y ) i s c o - l o c a l i z e d a n d c o -r e l e a s e d w i t h n o r e p i n e p h r i n e i n s y m p a t h e t i c n e u r o n s . T h i s p e p t i d e h a s b e e n s h o w n t o p o t e n t i a t e t h e r e s p o n s e o f t h e i s o l a t e d r a b b i t e a r a r t e r y t o f i e l d s t i m u l a t i o n , p r o v i d e d t h a t t h e v a s c u l a r e n d o t h e l i u m i s i n t a c t ( D a l y a n d H i e b l e , E u r o p . J . P h a r m . 1 3 8 : 4 4 5 ) . O u r c u r r e n t e f f o r t i s d i r e c t e d t o w a r d t h e e l u c i d a t i o n o f t h e m e c h a n i s m b y w h i c h NPY p r o d u c e s t h i s p o t e n t i a t i o n . T h e r e s p o n s e o f t h e p e r f u s e d r a b b i t e a r a r t e r y t o b r i e f i n t e r m i t t e n t f i e l d s t i m u l a t i o n ( 1 0 - 1 5 H z , 0 . 5 s e c ) w a s s i g n i f i c a n t l y e n h a n c e d b y NPY ( 1 0 0 n M ) ( c o n t r o l = 2 2 + 4 m m H g , t r e a t e d = 3 6 + 5 mm H g ) . S e v e r a l e n d o t h e l i u m d e p e n d e n t c o n t r a c t i l e r e s p o n s e s a p p e a r t o b e m e d i a t e d b y a n a r a c h a d o n i c a c i d m e t a b o l i t e ( e . g . t h r o m b o x a n e A2). I n c o n t r a s t , a d m i n i s t r a t i o n o f i n d o m e t h a c i n ( 3 0 uM) t o i n h i b i t c y c l o o x y g e n a s e d i d n o t a f f e c t t h e a b i l i t y o f NPY t o p o t e n t i a t e n e u r o g e n i c v a s o c o n s t r i c t i o n . I n v o l v e m e n t o f e x t r a c e l l u l a r c a l c i u m w a s t e s t e d b y t h e u s e o f n i f e d i p i n e . B l o c k a d e o f c a l c i u m c h a n n e l s w i t h t h i s a g e n t ( 1 uM) d i d n o t p r o d u c e a s u b s t a n t i a l a t t e n u a t i o n o f t h e NPY e f f e c t . O u r s t u d i e s t h e r e f o r e s u g g e s t t h a t n e i t h e r a n a r a c h a d o n i c a c i d m e t a b o l i t e n o r t r a n s l o c a t i o n o f e x t r a c e l l u l a r c a l c i u m i s i n v o l v e d i n NPY i n d u c e d p o t e n t i a t i o n o f t h e r e s p o n s e o f t h e r a b b i t e a r a r t e r y t o s y m p a t h e t i c f i e l d s t i m u l a t i o n .

[ 1 1 6 0

NEW PATHWAYS FOR R E N I N P R O D U C T I O N : F U R T H E R EVIDENCE FOR A RENAL PRORENIN " C O N V E R T A S E " . R . I s m a i l , L . M a v r o g i a n n i s , D . H . O s m o n d * , D e p t . o f P h y s i o l o g y , U n i v . o f T o r o n t o , T o r o n t o , C a n a d a .

R e n a l r e l e a s e o f a c t i v e r e n i n i s w e l l r e c o g n i z e d . R e c e n t l y , s y s t e m i c p r o d u c t i o n o f r e n i n f r o m c i r c u l a t i n g p r o r e n i n o f r e n a l o r e x t r a r e n a l o r i g i n b y a n u n k n o w n a c t i v a t o r h a s a l s o b e e n s u g g e s t e d . We h a v e p r o p o s e d a n u n i d e n t i f i e d r e n a l e n z y m e o r " c o n v e r t a s e " w h i c h i s a p p a r e n t l y a b l e t o p r o d u c e n e w r e n i n f r o m c i r c u l a t i n g p r o r e n i n . I n t h i s s t u d y , we u s e d a w e l l - c o n t r o l l e d a s s a y s y s t e m c o n t a i n i n g e x t r a r e n a l p r o r e n i n f r o m n e p h r e c t o m i z e d r a t p l a s m a a n d i n c u b a t e s f r o m r a t r e n a l c o r t i c a l s l i c e s . E n o u g h " c o n v e r t a s e " w a s r e l e a s e d i n t o t h e s e i n c u b a t e s i n 3 0 m i n a t 3 7 ° C , pH 7 . 4 , t o a c t i v a t e a l m o s t a l l t h e p r o r e n i n i n t h e a s s a y s y s t e m . We t h e r e f o r e c o n s t r u c t e d a " d o s e - r e s p o n s e c u r v e " u s i n g l o w t o h i g h v o l u m e s o f i n c u b a t e m i x e d w i t h t h e p r o r e n i n p r e p a r a t i o n a n d f o u n d t h a t a c t i v a t i o n d e p e n d e d o n e n z y m e c o n c e n t r a t i o n . S u c h a c t i v a t i o n w a s i n h i b i t e d b y t h e p r o t e a s e i n h i b i t o r s L B T I a n d S B T I a t 3 0 m g / m l b u t n o t a t 7 . 5 o r 1 5 m g / m l . N - e t h y l m a l e i m i d e ( 1 0 mM) , b e n z a m i d i n e ( 5 0 mM) a n d t r a s y l o l ( 6 6 6 o r 1 3 3 3 K l U / m l ) w e r e i n e f f e c t i v e i n h i b i t o r s . " C o n v e r t a s e " a c t i v i t y w a s d e t e c t e d i n a n i s o e l e c t r i c f o c u s i n g s y s t e m w i t h i n pH 4 . 8 - 5 . 4 . We c o n c l u d e t h a t r e n a l s l i c e s r e l e a s e d l a r g e a m o u n t s o f " c o n v e r t a s e ( s ) " c a p a b l e o f r a p i d l y a c t i v a t i n g e x t r a r e n a l p r o r e n i n i n p l a s m a i n a c o n c e n t r a t i o n - d e p e n d e n t m a n n e r . " C o n v e r t a s e " d o e s n o t a p p e a r t o b e a p l a s m a o r g l a n d u l a r k a l l i k r e i n , o r c a t h e p s i n Β o r D .

1 1 5 9

ENALAPRIL VS. LABETALOL AS MONOTHERAPY IN HYPERTENSION BLACK PATIENTS, J . Robinson. J . Wallin,* L. Watkins, W. Flamenbaum,* D. Due,* M. Sirgo,* Tulane Medical Center, New Orleans, LA

The safety and efficacy of enalapril (E) and labetalol (L) were compared in 67 black patients with mild to moderate hypertension(HTN). After a 4 week placebo run-in, patients entered a 12 week active phase and were t i t r a t e d on Ε (5-40mg qd) or L (100-400mg bd) biweekly to blood pressure control (standing dias to l ic blood pressure [DBP] <90mmHg). The standing systol ic blood pressure (SBP), DBP and heart rate (HR) mean + sem are:

BASELINE TREATMENT

Ε L Ε L Ν 36 31 32 27 SBP(mmHg) 149+.1.9 151+.3.2 137+.2.8* 139+.3.6* DBP (mmHg) 1 0 2 1 1 . 0 103+.1.0 93±1.8* 94+.2.0* HR(bpm) 81+.1.7 79+.2.0 82+_2.3 77+.1.9 *(p<0.05 from baseline; no significant changes between active treatments)

Eighteen of 36 (50%) Ε and 17 of 31 (55%) L patients reached BP control at mean daily doses of 13 + 2.6mg and 482 + 54.4 mg, respectively. Ε patients did not appear to benefit from increasing doses (5/18-27% controlled at doses>10mg/day) vs . L(9/17-53% controlled at doses >400mg/day).

Both Ε and L were well tolerated. Drug related adverse events consisted of headache, pressure in chest and pedal edema on E; headache, dizziness and nausea on L.

These results indicate that both Ε and L were effect ive as monotherapy in approximately 50% of black patients with HTN. I t appears that additional BP control can be obtained by increasing doses of L but less so with E.

|1161|

REGULATION OF NEW PATHWAYS FOR RENIN PRODUCTION. P . I o a n n o u , R . I s m a i l , D . H . O s m o n d * , D e p t . o f P h y s i o l o g y , U n i v . o f T o r o n t o , T o r o n t o , C a n a d a .

S y s t e m i c r e n i n p r o d u c t i o n f r o m r e n a l o r e x t r a r e n a l p r o r e n i n w o u l d r e q u i r e a n e n d o g e n o u s a c t i v a t i n g m e c h a n i s m o r " c o n v e r t a s e " i n o r d e r t o b e p h y s i o l o g i c a l l y r e l e v a n t . We h a v e p r o p o s e d s u c h a r e n a l " c o n v e r t a s e " a n d s u g g e s t e d t h a t t h i s m e c h a n i s m c o u l d b e c o - r e g u l a t e d w i t h r e n i n r e l e a s e b y t h e k i d n e y . S i n c e r e n i n r e l e a s e i s i n h i b i t e d b y a n g i o t e n s i n ( A n g ) I I a n d s t i m u l a t e d b y p r o s t a g l a n d i n s ( P G s ) we p o s t u l a t e d t h a t a n y r e n a l " c o n v e r t a s e " s h o u l d a l s o b e r e g u l a t e d b y t h e s e a g e n t s . U s i n g a w e l l - d e f i n e d r a t r e n a l c o r t i c a l s l i c e p r e p a r a t i o n we d e m o n s t r a t e d m a j o r r e l e a s e o f p r o r e n i n " c o n v e r t a s e " a n d s i g n i f i c a n t n e g a t i v e f e e d - b a c k i n h i b i t i o n o f i t b y Ang I I ( 2 u M ) . I n c u b a t e s f r o m r a t s p l e e n s l i c e s a n d a o r t i c s t r i p s d i d n o t e x h i b i t a n y " c o n v e r t a s e " a c t i v i t y . PGE2 a n d P G I 2 , b o t h a t 2 u g / m l , a s w e l l a s t h e i r m e t a b o l i c p r e c u r s o r a r a c h i d o n i c a c i d ( A A , 2 5 u g / m l ) i n t h e s l i c e i n c u b a t i o n m e d i u m , a l l s t i m u l a t e d r e n i n r e l e a s e d u r i n g 3 0 m i n o f i n c u b a t i o n a t 3 7 ° C . H o w e v e r , o n l y P G E 2 s t i m u l a t e d b o t h r e n i n a n d " c o n v e r t a s e " r e l e a s e w h i l e AA a n d i t s m a j o r m e t a b o l i t e i n t h e r e n a l c o r t e x , P G I 2 , s t i m u l a t e d r e n i n o n l y . I t a p p e a r s t h a t P G E 2 i s t h e i m p o r t a n t PG f o r r e g u l a t i n g b o t h r e n i n a n d " c o n v e r t a s e " r e l e a s e , a n d i t i s n o t c l e a r why P G I ~ d i d n o t c o - r e g u l a t e i n a c o m p a r a b l e f a s h i o n .

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ISOELECTRIC HETEROGENEITY OF HUMAN PRORENIN IN BODY FLUIDS. Ν. Khalidi, I. McKenzie, J. McKenzie* Departments of Medicine and Pharmacology, University of Manitoba, Winnipeg, Canada

Using initial flat-bed isoelectric focusing (IEF), the patterns of peaks for prorenin were determined after trypsin activation. As seen in the table, normal human plasma showed six reproducible peaks similar in pH to those of ovarian follicular fluid and amniotic fluid, but different from fetal (cord) blood, mean pH (SEM)

Normal Follicular Amniotic Cord Peak Plasma(6)* Fluid(5) Fluid(5) Plasma(S)

I 4.98(.03) + 4 9K.02) 5 00 (.02) II

III IV V

VI

5.14(.02) 5.29(.01) 5.47C.01) 5.63(.01) 5 . 9 K.02)

5 5 5 5 5

16(.02) 36(.01) 5K.01) 70(.02) 93(.01)

5 5 5 5

16(.01) 30(.01) " 49(.01) " 69(.03)J

-5.24( -5.40( -5.53( -5.83( ο

ο ο

ο

•k = number of samples + = mean pH (SEM) Peak heights were different also, with

amniotic fluid showing large peaks at positions I,II,III, normal plasma at IV,V, follicular fluid at III,IV, and cord blood at peak 5.40. Prorenin in anephric plasma, pleural fluid and lymphocele fluid were not different from normal plasma in pH nor activity of their peaks.

Fetal and amniotic fluid prorenins are distinguishable by IEF from other prorenins. Fetal prorenin appears not to gain access to the maternal circulation, while amniotic fluid prorenin may not enter either fetal or maternal circulations. Prorenins from ovary, normal plasma, anephric plasma, or other tissue fluids are not distinguishable by IEF.

|1164|

COMPARISON OF EFFECTS ON OFFICE, HOME, AMBULATORY BLOOD PRESSURE BETWEEN NIFEDIPINE SR AND ENALAPRIL, Τ Ashida-"-, Η Abe", Y Kawano", Κ Yoshida, G Kimura" , S Kojima, Μ Kuramochi, Τ Omae. Dep. of Medicine, National Cardiovascular Center, Osaka, Japan.

We examined the effects of nifedipine slow release tablet(N) and enalapril(E) on office, home and ambulatory blood pressure (OBP, HBP, ABP, respectively). After the control period of 2-3 months, Ν 20 mg/day b.i.d. was administered to 20 patients with essential hypertension(EH) (aged 54+ 3 years), and Ε 5-10 mg/day b.i.d. to 21 EH (aged 54+2 years), each for 2-3 months. Sleep ABP(SBP), awake ABP (NSBP), OBP and HBP were measured before and after the treatment. Patients were classified into 2 groups: Patients whose observed systolic ABP was below the level predicted from the regression line between systolic ABP and systolic OBP were designated "low" ABP group. Others were designated "high" ABP group. OBP were 165+3/98+2 mmHg in "high"ABP and 164+3/98+2 mmHg in "low" ABP. ABP were 151+2/89+1 mmHg in "high" ABP and 130+2/76+1 mmHg in "low" ABP(p<0.001). There was no significant difference in OBP or HBP decrease by Ν or Ε between "high" and "low" ABP. Ν decreased NSBP in "high" ABP(14+3/l4+2%) more than in "low" ABP(5+1/ 5+2%)(p<0.01). There was no significant difference in NSBP decrease by Ε between "high" (8+2/10+2%) and "low" ABP(7+2/9+3%). Ν decreased SBP in "high" ABP (11+2/11+2%) more than in "low" ABP (3+2/3+2%) (p<0.01). There was no significant difference in SBP decrease by Ε between "high" (11+3/12+3%) and "low" ABP (8+2/10+2%). In "low" ABP, Ε decreased diastolic SBP more than Ν (p<0.05). These results suggest that compared with Ν, Ε has a possibility of overtreatment to patients with EH whose ABP are relatively low.

1 1 6 3

REGULATION OF ALDOSTERONE BIOSYNTHESIS IN TREATED PRIMARY ALDOSTERONISM Β Winterberg Η Stiebler , W Tenschert, G Winterberg, KG Dorst, Η Vetter* Medical P o l i c l i n i c , University of Muenster; Medical Pol i c l in ic , University of Bonn, F. R. G.

The regulation of aldosterone biosynthesis has been studied in three groups of patients : in unilateral ly adrenalectomized patients ( Conn syndrome, n=13) and in 10 patients with primary aldosteronism treated with a 3- β - dehydrogenase inhibitor ( t r i l o s t a n e ) . In a l l patients and in 12 healthy volunteers plasma renin a c t i v i t y (PRA), plasma aldosterone (PA) and plasma Cortisol (PC) has been determined in recumbant position ( 8 . 0 0 ) , under active orthostasis and af ter ACTH-infusion. In the control group there was an equivalent influence of ACTH and angiotensin II on aldosterone biosynthesis; in contrast , in a l l patients-groups ACTH was a better stimulator of aldosterone biosynthesis than angiotensin I I .

postop. t r i l o s t a n Control pat. pat.

ΔΡΑ (0RTH.) 89+18 68+ 16 83+31 pg/ml ΔΡΑ (ACTH) 103+34 237+140 337+70 pg/ml

In adrenalectomized patients (Conn syndr.) there was a parallel r ise of PC and PA under active orthostasis , which can be suggested as an ACTH-induced r i s e . As a result of long-term renin suppression in untreated primary aldosteronism the zona gomerulosa seems to get less sensitive for angiotensin I I . The balance between the two stimulators of hormone biosynthesis of the adrenal cortex is altered in favor of ACTH; this remains established even in treated patients (adrenalectomy, t r i lostane treatment) with normalized plasma aldosterone.

1 1 6 5

A VALIDATION STUDY OF THE SPACELABS 90207 AMBULATORY BLOOD PRESSURE MONITOR. EM Cates, YR Schlussel, GD James-, TG Pickering-, Cardiovascular Center, Cornell Medical Center, NY, NY.

The purpose of this study was to assess the accuracy of the Spacelabs' third generation 90207 (S7) blood pressure monitor. A total of 52 subjects were studied (31 hypertensives, 21 normals). Ten readings were taken per subject. Machine measurements were compared to simultaneous auscultatory readings taken by two observers (01 and 02 ) . Accuracy was assessed by examining the differences among 01, 02, and S7 using analysis of variance and regression models.

Systolic(SP) Diastolic(DP)

01 vs 02 -0.6+3.6 .99 81 S7 vs 01 1.0+5.7 .98 70 S7 vs 02 0.4+5.9 .98 69 S7 vs 03° 0.7+5.4 .99 70

0.5+4.8 .95 74 2.0+5.6 .93 72 2.5+5.9 .92 67 2.2+5.2 .94 71

a-regression slope, b-% readings within 5mmHg, c- (01+02) /2

The results show that the monitor tended to slightly overestimate diastolic pressure while systolic pressures were, on average, quite similar to the observers. Compared to i t s predecessor (Spacelabs 90202), the S7 is at least as accurate and re l iable . However, the S7 has new features such as lower noise output and size reduction which are likely to improve patient compatibility and compliance.

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PARADOXICAL INCREASED GLUCOHEPTONATE UPTAKE IN EXPERIMENTAL RENOVASCULAR HYPERTENSION. HB Lee. Β Gale, MD Blaufox*, Albert Einstein College of Medicine, Bronx, N.Y.

99m-Tc glucoheptonate (Tc GHA) accumulation was studied in an experimental model of renovascular hypertension (two kidneys,one renal artery clamped). Two groups of rats were evaluated based on the function of the clamped kidney CIK): I) mild function reduction (ERPF >0.6 ml/min/IOOg Bwt), and 2) severe function reduction (ERPF <0.6 ml/min/IOOg). Tc GHA uptake per g of kidney was measured with captopril administration (1.7 mg/IOOg Bwt) and without captopril administration. ERPF was measured pre and, in animals receiving captopril, post captopril. 50 uCi (0.1 ml) Tc GHA was injected following the ERPF study. The kidneys were removed 3-5 min after Tc GHA administration. After captopril the rats (η = II) with CIK ERPF >0.6, had a higher Tc GHA uptake (6.9%.+0.5 S.E.) in the CIK than in the normal kidney (NK) (4.9%+0.2, ρ <0.003). The rats (n = 7) with initial CIK ERPF <0.6 had a lower Tc GHA uptake in the CIK (l.5%+0.3) than in the NK (4.5%+0.9 (p <0.002). Tc GHA uptake between >0.6 ml/min/IOOg and <0.6 ml/min/IOOg groups after captopril treatment was significantly different in the CIK (p <0.005). In the NK the Tc GHA uptake was not significantly different. Tc GHA uptake between no captopril and captopril treated groups was significantly different both in the CIK (p <0.0025) and NK (p <0.0005) when the initial ERPF was <0.6. In the animals with mildly impaired renal function (>0.6 ml/min/IOOg), the Tc GHA uptake increased paradoxically after captopril treatment. With severely depressed renal function (<0.6 ml/min/IOOg) Tc GHA uptake decreased as was expected.

|11681 EFFECT OF CANOLA OIL ADDENDUM UPON BLOOD PRESSURE & SERUM LIPIDS IN HUMANS. Μ .L. Bierenbaum*, W.P. M a g i n n i s , T.R. W a t k m s and R.P. Reichstein. Jordan Research G r o u p , M o n L c l a i r , NJ.

Recent work has been done using fish oil supplements as an anti1ipemic, p l a t e let anti-aggregant and antihypertensive. Several shortcomings of this approach have led to the search for terrestrial sources of omega 3 fatty acids able to produce similar effects. Attempting to evaluate possible effects upon blood pressure (BP) and blood lipids (L) , 22 n o r m o t e n s i v e , hyperlipemias were fed a daily supplement (30 %) of CANOLA oil along with their self-selected diets. The oil contained ( w t . % ) : o l e a t e , 6 2 ; linoleate, 2 2 ; & ex. - l i n o l e n a t e , 10. After a four-week b a s e line period, subjects included the oil with m e a l s . Preliminary RBC acyl data indicated that oil was consumed a p p r o p r i ately. Mean weights did not change. N e i ther systolic BP, 126 v s . 126, nor diastolic BP 97.3 v s . 9 7 . 2 , changed (mmllg, baseline v s . t e s t ) . Though mean total CHOL did not change significantly (2 70 v s . 264 m g / d n , the LDL-CHOL decreased from 193 to 173 m g / d l by the end of the 16-week supplementation period, P<0.0^>, in contradistinction to fish oils which pear to raise LDL-CHOL. Serum triglycc:— ide did not change. These data suggest that CANOLA oil may have promise in d i e t ary strategies to reduce serum LDL-CHOL, perhaps at higher doses incorporated into oil-bearing food products.

1 1 6 7

THE TAIM STUDY; E F F E C T I V E N E S S OF PHARMACOLOGIC AND DIETARY THERAPY OF HYPERTENSION. MD Blaufox*. Albert Einstein College of Medicine, Bronx, N.Y. Η Oberman, Η Langford, Β Davis, S Smoller, Μ Hawkins, Ν Zimbaldi, J Rosett, for the TAIM Study Group.

The Optimal therapy of mild hypertension and, in particular,the relative role of pharmacologic and dietary therapy is widely debated. TAIM (Trial of Antihypertensive Intervention and Management) evaluated changes in blood pressure, risk factor scores and quality of life in mild hypertensives receiving either placebo or Chlorthalidone(25 mg)or Atenolol(50mg) combined with either usual diet or weight loss or low sodium,high potassium diet.Participants were 21-65 years with DBP 90-100 mmHg. Diet change was provided in behaviorly based nutritional programs. 878 people were randomized(mean age 48.4 yrs,33.3% black) and 787 participants with 6 month blood pressure data available are presented here. Participants assigned to weight reduction lost an average of 10.4 lbs., the low Na-high Κ group decreased 24 hr urine NA 27.4 mEq and increased Κ 10.9 mEq. Weight loss plus active drug treatment was most effective in lowering BP (Delta BP for Chlorthalidone + wt reduction vs placebo-usual diet = 7.1 mmHg, Delta BP for Atenolol + wt reduction vs placebo-usual diet = 6.9 mmHg.

Weight loss plus active drug therapy (beta-blocker or thiazide type diuretic) compared to drug therapy or diet therapy alone, produces significant improvement in BP control. Adequate control of BP was not achieved with low Na diet alone. Pharmacologic therapy was more effective than diet in lowering BP but further benefit was obtained by addition of weight reduction to either drug.

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S Y N E R G I S T I C EFFECTS OF C A L C I U M CHANNEL BLOCKERS v s . A C E - I N H I B I T O R S W I T H D I U R E T I C S I N LOWERING BLOOD PRESSURE. WJ E l l i o t t * . T J P o l a s c i k , MB M u r p h y * . T h e U n i v e r s i t y o f C h i c a g o , C h i c a g o , I L .

I n s t i t u t i o n o f t h e r a p y w i t h c a l c i u m c h a n n e l b l o c k e r s ( C C B s ) o f t e n r e s u l t s i n d i u r e s i s , a n d some r e p o r t s s u g g e s t t h a t a d d i t i o n o f a d i u r e t i c ( D ) r e s u l t s i n n o f u r t h e r l o w e r i n g o f b l o o d p r e s s u r e . T o t e s t t h i s h y p o t h e s i s we e x a m i n e d t h e r e c o r d s o f 8 4 c o n s e c u t i v e p a t i e n t s ( 2 6 m a l e , 7 3 b l a c k , a g e d 5 7 + 2 y e a r s ) i n w h o m t h e o n l y c h a n g e w a s t h e a d d i t i o n o f a D ( n = 2 7 ) o r CCB ( n = 5 7 ) t o t h e o t h e r a g e n t . E a c h p a t i e n t s e r v e d a s h i s / h e r o w n c o n t r o l . T h e s e b l o o d p r e s s u r e r e s p o n s e s w e r e c o m p a r e d t o t h o s e o f a n o t h e r g r o u p o f 1 2 8 c o n s e c u t i v e p a t i e n t s ( 4 0 m a l e , 1 1 0 b l a c k , a g e d 5 5 + 2 y e a r s ) a d d i n g e i t h e r a D ( n = 1 4 ) o r A C E - i n h i b i t o r ( A C E - I , n = l l l ) t o t h e o t h e r a s t h e o n l y c h a n g e i n t h e i r m e d i c a l r e g i m e n s . D e c r e a s e s i n s y s t o l i c ( S B P ) a n d d i a s t o l i c ( D B P ) b l o o d p r e s s u r e s ( m e a n + S . E . M . , i n mm H g , c o m p a r e d t o m o n o t h e r a p y ) w e r e : Agent SBP DBP Added Supine Erect Supine Erect

D 19 ± 3 * * * 16 ± 5 * * * 7 ± 2 * * 9 ± 2 * * CCB 13 + 3 * * * 17 + 3 * * * 6 + 1 * * 6 + 2 * *

D 17 ± 3 * * * 15 ± 5 * * 7 ± 3 * * 8 + 4 * A C E - I 13 + 2 * * * 13 ± 3 * * * 8 ± 1 * * 8 ± 1 * * * ρ < 0 . 0 5 , * * ρ < 0 . 0 1 , * * * ρ < 0 . 0 0 1 .

T h e s e d a t a i n d i c a t e t h a t , r e g a r d l e s s o f t h e o r d e r o f a d d i t i o n , t h e c o m b i n a t i o n o f CCB + D w a s m o r e e f f e c t i v e i n l o w e r i n g b l o o d p r e s s u r e t h a n e i t h e r CCB o r D u s e d a l o n e , a n d t h a t t h e c o m b i n a t i o n o f CCB + D w a s a s e f f e c t i v e a s t h e A C E - I + D c o m b i n a t i o n . S u p p o r t e d b y N I H : A M - 3 7 3 2 3 , t h e K r a f t F o u n d a t i o n a n d t h e PMAF.

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AJH-MAY 1989-VOL 1, NO. 5, PART 2 ASH 1989 43A

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COMPARISON OF C A P T O P R I L CHALLENGE AND S C I N T I G R A P H I C T E S T S I N SCREENING FOR RENAL ARTERY S T E N O S I S . WJ E l l i o t t * , WB M a r t i n , a n d MB M u r p h y * . U n i v e r s i t y o f C h i c a g o , C h i c a g o , I L .

I d e n t i f i c a t i o n o f p a t i e n t s w i t h r e n a l a r t e r y s t e n o s i s ( R A S ) i s i m p o r t a n t , d e s p i t e i t s r e l a t i v e r a r i t y i n u n s e l e c t e d h y p e r t e n s i v e p a t i e n t s . A s p r e v i o u s s c r e e n i n g t e s t s f o r r e n a l a r t e r y d i s e a s e h a v e b e e n i m p e r f e c t , w e c o m p a r e d t h e a c c u r a c y o f t w o n e w e r t e s t s i n a c o h o r t o f 2 4 h y p e r t e n s i v e p a t i e n t s t h o u g h t o n c l i n i c a l g r o u n d s t o h a v e a h i g h l i k e l i h o o d o f h a v i n g R A S . T h e c a p t o p r i l c h a l l e n g e t e s t w a s p e r f o r m e d i n t h e m a n n e r o f M u e l l e r e t a l . ; s c i n t i g r a p h y w i t h t e c h n e t i u m - S S m d i e t h y l e n e t r i a m i n e p e n t a a c e t i c a c i d w a s c a r r i e d o u t b e f o r e a n d a f t e r a n g i o t e n s i n c o n v e r t i n g e n z y m e i n h i b i t o r t h e r a p y ( t y p i c a l l y , 2 5 mg o f o r a l c a p t o p r i l ) . R e n a l a r t e r i o g r a p h y w a s p e r f o r m e d i n 16 p a t i e n t s w h e n e i t h e r t e s t w a s n e g a t i v e , a n d d e m o n s t r a t e d a t h e r o s c l e r o t i c RAS i n 8 p a t i e n t s . T h e s e n s i t i v i t y a n d s p e c i f i c i t y o f t h e c a p t o p r i l c h a l l e n g e t e s t w e r e 8 0 % a n d 6 9 % , r e s p e c t i v e l y . T h e s c a n h a d a s e n s i t i v i t y o f 9 4 % a n d a s p e c i f i c i t y o f 9 2 % . A l t h o u g h t h e n u m b e r s o f p a t i e n t s a r e s m a l l , t h e r e w a s a s i g n i f i c a n t r e l a t i o n s h i p b e t w e e n t h e p r e s e n c e o r a b s e n c e o f RAS a n d t h e r e s u l t s o f t h e s c a n ( c h i - s q u a r e = 1 4 . 3 , ρ < 0 . 0 0 1 ) , b u t n o t t h o s e o f t h e c h a l l e n g e t e s t ( c h i - s q u a r e = 3 . 5 4 , ρ > 0 . 0 5 ) . T h e s e d a t a s u g g e s t t h a t t h e r e n a l s c i n t i g r a p h i c s c a n w i t h c a p t o p r i l i s a b e t t e r s c r e e n i n g t e s t f o r RAS t h a n t h e c a p t o p r i l c h a l l e n g e t e s t . S u p p o r t e d b y N I H : AM 3 7 3 2 3 a n d t h e PMAF.

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ORAL MAGNESIUM SUPPLEMENTATION IN DIURETIC TREATED PATIENTS. M.B. Murphy*, D. Zebrauskas, S Schutte, R. Wood, R Geiser, F.L. Douglas, W.J. Elliott* # The University of Chicago, Chicago, IL 60637.

Hypotensive and hormonal effects of dietary magnesium supplementation should be most obvious in Mg depleted subjects. Accordingly, 22 hypertensive patients (14 blacks, 10 females aged 54+8 years) on long-term diuretic therapy, e x c l u d i n g a m i l o r i d e , t r i a m t e r e n e or spironolactone, were randomized to receive Mg aspartate hydrochloride (20 mEq b.i.d.) or placebo for 3 months. Antihypertensive drug therapy was held constant throughout and 18 subjects completed the study.

Neither Mg nor placebo altered supine BP: 143+11/94+4 mm Hg at baseline vs. 144+13/91+6, the average of three monthly visits on Mg, in contrast to 146+17/92+5 at baseline v. 141+15/89+5 on placebo (all p>0.05). Standing pressures were also unchanged. Urine Mg increased (5.3+1.5 to 8.4+2.7 mmol/g creatinine, p<0.05) in the Mg but not in the placebo group (4.4+1.3 to 5.5+2.2 mmol/g creatinine). Serum and red blood cell Mg levels, serum ionized calcium, parathormone, and 1,25 dihydroxyvitamin D and plasma renin concentrations were comparable at baseline, and did not change in either group. Serum potassium concentration increased in the Mg (4.0+0.3 to 4.2+0.3 mmol/1, p<0.05) but not in the placebo group. In s u m m a r y , b e n e f i c i a l e f f e c t s of Mg s u p p l e m e n t a t i o n , in d i u r e t i c treated hypertensive patients, appear to be confined to serum potassium repletion.

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C 0 L U M B I N I C A C I D S U P P L E M E N T A T I O N LOWERS BLOOD PRESSURE AND SERUM CHOLESTEROL L E V E L S I N NORMAL R A T S . WJ E l l i o t t * . ZY H u o , a n d WY W a n g . T h e U n i v e r s i t y o f C h i c a g o , C h i c a g o , I L .

T o t e s t t h e e f f e c t s o f c o l u m b i n i c a c i d ( C A , d e l t a - 5 t r a n s - 1 i n o l e i c a c i d ) a g a i n s t o t h e r e s s e n t i a l f a t t y a c i d s , f o u r g r o u p s o f 1 0 n o r m a l m a l e S p r a g u e - D a w l e y r a t s w e r e f e d s t a n d a r d c h o w a n d g i v e n 3 3 m g / d a y o f t h e e t h y l e s t e r s o f C A , 1 i n o l e i c a c i d ( L A ) , p u r i f i e d e i c o s a p e n t a e n o i c a c i d ( E P A ) , o r v e h i c l e ( V , 1 8 0 u l o f e t h a n o l : p r o p y l e n e g l y c o l : : 7 0 : 3 0 , u s e d a s d i l u e n t f o r a l l g r o u p s ) . S y s t o l i c b l o o d p r e s s u r e ( S B P , mm H g ) w a s m e a s u r e d b y t a i l - c u f f e l e c t r o s p h y g m o m a n o m e t r y w i t h o p t i c a l p u l s e d e t e c t i o n a n d c h o l e s t e r o l l e v e l s ( c h o l , m g / d l ) d e t e r m i n e d b y t h e L i e b e r m a n n B u r c h a r d t m e t h o d b e f o r e a n d a f t e r 1 4 d a i l y i n t r a p e r i t o n e a l i n j e c t i o n s o f t h e e t h y l e s t e r s . D a t a a r e g i v e n a s m e a n + S . E . M . :

C A L A E P A V SBP b e f o r e 1 2 3 ± 3 1 2 3 ± 4 1 2 4 ± 4 1 2 2 ± 4 SBP a f t e r 9 8 ± 4 * * * 1 0 1 ± 3 * * * 9 9 ± 4 * * * 1 2 3 ± 4 c h o l b e f o r e 9 3 ± 3 9 6 ± 3 9 4 ± 3 9 7 ± 3 c h o l a f t e r 8 6 ± 4 * * 9 2 ± 3 * 9 1 ± 3 * 1 0 1 ± 3

* ρ < 0 . 0 5 , * * ρ < 0 . 0 2 , * * * ρ < 0 . 0 0 2 v s . V .

A l t h o u g h CA d o e s n o t e n t e r t h e a r a c h i d o n a t e p o o l a n d h a s l i t t l e e f f e c t ( e v e n i n v i t r o ) o n a r a c h i d o n a t e m e t a b o l i s m a t t h e s e d o s e s , CA n o n e t h e l e s s h a s s i m i l a r h y p o t e n s i v e a n d h y p o c h o l e s t e r o l e m i c p r o p e r t i e s t o t h e e s s e n t i a l f a t t y a c i d s w h i c h s t r o n g l y i m p a c t o n t h e a r a c h i d o n a t e c a s c a d e . T h e s e d a t a s u g g e s t t h a t e s s e n t i a l f a t t y a c i d s m a y h e l p m o d u l a t e SBP a n d c h o l e s t e r o l l e v e l s i n d e p e n d e n t l y o f t h e e i c o s a n o i d p a t h w a y . S u p p o r t e d b y N I H : AM 3 7 3 2 3 a n d t h e PMAF.

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DIURNAL BLOOD PRESSURE DIFFERENCES ARE ASSOCIATED WITH INTER-RACIAL DIFFERENCES IN CARDIAC HYPERTROPHY. Μ. B. Murphy*, R. L. Lang, K. S. Nelson, J. Bednarz, W.J. Elliott*. Hypertension Program and Section of Cardiology, The University of Chicago, Chicago, II. U.S.A.

We have reported that American blacks exhibit higher nocturnal mean blood pressure (MBP) than whites with comparable daytime MBP. To determine whether this difference in night-time MBP is associated with more cardiac hypertrophy, we performed 24 hour ambulatory BP monitoring and M-mode echocardiography in 68 blacks (47% [32 of 68] male, mean (+ s.d.) age 45+15 years) and 59 whites (55% [32 of 59] male, 44+14 years). All were previously untreated. The average daytime MBP was similar in both groups (98.9+11.1 mm Hg in blacks versus 97.8+9.7 mm Hg in whites), however, the blacks had higher nocturnal MBP (88.1+14.1 mm Hg in blacks versus 83+11 mm Hg in whites; p<0.03). Left ventricular mass index (LVMI) correlated best with nocturnal as compared with clinic or daytime MBP in both groups. LVMI was significantly greater in the blacks (119.1+26.6 g/m 2 versus 110.1+22.7 g/m 2 in whites; p<0.05) . Expression of LVMI as a function of 24 hour MBP revealed that blacks' LVMI equalled 1.21 g/m 2

per mm Hg compared with 1.13 g/m 2 per mm Hg in whites (p=0.07). The data indicate that higher nocturnal MBP is associated with greater cardiac hypertrophy in blacks compared with whites with similar daytime MBP. Supported by NIH Grant #GM-07019, NIH AM-37323.

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CEREBRAL BLOOD FLOW DURING THE ACUTE THERAPY OF SEVERE HYPERTENSION WITH ORAL CLONIDINE C.S. Greene, P.P. Gretler, K. Cervenka, C E . McCoy, F.P. Brown, and M.B. Murphy*. University of Chicago, Chicago, IL

One of the major risks associated with the acute treatment of severe hypertension is a reduction in cerebral blood flow (CBF) and ischemic injury to the central nervous system. We used the 133 Xenon washout technique to study CBF before and after the acute treatment of severe hypertension (diastolic blood pressure > 115 ram Hg) in 12 patients. Oral clonidine (0.2 rag) was given initially and 0.1 mg hourly thereafter until goal blood pressure (BP) or a total of 0.6 mg were reached. There were 7 females and 5 males, mean (±SEM) age was 49.7 ± 3.6 years, and mean weight 77.4 ± 4.9 kg. After 0.2 - 0.3 rag of clonidine mean BP decreased from 201.7 ± 5.2 / 126.3 ± 2.1 mm Hg to 149.4 ± 5.5 / 96.8 ± 1.8 mm Hg (P<0.001). No significant adverse effects were observed. Although mean CBF for the group did not change (72.6 vs 73.7 ml/lOOmg/min), a significant change (>10%) occurred in 9 of 12 patients (5 increases and 4 reductions) . The magnitude and direction of the alteration was dependent upon initial CBF (r=-0.651, P<0.05). In patients with low initial values, CBF usually increased, while it tended to decrease in patients with high pretreatment CBF. These data suggest that contrary to previous reports, acute therapy of severe h y p e r t e n s i o n w i t h clonidine does not consistently reduce CBF. Supported by PMAF, NTH: GM-07019 and Boehringer Ingelheim.

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C O R R E L A T E S O F L V MASS A N D D I A S T O L I C F I L L I N G IN Y O U N G P A T I E N T S W I T H N O R M A L OR M A R G I N A L L Y E L E V A T E D B L O O D P R E S S U R E A L Hinderliter*. P W Willis IV, K C Light. University of North Carolina, Chapel Hill, NC

The relationships between L V mass, diastolic filling parameters, and BP were evaluated in 55 young pts (mean age = 30+7 yrs) with normal casual blood pressure (n=43) or borderline hypertension (n=T2). E a c h pt underwent ambulatory BP monitoring during a workday. M-mode echocardiographic measurements of wall thickness and chamber dimensions were used to calculate L V mass ( L V M ) and L V mass index (LVMI) . L V diastolic filling was assessed by pulsed Doppler sampling of transmitral flow, and expressed as early ( E ) and the ratio of early to late ( E / A ) peak filling velocities.

Casual systolic BP, obtained systematically from 4 consecutive laboratory auscultations at the same time of day (5-6 PM), was closely related to L V M (r=60 , p<0001) and L V M I ( r=54 , p<0001). Significant correlations were also found between average daytime ambulatory systolic B P and L V mass measurements ( r = 4 3 for L V M , r=.31 for LVMI) . Diastolic BP measurements, either casual or during the workday, were less strongly related to both L V M and L V M I (r value range = .34-.42).

Doppler indices of diastolic filling were not significantly related to either ambulatory or casual measurements of systolic or diastolic BP. Age, however, was an important determinant of L V filling characteristics; there were strong negative correlations between age and both Ε (r=-.36, p < 0 1 ) and E / A (r=-.52, p<0001).

Conclusions: In a group of young pts with normal or marginally elevated BP, 1) Systolic BP was more closely correlated with L V M and L V M I than was diastolic BP; 2) Casual BP was as accurate as average daytime ambulatory B P in predicting L V M ; and 3)Age was a more important determinant of L V diastolic filling than was BP.

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THE EFFECT OF CHRONIC INFUSION OF ATRIAL NATRIURETIC PEPTIDE (ANP) IN PUR0MYCIN AHIN0NUCLE0SIDE (PAN) NEPHROSIS. MJ Radin. Dept. of Veterinary Pathobiology, The Ohio State University, Columbus, OH.

Administration of PAN to rats results in renal functional alterations leading to avid sodium retention, protein loss, and edema that closely resemble naturally occurring nephrotic syndrome (NS) in human patients. Acute infusion of ANP in human NS patients results in a delayed and blunted natriuretic and diuretic response. This study examined the effects of chronic administration of ANP to rats given PAN. Group I (n=4) and II (n=5) were given 15 mg/100 gm body weight PAN intraperitoneally. Rats were allowed food and water ad libitum and kept in metabolic cages in order to measure 24 hour sodium, potassium and protein excretion. Group III (controls, n=4) were given saline ip. On day 4 post injection (PI), carotid catheters were implanted in all groups. Group I was implanted with a minipump administering 1 /ig/hr of rat ANP. Group II and III were implanted with sham pumps. On day 8 PI, glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured in conscious unrestrained rats using a single injection of H-inulin and C-tetraethylammonium bromide, respectively. The results are given as mean (+ SEM): Group GFR ERPF protein Na Κ

ml/min/kg ml/min/kg mg/24 hr mEq mEq I 8.09 17.66 639.63 .318 1.077

(2.41) (2.70) (284.44) (.159) (.257) II 2.57 14.46 425.88 .347 .927

(0.43) (3.57) (121.14) (.147) (.3») III 16.24 41.24 27.87 1.173 2.114

(1.40) (5.82) (7.45) (.391) ( 3 6 ) GFR, ERPF, Na, and Κ excretion were significantly decreased (p<0.05) in rats given PAN (I and II) compared to controls (III). ANP significantly increased GFR (p<0.05) without increasing ERPF (p>0.05) in rats given PAN (I vs II), however, Na and Κ excretion were unchanged (p>0.05). While not significant, protein excretion tended to be greater in rats given ANP. Chronic administration of ANP in NS results in increases in GFR without increases in natriuresis.

DOUBLE-BLIND COMPARISON OF BENAZEPRIL HYDROCHLOROTHIAZIDE, AND PLACEBO IN MILD TO MODERATE HYPERTENSION. M. Moser, J . Whalen*, L. Gourley*, J . DeSilva*, White Plains, NY. Benazepril* HCL (BZ) is a new, nonsulfhydryl, angiotensin-converting-enzyme-inhibitor (ACEI) being evaluated as an antihypertensive agent. We compared multiple doses of BZ of 2, 5, 10 and 20 mg, hydrochlorothiazide (HCTZ) 25 mg and placebo (P) given once daily (QD). Two hundred six patients (pts) with a sitting diastolic blood pressure (SDBP) of 95-114 mnllg after 4 weeks (wks) of Ρ were randomized to one of the 6 treatment groups. Pts. were evaluated for safety and efficacy at weekly intervals for 4 wks. Nonresponders were then treated with BZ and HCTZ combination therapy. SDBP (mmHg) at the end of Ρ baseline and the change in SDBP after 4 wks of BZ and in

Treatment (n) Baseline BZ (n) Β ζ +; Placebo (30) 102 -4 (18) -3 HCTZ (33) 102 -8* (20) -6 BZ 2 mg (34) 102 -3 (24) -6 BZ 5 mg (38) 101 -6 (25) -8 BZ 10 mg (34) 102 -5 (21) -6 BZ 20 mg (36) 102 -8* (20) -9 *P < 0.05 vs placebo ** additional decrease in SDBP The overall incidence of adverse experiences was similar in the 5 active-treated groups. Dizziness, upper respiratory infections and drowsiness occurred more frequently in the BZ groups than in P. BZ 20 mg QD appears to be an orally effective and well tolerated ACEI with an efficacy equivalent to HCTZ, 25 mg QD.

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j 11781 PEAK AND TROUGH EFFECTS OF 3 ONCE DAILY DOSE LEVELS OF BENAZEPRIL IN MILD-MODERATE HYPERTENSION, J. WHALEN* , C. SKALKY, J. DESILVA*, M. WEBER, RESEARCH MEDICAL CLINIC, LONG BEACH, U. OF CALIFORNIA IRVINE, CIBA-GEIGY INC. Benazepril.HC1 (BZ) is a novel, nonsulfhydry1 converting enzyme inhibitor. Patients (165) with sitting diastolic blood pressure (SDBP) of 95 - 114 mmHg after a 2-4 weeks of placebo (P) were randomized equally to P, BZ 20, 40, or 80 mg once daily for 8 weeks. BP was measured at baseline; 24 hours after dosing (trough) at 2 week intervals; and 2 hours post dose (peak) at Wks 0 and 6. Shown are BPs at baseline and changes in BPs from baseline in mmHg.

Placebo BZ 20 BZ 40 BZ 80 (n=40) (n=45) (n=43) (n=37)

Baseline 154/103 156/103 154/102 161/104 Wk 0, Hr 2 -4/-5 -10/-9 -12/-8 -14/-11 Wk 2, Hr 0 -7/-4 -6/-7 -11/-8 -11/-8 Wk 4, Hr 0 -5/-4 -10/-8 -14/-9 -16/-10 Wk 6, Hr 0 -8/-5 -8/-9 -13/-9 -15/-11 Wk 6, Hr 2 -7/-7 -16/-13 -18/-13 -24/-18 Wk 8, Hr 0 -3/-4 -11/-9 -15/-8 -19/-13

All reductions in SDBP were significantly different (p < 0.05) from P, except at Wk 2, Hour 0, (all BZ groups) and at Wk 8 (40 mg). Importantly, effect at trough ranged from 61-6970

of that at peak. There were no differences in overall incidence of adverse experiences (AEs) between Ρ and BZ groups. The most common AEs with BZ were dizziness (10 pts) and cough (7 pts.). Benazepril given once daily is well tolerated and is effective throughout the full 24-hour dosing period.

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CIRCULATING ACTIVE RENIN HETEROGENEITY CHANGES AFTER STIMULATION OF RENIN SECRETION. SA Katz, JA Opsahl*, CE Halstenson*, and PA Abraham*. Hennepin County Medical Center, and Univ. of Minnesota, Minneapolis, MN.

Human active renin is composed of multiple forms with variable i s o e l e c t r i c points between 5.46 and 4 . 8 4 . The re la t ive proportions of five major renin forms were compared in human essential hypertensive peripheral venous plasma before and 2 hrs a f ter stimulation of renin release with converting enzyme inhibition (Quinapril) and upright posture. Five major active renin forms were separated by shallow gradient i s o e l e c t r i c focusing and quantitated by radioimmunoassay of generated Angiotensin I .

Plasma renin a c t i v i t y increased significantly from 1.2 to 5.1 a f ter renin stimulation (N=5).

I s o e l e c t r i c point (IP) and average proportions (%) of c irculat ing active renin forms before (B) and af ter stimulation (S) of renin secretion (N=5) (MearrhSEM): *p < .05 ; Β vs S

IP 5.46 5.22 5.05 4 .88 4 .84 Β 13 .8±2 .1 19 .9±1.9 22.8±4 21.L+2.3 22 .4±5 .4 S 22±2.3 24±1.7 22 .2±2 .6 19 .3±1 .1 12.5±2.7 %Δ *+59.4% *+20.6% -2.6% -8.5% * -44 .2

Thus, stimulation of renin secretion was accompanied by a significant increase in the proportions of the two most basic renin forms and a significant decrease in the proportion of the most acidic form. These changes during increasing plasma renin a c t i v i t y could occur by acute preferential renal secretion of more basic forms and/or chronic preferential hepatic degradation of the more basic forms.

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BENAZEPRIL AS A SAFE AND MORE EFFECTIVE ALTERNATIVE TO DIURETICS IN THE TREATMENT OF MATURE HYPERTENSIVE PATIENTS J .K. deSilva*. R. Seshamani, L. Ivankoe, Y.-T. Chiang, L.G.T. Ribeiro, CIBA-GEIGY Corporation, Summit, NJ and Thomas Jefferson University, Philadelphia, PA

A multicenter, double-blind study was designed to compare the eff icacy, safety and t o l e r a b i l i t y of Benazepril, a new non-sulfhydryl angiotensin converting enzyme inhibitor, versus hydrochlorothiazide (HCTZ). Eighty-five patients aged between 55 and 65 years old, with diastol ic blood pressure (DBP) between 90-114 mmHg, af ter a 2-week placebo run-in period, were randomized to receive either HCTZ (n=43) 25mg or Benazepril (n=42) 10 mg q.d. for s ix weeks. After three weeks of treatment the dose was doubled in the patients with DBP>90 and not at least a 5 mmHg decrease. After one week of treatment, 57% in the Benazepril group versus 16% in the HCTZ group (p<.01) were responders (<90 or >10 mmHg reduction) . The percentage of responders was also greater in the Benazepril group at weeks three and s ix ( p < . 0 5 ) . By the end of six weeks the Benazepril group had a reduction in DBP from 95 .8±0 .8 mmHg at baseline to 73 .6±1 .4 mmHg (p< .05 ) . In the HCTZ group the response was from 96 .6±0 .9 mmHg to 88 .7±1.2 mmHg (p< .05) . The sys tol ic blood pressure was also reduced to a greater magnitude with Benazepril (from 147±2.3 to 101±2.5 mmHg) when compared to HCTZ (from 147± 2.5 to 133±2.1 mmHg). There were no serious reactions reported with either one of the drugs.

In conclusion, Benazepril is safe and more efficacious than HCTZ when given once a day in mature hypertensive pat ients .

1 1 8 1

ALTERED A T R I A L N A T R I U R E T I C P E P T I D E GENE EXPRESSION I N A T R I A OF RATS ADAPTED TO CHRONIC N0RM0BARIC H Y P O X I A . YF C h e n , Τ E l t o n , Ρ B o u n e l i s , Η J i n , S O p a r i l * . H y p e r t e n s i o n P r o g r a m , U n i v e r s i t y o f A l a b a m a a t B i r m i n g h a m , A L .

We p r e v i o u s l y d e m o n s t r a t e d t h a t c i r c u l a t i n g l e v e l s o f a t r i a l n a t r i u r e t i c p e p t i d e ( A N P ) a r e e l e v a t e d i n r a t s w i t h h y p o x i a i n d u c e d p u l m o n a r y h y p e r t e n s i o n . I n t h e c u r r e n t s t u d y , we t e s t e d t h e h y p o t h e s i s t h a t ANP g e n e e x p r e s s i o n i n r i g h t a n d l e f t a t r i a i s a l t e r e d i n h y p o x i a - a d a p t e d r a t s c o m p a r e d t o c o n t r o l r a t s e x p o s e d t o r o o m a i r . R i g h t a n d l e f t a t r i a l ANP mRNA l e v e l s w e r e m e a s u r e d i n r a t s w h i c h h a d b e e n e x p o s e d t o 10% 0 « a t a m b i e n t p r e s s u r e f o r 4 w e e k s . L e v e l s o f 18S r i b o s o m a l RNA w e r e u s e d a s a n i n t e r n a l c o n t r o l t o q u a n t i t a t e t h e a m o u n t o f t o t a l RNA m e a s u r e d . (ANP m R N A / 1 8 S RNA) r a t i o s ( A N P : 1 8 S ) a n d t o t a l t i s s u e ANP mRNA ( t A N P ) e x p r e s s e d a s p e r c e n t o f t h e a i r c o n t r o l l e v e l s a r e ( m e a n ± S E ) :

L e f t A t r i a R i g h t A t r i a ANPTTUS tA"NP A N P : 1 8 S tA~NP

H y p o x i c ( 1 2 ) 1 5 4 ± 1 3 * 1 9 4 ± 2 2 * * 5 7 + 4 * * 82±6Δ A i r C o n t r o l ( 1 2 ) 1 0 0 ± 1 0 1 0 0 + 1 6 1 0 0 ± 8 1 0 0 ± 8 * * p < 0 . 0 1 , * p < 0 . 0 5 , Δρ<0.08 c o m p a r e d t o a i r c o n t r o l . T h e d a t a i n d i c a t e t h a t ANP g e n e e x p r e s s i o n w a s s i g n i f i c a n t l y i n c r e a s e d i n l e f t a t r i u m a n d s i g n i f i c a n t l y d e c r e a s e d i n r i g h t a t r i u m i n 4 w e e k h y p o x i a - a d a p t e d r a t s . T h e s e r e s u l t s s u g g e s t t h a t i n c r e a s e d c i r c u l a t i n g ANP l e v e l s m a y b e r e l a t e d t o t h e i n c r e a s e i n l e f t a t r i a l ANP g e n e t r a n s c r i p t i o n i n t h i s m o d e l .

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DISCORDANCE BETWEEN PROXIMAL AND DISTAL CORONARY EFFECTS OF ATRIAL NATRIURETIC PEPTIDE (ANP) IN CONSCIOUS DOGS: RELATION TO PLASMA ANP AND CYCLIC GUANOSINE MONOPHOSPHATE (cGMP). A Chu, A S t a k e l y , Μ R u s s e l l , C-C L i n , W Kuehl , U S c h w e r t s c h l a g , FR Cobb, Duke & VA Medical C e n t e r s , Durham, NC

This s tudy r e l a t e s t h e changes in plasma cGMP and ANP l e v e l s t o proximal c o r o n a r y d i l a t i o n s and c o r o n a r y flow (CBF) ( d i s t a l c o r o n a r y d i l a t i o n s ) a f t e r i n f u s i o n of α human a t r i a l n a t r i u r e t i c p e p t i d e (ANP). In 7 awake d o g s , ANP (3 ug/kg) was i n f u s e d as a bolus in t h e l e f t a t r i u m . Proximal c o r o n a r y dimension (measured by c h r o n i c a l l y implanted u l t r a s o n i c c r y s t a l s ) and CBF (by c u f f type Doppler probe) were c o n t i n u o u s l y m o n i t o r e d . Plasma samples were s e r i a l l y withdrawn from t h e a o r t a f o r ANP and cGMP a s s a y s . ANP did not s i g n i f i c a n t l y a l t e r h e a r t r a t e , a o r t i c and l e f t v e n t r i c u l a r (LV) e n d - d i a s t o l i c p r e s s u r e s and LV d P / d t . Proximal c o r o n a r y d i a m e t e r s i g n i f i c a n t l y i n c r e a s e d from 3 . 8 1 ± 0 . 1 4 t o a peak o f 3 . 9 3 ± 0 . 1 3 mm l a s t i n g >40 min". CBF- i n c r e a s e d from 1 .71 ± 0 . 3 6 t o 2 . 0 0 ± 0 . 3 6 KHz s h i f t u n i t s , l a s t i n g " <5 min. Plasma cGMP (p mol /ml) was e l e v a t e d f o r > 40 min ( 1 3 . 5 ± 1 . 9 c o n t r o l , 1 4 0 . 0 ± 4 9 . 0 p e a k ) . Plasma ANP ( p g / m l ) was e l e v a t e d f o r 20 min a f t e r i n f u s i o n ( 1 5 . 2 ±2 .1 c o n t r o l , 185±57 p e a k ) . I n c r e a s e s in cGMP c o r r e s p o n d e d t o d u r a t i o n of proximal c o r o n a r y d i l a t i o n s whi le plasma ANP l e v e l s appeared t o r e t u r n t o b a s e l i n e e a r l i e r . These s t u d i e s demonstra ted a marked d i s c o r d a n c e between proximal c o r o n a r y and d i s t a l c o r o n a r y d i l a t i o n r e s p o n s e s t o ANP in c o n s c i o u s dogs and t h a t plasma cGMP may be used as an i n d i c a t o r f o r v a s o d i l a t o r e f f e c t s of ANP on proximal but not d i s t a l c o r o n a r y a r t e r i e s .

|1184| A COMPARISON OF FELODIPINE AND NITRENDIPINE IN THE TREATMENT OF HYPERTENSION. J. Frlmodt-Moller and E. Lassen for the Danish Multicenter Study Group, Denmark

The aims of this double-blind, parallel group study were to compare the effects on blood pressure (BP) and tolerability of felodipine (PlendilR) and nitrendipine (BaypressR). Hypertensive patients with a diastolic blood pressure (DBP) 95-120 mmHg at the end of a four week run-in period on placebo alone or in addition to a β-blocker were randomised to six weeks' double-blind treatment with felodipine 10 mg o.m. (n = 65) or nitrendipine 10 mg o.m. (n = 65). If this BP was > 90 mmHg after three weeks, the dose was doubled to 20 mg o.m. Blood pressure were recorded in the morning. 24 hours after the previous dose administration. Side effects were recorded at every visit by open questioning. Results: Supine BP (mmHg) 24 hours after previous dose are given in the table. Mean ± SD as well as the adjusted delta values and the 95% confidence intervals for delta are given.

0 week 6 weeks delta (6-0) w

CI p-value

Felodipine SBP 168±18 149±16 -21 (-25, -16) -(n = 60) DBP 105 ± 6 90 ± 9 -15 (-17. -13) 0.001 η

Nitrendipine SBP 170±19 159 + 19 -10 (-15. -6) _ 0.03 (n = 65) DBP 105 ± 6 94±10 -11 (-13. -8) -J

Five patients treated with felodipine were withdrawn due to vasodilatory side effects. Conclusion: Felodipine produced greater effects on BP than nitrendipine 24 hours after dose intake. Felodipine also resulted in a higher withdrawal rate due to vasodilatory side effects. It thus appears that felodipine caused a more pronounced precapillary vasodilation than nitrendipine in the doses chosen.

1 1 8 3

PREFERENTIAL EFFECTS OF ATRIAL NATRIURETIC PEPTIDE (ANP) ON PROXIMAL CORONARY ARTERIES IN MAN: RELATION TO PLASMA ANP AND CYCLIC GUANOSINE MONOPHOSPHATE (cGMP). A Chu, W Kuehl , Κ M o r r i s , J Cusma, CC L i n , F N a v e t t a , and FR Cobb. Duke and VA Medical C e n t e r s , Durham, NC

In 15 p a t i e n t s wi thout s i g n i f i c a n t c o r o n a r y d i s e a s e , " a lpha human ANP ( 2 . 5 pg/kg b o l u s ) i n j e c t e d in t h e l e f t v e n t r i c l e (LV) induced t r a n s i e n t ( 5 - 1 0 min) d e c r e a s e s in a o r t i c p r e s s u r e (10%) and LV " e n d - d i a s t o l i c p r e s s u r e ( 9 ± 3 t o 7±3 mm H g ) . T r a n s i e n t i n c r e a s e s o c c u r r e d in h e a r t r a t e (9%), LV d P / d t ( 1 3 $ ) and c a r d i a c o u t p u t ( 1 0 % ) . Proximal c o r o n a r y diameter (PCD) ( d i g i t a l a n g i o g r a p h y ) measured a t 10 and 30 min a f t e r ANP ( 4 . 0 1 ± 0 . 7 2 and 4 . 1 5 ± 0 . 7 5 ' mm) was s i g n i f i c a n t l y i n c r e a s e d from c o n t r o l ( 3 · 5 5 ± 0 . 5 8 mm) p < 0 . 0 5 . N i t r o g l y c e r i n ( 0 . 3 mg i . e . ) g iven 40 min a f t e r ANP did not f u r t h e r i n c r e a s e PCD ( 4 . 1 0 ± 0 . 7 7 mm). D i s t a l c o r o n a r y vasomotion r e f l e c t e d by c o r o n a r y flow (Doppler v e l o c i t y s h i f t X c r o s s - s e c t i o n a r e a ) a t 5 min a f t e r ANP was unchanged from c o n t r o l ( 9 2 . 9 ± 5 1 . 3 vs 8 2 . 6 ± 5 6 . 3 volume flow u n i t s / m i n ) . Plasma samples were c o l l e c t e d b e f o r e and s e r i a l l y a f t e r ANP f o r ANP and cGMP r a d i o immunoassays. ANP i n c r e a s e d 6 . 9 - f o l d dur ing t h e f i r s t min and r e t u r n e d t o b a s e l i n e by 25 min. cGMP i n c r e a s e d 3 . 4 - f o l d and p e r s i s t e d f o r >25 min. These d a t a demonstra ted t h a t bolus i n j e c t i o n s o f ANP in man induce 1) s u s t a i n e d ( > 3 0 m i n ) , p o t e n t ( 1 7 ? ) d i l a t i o n o f proximal c o r o n a r y a r t e r i e s , 2 ) no s i g n i f i c a n t change in d i s t a l c o r o n a r y v a s o m o t i o n , and 3) minor t r a n s i e n t changes in s y s t e m i c hemodynamics. The d u r a t i o n o f proximal c o r o n a r y d i l a t i o n f o l l o w s more c l o s e l y t h a t of plasma cGMP r a t h e r than ANP l e v e l s .

1 1 8 5

ANTIHYPERTENSIVE AND NETABOLIC EFFECTS OF NIFEDIPINE GASTROINTESTINAL TrERAPEUTIC SYSTEM (NGITS) IN ESSENTIAL HYPERTENSION. L .R . K r a k o f f * , E . L . B r a v o , M.K. T u c k * , C P . F r i ec taan , Mount S i n a i Med ica l C e n t e r , New Y o r k , NY. GITS, a p u s h - p u l l o s m o t i c s y s t e m , d e l i v e r s n i f e d i p i n e a t a c o n s t a n t r a t e o v e r 24h w i t h once d a i l y o r a l d o s i n g . E f f i c a c y was assessed i n t h e gene ra l p o p u l a t i o n o f m i l d - modera te h y p e r t e n s i v e s ( s i t t i n g d i a s t o l i c b l o o d p r e s s u r e (SDBP) 95 -110 mmHg), i n a m u l t i c e n t e r t r i a l a t 127 s i t e s des i gned t o e n r o l l 1270 p a t i e n t s . To d a t e 1083 have been e n r o l l e d . R e s u l t s o f t h e f i r s t 164 who have comp le ted t h e s t u d y (104 M, 60 F , age 53+ 12 (SD) y e a r s ) a r e r e p o r t e d . A f t e r two weeks on p r e v i o u s a n t i h y p e r t e n s i v e m e d i c a t i o n , p t s . e n t e r e d a two-week p l a c e b o p e r i o d f o l l o w e d by an upward s i x -week t i t r a t i o n on NGITS a l o n e t o a c h i e v e goa l BP, d e f i n e d as a SDBP o f l e s s t h a n 90 nrnHg and a 10 mrHg f a l l i n SDBP. NGITS began a t 30 mg/day and was i n c r e a s e d by 30 mg/day each week. A f t e r goa l BP was m e t , a twe lve -week e v a l u a t i o n p e r i o d f o l l o w e d . 69% o f p t s . a c h i e v e d goa l BP a t end t i t r a t i o n ; t h e mean d a i l y dose o f NGITS was 74 mg /day . Loca l edema was t h e mos t ca imon s i d e e f f e c t . S i t t i n g BP and h e a r t r a t e (HR) measured 24h a f t e r t h e p r e v i o u s dose a t b a s e l i n e and l a s t v i s i t a r e shown i n t h e t a b l e :

SYST BP DIAST BP HR B a s e l i n e 152 + 17 100 + 4 75 ~ 10 L a s t V i s i t 135 + 14 87 + 8 76 + 11 Change - 17 + 1 5 * * - 1 3 + 8 * * +1 + 9 * * ρ = 0.0001 No o r t h o s t a t i c h y p o t e n s i o n o r i n a p p r o p r i a t e i n c r e a s e i n HR o c c u r r e d i n t h e s t a n d i n g p o s i t i o n . Body w e i g h t f e l l s i g n i f i c a n t l y by 1 .6 + 9 . 2 l b . (p = 0 . 0 0 0 2 ) . No s i g n i f i c a n t changes o c c u r r e d i n K^, f a s t i n g g l u c o s e , t r i g l y c e r i d e s , t o t a l , HDL o r LDL c h o l e s t e r o l . U r i c a c i d dec reased by 0 . 4 + 1 .4 mg/d l (p = 0 . 0 0 3 ) . C o n c l u s i o n : NGITS i s h i g h l y e f f e c t i v e and s a f e once a day monotherapy f o r h y p e r t e n s i o n .

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REPEATED BOLUS INJECTION OF HUMAN ATRIAL NATRIURETIC PEPTIDE IN ACUTE CONGESTIVE HEART FAILURE AND HEALTHY VOLUNTEERS

M.Kentsch, H .J .Ludw ig , D.Ludwig , B.Hentschel, G.Muller-Esch Medica l U n i v e r s i t y Lubeck, L i ibeck, FRG

Aim of the study was to i n v e s t i g a t e the hemodynamic and d i u r e t i c e f f e c t s of repeated intravenous high dose bolus i n j e c t i o n of human a t r i a l n a t r i u r e t i c peptide (<*-hANP) in h e a l t h y v o l u n t e e r s (VOL) and p a t i e n t s with acute congestive hear t f a i l u r e (CHF) . 6 VOL and 6 CHF r e c e i v e d 2 b o l i (B1,B2) of 200 ; jg «t-hANP (Bissendorf,FRG) with a 30 minute interval at tO and 130. Compared to b a s e l i n e (t0,t30), B1 and B2 s i g n i f i c a n t l y i nc reased c a r d i a c index (CI,l/min/m2, t h e r m o d i l u t i o n method) and u r i n e volume (UVol,ml/min) and decreased sys temic vascu la r r e s i s t a n c e (SVR, dyn-sec-cm"S) and pulmonary v a s c u l a r r e s i s t a n c e (PVR).

to Max1 Ρ t30 Max2 Ρ CI 3 . 9 t . n 3 5 .H± .36 .001 4.0*.14 5 .2+-71 .005 SVR 845+195 555± 79 .003 820*17* 582± 8* .002 PVR 118±. 20 78+ 11 .002 109± 19 73 ± 15 Μ

UVol 1 .2+.75 22± 10 .025 21±6.8 .008 CI 2 .9±-69 3-5±-83 .006 3 .1±-72 3 .5±.72 .003 SVR 1706±520 1260±407 .000 1561±51* 1266*3H .012 PVR 208±132 117* 98 .007 188± 81 1 0 2 * 79 . 0 0 * UVol .87±.46 3.6±2.9 Μ 5M.2 .049

Max1,Max2: maximum e f f e c t after B1,B2; ( u r i n e samples at 30 min i n t e r v a l s )

In CHF mean pulmonary a r t e r i a l p ressu re (37 .8±7-8 to 2 7 - 1 * 1 0 . 7 mmHg, p = . 0 0 l ) and pulmonary c a p i l l a r y wedge pressure were reduced ( 2 5 - 6 * 5 - 9 to 1 9 . 0 * 7 . 9 mmHg, p=.00l). In VOL o£-hANP i nc reased u r i n e volume 1 8 - f o l d , i n CHF 6-fold. οί-hANP evoked s i g n i f i c a n t hemodynamic e f f e c t s i n CHF w h i l e , compared to VOL, the d i u r e t i c response was a t t e n u a t e d . C o n c l u s i o n : Desp i te d i m i n i s h e d d i u r e t i c e f f e c t s , repeated bo lus i n j e c t i o n of *-hANP may be b e n e f i c i a l i n CHF, p redom inan t l y due to hemodynamic a c t i o n s .

1 1 8 8

INHIBITION OF RED BLOOD CELL (RBC) MEMBRANE PUMP ENZYMES BY DIGOXIN LIKE IMMUNOREACTIVE SUBSTANCES (DLIS) FROM HYPERTENSIVE (HTN) PATIENTS ( p t s ) . SMH S a d r a z d e h , TR Hinds , FF V i n c e n z i , Κ H a l v e r s o n , S Ahmad*, MA Kenny, D e p t s . of Lab . M e d i c i n e , Medicine and Pharmacology Univ. of Washington, S e a t t l e , WA 9 8 1 9 5 .

There a r e a number of proposed c i r c -l a t i n g 'HTN f a c t o r s . ' We have r e c e n t l y d e s c r i b e d f a c t o r s from plasma of HTN p t s which c r o s s r e a c t wi th d i g o x i n a n t i b o d y and i n h i b i t Na,Κ pump ATPase. I n h i b i t i o n of Na,Κ t r a n s p o r t i n c r e a s e s smooth muscle a c t i v i t y due t o i n c r e a s e d i n t r a c e l l u l a r Na & Na/Ca exchange ( B l a u s t e i n & Hamlyn, Am.J.Med. 7 7 : 4 5 , 1 9 8 4 ) . The o b j e c t i v e of t h e s t u d y was t o i n v e s t i g a t e p o s s i b l e d i r e c t e f f e c t s of DLIS on Ca t r a n s p o r t . DLIS was i s o l a t e d from t h e plasma of HTN p t s wi th m o d i f i e d method of Dasgupta e t a l (Biochim Biophys A c t a 1 4 8 : 6 2 3 , 1 9 8 7 ) . DLIS e f f e c t s were measured in v i t r o on ATPase a c t i v i t i e s of membranes from o u t d a t e d human RBC's ( R a e s s and V i n c e n z i , J . P h a r m . M e t h o d s 4 : 3 9 1 , 1 9 8 0 ) . DLIS i n h i b i t e d Na,Κ pump and Ca pump ATPases ( t h e l a t t e r in both b a s a l and c a l m o d u l i n - a c t i v a t e d s t a t e s ) in a c o n c e n t r a t i o n - d e p e n d a n t manner, with l i t t l e or no i n h i b i t i o n of Mg AtTPase a c t i v i t y . P o t e n c y was comparable a g a i n s t t h e Na,Κ and Ca pump ATPases . I t i s s u g g e s t e d t h a t , in a d d i t i o n t o i n f l u e n c i n g Na,Κ t r a n s p o r t , some h y p e r t e n s i v e f a c t o r s i n h i b i t plasma membrane Ca t r a n s p o r t .

1 1 8 7

DOES AGE AFFECT HEMODYNAMICS IN ESSENTIAL HYPERTENSION?

WM J e n s e n , J L M o r i t z - S u h a i l Ahmad*, Dept . o f M e d i c i n e , Univ . o f Washington , S e a t t l e , WA.

In 66 a d u l t s w i t h e s s e n t i a l h y p e r t e n s i o n , blood p r e s s u r e m e d i c a t i o n s were r e p l a c e d w i t h p l a c e b o t a b l e t s in a s i n g l e b l i n d f a s h i o n . A f t e r a p e r i o d o f 3 . 5 weeks t h e i r mean a r t e r i a l p r e s s u r e (MAP) was 1 1 6 + 1 . 1 . At t h i s t ime t h e i r c a r d i a c o u t p u t (CO) was measured by a n o n - i n v a s i v e d o p p l e r - u l t r a s o u n d method, UltraCOM; and p e r i p h e r a l v a s c u l a r r e s i s t a n c e (PVR) was c a l c u l a t e d from CO and MAP. T h i s n o n - i n v a s i v e method c o r r e l a t e s w e l l ( r > . 9 ) w i t h i n v a s i v e methods , and has been v a l i d a t e d by 4 d i f f e r e n t groups of i n v e s t i g a t o r s . There was no c o r r e l a t i o n between age and c a r d i a c i n d e x ( C I ) o r age and PVR ( r < 0 . 1 6 , p = n s ) . P a t i e n t s were d i v i d e d i n t o two g r o u p s : younger t h a n 45 ( n = 1 8 ) and o l d e r ( n = 4 8 ) . The c a r d i a c i n d e x ( C I ) and PVR were n o t d i f f e r e n t in t h e two groups ( 2 . 9 + . 1 6 v s 2 . 8 + . 1 , and 1 6 1 2 + 1 0 9 v s 1 8 0 3 + 6 1 , r e s p e c t i v e l y , p > 0 . 1 , t - t e s t ) . Thus t h e l o n g - h e l d b e l i e f t h a t h y p e r t e n s i o n in younger p a t i e n t s i s a s s o c i a t e d w i t h i n c r e a s e d CI and in o l d e r p a t i e n t s w i t h PVR needs t o be r e - e v a l u a t e d . A l s o in q u e s t i o n i s t h e JNC-IV recommendation t o t r e a t younger p a t i e n t s w i t h b e t a - b l o c k e r s .

1 1 8 9

ANTIDIURETIC AND ANTINATRIURETIC ACTIONS OF ENDOTHELIN. Τ Yukimura*, Y Yamashita, Κ Shichino, Τ Shimmen, Μ Saito, Κ Miura, Μ Okumura, Μ Imanishi and Κ Yamamoto. Dept. of Pharmacology, Osaka City Univ. Medical School and Div. of Nephrology and Hypertension, National Cardiovascular Center, Osaka, Japan. Endothelin(ET) is a vasoconstrictor peptide and may have a role in the regulation of local hemodynamics. The present experiment was conducted to study the effects of synthetic porcine ET on renal hemodynamics, urine flow(UF) and urinary excretion of sodium(UNaV) and calcium(UCaV) in anesthetized dogs. Effects of renal secretion of prostaglandin (PG) E2 and 6-ketoPG Fl were also assessed. Intra-!eual arterial(i.r.a.) infusion of iir± at dose of 0.2ng/kg/min (for 25 min) decreased renal blood flow(RBF) with no change in blood pressure (BP). UF doeroauod from the control value of 0.5'!± 0.11 to 0.23±0.06ml/min, UNaV and UCaV from 71±13 meq/min and 0.50±0.09mmol/min to 29±9meq/min and 0.20±0.06mmol/min, respectively. Glomerular filtration rate(GFR) did not change, thereby suggesting enhanced tubular reabsorption of water and electrolytes. Higher dose of ET(1.0-5.Ong/kg/min, i.r.a.) decreased RBF, GFR, UF, UNaV and UCaV, while BP remained unchanged. ET administered i.r.a. stimulated renal secretion of PGs, calculated by arterial and renal venous plasma concentration of PGs and RBF. ET exerted not only the renal vascular constriction but decreased UF and urinary electrolytes excretion, in sodium-repleted dogs. Although ET did not alter BP at doses used, it is possible that antidiuretiv and antinatriuretic actions and stimulation of PGs release from the kidney would contribute to ET-induced cardiovascular effects.

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ENDOTHELIN (E) INHIBITS Na/K-ATPase IN KIDNEY COLLECTING DUCT(IMCD) CELLS: ROLE OF ARACHIDONATE DERIVATIVES. M.L.Zeidel*, B.Kone*, H.Brady*, S.Gullans*, B.M.Brenner*., Harvard Medical School, Boston, MA 02115.

E, a potent vasoconstrictor released by vascular endothelial c e l l s , can induce natr iuresis in vivo. We examined the regulation of Na transport by Ε in rabbit proximal tubule (PT) and IMCD c e l l s . Ε reduced 0 consumption (Q0 ) by 18 ± 1% in IMCD c e l l s , but did not a l t e r Q02 in PT c e l l | . Ε inhibited Q0 half maximally at 5 χ 10 Μ. Ε reduced QO by inhibiting the Na/K-ATPase: 1) Ε gave non-additive inhibition with ouabain and blocked the stimulatory effect of amphotericin Β on Q0 (+29 ± 4% in the absence of Ε, 0 ± 5% in the presence of E; 2) Ε inhibited ouabain-sensitive

Rb uptake by 46.6 ± 8.6% at 10 sec, and by 35.4 ± 5.3% at 30 sec, without altering uptake at 60 min. In permeabilized c e l l s , Ε did not inhibit ouabain-sensitive ATPase (veh.: 110 1 27 nmole ATP degraded/min/mg protein vs endothelin: 97 ± 23; n=5) . Several experiments suggest that arachidonate derivatives may mediate IMCD response to E: 1) The cyclooxygenase inhibitor, ibuprofen (I) abolished response to Ε in Q0 , and Rb uptake assay; 2) PGE which inhibits Na/K-ATPase in these c e l l s (Kidney Int . 33:268) and Ε gave equivalent, nonadditive inhibition of ouabain-sensitive Rb uptake. In conclusion, Ε inhibitSgga/K-ATPase in IMCD c e l l s as shown by Q0„ and Rb uptake. Ε requires the intact c e l l to inhibit Na/K-ATPase, and may act via arachidonate derivatives such as PGE^.

[11921 THE BIPHASIC HEMODYNAMIC RESPONSE TO ENDOTHELIN IN THE RAT. A.J. King. J.M. Pfeffer,* Μ .A. Pfcffcr, and B.M. Brenner.* Brigham & Women's Hospital, Boston MA 02115.

Endothelin (E), an endothelial cell-derived peptide, is a potent vasoconstrictor in vitro. To examine its systemic hemodynamic effects in vivo, single bolus doses (vehicle, 75 and 300 pmol) of Ε were infused i.v. into anesthetized, male, Munich-Wistar rats. Mean arterial pressure (AP, mmHg) and cardiac index (CI, ml/min/kg, EM flowmetry) were measured over a 20 minute period.

D o s e T i m e ( m i n ) ( p m o l ) Base OJi 1 2 1 0 2 0

_ _ V e h 1 0 9 ± 2 1 0 9 ± 1 1 0 9 ± 1 1 0 9 ± 1 1 1 1 ± 2 1 1 1 ± 2 A P 7 5 1 1 0 ± 6 9 5 ± 7 9 6 ± 8 1 0 6 ± 8 1 1 3 ± 9 1 1 7 ± 8

3 0 0 1 0 8 ± 3 9 0 ± 6 * 1 1 7 ± 5 1 4 1 ± 4 * 1 2 5 ± 6 1 2 3 ± 8

V e h 2 4 5 ± 1 9 2 4 0 ± 2 1 2 3 6 ± 1 7 2 3 1 ± 1 7 2 3 2 ± 1 9 2 1 3 ± 1 7 C I 7 5 2 2 1 ± 1 7 2 2 3 ± 1 5 2 2 6 ± 1 5 2 0 5 + 1 9 1 6 3 ± 1 5 * 1 6 8 ± 1 5

3 0 0 2 4 3 ± 3 4 2 4 9 ± 4 4 2 4 1 ± 4 5 1 7 9 ± 5 0 8 2 ± 1 8 * 9 9 ± 2 1 *

( M e a n s ± S E M , n = 5 - 6 p e r d o s e , * p < 0 . 0 5 vs. vehicle) A biphasic pressure response to Ε was observed for all dosages. The maximal hypotensive effect occurred within the first minute of infusion; since CI did not change, this early response was due to systemic vasodilation. Subsequently, there was a vasoconstrictor re^ sponse: a rise in AP despite a fall in CI. With 75 pmol of E, AP was at baseline levels at 20 minutes despite a significant reduction (24%) in CI. With 300 pmol of E, AP fell significantly by 30 seconds, then sharply increased by 31% over baseline to a maximal level by 2 minutes, despite a progressively falling CI. Heart rate was not altered during either the hypo- or early hypertensive response, although there was a modest bradycardia by 20 minutes (325±8 vs. 353±4 beats/min, p< 0.01). Following 300 pmol, values for hematocrit were higher than vehicle (44 ±1 vs. 55 ±1 vol/dl at 20 min., ρ<0.05), suggesting the loss of plasma water to the interstitium. Thus, Ε is distinguished from other endogenous vasoconstrictors by its biphasic pressure effect, and its sustained duration of action. The early hypotensive effect suggests the release of a vasodilatory mediator, e.g., EDRF. Its vasoconstrictor properties raise the possibility of an important role for endothelin in the pathogenesis of systemic hypertension and other vasculopathies.

1 1 9 1

DIFFERENTIAL SELECTIVITY OF ANP RECEPTORS FOR NATRIURETIC PEPTIDES (NP). Μ Gunning*, BJ Balleraann*, Ρ Silva, BM Brenner*, ML Zeidel*, Harvard Medical School, Boston, MA.

In order to further elucidate the receptor system for ANP in the kidney, we have examined the interaction between Brain(BNP) and Iso rat Atrial (Iso rANP) NPs with the ANP receptors of inner medullary collecting duct (IMCD) c e l l s and of glomeruli, and their signal t r a n s a c t i o n systems. In IMCD c e l l s incubated with IANP, BNP and Iso rANP had a lower af f ini ty for ANP receptors as compared to ANP(IC : ANP 0.2nM, BNP 0.5nM, Iso rANP 9nM). The potency order of the NPs in stimulating part iculate guanylate cyclase (PGC) paralleled the binding data (half-max.stim.: ANP > BNP >> Iso rANP). Both ANP and BNP inhibited amiloride sensitive Na uptake. In glomeruli a similar pattern of re la t ive a f f i n i t i e s was found (IC : ANP 0.2nM, BNP 0.6 nM, Iso rANP 6nM), but when glomeruli were pre-incubated with dANP, a synthetic analogue which blocks binding to the 64 kD yegeptor, neither BNP nor Iso rANP displaced

IANP, except at uM concentrations, while the a f f in i ty of ANP was unchanged (IC ϊ 0.2nM). In glomeruli the potency order for stimulation of cGMP was (ANP> Iso rANP >> BNP). Thus in IMCD, BNP interac ts with high af f ini ty and potency with the PGC linked 130 kD receptor, whereas in glomeruli BNP interacts only with the 64 kD receptor, and very ineffectively with the glomerular PGC linked receptors . Therefore PGC coupled NP receptors in IMCD must differ from PGC linked receptors in glomeruli.

1 1 9 3

RENAL HEMODYNAMIC EFFECTS OF ENDOTHELIN. AJ King, BM Brenner*, and S Anderson*. Brigham and Women's Hospital, Boston, MA.

To examine the renal and systemic hemodynamic effects of endothelin (E) in vivo, anesthetized ra ts received single i . v . bolus injections of E. Maximal absolute changes from baseline in mean a r t e r i a l pressure (AP), glomerular f i l t r a t i o n rate (GFR), and renal plasma flow rate (RPF), occurred within 15-20 mins: (Means+SEM; n=4-5; *p<.05 vs . baseline; tp< .05 v s . vehicle , V): Dose AP GFR RPF pmol mmHg ml/min-V + 111 + O.ltO.l + 0 .2+0 . 4 25 + 4±1* - 0 .110.1 - 0 .6+0 . 1* 150 + 24±2*t - 0 . 3+0 .1* - 1 .6+0. l* t 300 + 42±2*t - 0 . 8 + 0 . l * t - 3 .2+0. 3*t Ε induced dose-dependent increases in AP, and declines in RPF and GFR. Additional ra ts (n=7-8) received continuous i . v . infusions of Ε (0 .63 pmol/min) , at a mildly pressor^dose: 1 f .

AP P G C SNGFR QA R^IO RE

x l ° —mmHg —nl/min— dyn«s - cm"5

V 116+3 4711 36+1 130+8 2 .31 .2 l . l + . l Ε 126+3* 59+2* 35+3 107+8 2 .81 .3 2 . 0 1 . 2 *

In Ε r a t s , glomerular capillary pressure ( P Q Q ) was markedly elevated, due to a proportionately greater effect on efferent (R^) than afferent (R^) a r t e r i o l a r resis tance . The high Ρ was offset by a lower glomerular capil lary u l t r a f i l t r a t i o n coefficient and a numerically lower plasma flow rate (Q ) ; thus single nephron (SN) GFR was preservecT. Presumably, higher doses would induce a further f a l l in and lead to reduction in SNGFR. Ε may play a role in the pathogenesis of microvascular injury.

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[11941 ENDOTHELIN: GENE EXPRESSION, RELEASE AND ACTION IN CULTURED CELLS OF THE RENAL GLOMERULUS. PA Marsden. ER Martin, D Dorfman, TA Brock, BM Brenner', Τ Collins, BJ Ballermann*. Brigham and Women's Hospital, Harvard Medical School, Boston, MA.

To determine whether endothelin (EN) may play a role in the local control of glomerular function, we studied EN gene expression and release in cultured bovine glomerular endothelial cells (GEN) as well as EN action in bovine mesangial cells (GMC). GEN express a 2.2 - 2.3 kb mRNA on blot hybridization analysis with a human cDNA preproendothelin probe. A quantitative radioreceptor assay utilizing glomerular microsomes detected the time-dependent release of EN(s) from GEN. In GMC loaded with fura 2, EN induced a concentration-dependent increase in [Ca2 +]i in the presence (EC50 20 nM) and absence of extracellular Ca 2 + . EN induced the rapid (15 sec), transient formation of Ins 1,4,5-P3 in GMC over the range 0 . 1 to 1 0 0 nM (EC50 32 nM) Porcine preproendothelin 1 1 οι 30 amide (ELP) did not induce Ca2 + transients or block EN-stimulated rises in [Ca2+]j. ELP did not compete with 125l-endothelin for binding to glomerular microsomes.

The demonstration that (i) GEN express mRNA for preproendothelin and release EN into culture medium, and (ii) that EN action on GMC involves phospholipase C-induced Ins 1 , 4 , 5 - P 3 production suggests that this novel peptide may be involved in the local control of glomerular hemodynamics IN VIVO, and microvascular tone in general.

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ANTAGONISM OF THE HYPERTENSIVE AND RENAL EFFECTS OF ENDOTHELIN BY ATRIAL NATRIURETIC FACTOR (ANF). T. J. Opgenorth and M. R. Hoist. Abbott Laboratories, Abbott Park, IL 60064.

Endothelin is a recently described potent vasoconstrictor peptide produced by mammalian endothelial cells. Atrial natriuretic factor and other agents which stimulate guanylate cyclase have been demonstrated to antagonize the vascular effects of endothelin in vitro. This study was designed to determine if ANF would antagonize the effects of porcine-endothelin (p-ET) in vivo. A step-up infusion dose-response protocol was followed in which p-ET was administered i.v. at 0.001, 0.003, 0.02, 0.03, 0.1 and 0.3 ug/kg/min (15 min at ea. dose) in Inactin anesthetized rats following three 20 min control clearance periods. Two groups of animals were done (N=6, ea.). An ET ALONE group was done as indicated above. A second group (ET + ANF) was done the same except that ANF was administered beginning 1 hr 15 min before p-ET and continued throughout the protocol. At doses greater than 0.03 ug/kg/min p-ET produced significant changes (p<0.05) in mean arterial pressure (MAP, mm Hg) and glomerular filtration rate (GFR, ul/min/100g B.W.). ANF blunted the effects of p-ET as shown in the table below.

MAP GFR ETALONE ET+ANF ETALONE ET+ANF

Control 100±1 1 01 ±5 1 1 71 ±1 37 895±90 0.1 ug/kg/min 1 1 5±6* 97±7 319±58* 863±178 0.3ug/kg/min 1 29±5* 108±7 186±44* 592±253

*p<0.05, within group comparison to Control

In conclusion, p-ET is a potent peptide which raises arterial blood pressure and lowers glomerular filtration rate in vivo. Continuous intravenous administration of ANF antagonizes these effects of p-ET.

|1195| RENAL HEMODYNAMIC AND NATRIURETIC EFFECTS OF MANGANESE (Mn ) IN VIVO. HM Lafferty* , Μ Gunning*, BM Brenner*, and S Anderson*. Brigham^and Women's Hosp., Boston, MA.

Mn acts as an inorganic calcium channel blocker, inhibiting transcellular calcium flux in muscle. To evaluate t^e potential in vivo hemodynamic ef fec ts of Μη , MnCl or CaCl^ was administered to ra ts by continuous i . v . infusion, and measurements begun at mins.

SNGFR R A x l 0 x v R E xl0 —dyn *s»cm~5

10 —nl/min— 62* 254* 1.0* 0.8

7 25 0.1 0.1 37 165 2.1 0.8

4 19 0.2 0.1 *p < .05 vs . CaCl 2)

Neither infusion changed mean a r t e r i a l pressure (AP). MnCl2 lowered afferent (R ) but not efferent (Rg) a r t e r i o l a r res is tance , resulting in elevated values for the glomerular capillary plasma flow rate (Q^), the glomerular capil lary pressure (P~CC) * and the single nephron (SN) glomerular f i l t r a t i o n rate (GFR). In addition to i t s hemodynamic e f f e c t s , MnCl_ was n a t r i u r e t i c , increasing the fract ional excretion of sodium by 314±46% (p<.05 vs . CaCl , 112±29%). Thus, MnCl exerts renal but not systemic hemodynamic ef fec ts similar to those seen with pharmacologic agents which block calcium entry. The marked glomerular hemodynamic changes in the absence of changes in systemic pressure suggest a possible direct intrarenal effect of MnCl^, wi|li specif ic actions on the glomerular vessels . Mn may prove to be a useful natr iuret ic agent which does not compromise systemic blood pressure.

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I D E N T I F I C A T I O N O F A P O T E N T P E P T I D E A N T A G O N I S T O F A T R I O P E P T I N - I I I ( A P - I I I ) S T I M U L A T I O N O F c G M P S Y N T H E S I S . GP B u d z i k , Y K i s o , TP D i l l o n , WH H o l l e m a n * . A b b o t t L a b o r a t o r i e s , A b b o t t P a r k , I L & K y o t o P h a r m a c e u t i c a l U n i v e r s i t y , K y o t o , J a p a n .

A n a t r i a l n a t r i u r e t i c f a c t o r ( A N F ) a n a l o g , A 7 2 7 4 7 , w a s d e v e l o p e d t h a t a n t a g o n i z e s cGMP s y n t h e s i s s t i m u l a t e d b y A P - I I I i n b o v i n e t r a n s f o r m e d a o r t i c e n d o t h e l i a l e e l 1 s ( B T A E C ) . A 7 2 7 4 7 i s s t r u c t u r a l l y r e l a t e d t o ANF b u t c o n t a i n s i n t e r n a l a m i n o a c i d r e p l a c e m e n t s a n d a m i n o a n d c a r b o x y t e r m i n a l t r u n c a t i o n s . T h e e f f e c t s o f A P - I I I a n d A 7 2 7 4 7 o n cGMP s y n t h e s i s i n BTAEC a r e :

cGMP pD2 %cGMP R e s p o n s e a t l O u M A 7 2 7 4 7 « 5 < 5 A P - 1 1 1 8 . 3 0 1 0 0 . 0

+ O . l u M A 7 2 7 4 7 6 . 2 5 8 0 . 0 + l . O u M A 7 2 7 4 7 5 . 7 5 6 7 . 2 + 1 0 . 0 u M A 7 2 7 4 7 4 . 2 5 2 5 . 1

A 7 2 7 4 7 d o e s n o t s t i m u l a t e cGMP s y n t h e s i s i n BTAEC d u r i n g i n c u b a t i o n f o r 2 h r , 3 7 C . T o a s s e s s A 7 2 7 4 7 p o t e n c y , BTAEC w e r e p r e i n c u b a t e d w i t h A 7 2 7 4 7 f o r 15 m i n , 3 7 C a n d t h e n c h a l l e n g e d w i t h i n c r e a s i n g A P - I I I c o n c e n t r a t i o n s f o r 2 h r . I n c r e a s i n g A 7 2 7 4 7 t o l O u M s h i f t e d t h e A P - I I I d o s e c u r v e u p 4 o r d e r s o f m a g n i t u d e . A S c h i l d p l o t o f t h e d a t a y i e l d s a l i n e , s l o p e = - 1 . 0 0 6 ( r = - 0 . 9 6 2 ) a n d p A 2 = 8 . 4 4 . BTAEC c o n t a i n 2 , A N F b i n d i n g c l a s s e s b y s a t u r a t i o n a n a l y s i s w i t h ' " i - A N F - a h i g h a f f i n i t y c l a s s , K . = 1 0 p M , c o u p l e d t o g u a n y l a t e c y c l a s e a n d l o w a f f i n i t y s i t e Κ.=10ηΜ. A 7 2 7 4 7 s h o w s a K , = 1 0 n M b y c o m p e t i t i o n b i n d i n g f o r t h e c y c l a s e - c o u p l e d s i t e a n d 2nM f o r t h e u n c o u p l e d s i t e 5 S i m i l a r b i n d i n g d a t a a r e f o u n d b y c r o s s l i n k i n g I - A N F t o r e c e p t o r s o n BTAEC i n t h e p r e s e n c e o f A 7 2 7 4 7 . T h i s u n i q u e , n e w a n t a g o n i s t s h o u l d b e v a l u a b l e t o f u r t h e r e v a l u a t e t h e r o l e o f cGMP i n m e d i a t i n g ANF d e p e n d e n t r e s p o n s e s .

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1 1 9 8

I S HYPERTENSION A S S O C I A T E D WITH EXTENT OF CORONARY D I S E A S E OR LEFT VENTRICULAR DYSFUNCTION? A N H L B I - C A S S ( C o r o n a r y A r t e r y S u r g e r y S t u d y ) R e g i s t r y S t u d y . PK Z a c h a r i a h * , BJ G e r s h , RA K r o n m a l a n d P a r t i c i p a n t s i n t h e C o r o n a r y A r t e r y S u r g e r y S t u d y ( C A S S ) , M a y o C l i n i c , R o c h e s t e r , M N .

T h e CASS r e g i s t r y i s a n e x c e l l e n t r e s o u r c e w i t h w h i c h t o d o c u m e n t t h e s e v e r i t y a n d e x t e n t o f c o r o n a r y a r t e r y d i s e a s e ( C A D ) i n p a t i e n t s ( p t s ) w i t h h y p e r t e n s i o n ( B P ) , w i t h a n d w i t h o u t l e f t v e n t r i c u l a r h y p e r t r o p h y ( L V H ) . F o u r g r o u p s o f p t s [ G r o u p 1 — n o BP a n d no LVH ( n = 1 3 4 1 7 ) ; G r o u p 2 - - B P a n d no LVH ( n = 6 7 9 9 ) ; G r o u p 3 — B P a n d LVH ( n = 2 8 7 ) ; a n d G r o u p 4 — n o BP a n d LVH ( n = 2 9 0 ) ] w e r e i d e n t i f i e d b a s e d u p o n h i s t o r y o f BP a n d E C G - d o c u m e n t e d L V H . G r o u p 3 h a d s i g n i f i c a n t l y m o r e s e v e r e C A D ; 5 0 % o f t h i s g r o u p h a d 3 - v e s s e l d i s e a s e a s c o m p a r e d t o 3 0 % w i t h a h i s t o r y o f BP b u t w i t h o u t L V H . H o w e v e r , 56% o f G r o u p 4 a l s o h a d 3 - v e s s e l d i s e a s e c o m p a r e d t o 2 8 % o f G r o u p 1 . A l a r g e r n u m b e r o f p t s i n t h e LVH g r o u p h a d m o r e e x t e n s i v e CAD ( C a g e - 5 0 ) t h a n i n p t s w i t h o u t LVH ( 4 0 % v s 2 0 % ) . T h e s e v e r i t y o f l e f t v e n t r i c u l a r w a l l m o t i o n a b n o r m a l i t i e s w a s a l s o h i g h e r a m o n g p t s i n G r o u p s 3 a n d 4 t h a n i n G r o u p s 1 a n d 2 . A h i g h e r p e r c e n t a g e o f p t s w i t h LVH h a d a p r e v i o u s h i s t o r y o f m y o c a r d i a l i n f a r c t i o n ( 6 4 % v s 4 7 % ) .

A m o n g a p o p u l a t i o n u n d e r g o i n g a n g i o g r a p h y f o r s u s p e c t e d C A D , t h e p r e s e n c e o f LVH w a s a m a r k e r o f m o r e e x t e n s i v e a n d s e v e r e CAD a n d l e f t v e n t r i c u l a r d y s f u n c t i o n i n p t s w i t h a n d w i t h o u t h y p e r t e n s i o n . T h e d i s t r i b u t i o n o f CAD a m o n g h y p e r t e n s i v e s w i t h o u t LVH w a s s i m i l a r t o o t h e r p t s w i t h o u t h y p e r t e n s i o n a n d w i t h o u t L V H .

1 2 0 0

PROSPECTIVE E V A L U A T I O N OF THE ABDOMINAL B R U I T ( A B ) I N ATHEROSCLEROTIC RENAL ARTERY S T E N O S I S ( A R A S ) . JW G r a v e s * , MF C a l l a h a n , VM B u c k a l e w J r . * . D e p t . o f M e d i c i n e , Bowman G r a y S c h o o l o f M e d i c i n e o f Wake F o r e s t U n i v e r s i t y , W i n s t o n -S a l e m , N C .

We p r o s p e c t i v e l y e x a m i n e d f o r t h e p r e s e n c e o f a n a b d o m i n a l b r u i t i n 4 2 p a t i e n t s w i t h r e s i s t a n t h y p e r t e n s i o n a n d 2 o r m o r e o f t h e f o l l o w i n g f e a t u r e s s u g g e s t i v e o f A R A S : a g e > 5 0 y e a r s , r e n a l f a i l u r e , D B P > 1 2 0 m m H g , p o o r r e s p o n s e t o BP t h e r a p y a n d r e n a l f a i l u r e w i t h ACE i n h i b i t o r s . A l l p a t i e n t s r e p o r t e d h a d a n g i o g r a p h i c a l l y p r o v e n A R A S , 27 w i t h u n i l a t e r a l a n d 15 w i t h b i l a t e r a l s t e n o s i s . T h e 4 2 p a t i e n t s c o n s i s t e d o f 2 2 f e m a l e s a n d 2 0 m a l e s , 3 9 w h i t e s a n d 3 b l a c k s , w i t h a m e a n a g e o f 6 2 ± 7 y e a r s . A t p r e s e n t a t i o n m e a n SBP w a s 1 8 9 ± 2 9 mmHg a n d DBP w a s 9 7 + 1 2 mmHg. 2 2 p a t i e n t s h a d n o r m a l r e n a l f u n c t i o n w h i l e 16 h a d m i l d - m o d e r a t e ( S c r 1 . 6 - 5 . 0 ) a n d 4 s e v e r e ( S c r > 5 . 0 ) r e n a l f a i l u r e . P r i o r t o a r t e r i o g r a m a l l p a t i e n t s w e r e s e e n b y o n e a u t h o r a n d 3 2 o f 4 2 ( 7 6 % ) p a t i e n t s h a d a n A B . A l l AB w e r e s y s t o l i c o n l y a n d 1 1 - 1 1 1 / V I i n i n t e n s i t y . I n p a t i e n t s w i t h A B , 2 2 h a d u n i l a t e r a l a n d 10 b i l a t e r a l s t e n o s i s . O f 10 p a t i e n t s w i t h o u t A B , 6 h a d u n i l a t e r a l a n d 4 b i l a t e r a l s t e n o s i s , 5 n o r m a l a n d 5 i m p a i r e d r e n a l f u n c t i o n . M e a n SBP w a s s i g n i f i c a n t l y l e s s ( 1 9 4 ± 2 9 v s 1 7 2 ± 2 3 m m H g , p < 0 . 0 3 ) i n p a t i e n t s w i t h o u t a n A B , a n d p a t i e n t s w i t h o u t AB v / e r e s i g n i f i c a n t l y l e s s l i k e l y t o h a v e a c a r o t i d b r u i t t h a n p a t i e n t s w i t h AB ( 2 / 1 0 v s 2 1 / 3 2 , p< 0 . 0 4 ) . We f i n d a h i g h e r t h a n p r e v i o u s l y r e p o r t e d p r e v a l e n c e o f AB ( 7 6 % ) i n ARAS i n a p r o s p e c t i v e s i n g l e o b s e r v e r s t u d y . S u c c e s s f u l r e d u c t i o n o f SBP i n ARAS m a y c o n t r i b u t e t o t h e f a i l u r e t o f i n d e n ΛΒ i n some p a t i e n t s .

[11991 AMBULATORY BLOOD PRESSURES AND BLOOD PRESSURE LOAD I N NORMAL S U B J E C T S . PK Z a c h a r i a h * , SG S h e p s * , KR B a i l e y a n d CM W i l t g e n , M a y o C l i n i c , R o c h e s t e r , M N .

A m b u l a t o r y b l o o d p r e s s u r e ( A B P ) r e c o r d i n g i s w i d e l y u s e d f o r d i a g n o s i n g a n d t r e a t i n g h y p e r t e n s i o n , b u t ABP r e c o r d i n g s f r o m n o r m a l s u b j e c t s w i t h o u t s i g n i f i c a n t c a r d i o v a s c u l a r r i s k f a c t o r s a r e l a c k i n g . ABP r e c o r d i n g s i n 1 2 6 n o r m a l men a n d women w e r e c a r r i e d o u t w i t h a D e l M a r A v i o n i c s P4 d e v i c e . S y s t o l i c ( S ) a n d d i a s t o l i c ( D ) BP m e a n s a n d BP l o a d s (% r e a d i n g s > 1 4 0 mmHg S a n d > 9 0 mmHg D d u r i n g a w a k e h o u r s ) a r e s h o w n :

AGE 2 0 - 2 9 ( n = 2 2 )

3 0 - 3 9 ( n = 2 2 )

4 0 - 4 9 ( n = 1 8 )

5 0 - 5 9 ( n = 2 5 )

6 0 - 6 9 ( n = 2 3 )

7 0 - 7 9 ( n = 1 6 )

+ 1 1 4 + 1 1 * 1 2 2 + 9 t 1 2 5 + 1 0

SYS 1 1 4 + 7 1 2 1 + 8 1 2 5 + 9

T O L I C m 1 1 4 + 1 0 1 2 0 + 1 0 1 2 4 + 1 1

mHg 1 1 6 + 1 3 1 2 4 + 1 2 1 2 7 + 1 2

1 2 5 + 1 4 1 2 7 ± 1 2 1 3 0 + 1 2

1 2 5 + 1 4 1 3 3 + 1 6 1 3 7 + 1 7

+ 7 2 + 4 * 6 7 + 7 t 7 0 + 8

D I A 7 6 + 4 7 1 + 5 7 4 + 5

S T O L I C 7 6 + 8 7 3 + 7 7 5 + 8

mmHg 7 7 + 6 7 5 + 7 7 7 + 7

7 8 + 8 7 5 + 4 7 7 + 5

7 0 + 7 6 9 + 9 7 1 + 9

BP LOAD (%) S 9 + 1 4 I 8 + 1 1 I 8 + 1 0 I 1 3 + 1 6 I 1 8 + 1 9 I 2 5 ± 2 0 D 3 + 7 I 4 + 6 I 6 + 8 | 6 + 7 | 6 + 7 | 4 + 7

+ o f f i c e ; * ABP 2 4 - h r ; t ABP a w a k e I n c o n c l u s i o n : 1 ) m e a n a w a k e ASBP i s 5 - 1 1 mmHg h i g h e r t h a n o f f i c e B P ; 2 ) m e a n a w a k e ADBP i s s i m i l a r t o o f f i c e B P ; 3 ) o n l y ASBP i n c r e a s e s w i t h a g e , n o t A D B P ; 4 ) no s i g n i f i c a n t d i f f e r e n c e s i n ADBP b e t w e e n m a l e s a n d f e m a l e s w e r e f o u n d a n d 5 ) o n l y ASBP l o a d c h a n g e s w i t h a g e , n o t D l o a d .

1 2 0 1

PLASMA VOLUME ( P V ) I N P A T I E N T S WITH R E S I S T A N T HYPERTENSION ( R H ) . JW G r a v e s * , VM B u c k a l e w J r * . D e p t . o f M e d i c i n e , Bowman G r a y S c h o o l o f M e d i c i n e o f Wake F o r e s t U n i v e r s i t y , W i n s t o n - S a l e m , N C .

T r u e RH i s r e l a t i v e l y r a r e , w h i l e t h e c a u s e s o f p s e u d o r e s i s t a n c e - - n o n c o m p l i a n c e , e x c e s s i v e s o d i u m i n t a k e a n d o f f i c e h y p e r t e n s i o n - - a r e c o m m o n . We p r o s p e c t i v e l y e v a l u a t e d t h e s t a t u s o f t h e PV i n 3 2 p a t i e n t s ( 2 0 n o r m a l , 12 a b n o r m a l r e n a l f u n c t i o n ) w i t h t r u e RH ( m e a n BP 1 8 2 ± 3 0 / 1 0 7 ± 1 3 mmHg) o n s t e p c a r e t h e r a p y . 2 3 p a t i e n t s h a d e x p a n d e d , 5 n o r m a l a n d 4 c o n t r a c t e d P V . A l l p a t i e n t s w e r e o n d i u r e t i c s ( 1 4 t h i a z i d e a n d 18 l o o p ) p l u s 1 t o 4 o t h e r a n t i h y p e r t e n s i v e s ( m e a n 2 . 4 ± 0 . 7 ) . No p a t i e n t s h a d e v i d e n c e o f p e r i p h e r a l e d e m a o r c o n g e s t i v e f a i l u r e . T h e r e w e r e 15 b l a c k a n d 17 w h i t e s u b j e c t s a n d t h e y t e n d e d t o b e o b e s e ( m e a n w t 9 5 . 8 ± 2 3 k g , w t 3 1 ± 2 4 % g r e a t e r t h a n i d e a l b o d y w e i g h t ) . O b e s i t y ( > 2 0 % a b o v e i d e a l b o d y w e i g h t ) w a s s e e n i n 17 o f 2 3 p a t i e n t s i n t h e v o l ume e x p a n d e d a n d 2 o f 4 i n t h e v o l u m e c o n t r a c t e d p a t i e n t s . R e p e a t PV m e a s u r e m e n t s w e r e m a d e i n 8 p a t i e n t s w i t h i n i t i a l v o l u m e e x p a n s i o n w h o a c h i e v e d g o a l BP w i t h i n t e n s i f i e d d i u r e t i c t h e r a p y ( w h i c h c a u s e d a s i g n i f i c a n t r e d u c t i o n i n PV f r o m 5 2 . 7 ± 5 . 3 c c / k g t o 4 6 . 3 ± 5 . 6 c c / k g , p < 0 . 0 2 ) , a n d i n 3 p a t i e n t s w h o a c h i e v e d g o a l b l o o d p r e s s u r e w i t h v a s o d i l a t o r s n o c h a n g e i n PV o c c u r r e d ( 3 5 . 3 ± 0 . 6 c c / k g t o 3 6 . 5 ± 5 . 3 c c / k g , p = . 3 5 ) . T h e s e d a t a s u g g e s t t h a t RH i s c o m m o n l y m e d i a t e d b y PV e x p a n s i o n a n d t h a t o b e s i t y i n d u c e s a s t a t e o f d i u r e t i c i n s e n s i t i v i t y . PV m e a s u r e m e n t l e n d s i n s i g h t i n t o t h e p a t h o p h y s i o l o g y a n d m a n a g e m e n t o f R H .

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1 2 0 2

COMPARISON OF EFFICACY, SAFETY, AND TOLERABILITY OF BENAZAPRIL TO PROPANOLOL AS ADD ON THERAPY TO HYDROCHLOROTHIAZIDE IN PATIENTS WITH MODERATE TO SEVERE HYPERTENSION. HA PUNZI, M.D.*, JK MILLS. TRINITY HYPERTENSION AND DIAGNOSTIC RESEARCH CENTER, CARROLLTON, TEXAS.

Twenty subjects initiated 4 weeks of hydrochlorothiazide (HCTZ) monotherapy 25mg bid. 9 subjects qualified with sitting diastolic blood pressures (SDBP) 100-114mmHg. 5 subjects (4 male, 1 female, mean age 44.8 yrs.) were randomized to have propanolol (P) 40mg bid added to HCTZ. 4 subjects (3 male, 1 female, mean age 50.8 yrs.) were randomized to have benazapril (B) 5mg bid added to HCTZ. Mean SDBP after HCTZ monotherapy for Ρ was 100.3mmHg and for Β was 101.3mmHg.

Subjects were evaluated at 2 week intervals and maintained on dosage levels to obtain SDBP^90mmHg. 2 of the 5 subjects on Ρ and 3 of the 4 subjects on Β were increased to dosage level 2 (B lOmg bid or Ρ 80mg bid). No subject was increased to dosage level 3 (B 20mg bid or Ρ 120mg bid). At week 10, blood pressure control was achieved in all patients in both groups: Ρ 88.9mmHg±0.16 and Β 86.9minHg±2.05.

Despite the small sample size, these findings suggest there is no significant difference between treatment groups indicating the effects of Ρ and Β are similar. Each patient reported 1 or more adverse experiences (AE). AEs were similar between both groups and there were no serious AEs reported. Β 20mg daily appears to be a more suitable initial dosage as adjunctive therapy in patients with moderate to severe hypertension.

112041 T h g T r o u q h - t o - P e a k R a t i o o f F e ^ o d i p i r y e a d m i n i s t e r e d t w i c e d a i l y a s m o n o t h e r a p y o r o n a b a c k g r o u n d o f b e t a - b l o c k a d e . EP F a i s o n * , D. E l m f e l d t t , B . j W e s t b e r g t , B . E d g a r f , DA S h a p i r o * , Depts o f " C l i n i c a l R e s e a r c h , Merck, Sharp and Dohme Research L a b o r a t o r i e s ^ West P o i n t , PA and y C a r d i o v a s c u l a r C l i n i c a l R e s e a r c h , A s t r a CV, AB H a s s l e , Molndal , Sweden. I t has been sugges ted by t h e U . S . Food and Drug A d m i n i s t r a t i o n t h a t t h e r e l a t i v e e f f i c a c y of an a n t i h y p e r t e n s i v e drug throughout the dos ing i n t e r v a l should be examined. The T r o u g h - t o - P e a k (TP) r a t i o ( f a l l in BP a t the end o f the dos ing i n t e r v a l : maximum f a l l in BP) has been proposed as a t e c h n i q u e t g e v a l u a t e t h i s p r o p e r t y ; a TP r a t i o o f 40% has been proposed t o be r e a s o n a b l e . F e l o d i p i n e i s a d i h y d r o p y r i d i h e c a l c i u m a n t a g o n i s t whose plasma c o n c e n t r a t i o n s c o r r e l a t e d with t h e f a l l s in BP. The TP r a t i o o f f e l o d i p i n e , , a d m i n i s t e r e d t w i c e d a i l y ( F - C T ) , as monotherapy and on a background o f b e t a - b l o c k a d e has been e v a l u a t e d . The TP^ r a t i o s shown below were c a l c u l a t e d from unrounded BP v a l u e s ; the d e c r e a s e s in BP shown have been rounded f o r c l a c i t y .

Trough mg BP ( 2 h r s ) ( 1 2 h r s ) Τ

Study η Drug bid Meas ( - mmHg) ( - mmHg) Rat i Monotherapy

A T 86 F-i

TP Ρ (%)

IS -CT 2 . 5 Sys Dia

5 Sys Dia

10 Sys Dia

Concomitant B e t a - B l o c k e r Theraff Β 74 F-CT 5 Sys

Dia 10 Sys

Dia 23 C 93 F-CT 2 . 5 Sys 16

Dia 13 5 Sys 24

Dia 17 10 Sys 26

Dia In t h e s e s t u d i e s , t h e TP V

r a t i o

9 59 6 58

14 61 5 44

12 53 9 58

18 65 12 57 19 55 14 60

8 48 8 60

14 58 8 47

12 48 9 54

range o f F-CT ( b i d ) a d m i n i s t e r e d as monotherapy (53%/44%-61%/58%) was s i m i l a r to t h a t on a background o f b e t a - b l o c k a d e (48%/47%-65%/60%). F-CT appears to demonstra te r e a s o n a b l e e f f i c a c y throughout the dosing i n t e r v a l when used a s ^ a f i r s t l i n e or second l i n e a n t i h y p e r t e n s i v e a g e n t . ^ m . J . H y p t . , 1 9 8 8 ; 1 ( 3 . 2 ) : 2 3 A

1 2 0 3

T h e T r o u o h - t o - P e a k R a t i o o f O n c e D a i l y E x t e n d e d - R e l e a s e F e l o d i p i n e A d m i n i s t e r e d a s M o n o t h e r a p y o r On a B a c k g r o u n d o f B e t a - B l o c k a d e DA S h a p i r o * , D. E l m f e l d t + , L. Mbberg+, E. S j o r g r e n + , B . Edgar+ , EP F a i s o n * , *Depts o f C l i n i c a l R e s e a r c h , Merck, Sharp and Dohme Research L a b o r a t o r i e s , West P o i n t , PA and + C a r d i o v a s c u l a r C l i n i c a l R e s e a r c h , A s t r a CV, AB H a s s l e , Molndal , Sweden. I t has been sugges ted by t h e U . S . Food and Drug A d m i n i s t r a t i o n t h a t t h e r e l a t i v e e f f i c a c y of an a n t i h y p e r t e n s i v e drug throughout t h e dos ing i n t e r v a l should be examined. The T r o u q h - t o - P e a k (TP) r a t i o ( f a l l in BP a t the end o f the dos ing i n t e r v a l : maximum f a l l in BP) has been proposed as a t e c h n i q u e t o e v a l u a t e t h i s p r o p e r t y ; a TP r a t i o o f 40% has been proposed t o be r e a s o n a b l e ' . F e l o d i p i n e i s a d i h y d r o p y r i d i n e c a l c i u m a n t a g o n i s t whose plasma c o n c e n t r a t i o n s c o r r e l a t e d with t h e f a l l s in BP. The TP r a t i o o f e x t e n d e d - r e l e a s e f e l o d i p i n e ( F - E R ) , a d m i n i s t e r e d once d a i l y as monotherapy and on a background o f b e t a - b l o c k a d e , has been e v a l u a t e d . The TP r a t i o s shown below were c a l c u l a t e d from unrounded BP v a l u e s ; the d e c r e a s e s in BP shown below have been rounded f o r c l a r i t y :

Study η Dn MppQtherapy

—Π • 100 F-ER 10

Copcomi t g n j Β 109 F-ER

BP Meas

Sys Dia Sys Dia

>cke Sys Dia Sys Dia Sys Dia Sys Dia Sys Dia

Peak Trough (2 h r s ) ( 2 4 h r s )

( - mmHg) ( - mmHg)

16 14 22 17

rapy 19 30 21 32 22 12 30 16 31 19

9 7

12 7

14 22 18 26 11 6

15 9

15 10

TP R a t i o (%)

58 48 56 43

74 73 86 81 49 51 51 39 49 54

In t h e s e s t u d i e s the TP r a t i o range of F-ER a d m i n i s t e r e d as monotherapy ( 5 6 / 4 3 % - 5 8 / 4 8 % ) was s i m i l a r t o t h a t on a background o f b e t a - b l o c k a d e ( 4 9 / 3 9 % - 8 6 / 8 1 % ) . F-ER appears t o demonstra te r e a s o n a b l e e f f i c a c y throughout the dos ing i n t e r v a l when used as f i r s t or second l i n e t h e r a p y . 'Am J . H y p t . , 1988 ; 1 ( 3 . 2 ) : 23A.

1 2 0 5

EXERCISE AND CIRCULATING ATRIAL NATRIURETIC FACTOR IN HEALTHY OLDER MEN TP Miller, RW Squires, PJ Rogers, AA Bove, JC Burnett Jr*, Mayo Clinic, Rochester, Minnesota.

Previous studies examining the effects of exercise on circulating atrial natriuretic factor (ANF) have shown ANF increases during acute exercise in both healthy younger subjects and older patients with various cardiovascular disorders. Furthermore, the rise in ANF during acute exercise may be blunted in well-trained individuals. Our purpose in this study was twofold: (1) to determine the ANF response to acute exercise in a healthy older population and (2) to determine if exercise training (ET) modulates ANF release both at rest and during exercise. Seventeen healthy men ages 52 to 75 underwent 16 weeks of stationary cycle ET. Each subject performed graded cycle ergometry to exhaustion both pre (Tl ) and post (T2) training. Peak oxygen uptake increased from 21.3 to 25.7 ml 0 2/kg/min (p<0.005). ANF was measured at rest (A), submaximal exercise (B), peak exercise (C), and recovery (D) (expressed as pg/ml, rne^n ± SD):

A B C D ANF (Tl) 41~F"22 40~£~16 55~ ϊ~24* 60~F"29* ANF (T2) 44 ± .141-47 ± 29t 65 ± 39#t 74 ± 35*t *p<.05 vs A; #p<.06 vs A; tp=NS vs Tl

We conclude: 1) ANF increases modestly during maximal exercise in healthy older men. 2) ET does not significantly alter rest or exercise ANF.

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11206| Ca ACTIVATION KINETICS OF Ca-ATPASE IN PLASMA MEMBRANES (PM) OF PLATELETS FROM ESSENTIAL HYPERTENSIVES (EH). J Takaya, Ν Lasker,* Μ Gutkin*, LH Byrd*, Β Fine*, A Aviv*. Hypertension Research Center, NJ Medical School, Newark, ΝJ.

Previous studies examined the Ca-ATPase in homogenates of p l a t e l e t s from EH. To explore the etiology of al tered Ca metabolism in EH, we studied parameters (Vmax and Km) of Ca act ivation kinetics of Ca-ATPase in purified PM (isolated by a sucrose gradient) from p l a t e l e t s of 20 EH, 10 normotensives with family history of HT (NT+) and 10 normotensives without family history of HT (NT-). Ca act ivation of the enzyme in a l l subgroups demonstrated negative cooperativity. Vmax values (mean ± SEM) were: HT=14 .0±2 .2 , NT+=22.4± 4 . 4 and NT-=29.8 ± 5 . 5 nmol Pi/mg prot/min (overa l l p=.011 by one way ANOVA). For the entire group, the systol ic BP was inversely related to the Vmax (p< .05 ) . There were no differences in the Km among the subgroups. (HT-1.9 ± .29 , NT+=1.5 ± .35 , and NT-=2.8± .56 uM). However, the plasma

renin a c t i v i t y (PRA) was inversely related to the Km in whites (p< .05 ) , but not in blacks. A tendency for a negative relat ion between PRA and Km of the Ca-pump in erythrocytes was also observed recently by Delsiera et a l ( to be presented in this meeting). Our findings indicate a primary defect in the a c t i v i t y of the Ca-pump in p l a t e l e t PM of HT that can explain the elevated cytosolic Ca in these c e l l s . Moreover, because a r i se in cytosolic Ca retards renin release from juxtaglomerular (JG) c e l l s , the inverse re la t ion between PRA and the Km for p l a t e l e t PM Ca-ATPase suggests that the Km for the enzyme is similar in platel e t s and JG c e l l s .

|1208|

CHROMAKALIM, A POTASSIUM CHANNEL ACTIVATOR, ANTAGONIZES PRESSOR RESPONSES IN PITHED RATS. R.W. Lappe*. J . L . Dinish and G. Oshiro. Division of Experimental Therapeuties, Wyeth-Ayerst Research, Princeton, N.J.

Previous studies have indicated that chromakalim (C), a novel vasodilator, could reduce mean arterial pressure by 30% (ED3q) at intravenous doses of 80 pg/kg in conscious spontaneously hypertensive rats . The present study was designed to examine the effects of C on vascular responses to vasoconstrictor stimuli in pithed rats . Pressor responses to graded electrical stimulation of the sympathetic nerves (spinal cord stimulation) or intravenous injection of increasing doses of norepinephrine (NE) or angiotensin II (All) were recorded before and after intravenous administration of vehicle (20% ethanol in saline) or C (1-250 Mg/kg). Nerve stimulation, NE and All caused frequency- or dose-related increases in mean arterial pressure prior to C injection. After administration of C at doses as low as 1 pg/kg, neurally-mediated pressor responses were significantly attenuated in the pithed rats, but responses to NE and All were not altered. At higher doses (80 or 250 pg/kg), C markedly inhibited the pressor actions of NE (decrease=-58±7%), AH (decrease=-61±16%), and sympathetic nerve stimulation (decrease=-64+l1%). Vehicle failed to alter the pressor responses to the vasoconstrictor stimuli. These data indicate that C attenuated the pressor actions of endogenous vasoconstrictor agents in the pithed rat . As these effects were observed at doses at or below the ED3Q dose of C, the suppression of vascular reactivity to pressor stimuli may contribute, in part, to the hypotensive actions of the potassium channel activator.

11207 COMPARISON OF THE RENAL EFFECTS OF THE POTASSIUM CHANNEL ACTIVATORS, PINACIDIL AND CHROMAKALIM, IN ANESTHETIZED DOGS. M. Desiato. L. Rovnyak and R.W. Lappe*. Division Exper. Therap., Wyeth-Ayerst Res., Princeton, N.J. Administration of pinacidil (P) in hypertensive patients has been assoicated with a relatively high incidence of salt and water retention. In the present study, renal responses to Ρ were compared to the renal actions of an equi-depressor dose of chromakalim (C) in pentobarbital-anesthetized dogs. Dogs received a single intravenous injection of Ρ (0.3mg/Kg), C (0.06mg/Kg) or vehicle (V; 1 ml ethanol+0.5 ml saline) and changes in renal function were monitored for 2 hours. Ρ and C reduced mean arterial pressure (Max Change = -21+ 4 and -29+3 mmHg, respectively) and renal vascular resistance (Max change=-27+6% and -34+8%, respectively) and increased heart rate. V had no effect on renal hemodynamics. Urine volume (UV) and sodium excretion (UNaV) were significantly reduced in the P-treated dogs. In contrast, UV and UNaV did not vary from pre-dose baseline values in the C-treated dogs. V modestly elevated UV and UNaV over the course of the experiment. V,C and Ρ produced similar increases in urinary potassium excretion. Plasma renin activity was increased after injecton of Ρ and C These data support the salt retentive actions of Ρ observed in the cl inic . Furthermore, the present study suggests that the untoward renal side effects observed with Ρ may be reduced or absent with C therapy.

• I 12091 MORPHINE STIMULATION OF ANF SECRETION. TE__0aks_, JA Magovern, GA Prophet, CA Miller, WS Pierce. College of Medicine, Pennsylvania State Univ., Hershey, PA.

The major stimulus to secretion of atrial natriuretic factor (ANF) is an increase in atrial pressure. However, the secretion of ANF also may be influenced by a varietv of drugs. Morphine has been shown to markedly increase ANF levels in rats. The reason for this increase is unknown since hemodynamic parameters have not been recorded. Some investigators have proposed a direct drug effect of morphine for ANF secretion. Accordingly, we studied the effect of morphine on ANF secretion in a large animal model and determined the relationship between ANF secretion and hemodynamic parameters. Adult mongrel dogs (n=5) were given morphine, 2 mg/kg, intravenously. ANF, heart rate (HR), mean arterial pressure (MAP), and central venous pressure (CVP) were measured at baseline and 5, 15, 30, 45, and 60 min following, morphine administration. (Date expressed as per cent of baseline (mean±SEM)):

Time Δ ANF Δ HR Δ MAP Δ CVP 5 114±24 -31±6 18±10 107±76

15 62±21 -35±7 11±10 87±54 30 45±28 -35±8 7±9 9C±59 45 24±13 -40±7 6±9 84±5C 60 19±10 -40±6 5±8 100±42

ANF levels were significantly elevated at 5 and 15 min, however, there was no correlation between Δ ANF and Δ HR, Δ MAP, or Δ CVP. We conclude that morphine causes an increase in circulating ANF levels which is not due to changes in HR. MAP, or CVP. Morphine may increase ANF levels by a direct drug effect.

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EFFECTS OF AN ORAL LOAD OF SODIUM ON POSTPRANDIAL PLASMA ATRIAL NATRIURETIC FACTOR (ANF) AND SODIUM EXCRETION IN DOGS WITH CHRONIC HEART FAILURE. D _ Villarreal*.R.Η. Freeman*. University of Missouri and H.S. Truman VA Hospital, Columbia, MO.

Previous studies in normal dogs demonstrated significant parallel increments in the concentration of plasma ANF (33+4 to 48+8pg/ml, p<0.05) and sodium excretion (14+9 to 171+29 /xEq/min, p<0.05) which reached maximal values 240 min postprandially after a meat meal containing 125mEq of sodium. In the present experiment, the same meat meal containing 125mEq sodium was fed to dogs (n=5) with an arteriovenous (AV) fistula and chronic compensated high output heart failure. Following ingestion of the meal, parallel increments were observed in the concentration of plasma ANF, sodium excretion and right atrial pressure. The peak changes were measured 180 min after the meal. Plasma ANF increased from high basal levels of 506+46pg/ml to reach 728+43pg/ml (p<0.05), an increase of 222pg/ml (+44%), while urinary sodium excretion increased from 15+3 to 187+40μΕς/πιιη (p<0.05). Right atrial pressure increased from a high basal value of 9 . 6+0. 5cmH 20 to a maximum of 10. 4+0. 6 cmH 20 (p<0.05). Total urinary sodium excretion averaged 40+4mEq over 6hrs in the normal dogs and 42+9mEq in the AV fistula dogs. These results suggest that the physiological natriuretic response to a meat meal containing 125mEq sodium in dogs with chronic compensated heart failure is not different from the natriuretic response obtained in normal dogs. However, the renal natriuretic response in the AV fistula dogs was associated with a greater increment of plasma ANF compared to the normal dogs.

1 2 1 2

EFFECT OF SUPERIMPOSED HYPERTENSION ON RENAL FUNCTIONS IN RHESUS MONKEYS WITH CHEMICAL OR SURGICAL DIABETES MELLITUS. EG John---, LC F o r n e l l , A Bauman, 0 J o n a s s o n . D e p t . o f P e d i a t r i c s , U n i v e r s i t y o f I l l i n o i s a t C h i c a g o , C h i c a g o , 1 1 1 .

P a t h o g e n e s i s o f e n d - s t a g e d i a b e t i c nephropathy remains c o n t r o v e r s i a l . All h y p e r g l y c e m i c type I d i a b e t e s m e l l i t u s (DM) p t s do not deve lop DM n e p h r o p a t h y .

Vie s t u d i e d t h e e f f e c t o f h y p e r t e n s i o n ( H T N ) on r e n a l f u n c t i o n s ( i n d u c e d by f 1 u d r o h y d r o c o r t i s o n e and high s a l t i n t a k e ) in r h e s u s monkeys made d i a b e t i c by s t r e p t o z o t o c i n a d m i n i s t r a t i o n (50 mg/Kg) o r p a n c r e a t e c t o m y ( D M ) ; small d o s e s o f i n s u l i n ( 2 - 1 7 u/d) was g i v e n t o p r e v e n t k e t o a c i d o s i s . Three groups were s t u d i e d : normal monkeys ( 1 ) , DM a l o n e ( 2 ) , DM+IITN ( 3 ) ; a v e r a g e d u r a t i o n o f DM was 10±6 y r s . Renal f u n c t i o n was measured by c l o f i l c l e a r a n c e (Cgl ml /min/SOM?) , PAH c l e a r ance (CPAH ml/min/50M,2) and 24 hr u r i n e p r o t e i n (UTP, mg) ; r e n a l b i o p s y was done t o a s s e s s h i s t o l o g i c a l c h a n g e s . R e s u l t s a r e g i v e n as M±SE. P < . 0 5 , *C vs Of;, * *C vs D M + N T N , tDM vs DM+NTN.

CPAH Cgl UTP BP T u f t Vol (TFV)

1 178± 6 75± 2 0 . 0 5 ± . 0 0 7 84± 1 898± 84 2 2 2 6 ± 1 0 * 117± 6 * 0 . 2 5 ± . 0 8 * 87± 2 * 2371± 2 7 9 * 3 165±15 6 5 ± l l t 0 . 5 4 ± . 2 * * 1 1 9 ± 1 6 * t 4 4 9 5 ± 2 1 8 2 * *

Blood sugar was s i g n i f i c a n t l y high in DM and DM+NTN ( 3 2 6 ± 1 7 , 2 2 6 ± 8 mg%) compared t o C ( 6 6 n i a c in DM, CPAII, C g l , UTP and TFV was high ( P < . 0 5 ) . In DM+Η.ΤΠ, Cgl was lower than in DM ( P < . 0 5 ) . In DM+KTN, a t w o - f o l d i n c r e a s e in u r i n e p r o t e i n and TFV was noted compared t o DM. In c o n c l u s i o n , HTN when superimposed on DM produces d e c l i n e in GFR and worsens p r o t e i n u r i a and r e n a l h i s t o l o g i c a l c h a n g e s .

1 2 1 1

THE EFFECT OF PROSTAGLANDIN El ANALOG MIS0PR0T0L ON ACUTE CYCLOSPORIN NEPHROTOXICITY. EG J o h n * , LC F o r n e l l , S A n u t r a k u l c h a i , 0 J o n a s s o n . D e p t . o f P e d i a t r i c s , U n i v e r s i t y o f I l l i n o i s a t C h i c a g o , C h i c a g o , I l l i n o i s .

C y c l o s p o r i n i s used e x t e n s i v e l y in t h e t r e a t ment o f organ t r a n s p l a n t a t i o n and in v a r i o u s imm u n o l o g i c a l d i s e a s e s . CSA produces reno.l d y s f u n c t i o n and v a s o c o n s t r i c t i o n which has been a t t r i b u t e d t o changes in v a s o d i l a t o r y p r o s t a g l a n d i n s (VDP).

We i n v e s t i g a t e d t h e e f f e c t o f i n t r a v e n o u s ( I V ) i n f u s i o n o f p r o s t a g l a n d i n El a n a l o g , m i s o p r o s t o l (MS) ( 1 0 0 ug/Kg o v e r 20 min) on a c u t e IV CSA ( 2 0 mg/Kg, o v e r 20 min) induced r e n a l d y s f u n c t i o n s . Two t o t h r e e 10 min u r i n e c o l l e c t i o n s and mid p o i n t b lood samples were o b t a i n e d in two groups o f r a t s , b e f o r e (C) and f o l l o w i n g (Ε) IV i n f u s i o n o f CSA a l o n e (group I n=6) o r MS i n f u s e d c o n c u r r e n t l y with CSA (group I I n = 6 ) , f o r measurements o f GFR ( I o t h a l a m a t e method, m l / m i n ) , and PAH c l e a r a n c e (CPAH, m l / m i n ) ; b lood p r e s s u r e was m o n i t o r e d c o n t i n u o u s l y . R e s u l t s a r e g i v e n as M±SE; *P v a l u e < . 0 5 i s c o n s i d e r e d s i g n i f i c a n t .

In group I , CSA caused a s i g n i f i c a n t d e c r e a s e in GFR (C 1 . 0 7 ± . 1 4 , Ε 0 . 5 5 ± . 0 6 ) * , CPAH (C 1 . 9 ± 0 . 1 9 , Ε 1 . 0 8 ± 0 . 1 3 ) * and an i n c r e a s e in b lood p r e s s u r e (C 7 5 ± 3 , Ε 8 6 ± 3 ) * . In group I I , MS p r e v e n t e d CSA induced d e c r e a s e in GFR (C 1 . 0 5 ± . 0 9 , Ε 1 . 1 0 ± . 1 5 ) and CPAH (C 2 . 1 5 ± . 2 2 , Ε 1 . 8 6 ± . 2 7 ) . Γ IS a l s o b l u n t e d t h e h y p e r t e n s i v e e f f e c t (C 6 9 ± . 3 , Ε 7 3 ± . 4 ) o f CSA during i n f u s i o n . In c o n c l u s i o n , MS p r e v e n t e d a c u t e CSA i n f u s i o n r e l a t e d r e n a l d y s f u n c t i o n and h y p e r t e n s i o n .

112131 O C C U P A T I O N A L A N D G E O G R A P H I C M O B I L I T Y : E E E E C T S

O N B L O O D P R E S S U R E . T . E . O b s t , V . K r o g h , Π .

T r e v i s a n * , W . W i n k e l s t e i n . S t a t e U n i v e r s i t y

o f N e w Y o r k a t B u f f a l o , B u f f a l o , N Y .

S e v e r a l s t u d i e s d e a l i n g w i t h t h e r e l a t i o n

s h i p b e t w e e n p s y c h o s o c i a l a n d s o c i o e c o n o m i c

v a r i a b l e s a n d c o r o n a r y h e a r t d i s e a s e c o n t a i n

d a t a s p e c i f i c t o t h e r o l e o f o c c u p a t i o n a s

a r i s k f a c t o r . O c c u p a t i o n a l l o n g e v i t y ^ n u m b e r s

o f j o b s , e m p l o y m e n t m o b i l i t y , a n d o c c u p a t i o n a l

i n s t a b i l i t y h a v e b e e n a s s o c i a t e d w i t h c o r o n a r y

h e a r t d i s e a s e o r i t s r i s k f a c t o r s . T h i s s t u d y

e x a m i n e d t h e e f f e c t s o f o c c u p a t i o n a l m o b i l i t y

a n d g e o g r a p h i c m o b i l i t y o n b l o o d p r e s s u r e .

T h e s a m p l e c o n s i s t e d o f 4 7 3 c u r r e n t l y - e m p l o y e d

w h i t e m a l e s a g e d 2 0 - 7 0 y e a r s w h o w e r e p a r t i c i

p a n t s i n t h e B u f f a l o B l o o d P r e s s u r e S t u d y .

I n d i c e s o f o c c u p a t i o n a l n o b i l i t y i n c l u d e d :

n u m b e r o f o c c u p a t i o n s , f r e q u e n c y o f e m p l o y m e n t

w i t h i n l o n g e s t o c c u p a t i o n a l s e t t i n g , a n d t h e

f r e q u e n c y o f e m p l o y m e n t o u t s i d e t h e l o n g e s t

o c c u p a t i o n a l s e t t i n g . I n d i c e s o f g e o g r a p h i c

m o b i l i t y i n c l u d e d : t h e n u m b e r o f c i t i e s a n d

s t a t e s i n w h i c h t h e r e s p o n d e n t h a d f o u n d e . i p l y - -

m e n t , t o t a l n u m b e r o f l o c a t i o n c h a n g e s d u r i n g ,

a d u l t h o o d , a n d t h e t o t a l n u i o r o f l o c a t i o n

c h a n g e s w h i c h l a s t e d g r e a t e r t h a n o n e y e a r .

U s i n g a n a l y s i s o f v a r i a n c e , a n d a d j u s t i n g f o r

a g e , r e l a t i v e w e i g h t , a n d e d u c a t i o n , n o r e l a

t i o n s h i p w a s f o u n d ' . e t w e e n a n y o f t h e i n d i c e s

o f o c c u p a t i o n a l / g e o g r a p h i c m o b i l i t y a n d m e a n

s y s t o l i c o r d i a s t o l i c b l o o d p r e s s u r e s . T h e s e

f i n d i n g s f r o m a p o p u l a t i o n - b a s e d s t u d y i n d i c a t e

t h a t i n c r e a s e d g e o g r a p h i c o r o c c u p a t i o n a l m o b i l

i t y i s n o t a s s o c i a t e d w i t h i n c r e a s e d b l o o d

p r e s s u r e .

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112141

THE ASSOCIATION BETWEEN BIRTH ORDE?. ΑΓΪΡ BLOOD PRESSURE. FINDINGS FROM THE BUFFALO LLOC-PRESSURE STUDY. L.L. Klirnowski, M. Trevisan*, V. Kro.gh,, W. W i n k e l s t e i n . State University of New York at Buffalo, Buffalo, NY.

An investigation on the relationship of birthorder to blood pressure was conducted on a representative sample of 676 white males and 796 white f e m a l e s s aged 20 to 70 years, who participated in the Buffalo Blood Pressure Study. Analysis of variance, considering relevant covariates such as. age. relative weight, education, and smoking s t a t u s ; revealed that only children (both male and female) had statistically significant higher mean systolic blood pressure (SBP) and diastolic blood . r e 3 -sure (DBP) values than participants with siblings. Previous findings from longitudinal studies have shown that only children experience higher mortality from coronary disease than those with siblings. The present findings suggest that this excess coronary heart disease mortality could be due, at least in ..art, to a high level of blood pressure in only children.

11216| SODIUM-POTASSIUM COTRANSPORT AND BLOOD PRESSURE: FINDINGS FROM THE GUBBIO POPULATION STUDY. M ^ Trevisan*, M. Laurenzi, V. Krogh, on behalf of the Gubbio Collaborative Study Group. State University of New York at Buffalo, Buffalo, NY.

The maximal velocity of the sodium-potassium cotransport (Na,K COT) in erythrocytes was determined in 553 males and females age 5 and over participating in the Gubbio Epidemiological Study on Hypertension. Men, on the average, had higher Na,K COT than women over the age range 15 to 6 4 . In the population as a whole, Na,K COT was significantly and directly related with body mass index and diastolic blood pressure in m a l e s , only with body mass index in females. In men age 25 to 6 4 , hypertensives exhibited higher mean Na,K COT than normotensives (.780 v s . .925 mmol/1 R B C / h r ) , while no differences were detected between hypertensive and normotensive w o m e n . This difference in Na,K COT between hypertensive and normotensive men was not independent of the confounding effect of age and body mass index. These findings from a population-based study indicate that the m a x i mal velocity of sodium-potassium cotransport is increased in hypertensive compared to normotensive men, but that this increase is largely due to differences in age and adiposity between these two groups.

1215 SLEEP PATTERNS AND BLOOD PRESSURE-RESULTS FROM THE BUFFALO BLOOD PRESSURE STUDY. M . L . Doemland, M. Trevisan*, V. Krogh, W. W i n k e l s t e i n . State University of New York at Buffalo, Buffalo, NY.

The relationship of sleep pattern and blood pressure has predominately been studied in c l i n i cal settings using individuals with frank sleep disorders or hypertension. The relationship b e tween sleep patterns and blood pressure in the general population is not known. We report here the findings from a population-based sample of 791 white males and 919 white females aged 15 to 80. Each study participant was interviewed in their home and 3 standardized blood pressure measures were takien during the interview. Questions concerning bedtime, time to fall asleep, waking at night, time up at night and napping habits defined sleep p a t t e r n s . Univariate analysis resulted in statistically significant differences between males and females regarding sleep p a t t e r n s . Females woke more during the night, went to bed later and slept less than m a l e s . The univariate relationship between mean blood p r e s s ures and sleep patterns were inconsistent for m a l e s , i.e., no apparent trend, while for females the mean blood pressure went up with greater time awake in the middle of the night and taking more than 30 minutes to fall asleep. Analysis of v a r i ance, controlling for age, weight and smoking behavior did not, however, provide any consistent statistically significant findings. The findings from this population-based study do not support a relationship between sleep pattern and blood pressure.

112171

ERYTHROCYTE SODIUM AND POTASSIUM CONTENT AND BLOOD PRESSURE IN A POPULATION-BASED STUDY. M ^ Laurenzi, M. Trevisan*, V. Krogh. On behalf of the Gubbio Collaborative Study Group, Center for Epidemiological Research, Merck Sharp & Dohme, Rome, Italy.

The erythrocyte sodium (RBC Na) and potassium (RBC K) content was determined in approximately 2500 males and females age 5 and older p a r t i c i p a ting in the Gubbio Epidemiological Study on Hypertension. Mean RBC Na was higher in men compared to women in the age range 15-54. Mean RBC Κ was higher in women than men in all age g r o u p s . In the population as a whole, RBC Na was p o s i tively associated with age, body mass index, plasma sodium and blood pressure in females, while no meaningful univariate correlation was detectable in men. RBC Κ was negatively associated with mean hemoglobin concentration and h e matocrit in both sexes. In univariate analyses in participants 55 years and older, RBC Na was higher in hypertensives compared to normotensives in both sexes, while RBC Κ was lower in hypertensive m e n . Adjustment for possible confounding effect of age and body mass index did not change the results. These findings from a population-based study indicate that RBC Na is increased in middle-aged and older hypertensives compared to normotensives in both sexes, while RBC Κ is lower in hypertensive men.

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11218| SOCIAL NETWORK AND BLOOD PRESSURE. S.H. Bland, Μ. Trevisan-', V. Krogh, W. Winkelstein. State University of New York at Buffalo, Buffalo, NY.

Social network (SN) variables such as marital status and church and group membership have been shown in past prospective studies to be associated with all-cause mortality as well as CHD mortality. Studies of special populations have assessed effects of such variables on blood pressure. The present study demonstrates the relationship between SN variables and blood pressure (SBP;DBP) in a representative sample of 1201 white males (583) and females (618) aged 20-70 years who participated in the Buffalo Blood-

Pressure Study. Regression analyses (controlling for the effects of sex, age, weight, smoking and education) revealed a significant relationship between increased social network and lower levels of BP. Factor analysis on the 13 SN variables resulted in three factors describing social network: factor 1-membership in clubs and lodges and meeting attendance; factor 2-church attendance; factor 3-participation in pastoral activities such as watching television, fishing and sewing. Factor 1 was significantly associated with lower SBP in males and lower SBP and DBP in females. These data demonstrate that social network is associated with BP.

1 2 2 0

A N T I H Y P E R T E N S I V E A C T I V I T Y OF Q U I N A P R I L I N CONSCIOUS SPONTANEOUSLY H Y P E R T E N S I V E R A T S . hJL R y a n , B . O l s z e w s k i a n d D. T a y l o r . P a r k e - D a v i s P h a r m . R e s . D i v . , W a r n e r - L a m b e r t C o . , A n n A r b o r , M I 4 8 1 0 5 .

Q u i n a p r i l ( Q ) , a p o t e n t i n h i b i t o r o f a n g i o t e n s i n c o n v e r t i n g e n z y m e , i s u n d e r g o i n g c l i n i c a l e v a l u a t i o n f o r t h e t r e a t m e n t o f h y p e r t e n s i o n . T h r e e s t u d i e s w e r e u n d e r t a k e n i n t h e s p o n t a n e o u s l y h y p e r t e n s i v e r a t ( S H R ) t o c h a r a c t e r i z e t h e a n t i h y p e r t e n s i v e r e s p o n s e o f Q i n a n o r m a l r e n i n m o d e l . T h e f i r s t s t u d y e s t a b l i s h e d a n a c u t e d o s e -r e s p o n s e t o s i n g l e o r a l d o s e s o f Q . D o s e s o f 0 . 3 , 1 , 3 , a n d 1 0 m g / k g c a u s e d r e d u c t i o n s i n b l o o d p r e s s u r e ( B P ) o f 1 1 + 2 , 1 7 + 7 , 2 8 + 8 , a n d 2 9 + 4 mm Hg ( N = 4 - 5 ) , r e s p e c t i v e l y f r o m a n a v e r a g e p r e t r e a t m e n t BP o f 1 7 0 + 3 mm Hg ( N = 1 9 ) . I n t h e s e c o n d s t u d y , Q w a s g i v e n o n c e d a i l y f o r 14 d a y s a t 1 a n d 3 m g / k g / d a y ( N = 1 3 - 1 4 ) . M a x i m u m r e d u c t i o n s i n BP o f 2 9 a n d 4 5 mm Hg w e r e o b s e r v e d b y d a y 3 a n d w e r e m a i n t a i n e d up t o d a y 1 4 . A t h i r d s t u d y e v a l u a t e d t h e a n t i h y p e r t e n s i v e e f f e c t s o f Q ( 0 . 3 m g / k g / d a y ) w h e n g i v e n i n c o m b i n a t i o n w i t h h y d r o c h l o r o t h i a z i d e ( H C T Z , 3 0 m g / k g / d a y ) f o r 3 c o n s e c u t i v e d a y s . Two h o u r s a f t e r t h e f i r s t d o s e BP w a s u n c h a n g e d w i t h e i t h e r Q ( 0 . 3 m g / k g / d a y ) o r HCTZ ( 3 0 m g / k g / d a y ) t r e a t m e n t a l o n e , b u t t h e c o m b i n a t i o n o f Q p l u s HCTZ r e d u c e d BP 2 4 mm H g . By t h e t h i r d d a y , e i t h e r Q o r HCTZ a l o n e r e d u c e d BP 2 5 mm Hg a t 2 h o u r s , w h i l e t h e c o m b i n a t i o n r e d u c e d BP 4 9 mm H g . T h e s e r e s u l t s d e m o n s t r a t e t h a t Q w h e n a d m i n i s t e r e d a t a l o w d o s e a c u t e l y i n c o m b i n a t i o n w i t h HCTZ h a s s y n e r g i s t i c a n t i h y p e r t e n s i v e a c t i v i t y , b u t w i t h r e p e a t e d d o s i n g t h e e f f e c t o n BP o f Q p l u s HCTZ i s a d d i t i v e . A t h i g h e r d o s e s w h e n g i v e n f o r u p t o 2 f u l l w e e k s , Q a l o n e h a s a n t i h y p e r t e n s i v e e f f i c a c y e q u a l t o t h a t o b t a i n e d w i t h t h e c o m b i n a t i o n .

|1219| RELATION BETWEEN AMBIENT TEMPERATURE AND BLOOD PRESSURE. K. Falkner, Μ. Trevisan*, Μ. Laurenzi, V. Krogh, on behalf of the Gubbio Collaborative Study Group. State University of New York at Buffalo, Buffalo, NY.

This investigation focuses on the relationship between blood pressures and ambient temperatures in the participants of a large epidemiological study. The present analyses focus on 1675 females and 1636 males, both normotensives and untreated hypertensives. Outside and inside ambient temperature was measured on a daily basis as part of the blood pressure measurement protocol. Univariate analysis showed a strong significant negative relationship between outside and inside ambient temperature and blood pressure in both sexes. These associations were independent from the possible confounding effect of age, adiposity, smoking and education. Multivariate analysis indicates that inside ambient temperature was negatively associated with blood pressure independent from outside temperature. These findings indicate that in large epidemiological studies focusing on blood pressure, both inside and outside ambient temperature should be measured and their effect should be carefully considered and analyzed.

1 2 2 1 ACUTE AND SUSTAINED RENAL AND SYSTEMIC HEMODYNAMIC EFFECTS OF

LISINOPRIL IN ESSENTIAL HYPERTENSION.

J . P . D E G A U T E * . M.LEEMAN, C.REUSE, E . C A R L I E R , .

H y p e r t e n s i o n C l i n i c , E r a s m e U n i v e r s i t y H o s p i t a l , B r u s s e l s , B e l g i u m .

A c u t e and s u s t a i n e d r e n a l and s y s t e m i c hemodynamic e f f e c t s o f

L i s i n o p r i l ( L ) , a new ACE i n h i b i t o r , w e r e s t u d i e d i n 12 p a t i e n t s

w i t h e s s e n t i a l h y p e r t e n s i o n (EH) m a i n t a i n e d on a n o r m a l Na d i e t .

A f t e r a 2 week p l a c e b o r u n - i n p e r i o d , t h e a c u t e e f

f e c t s o f L w e r e e v a l u a t e d ( v i s i t l ) . A f t e r 2 b a s e l i n e d e t e r m i n a t i o n s

( H O ) , m e a s u r e m e n t s w e r e r e p e a t e d 2 , 4 and 6 ( H 6 ) h o u r s a f t e r o r a l

i n t a k e o f L 2 0 mg. S y s t o l i c and d i a s t o l i c b l o o d p r e s s u r e ( S B P , DBP)

and h e a r t r a t e (HR) w e r e d e t e r m i n e d u s i n g an o s c i I l o m e t r i c d e v i c e .

C a r d i a c o u t p u t ( C I ) was m e a s u r e d by D o p p l e r e c h o g r a p h y , r e n a l b l o o d

f l o w ( R B F ) and g l o m e r u l a r f i l t r a t i o n r a t e (GFR) by c o n s t a n t i n f u s i o n

t e c h n i q u e s u s i n g 1 2 3 I i o d o h i p p u r a t e and 5 1 - C r - E D T A r e s p e c t i v e l y .

The f i l t r a t i o n f r a c t i o n ( F F ) was c a l c u l a t e d . A f t e r 3 months o f L 2 0

mg o n c e - d a i l y , t h e same p r o t o c o l was r e p e a t e d ( V i s i t 2 ) .

R e s u l t s a r e e x p r e s s e d a s means ± SEM. * i n d i c a t e ρ < 0 . 0 5 H6 v s HO

and * * p< 0 . 0 1 H 0 ( v i s i t 2 ) v s H 0 ( v i s i t 1 ) .

v i s i t 1 ( V 1 ) v i s i t 2 ( V 2 ) HO H6 HO H6

SBP(mmHg) 1 6 2 ± 3 1 4 1 ± 3 * 1 4 1 ± 4 * * 1 3 6 ± 4 *

DBP(mmHg) 1 0 3 ± 2 8 8 ± 3 * 9 0 ± 3 * * 8 4 ± 3 *

H R ( b e a t s / m i n ) 7 5 ± 2 7 5 ± 2 7 3 ± 3 7 4 ± 3

C I ( L / m i n / m 2 ) 3 . 9 ± 0 . 3 3 . 8 ± 0 . 3 3 . 9 ± 0 . 3 4 . 0 ± 0 . 3

R B F ( m l / m i n / m 2 ) 3 8 6 ± 2 3 4 2 3 ± 2 7 * 4 0 8 ± 2 4 4 4 8 ± 3 8 *

G F R ( m l / m i n / m 2 ) 5 7 ± 2 5 5 ± 2 5 8 ± 3 5 6 ± 3

FF (%) 2 7 ± 1 2 4 ± 1 * 2 5 ± 1 2 2 ± 1 *

URINARY Na ( m e q / 2 4 h ) 1 1 3 + 1 8 1 3 3 ± 1 4

URINARY UREA ( g / 2 4 h ) 2 1 ± 3 2 3 ± 3

A c u t e a d m i n i s t r a t i o n o f L b o t h i n V1 and V2 r e s u l t e d i n a d e c r e a s e

o f b l o o d p r e s s u r e ( B P ) , w h i l e RBF i n c r e a s e d , GFR was n o t m o d i f i e d

and FF d e c r e a s e d . D u r i n g l o n g t e r m t r e a t m e n t , d e s p i t e t h e

p e r s i s t e n t f a l l i n BP, RBF and GFR w e r e m a i n t a i n e d .

I n c o n c l u s i o n , L i s an e f f e c t i v e a n t i h y p e r t e n s i v e a g e n t w i t h

p r e s e r v a t i o n o f r e n a l h e m o d y n a m i c s .

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PATTERNS OF DEVELOPMENT OF HYPERTENSION WITH RECOMBINANT HUMAN ERYTHROPOIETIN (rHuEPO) THERAPY: A PROSPECTIVE STUDY. N.R. H a l e v . R . C . D a v i d s o n * , J . W . E s c h b a c h , and J . W . Adamson, T. E a s t e r l i n g . U n i v . o f W a s h i n g t o n , S e a t t l e .

I n 35% o f h e m o d i a l y s i s p a t i e n t s (HDP) i n c l i n i c a l t r i a l s on rHuEPO (AMGEN, Thousand Oaks, CA), a r i s e i n h e m a t o c r i t (Hct ) l e d t o i n c r e a s e d b l o o d p r e s s u r e ( B P ) , i . e . a r i s e i n d i a s t o l i c BP > 1 0 mm o r an i n c r e a s e i n a n t i - h y p e r t e n s i v e d r u g s . HDPs w i t h a b a s e l i n e Hct <22 had an i n c r e a s e d r i s k f o r h y p e r t e n s i o n . I t was n o t c l e a r w h e t h e r o t h e r r i s k f a c t o r s were t h e d o s e o f rHuEPO a n d / o r t h e r a t e o f r i s e o f H c t . I n a p r o s p e c t i v e s t u d y , 20 p a t i e n t s r e c e i v e d e i t h e r 50 o r 150 u / k g rHuEPO IV t h r i c e w e e k l y . Hemodynamic p a r a m e t e r s were measured monthly ( U l t r a c o m , Lawrence M e d i c a l S y s . ) . In t h e 50 u / k g d o s e g r o u p , a l l 10 had i n c r e a s e d BP i n t h e f i r s t 3 months o f t r e a t m e n t , w i t h Hct r i s e from 1 9 . 7 ± 2 . 4 to 2 7 . 6 ± 2 . 9 . T h e i r t o t a l p e r i p h e r a l r e s i s t a n c e i n d e x (TPRI) r o s e from 1 4 2 9 ± 6 4 2 to 2 1 1 4 ± 4 3 6 . 7 . C a r d i a c i n d e x and s t r o k e i n d e x d e c r e a s e d . V a s o d i l a t o r t h e r a p y in f o u r p a t i e n t s between months 3 and 4 c o r r e c t e d t h e TPRI and BP t o w a r d s n o r m a l .

H y p e r t e n s i o n c a n d e v e l o p when Hct r i s e s due t o rHuEPO t h e r a p y i n HDPs, even w i t h a low d o s e . T r e a t m e n t i s more e f f e c t i v e when t h e hemodynamics o f t h i s p r o c e s s a r e m o n i t o r e d .

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ROLE OF VAGAL AFFERENTS AND EFFERENTS IN THE CARDIOVASCULAR AND RENAL RESPONSES TO IS0-rANP(17-46). DB Jennings*. S Behki, TG Flynn. Dept. of Physiology, Queen's Univ., Kingston, Ontario, Canada.

We previously confirmed the importance of vagal afferents in mediating the hypotension and bradycardia associated with a t r i a l nat r iuret ic p e p t i d e { r A N P ( 9 9 - 1 2 6 ) } . Furthermore, we demonstrated that most of the increase in urine flow and e l e c t r o l y t e excretion following injection of rANP(99-126) was also mediated by a vagal ref lex mechanism (Robertson et a l . , Physiologist 31:A2,1988) . The purpose of these studies was to examine the effec ts of vagotomy in pentobarbital anaesthetized ra ts on the cardiovascular and renal responses to a 10 μg (3nM) bolus injection of iso-rANP(17-46). Iso-rANP(17-46) injected into vagotomized rats caused an immediate decrease in mean a r t e r i a l pressure that returned to control by 5 min. However, the sustained hypotension and bradycardia observed with injections of iso-rANP in intact ra ts was abolished. Compared to intact studies, vagotomy had no ef fec t on the increase in urine and renal e lec t ro ly te excretion observed following iso-rANP(17-46) injection. As well, parasympathetic block with atropine did not effec t c irculatory or renal responses of iso-rANP(17-46). We can therefore report that unlike rANP(99-126), c i rculatory effec ts of iso-rANP(17-46) were not only mediated via vagal afferents , but by a direct mechanism and that a l l of the renal e f fec ts of iso-rANP(17-46) were direct ly mediated. Supported by Queen's Univ. and the Medical Research Council of Canada.

[12241

ATRIAL NATRIURETIC PEPTIDE IN THE HUMAN FETUS. J.Kingdom, A.Jardine, J.McQueen, ΜJ Whittle, JMC Connell. MRC Blood Pressure Unit, Western Infirmary, Glasgow, Scotland.

Atrial Natriuretic Peptide (ANP) was measured by radioimmunoassay in human fetal plasma obtained at umbilical cord sampling under ultrasound control for assessment of red cell isoimmunisation (n=ll) or karyotype analysis (n=9). Simultaneous maternal samples were taken and in 8 fetuses samples were taken before and after transfusion of 40-60 mis washed red cells. Gestational age ranged from 20-34 weeks.

Fetal ANP was significantly higher (153.4±14.6) than maternal (44.6±5.5 pg/ml, mean±SEM, P<0.001) suggesting active production by the fetus. In addition fetal levels were higher in the isoimmunised group than the karyotype analysis group (186.2±19.8 vs. 113.2±12.8, P<0.05). Blood transfusion increased plasma ANP from 183.3±87.1 to 307.31170.9 (P<0.05). These results demonstrate that ANP circulates in the human fetus and increases in response to intravascular volume expansion as in the adult. The higher plasma levels in red cell isoimmunisation may contribute to the development of oedema in this condition.

[12251

ATRIAL NATRIURETIC PEPTIDE (ANP) AND ANGIOTENSIN II (All) IN HUMAN PLACENTAL VASCULATURE. J.McQueen, A.Jardine, J.Kingdom, A.Templeton, ΜJ Whittle, JMC Connell. MRC Blood Pressure Unit, Western Infirmary, Glasgow, Scotland.

ANP receptors are present in the human placenta but their precise localisation and function is unknown. We have identified ANP and All receptors in membrane preparations of human fetoplacental vasculature. High and low affinity All receptors (K D 1.7nM, 15.2nM ) and ANP receptors (K D 0.2 nM, 70.2 nM ) were present. The number of high affinity All receptors was dependent on divalent cation concentration rising from 92.2±23.5 fmol/mg membrane protein (meantSE) in EGTA to 241.7±20.9 fmol/mg membrane protein in the presence of 12.5mM Ca 2 +.The numbers of high affinity ANP receptors (319.9±25.0 fmol/mg protein) or low affinity receptors of either type were not significantly altered by cation concentration.

Using the isolated human placenta perfused with HEPES buffered physiological solution at a flow rate of l-2mls/100g tissue/minute, bolus doses of All (10" 1 4-10" smoles) produced a dose-dependent increase in perfusion pressure. Bolus doses of ANP (3x10" 1 9-3xl0" 1 1moles) were ineffective alone but reduced the subsequent response to AII(10" 1 0moles) by up to 60%. Adding ANP (35pM) to the perfusate produced a significant reduction in the dose response curve to All. These findings suggest ANP and All may have a physiological role in the regulation of human fetoplacental blood flow.

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1122β| A VALIDATION STUDY OF THE INSTROMEDIX BARO-GRAF QD HOME BLOOD PRESSURE MONITOR. GD James*, LS Yee, EM Cates, YR Schlussel, MS Pecker*, TG Pickering*, Cardiovascular Center, Cornell Medical Center, New York, NY. The purpose of this study was to assess the accu

racy of the Instromedix Baro-Graf QD monitor. Forty subjects were studied who were divided among 3 blood pressure categories: Low (BP<110/70, N=ll); Medium (BP 110/70 to 140/90, N=17) and High (BP>140/90,N=12). Five seated readings were taken per subject. Accuracy was assessed by examining the differences between simultaneous auscultatory and machine readings using ANOVA and regression models .

Systolic(SP) Diastolic(DP)

X Difference % X Difference

L o w ^ Medium Hitfh*

-0.23+3.23 1.14+3.83 1.40+4.04

96 1.62+2.81 86 3.87+6.28 83 3.28+3.98

96 85 82

r=.99 r=.95 a-% of readings within 5mmHg b-Higher than Low group for both SP & DP, p<.05 The results showed that the device, while highly

accurate, tended to become less so as pressure increased. However, its accuracy at all levels of pressure is superior compared to most available home pressure devices, and because of features such as a computer memory that stores time and events as well as blood pressure, this monitor will be a useful tool for clinical studies of long term blood pressure changes.

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RADIOIMMUNOASSAY (RIA) FOR ENDOTHELIN AND IMMUNOREACTIVE (IR-) ENDOTHELIN IN CULTURE MEDIUM OF BOVINE ENDOTHELIAL CELLS Y Kato, Μ Naruse*, Κ Naruse*, F Kurimoto, J Horiuchi, ZP Zeng, Η Sakurai, Κ Shizume*. Dept. of Medicine, Inst, of Clinical Endocrinology, Tokyo Women's Medical College, Tokyo 162

Endothelin possesses a potent vasoconstrictive activity. In an attempt to elucidate a pathophysiologic significance of the peptide, we have developed a RIA of endothelin. Antibodies were generated in rabbits using synthetic endothelin (Peptide Institute, Osaka, Japan) conjugated to bovine thyroglobulin as antigen. The antiserum obtained was used at a final dilution of 1 : 1.5x10 5 yielding maximum binding of about 35% of 1 2 5I-endothelin (Amersham). The sensitivity of the RIA was 1 pg/tube with 50 % displacement at 35 pg/tube. Crossreactivity with angiotensin II, arginine vasopressin, and atrial natriuretic peptide was less than 0.001%. Endothelial cells of bovine pulmonary artery obtained from the ATCC were cultured in Eagle's MEM containing 10 % fetal bovine serum. Endothelin was extracted using Bondelute C~ cartridge. Ir-endothelin in the medium was 7.4 ng/ml. The dilution curves of the medium were parallel to the standard curve. In contrast, the fresh medium did not contain significant amount of ir-endothelin. The ir-endothelin in the medium was characterized by RP-HPLC and was found to be comprised of one major peak corresponding to synthetic endothelin. These results suggest that endothelin is released from the endothelial cells. The RIA for endothelin established could be a useful tool to clarify the pathophysiologic role of the peptide.

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IDENTIFICATION OF A C A R D I A C - S P E C I F I C R E G U L A T O R Y E L E M E N T IN T H E 5 1 - F L A N K I N G SEQUENCE OF THE HUMAN A T R I A L N A T R I U R E T I C FACTOR (hANF) G E N E . J P W u , DG G a r d n e r * . M e t a b o l i c R e s e a r c h U n i t , U n i v e r s i t y of California at San F r a n c i s c o , CA.

U s i n g d e l e t i o n a n a l y s i s , w e previously identified a c a r d i a c - s p e c i f i c , cis-acting DNA element w i t h i n a 68 bp fragment lying b e t w e e n -4 00 and -3 3 3 in the hANF g e n e . T h i s fragment confers c a r d i a c - s p e c i f i c expression upon a h e t e r o l o g o u s p r o m o t e r (i.e. t h ymidine kinase) w h e n placed in a t r a n s c r i p t i o n a l l y - c o r r e c t orientation u p stream from that s t r u c t u r e . Gel shift a n a lysis indicates that this region of the gene forms h i g h - a f f i n i t y associations with a subset of cardiocyte n u c l e a r proteins in a s e q u e n c e - and t i s s u e - s p e c i f i c fashion. W i t h m o r e refined analysis (i.e. DNAse I sensitivity and m e t h y l a t i o n i n t e r f e r e n c e ) , w e have identified a region of DNA-protein association b e t w e e n -369 and -352 relative to the CAP site. M u t a t i o n s (15 bp) introduced into this region eliminate the functional activity of this c i s - e l e m e n t . O l i g o n u c l e o t i d e s spanning this protected region (positions -377 to -338) r e c o n stitute the functional activity and a s s o ciate w i t h cardiocyte nuclear p r o t e i n s in a sequence-specific fashion. The results suggest that cardiac specific expression of the hANF gene d e r i v e s , at least in p a r t , from the interaction of cis-acting DNA elements p r e s e n t in the 5 1 - F S of the gene w i t h specific trans-acting nuclear p r o t e i n s p r e s e n t in m y o c a r d i a l c e l l s .

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DETERMINATION OF PLASMA INACTIVE RENIN BY A COMBINED USAGE OF DIRECT IMMUN0RADI0METRIC ASSAY OF ACTIVE RENIN AND TRYPSIN ACTIVATION Κ Naruse*, Μ Naruse*, Κ Shizume* Dept. of Medicine, Inst, of Clinical Endocrinology, Tokyo Women's Medical College, Tokyo 162, Japan

Plasma inactive renin has a potential clinical significance. In the present study, plasma inactive renin was determined by a combination of direct immunoradiometric assay and trypsin activation. Plasma samples were obtained from normal subjects and patients with essential hypertension (EH)(n=27), primary aldosteronism (n=9), Cushing's syndrome (n=6), renovascular hypertension (n=1l), renin producing tumor(n=4), Bartter's syndrome (n=12), and diabetes mellitus (n=52). Plasma renin concentrations were measured by direct immunoradiometric assay kits (Diagnostic Pasteur) before and after trypsin activation. Inactive renin concentrations were estimated by subtracting the renin concentration before activation from that after activation. Inactive renin concentrations were decreased in patients with low renin type of EH and primary aldosteronism. Inactive renin concentrations did not show a significant change in patients with high renin type of EH and renovascular hypertension. In contrast, inactive renin as well as active renin concentrations were markedly elevated in patients with renin producing tumor. In addition, inactive renin concentrations were increased in patients with diabetes mellitus, especially in those with diabetic neuropathy. These results suggest that determination of plasma inactive renin concentrations is useful for a differential diagnosis of' high renin type hypertension and also for a detection of neuropathy in diabetic patients.

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112301 EFFECTS OF ENDOTHELIN ON SYSTEMIC HEMODYNAMICS AND RENAL FUNCTIONS IN ANESTHETIZED DOGS Μ Naruse*, Κ Tsuchiya 1 , Τ Sanaka 1, Κ Naruse*, ZP Zeng, Κ N i t t a 1 , Ν Sugino 1, Κ Shizume*. Dept. of Medicine, Inst . of Clinical Endocrinology, and ^ e p t . o f Medicine, Kidney Center, Tokyo Women's Medical College, Tokyo 162, Japan.

Endothelin, a potent vasoactive peptide with 21-amino acids sequence, has been purified from the culture medium of the porcine endothelial c e l l s . In the present study, the effects of endothelin on systemic hemodynamics and renal functions were investigated in anesthetized dogs. Infusion of endothelin at a rate of 1 ng»kg 1 »min 1

resulted in a slight but significant decrease in renal blood flow and increases in renal vascular resistance and f i l t r a t i o n fract ion. Endothelin at doses higher than 10 ng ^kg 1

•min 1 s ignificantly decreased cardiac output, glomerular f i l t r a t i o n r a t e , urine volume, and urinary sodium and potassium excretion af ter 30min of infusion, whereas i t increased systemic vascular resis tance . These effects lasted for more than 60 min. Mean a r t e r i a l pressure and systemic vascular resistence, however, showed a transient but significant decrease at doses higher than 50 ng»kg 1

•min whereas heart rate and cardiac output showed a transient increase. Plasma renin a c t i v i t y and plasma aldosterone concentrations were_increased only at the dose of 100 ng«kg 1

•min These results suggest that endothelin may have an important role in the modulation of renal functions as well as in the modulation of systemic hemodynamics.

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E F F E C T O F T H E T H R O M B O X A N E S Y S T E M ON R E N A L H E M O D Y N A M I C S A N D T H E D E V E L O P M E N T O F H Y P E R T E N S I O N IN D A H L SALT-RESISTANT ( D R / J R ) AND -SENSITIVE RATS ( D S / J R ) . L. Persan. F J . Kaskel*, T.A. Wilson*, and J.A. McCaughran Jr. S U N Y School of Medicine, Stony Brook, NY.

W e have previously demonstrated that early exposure to high-salt (2 .0% NaCl) intake impairs renal function and induces hypertension in D S / J R rats. Recent evidence suggests that abnormalities in the renal thromboxane system also contribute to the pathogenesis of hypertension in organisms with a genetic predisposition to the disease. To determine the role of the thromboxane system in the development of hypertension and abnormalities in renal hemodynamics in Dahl rats, D R / J R rats were weaned and fed a diet of either low (0 .15%) or high (2 .0%) NaCl. After 3-4 weeks on a specific diet, male rats were anesthetized (inactin, 100 mg/kg) and prepared for renal clearance studies. Systemic blood pressure (BP) , glomerular filtration rate ( G F R ) and renal blood flow ( R B F ) were determined. The specific thromboxane receptor antagonist (TxRA), sulotroban (SK&F, B M 13.177) was infused (30 mg/kg) over 45 mins and repeat measurements performed. * p < 0 . 0 5 , flows expressed per gm kidney weight, η = animals.

D R / J R BP(mmHg) GFR(ml /min) RBF(ml/min)

Pre-TxRA 108 ± 2 0.58 ± 0 . 1 4.72 ± 0 . 8 n = 7 7 6

Post-TxRA 98 ± 3 0.62 ± 0 . 0 4 5.96 ± 0 . 4 n = 7 7 4

Acute TxRA lowered B P but had no effect on renal hemodynamics in the D R / J R group. Current studies are evaluating the interaction of the thromboxane system and salt intake on BP and renal hemodynamics in the D S / J R strain.

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E F F E C T O F R E N A L D E N E R V A T I O N ON T H E C O N T R O L O F V A S O P R E S S I N S E C R E T I O N A N D B L O O D P R E S S U R E IN C O N S C I O U S R A B B I T S . S Matsukawa. L C Keil, IA Reid. Dept. o f Physiology, Univ. of California, San Francisco, CA.

There have been reports that electrical stimulation of afferent renal nerves increases plasma vasopressin ( A V P ) concentration, but the role of the renal nerves in the control of A V P secretion is not known. In the present study, the effects of renal denervation on the A V P responses to osmotic stimuli (hypertonic saline infusion, 2 0 m E q / 4 0 min and 24h water deprivation) and non-osmotic stimuli (nitroprusside infusion, 1 -10 μg/kg/min and hemorrhage, 2 0 ml/kg) were studied in conscious rabbits. The A V P responses to hypertonic saline (2 .7 + 0 .2 to 9 .6 + 2 .6 pg/ml, P < 0 . 0 5 , n = 6 ) and water deprivation (2 .2 + 0 .6 to 5 .9 ± 0 .6 pg/ml, P < 0 . 0 5 , n = 6 ) in the denervated rabbits were not significantly less than the responses in the intact rabbits (4 .0 ± 0.7 to 9 .6 ± 2.3 pg/ml, P < 0 . 0 5 , n = 8 and 4.1 ± 0 .6 to 6.9 ± 0 .6 pg/ml, P < 0 . 0 5 , n = 6 , respectively). Furthermore, the relationship between plasma A V P and plasma osmolality was not significantly different in the two groups. The A V P responses to nitroprusside (2 .7 + 0 .3 to 4.7 ± 1 . 0 pg/ml, P < 0 . 0 5 , n = 1 3 ) and hemorrhage (2 .3 ± 0 .2 to 102 .9 ± 4 9 . 2 pg/ml, P < 0 . 0 1 , n = 1 3 ) in the denervated rabbits tended to be less than the responses in the intact rabbits (2 .4 + 0 .3 to 5.8 ± 1.0 pg/ml, P < 0 . 0 1 , n = 1 2 and 2 .8 ± 0 .3 to 159.1 ± 39 .8 pg/ml, P < 0 . 0 1 , n = 1 2 , respectively) but again, there were no significant differences. The relationship between plasma A V P and mean arterial pressure was also not different between the two groups. The blood pressure and heart rate responses to nitroprusside infusion and hemorrhage were not significantly different in the intact and denervated rabbits. These results indicate that the renal nerves do not contribute to the osmotic and non-osmotic regulation of A V P secretion or to blood pressure regulation.

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PRE-ftWAKENING RISE OF BLOOD PRESSURE (BP) OS PI "SPEED" INCREASE IN ft UNIT OF TIME. G. German 6 ·*, S. Damiani - University "La Sapienza",Roma, Italy.

The debated question regarding t h e p r e -awakening rise of BP,given the h y p o t h e s i s of the existence of a circadian rhythm, can be approached by appropriate p r o c e d u res. We employed 114 males and 101 females (where age st a n d s for 140,36-60,2:56) recruited during a study with p a r t i c i pation of six Italian U n i v e r s i t i e s . The req u i red cr i t er i a w e r e : οff i ce BP within norma 1 limits,norma 1 physi ca1 ex am i nat i on ECG , h e m a t o l o g i c profile, absence of r e t i nal changes. Each subject underwent £4 BP ambulatory monitoring with Del Mar and Spacelab d e v i c e s . T o take into account the loss of eq u i s p a c e among data o b t a i n e d , m o ving a v e r a g e s were calculated by m e a n s of wei g h t s inversely proportional to the tim e - d i s t a n c e among data.The upward slope from the lowest BP level during n o c t u rnal h o u r s to the awakening as described by the Fourier s e r i e s curtailed to three h a r m o n i c s , c a n be evaluated by the angular coefficient revealing the "speed"in which blood pressure increases in a unit of time. W e observed in male s u b j e c t s that this "speed" is around 6 mmHg per hour w h e r e a s d i a s t o l i c shows minor increases around 1 , 5 mmHg decreasing with the p a s sing of ye a r s . F e m a l e s y s t o l i c " s p e e d s " a r e inferior to males'and superior to d i a s t o lic. The length of intervals during which the sharp increase t a k e s place is al w a y s more than three and less than four hours.

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L1234I IMPORTANCE OF THE RENIN ANGIOTENSIN SYSTEM A N D DOPAMINE IN SODIUM REGULATION IN E S S E N T I A L HYPERTENSION.. H. K a w a b e * , T. Furukav/a*, I. Saito, T. Saruta. Dent, of Internal M e d i c i n e , Tokyo Dental College H o s p i t a l , Chiba & Keio U n i v e r s i t y , T o k y o , J a p a n . The renal sodiun handling to saline in

fusion, 1500 m l / 3 h r , was studied in 12 patient s with essential hypertension(EHT) and 7 acre-matched normotensive s u b j e c t s . A f t e r saline infusion(ASI) , both c r o u d s showed a similar increase in urinary s o d i um e x c r e t i o n ( U N a V ) . The increase in'GFR, atrial natriuretic peptide (ANP) and. ur i n a ry dopamine excretion(UDAV) and s u p p r e s s ion of PRA were observed in both groups in a similar m a n n e r . There was a linear n e g a tive relationship .between % change in UUaV and basal level of PRA only in E H T . T h e r e f o r e , p a t i e n t s w i t h EHT w e r e divided into 2 subgroups accoding to their level of PRA. The increments of UNaV, GFR and UP/T'' in high-renin(H-R) subgroup ASI w e r e s m a l ler than those in low-renin(L-R) subcroup. T u t h e r m o r e , the increment of UNaV in L-R subgroup ASI w a s paralleled with the increment of UDAV. H o w e v e r , no sianificant diffprences in changes in blood pressure and ANP between 2 s u b f r o u n F ; w e r e seen. After treatment w i t h enalapril H-R subgroup exhibited an increase in UNaV with a tendency to improve their GFR ASI compared to n r e - e n a l a n r i l d a t a , while UNav in L-P. subrroup was decreased. These result suaa-st that renin angiotensin system, and d o n a -mine play an imnortant role in sodium regulation in E H T .

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A NOVEL CELL TYPE IN THE PARATHYROID GLAND OF SPONTANEOUSLY HYPERTENSIVE RATS. Τ. KANEKO, R. OHTANI, R.Z. LEWANCZUK*, P.K.T. PANG. Department of Physiology, University of Alberta, Edmonton, Canada.

Recently, we described a circulating hypertensive factor, present in the plasma of spontaneously hypertensive rats (SHR). This factor seems to be produced by the parathyroid gland, but is not identical to parathyroid hormone. In view of these findings, we attempted to search for histological differences in parathyroid glands between hypertensive SHR and normotensive WKY rats by light and electron microscopy. Abnormal cells, distinct from chief cells, were frequently found in parathyroid glands of SHR rats, whereas they were scarcely observed in WKY rats. In some cases, abnormal cells occupied up to 20% of the parathyroid gland. These cells mostly appeared as clusters which were scattered all over the gland, but sometimes located at the edge of the gland. They were irregular in shape and their cytoplasm and nucleus were stained more intensively with hematoxylin than those of chief cells. Ultrastructurally, both endoplasmic reticulum and Golgi apparatus had dilated cisternae, which contained an electron lucent material. At present, it is not clear whether abnormal cells are a different cell type from chief cells or represent a different physiological phase of chief cells. Our finding, however, that abnormal cells frequently appeared in SHR rats, but not in WKY rats, suggests their involvement in development of hypertension in SHR rats.

Supported by The Alberta Heritage Foundation for Medical Research.

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MULTICENTER COMPARISON OF ONCE AND TWICE DAILY ! W 0 T ? T ' I F ( I S ) TO HYDROCHLOROTHIAZIDE ( H C T Z ) FOR HYPERTENSION IN THE ELDERLY. J L Holtzman, R C u t l e r , Β Hani 1 t o n * , W K i r k e n d a l l * , J Rowe, ,1 S c h o e n b e r q e r * , G. S t e i n * , K. M a t t h e w s * . D e p t . o f M e d i c i n e , VA Medical C e n t e r % U n i v . o f M i n n e s o t a , M i n n e a p o l i s , MM.

I S , a d i h v d r o p y r i d i n e C a + + b l o c k e r , i s an e f f e c t i v e b i d a n t i h y p e r t e n s i v e . S i n e * t h e e l d e r l y c l e a r **on? d r m s s l o w l y , we have compared I S t o HCTZ i n a p l a c e b o - c o n t r o l l e d ( ? ) , d o u b l e - b l i n d t r i a l t o d e t e r m i n e t h e i r e f f e c t s in the e l d e r l y . At wk 0 , ?23 p a t i e n t s > 60 y r s a f t e r Ρ f o r 2 - 4 wks with DPP ( r i t t i n q ) > Q?T rmHq and < l?Q m\Hq were randomized t o I S and t i t r a t e d t o 2 . 5 , 5 , or 7 . 5 rrn b id or HCTZ 1 2 . 5 , 25 or 3 7 . 5 mg b i d . At 3 , o a t i e n t s were r^randomized t o P , I S o r HCTZ once d a i l y ( q d , same dose r a n q e ) and t i t r a t e d f o r 4 wks. The r e s u l t s w e r e : Meek % Response T o t a l Mean D a i l v

DBP(nmHq) <<35 d e c > 1 0 l o s e ( n q ) 3 ( b i d ) I S T 9 36 35 10

HCTZ 35 33 69 5^ V: (qd) I S t o I S 24 23 52 12

I S t o Ρ 15 21 35 HCTZ t o Ρ 13 32 50 HCTZ t o HCTZ 37 33 70 56

I S was more e f f e c t i v e b i d than qd; w h i l e HCTZ was e q u a l l y e f f e c t i v e when q i v e n b id or a d . S i q n i f i -c a n t l y more p a t i e n t s responded t o I S b id than HCTZ ( P < 0 . 0 0 4 6 ) . T ^ r e e p a t i e n t s w » r ? d i s c o n t i n u e d f o r non druq r e l a t e d a d v e r s e e f ^ c t s from I S and HCTZ b i d . One I S p a t i e n t had i n c . SG0T/SGPT. Durinq I S qd 3 p a t i e n t ? w«re d i s c o n t i n u e d : 1 f o r f a t i q u e , 1 f o r d i z z i n e s s and T f o r an MT. T h e s e udta i n d i c a t e t h * t I S i s e f f e c t i v e , s a f e monotherapy p a r t i c u l a r l y when q i v e n b id f o r h y p e r t e n s i o n f n t h e e l d e r l y .

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HORMONAL AND HEMODYNAMIC RESPONSES TO INFUSION OF RECOMBINANT HUMAN PRORENIN IN RHESUS MONKEYS. J .E .Sealey* , T.Lenz*, R.W.Lappe*, C. C a r i l l i * , G. Oshiro*, D.H.K. Lee, T . J . Colatsky, J . Baxter*, J .H. Laragh." Cardiovascular C t r . , Cornell University Medical College, NY, Wyeth-Ayerst Research, Princeton, NJ, and California Biotechnology, Mountain View, CA.

Prorenin, the biosynthetic precursor of active renin, is present in high concentrations in the kidney and reproductive organs. We have proposed that prorenin may be the vehicle of local renin systems, separating the functions of circulating and tissue renin systems. In the present study, we investigated the effect of intravenous infusion of purified recombinant human prorenin (400 ng/min) for 40 minutes into male rhesus monkeys (N=4). The study included 20 minute baseline and 40 minute recovery periods. Plasma prorenin increased from 72+16 ng/ml/h to a maximum of 246+21 ng/ml/h during the infusion and f e l l to 169 + 27 ng/ml/h 40 minutes after the infusion was stopped. Active renin did not change. Blood pressure, heart r a t e , GFR, RBF and plasma aldosterone, as well as urine flow and sodium and potassium excretion, did not change. Plasma testosterone f e l l s l ightly from 1 . 8 7 ± 0 . 1 6 ng/ml to 1.55±0.11 ng/ml during the infusion and 1.35±0.08 ng/ml during the post-infusion period (p< .05 ) . These results demonstrate that human recombinant prorenin is not converted to active renin in the circulat ion of rhesus monkeys. An acute 4-fold increase in circulating prorenin has no apparent effect on cardiovascular or renal hemodynamic parameters or on urinary e lec t rolyte excretion.

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"CONCORDANCE OF RENAL ARTERIAL DAMAGE, CEREBRAL ARTERIAL DAMAGE AND PLASMA RENIN IN STROKE-PRONE SHR (SHRsp). W.G. Campbell, Jr, M.J.F. Camargo*, M. Volpe*, J.E. Sealey*, J.H. Laragh*. Cardiovascular Ctr., Cornell Univ. Med. Coll., NY

In SHRsp arterial necrosis often associated with fibrin-platelet thrombi results in malignant nephrosclerosis (involving principally the inner half of the renal cortex) and in ischemic strokes. Both are common fatal complications of a malignant phase of hypertension. Six-week old SHRsp fed one of three diets for 9 to 12 weeks were killed. Characteristic lesions of kidney and brains were quantitatively indexed on standard histologic sections. Morphologic evidence of a moderate to severe malignant phase was found in 11 of 13 (85%) rats fed high N a + | 4 % NaCl), 8 of 16 (50%) rats fed high Na +/ high Κ (4% NaCl, 2.1% K-citrate), and 2 of 13 (15%) rats fed normal chow. Regardless of diet, morphologic concordance was as follows: a) of 21 rats with moderate to severe malignant nephrosclerosis, 18 had two or more ischemic strokes; b) of 21 rats with no or mild malignant nephrosclerosis, all had no or one ischemic stroke. Terminal plasma renin activity (PRA) was studied in 38 of these rats. Of 18 rats with elevated PRA, a) all had moderate to severe malignant nephrosclerosis; b) 15 had more than 2 ischemic strokes. Our results show that in SHRsp: 1) High-Na diets for 9-12 weeks accelerate end-organ damage; 2) Concurrent high Κ -supplementation protects nearly half against end-organ damage; 3) A similar degree of end-organ damage usually occurs in kidneys and brains of individual rats; 4) In both kidney and brain severe damage is almost invariably associated with elevated PRA regardless of diet.

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REVERSIBLE CRY0ACTIVATI0N OF HUMAN RECOMBINANT PRORENIN. Tina Pitarresi, Speranza Rubattu*, Gordon A. Campbell*, Robert L. Heinrikson, John Hui, Jean E. Sealey*. Cardiovascular Center, Cornell Univ. Med. Coll., NY and The Upjohn Company, Kalamazoo, MI.

The production of pure recombinant human prorenin allowed the study of cryoactivation of prorenin in the absence of proteases which could cleave the prosequence. The catalytic activity of two pools of prorenin was measured in the presence of human angiotensinogen (at Km) after incubation at either 0 C, room temperature, or 37 C and compared to the maximal catalytic activity after limited proteolysis with trypsin. The activity averaged 22±3% of maximum at 0 C, 6±3% at room temperature and 3±3% at 37 C. For prorenin at equilibrium at 0 C (22% active) the t^ to a new equilibrium at 37 C was 8 minutes and 180 minutes at room temperature. For prorenin at eguilibrium at 37 C, th to a new equilibrium at 0 C was 18 hours. The concentration of prorenin did not appreciably affect these rates. A direct radioimmunoassay for active renin detected active prorenin but not inactive prorenin. These results demonstrate that human prorenin can be reversibly cryoactivated. The results are consistent with a hydrophobic interaction anchoring the prosequence to the active site, and a temperature dependent dynamic equilibrium between active and inactive prorenin. These observations may have physiological relevance since they demonstrate that prorenin can have intrinsic catalytic activity without cleavage of the prosequence.

1 2 3 9

KETAMINE INCREASES PLASMA PRORENIN, BUT NOT RENIN IN CATS: DEXAMETHASONE BLOCKS THE EFFECT. Speranza Rubattu*, Donald Marion, Mark Peterson, Jean Sealey*. Cardiovascular Center and Research Animal Resources, Cornell University Medical College, NY.

We studied the effect of ketamine, a centrally acting non-barbiturate anesthetic, on plasma prorenin and renin in cats. Intramuscular injection of ketamine (20 mg/kg, 3 times a day) for 4 days increased plasma prorenin 4-fold, from 7.4+1.4 (SEM)(p<.001) to 11.4±2.2, 17.1+2.5, 20.2±3.0 and 29.2±3.4 ng/ml/hr (p<.001) on days 1,2,3 and 4 respectively. Ketamine did not change plasma active renin, renin substrate or C o r t i s o l . Nephrectomy reduced the stimulated plasma prorenin to undetectable levels. Pretreatment with an+

α-blocker, β-blocker, ACE inhibitor or Ca antagonist failed to prevent the ketamine induced increase in plasma prorenin. Sub-cutaneously implanted pellets of dexamethasone, releasing 100 mg at a constant rate over 3 weeks, did not affect plasma prorenin or renin. During dexamethasone treatment ketamine failed to increase plasma prorenin. These results suggest that renal prorenin secretion may be regulated independently of active renin and that glucocorticoids may block stimulation of prorenin secretion in cats without affecting baseline prorenin levels.

1 2 4 1

EFFECT OF HIGH CALCIUM DIET ON DEVELOPMENT OF HIGH BLOOD PRESSURE IN ADRENALECTOMIZED (ADX) SPONTANEOUSLY HYPERTENSIVE RAT (SHR) TREATED WITH ALDOSTERONE (ALDO) AND IN INTACT SHR. W.E.B. Semafuko and D.J. Morris*, Dept. of Pathol, and Lab. Med., Miriam Hospital and Div. of Biol, and Med. Brown Univ. Providence, RI.

High calcium diets (HCaD) have been associated with lowering of systolic blood pressure (BP) in animals and humans. In the present study the effect of a diet containing 2.5% Ca (0.5% P0 4, 2% CaC0 3 ) (HCaD) on the development of high BP in young ADX SHR treated with ALDO was investigated. The control diet (CCaD) contained 0.5% Ca as P0 4 . After weaning the SHR were fed either CCaD or HCaD and given water or 0.9% NaCl after ADX ad libitum.

At 6 weeks of age SHR were ADX and implanted with ALZET mini-osmotic pumps loaded with vehicle (Sham) or ALDO (1 μg/day, 2 wks). The infusion of ALDO for 2 wks to young ADX SHR fed CCaD caused a significant increase in BP (ALDO=200+5 mmHg Sham=129+4 mmHg, p<0.001, n=4-6 ) . ALDO-induced high BP was reversed by feeding rats HCaD (CCaD=200+5 mmHg HCaD=138+8 ' mmHg P<0.001 n=4-5). In young intact SHR, HCaD blunted the development of high BP (at 6 wks CCaD=135+3 mmHg HCaD=117+2 mmHg P<0.001 n=8-10) and this trend was maintained as the rats grew older (at 11 wks CCaD=215+3 HCaD=164+3, P<0.001 n=8-10) confirming other worker's findings. The lowering of BP by high calcium diet may be associated with changes in Na* and K* metabolism in the SHR. (Supported by the National Diary Board, administered in cooperation with the National Diary Council).

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EFFECTS OF GLYCYRRHETINIC ACID (GA) ON 5a- AND otf-RKDUCTASE PATHWAYS OF METABOLISM OF ALDOSTERONE (ALDO). S.A.Latif* and D.J. Morris*. Dept. of Lab. Med. The Miriam Hospital and Div. of Biol , and Med. Brown Univ. Providence, R . I .

Ingestion of l i c o r i c e or treatment with derivatives of GA an act ive principle of l i c o r i c e , can cause hypertension, sodium retention and hypokalemia. I t has been shown that GA inhibits Ιΐβ-hydroxysteroid dehydrogenase (Ιΐβ-HSD).

This paper describes the e f f e c t of GA on other enzymes such as 5a- and δβ-reductases and 3a and 3&-HSD present in male r a t l i v e r . Varying cone, of (3H)-ALDO were incubated with microsomal (MS) and cytosol ic (CYT) fract ions (l-2mg protein) with or without GA (0 .1 -1500 μΜ). As the substrate (ALDO) cone, was increased cytosol ic 50-reductase and 3a-HSD yielded increasing amounts of 3a,50-THAldo. In dose-dependent fashion, GA inhibited the formation of 3a,50~THAldo by a non-competitive mechanism even a t a GA cone, as low as 0 . 1 uM indicating GA i s a potent inhibitor of 5 0 -reductase. GA inhibited the formation of 3 0 , 5 a -THAldo by inhibiting s p e c i f i c a l l y , microsomal 30-HSD in a dose-dependent fashion causing build up of the intermediate; 5a-DHAldo.

Thus GA not only inhibits Ιΐβ-HSD but also 50-reductase and 30-HSD a c t i v i t y without affect ing 5a-reductase. All of these enzymes may be involved in the mechanism causing GA to display mineralocorticoid-like actions in human and experimental animals.

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H E M O D Y N A M I C A N D E N D O C R I N E E F F E C T S O F M E N T A L S T R E S S I N U N T R E A T E D B O R D E R L I N E H Y P E R T E N S I V E S . Spence J . D . , Manuck S.*, Munoz C , Huff M., Borkowski K., Cheung, H . Univ. Western Ontario London Canada, and U . Pittsburgh * Mental Arithmetic ( M A ) and Mirror Tracing ( M T ) were compared in 4 0 untreated patients with borderline hypertension, tested in random sequence a week apart in standard protocols. Both tasks significantly increased systolic (Syst) and diastolic (Diast) blood pressure, heart rate ( H R ) , cardiac index ( C I ) , total cholesterol ( T C ) and plasma renin, and significantly decreased peripheral resistance ( T P R ) ; plasma catecholamines were not changed significantly; lipid changes were significantly correlated with pressure changes.The table gives significant changes ( p < . 0 5 ; 2 - w a y A N O V A ; two-tailed).

SYST DIAST HR CI TPR TCH0L TG RENIN MA 129.5 75.1 69.2 4.9 25.5 5.04 1.17 3.06 baseline ±15 +12 +97 +1.4 +12.4 ±•9 + .57 +1.83

MA 149.6 90.5 78.3 6.2 21.25 5.19 1.22 4.39 peak +21 +13.6 +14.2 +1.83 +9.8 + .62 +3.01

MT 126.1 74.8 69.8 4.00 28.6 5.11 NS 3.44 baseIine + 15.4 +11.4 +11 +1.24 +13.5 +1.07 +2.04

MT 146.9 87.4 76.6 5.6 20.2 5.37 NS 4.43 peak +21.6 +13.1 +13.6 +2.01 +6.7 +1.13 +2.4 M A was a m o r e potent stimulus, though not significantly different; we cannot confirm the previously reported difference in effects on peripheral resistance. These methods will be useful in exploring the relationships between hemodynamic and metabolic reactivity to stress, and the presence and progression of atherosclerosis, as well as testing the effects of antihypertensive drugs on stress-induced changes that may influence atherosclerotic complications of hypertension.

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UREMIC SERUM INDUCES DNA DAMAGE IN HUMAN VASCULAR ENDOTHELIAL CELLS G. HAMPEL, D e n t o f M e d i c i n e , D i v i s i o n o f N e p h r o l o g y , U n i v e r s i t y H o s p i t a l , E r l a n g e n , FRG The h i g h i n c i d e n c e o f v a s c u l a r d i s o r d e r s f o u n d i n d i a l y s i s p a t i e n t s s u g g e s t s t h a t u r e m i a p l a y s an i m p o r t a n t r o l e i n t h e i r p a t h o g e n e s i s . I n o r d e r t o e x a m i n e t h i s r e l a t i o n s h i p , human e n d o t h e l i a l c e l l s f r o m u m b i l i c a l v e i n s (HUVEC) w e r e c u l t u r e d i n medium w h i c h was s u p p l e m e n t e d e i t h e r w i t h 2 0 % p o o l e d s e r u m f r o m h e a l t h y c o n t r o l s o r froijn h e m o d i a l y s i s p a t i a n t s ( H D ) . D e n s i t y u j a s 1 0 c e l l s p e r d i s h . C e l l g r o w t h i n t h e HD g r o u p r e m a i n e d s t a t i c b u t u a s e x p o n e n t i a l i n t h e c o n t r o l g r o u p . On d a y 5 c e l l c o u n t u a s 1 5 , 7 2 9 a n d 1 9 1 , 9 7 9 r e s p e c t i v e l y ( p 0 . 0 0 1 ) . I f s e r a w e r e e x c h a n g e d t h e n t h e e f f e c t o f t h e o r i g i n a l s e r u m u a s r e v e r s e d i n 4 8 h o u r s . The i n c i d e n c e o f DNA s t r a n d b r e a k s u a s t a k e n a s an i n d i c a t o r o f DNA d a m a g e i n u r e m i a . DNA f r o m HUVEC e x p o s e d t o u r e m i c s e r u m f o r 1 0 - 1 4 d a y s s h o w e d an a c c e l e r a t e d r a t e o f u n w i n d i n g i n a l k a l i i n d i c a t i v e o f an i n c r e a s e d n u m b e r o f s i n g l e s t r a n d b r e a k s when c o m p a r e d t o c o n t r o l s ( p 0 . 0 1 , 2 -uay-ANOV/A) . We c o n c l u d e f r o m t h e s e d a t a t h a t u r e m i c t o x i n s may e n t e r e n d o t h e l i a l c e l l s a n d i n t e r f e r e w i t h DNA f u n c t i o n .

[1245J P R O S P E C T I V E S T U D Y O F A M B U L A T O R Y B P A N D E C H O L V H IN

U N T R E A T E D B O R D E R L I N E H Y P E R T E N S I O N . ( B H ) Spence, J . D . * , Bass, M.,

Robinson, C. Melendez, L J . , Cheung, H . U . W e s t e r n Ontar io . London, Canada

One hundred patients with untreated office B H ( D B P 9 0 - 1 0 0 ) were followed for two

years, with ambulatory (Space L a b s ) ( S L ) B P recording every 6 months, and annual

echo. Ambulatory recordings were compared with the mean o f 6 clinic readings

taken with random zero ( R Z ) sphygmomanometer . 4 0 % o f patients were

normotensive when seen by a study nurse in the Hypertension Research Unit, in the

absence of a physician. T h e table gives results for all patients at yearly intervals.

BASELINE 12 MONTH 24 MONTH RZ SBP 132.7 130. 130.9

+14.1 +15.8 +13.3 RZ DBP 86.1 86.9 87.3

+7.6 +10.3 +9.2 HEART RATE 77.1 77.0 75.3

+11.7 +11.6 +11.0 SL SBP 134.7 133.8 134.4

+13.3 +3.8 +13.3 SL DBP 85.6 86.9 84.5

+7.7 +7.3 +8.9 SL HR 82.6 83.2 81.9

+10.5 +10.3 +10.6 LV mass index 98.5 108.8 106.4

+23.3 +27.2 +21.3 W h e n divided above and below L V M I of 110, those below had ambulatory

pressures of 1 3 2 . 7 / 8 3 . 5 ; those above 1 3 8 / 8 7 ; B P variability ( m a x B P - mean B P ) was

22.2 below and 27 .6 above, and the change in L V M I from base line t o 24 months was

-6.1 below and + 2 6 . 1 above. Mental arithmetic and mirror tracing responsivity are

being explored as variables that may explain progression of blood pressure and

L V M I in these patients. R a n d o m zero B P taken by a nurse in the absence o f a

physician may be as predictive of L V H and hypertension as ambulatory B P .

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INCREASED β2-ADRENOCEPTOR NUMBER IN P E R I PHERAL SYMPATHETIC GANGLIA OF SPONTANEOUSLY HYPERTENSIVE RATS ( S H R ) . JM Saave-dra*. AJ N a z a r a l i , J E B Pinto, Τ Torda. Unit Preclin N e u r o p h a r m a c o l , Lab Clin Sci, NIMH, Bethesda, M D .

In the rat, sympathetic ganglia contain a high concentration of β2-adrenoceptors, considered as "hormonal" receptors responsive to epinephrine. SHR have increased peripheral sympathetic activity, and high epinephrine content in their peripheral sympathetic ganglia. In h y p e r t e n s i v e p a tients, the lymphocyte β2-adrenoceptor density and the receptor m e d i a t e d cyclic AMP response are elevated. W e determined the concentration of ,92-adrenoceptors in single rat sympathetic ganglia w i t h quantitative a u t o r a d i o g r a p h y after incubation of adjacent sections w i t h 1 2 5 I - i o d o c y a n o -pindolol with or without excess of unlabeled (-)-propranolol, the specific ,91-antagonist CGP 20712A or the specific ,92-antagonist ICI 118,551. In SHR, the concentration of ,92-adrenoceptors is elevated when compared to n o r m o t e n s i v e W i s t a r Kyoto (WKY) rats in both the superior cervical ganglia (WKY: 30 ± 3, SHR: 71 ± 5 fmol/mg protein, P<0.05) and in the stellate ganglia (WKY: 30 ± 4 , SHR: 127 ± 20 fmol/mg protein, P < 0 . 0 5 ) . Our results indicate that ,92-adrenergic stimulation may be enhanced in sympathetic ganglia of SHR, and could play a role in the m a i n t e n a n c e of increased peripheral sympathetic activity in this m o d e l .

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HOMOREGULATION AND HETEROREGULATION OF ATRIAL NATRIURETIC FACTOR RECEPTORS IN VASCULAR SMOOTH MUSCLE CELLS. PE Chabrier*, Ρ Roubert, Ρ Plas and Ρ Braquet. Institut Henri Beaufour Res. Labs. 1 avenue des Tropiques 91952 LES ULIS, France.

Two atrial natriuretic factor (ANF) receptor subtypes are present in vascular smooth muscle cells : the Β receptors and the C receptors (95 % of the total number of ANF binding sites). Using binding experiments with [3( 1 2 5-I) iodotyrosyl] ANF and measurement of cGMP production stimulated by ANF, we compared the homologous (induced by ANF) and heterologous regulation [induced by angiotensin II (Ang II)] of ANF receptors in rat cultured vascular smooth muscle cells. The effect of the two hormones showed marked differences, in their time course (up to 18 hrs), their reversibility and their consequence on guanylate cyclase activity. Although both ANF and Ang II dose-dependently reduced the total number of ANF binding sites after 18 hrs, ANF induced a desensitization of the guanylate cyclase whereas Ang II elicited a potentialization of this system. Moreover, Ang II showed a biphasic effect on the guanylate cyclase whereas the one induced by ANF was monophasic. These results show that homologous and heterologous regulation of ANF receptors are different in their mechanisms and complex events leading to opposite consequences. It appears that Β receptors are more sensitive to homologous regulation and C receptors more sensitive to heterologous regulation.

[12471

REGIONAL HEMODYNAMIC RESPONSES TO ENDOTHELIN IN CONSCIOUS RAT. S Cornet, Ε Pirotzky, A Braillon, PE Chabrier* and Ρ Braquet. Institut Henri Beaufour Res. Labs. 1 avenue des Tropiques 91952 LES ULIS, France.

Endothelin is an endothelium derived peptide which induces a vasoconstriction and a systemic increase of blood pressure. This study was attended to measure regional hemodynamic responses in conscious rat. Male Wistar rats (252 + 27 gr ; η = 6) were catheterised at the right carotid artery for mean arterial pressure. Pulsed doppler flow probes were placed around the abdominal aorta, mesenteric and left renal artery. Results were obtained at baseline conditions, and at the peak changes in the vessels. Results are expressed as % of maximal variation in relationship to control. % of maximal variation in comparison with control

Mean a r t e r i a l Cardiac Mean blood flow blood p r e s s u r e r a t e a o r t i c r e n a l m e s e n t e r i c

0 . 2 nmol/kg + 1 4 . 4 - 8 . 9 - 3 . 2 - 2 4 . 5 - 3 5 . 1 0 . 4 nmol/kg + 1 9 . 8 - 6 . 5 - 1 2 . 1 - 3 3 . 4 - 4 3 . 6

1 . 0 nmol/kg + 2 5 . 3 - 6 . 8 - 2 2 . 7 - 4 4 . 1 - 5 3 . 3 2 . 0 nmol/kg + 4 1 . 6 - 2 9 . 8 - 4 3 . 6 - 7 9 . 2 - 6 4 . 3

Endothelin also induced a biphasic response, the initial effect being according the vessel (a vasodilation or a vasoconstriction). Endothelin provoked in the first seconds an hypotensive effect followed by a long and sustained hypertension, the regional hemodynamic responses to endothelin presented differences according to the vascular beds.

DOWN REGULATION OF ENDOTHELIN BINDING S I T E S IN RAT VASCULAR SMOOTH MUSCLE CELLS. Ρ Roubert, V Gillard, Ρ Plas, PE Chabrier* and P. Braquet. Institut Henri Beaufour Res. Labs. 1 avenue des Tropiques 91952 LES ULIS, France.

Endothelin is a 21 amino-acid peptide isolated from the culture medium of porcine endothelial cells that presents potent vasoconstrictive properties in vitro and in vivo. Since we recently demonstrated that endothelin does not act through calcium voltage-dependent channels but probably via specific binding sites ; we investigated the binding of endothelin and its regulation on vascular smooth muscle cells.

1 2 5I-endothelin bound to a single class of hight affinity binding sites in vascular smooth muscle cells. After 2 hours incubation at 37° C, dissociation constant (Kd) was 1.2 + 0.3 nM and binding capacity (Bmax) was 59 + 11 fmol/10 6

cells (n = 5). 1 2 5I-endothelin was displaced by unlabelled endothelin with a inhibition constant (Ki) of 0.2 nM in competition experiments. 1 2 5I-endothelin binding was not reversible by addition of unlabelled endothelin (1 μΜ) and not dissociable by acetic acid (10 mM) or trypsin (0.1 %) treatment of the cells. Furthermore, preincubation of vascular smooth muscle cells with endothelin (1 nM) at 37° C induced a dose-dependent and rapid down-regulation of endothelin binding capacity which persisted up to 18 hrs.

These data indicate that specific endothelin binding sites are present and can be regulated in smooth muscle cells, and suggest a tight binding or a rapid captation of endothelin into the cell membrane leading to contractile events.

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112501 LONG LASTING EFFECT OF ENDOTHELIN IN VIVO. WEAK INHIBITION BY VERAPAMIL. JM Guillon, Ε Etiemble, Μ Auguet, PE Chabrier* and Ρ Braquet. Institut Henri Beaufour Res. Labs. 1 avenue des Tropiques 91952 LES ULIS, France.

Endothelin (E), a new vasoconstrictor peptide, induces a dose-dependent and long lasting hypertension in the pithed rat without affecting significantly heart rate.

D i a s t o l i c b lood pressure Time o f recovery (nm Hg) (min) t o

3 min a f t e r i n j e c t i o n normale values

dose (nmoles/kg)

0 5 0 . 0 + 5 82 0 0 . 2 5 6 7 . 6 + 3 71 10 0 . 5 8 2 . 3 + 4 83 20 1 8 8 . 3 + 2 16 30 2 1 1 1 . 0 + 3 53 60 4 1 2 8 . 0 + 1 15 Death a f t e r 5 minutes

Verapamil (0.3 mg/kg i.v.) diminishes slightly the increase of blood pressure induced by Ε (1 nmole/kg i.v.) (- 16 mm Hg) to the same extent that it affected hypertension elicited by methoxamine (70 μg/kg) (- 11 mm Hg) which induces at this dose a similar level of hypertension. These data suggest that endothelin does not exert exclusively its action via voltage-dependent channels.

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HYPERKALEMIA DURING CAPTOPRIL ADMINISTRATION IN PATIENTS ON REGULAR HEMODIALYSIS. M. Papadimitriou*; Chr. Zamboulis; G. Sakellariou; D. Memmos. Dept. of Nephrology, Aristotel ian University, Hippo kration Gen. Hospital, Thessaloniki, Greece.

I t is well known that hyperkalemia is an alartmig finding in the e l e c t r o l y t i c prof i le of patients on RH (regular hemodialysis). Sixteen hypertensive pat i e n t s out of a to ta l of 76 patients on RH were g i ven captopril and studied in comparison with cont r o l s (34 patients) and with 26 patients on conventional antihypertensive therapy and/or 3-blockers . Twice a month, oredialysis plasma potassium, sodium urea, and creat inine levels were estimated for a period of up to six months. After a month on captopri l treatment, a l l 16 patients has s ign i f i cant ly elevated plasma potassium leve ls , which rose from a mean value of 5.0 (+0.60) to 5.8 (+0.15) mEq/L. No s igni f i cant changes in plasma potassium levels were GDseryed in the other two groups. In addition, during captopril administration, tne number of pat i e n t s with oredialysis plasma potassium I j v e i s above 5.5 rnWL increased from four to 12 out of the 15 cases* Final ly , in f ive patients in whom captopril was discontinued plasma potassiur.i declined towards normal l e v e l s . During the period of study a l l the other examined parameters did not show any s t a t i s t i c a l l y s igni f i cant changes in a l l groups of pat ients . Therefore, in patients on RH receiving captopri l , plasma potassium levels should be regular ly monitored, especia l ly when other factors indu cing hyperkalemia c o e x i s t .

[12521

SINGLE KIDNEY99mTc-DTPA CLEARANCE IN DIFFERENTIATION BETWEEN RENOVASCULAR AND ESSENTIAL HYPERTENSION. EB Pedersen, 1! E i s k j e r , MM Hansen, FT Jensen, Β Jespersen, Β Msdsen, SS S0rensen, J The i l . Dept. of Medicine C, Nuclear Medicine, and Radiology R, Aarhus Kommunehospital, University Hospital of Aarhus, Denmark

Single kidney 99mTc-DTPA clearance was determined in patients with a r t e r i a l hypertension on two consecutive days using exact ly the same procedure with th is exception that captopril 25 mg was given ora l ly one hour before the measurement on day 2 . Group 1 comprised 15 patients with moderate to severe renal artery s tenos i s , group 2 comprised 16 patients with essent ia l hypertension with a normal renal angiogram, and group 3 comprised 6 patients with uni lateral renal artery stenos i s examined before and 5-12 months a f ter a successful ΡΤλΑ, i . e . a complete removal of the s t e nosis and a normalization of the blood pressure without antihypertensive treatment. In croup 1 s ingle kidney 99mTc-DTPA clearance was s i g n i f i cantly reduced by captopril (-42.75? (median), range - 8 4 . 7 - ( - Ί 9 . 8 ) ) on the affected/most a f f e c ted s ide , whereas in group 2 this parameter was not s i g n i f i c a n t l y changed on any side (-1.5%, - 1 5 . 9 - 1 3 . 0 and -1.5%, - 2 3 . 0 - 1 4 . 0 ) . In group 3 the reduction in s ingle kidney 99 mTc-DTPA clearance on the affected side induced by captopril was eliminated bv PTRA (before: -15.5%, -59 .7- ( -20 9 ) ; a f t e r : 14.7%", - 5 . 4 - 2 7 . 8 ) . I t is concluded that these resul ts c i ν e further evidence for the value of using changes in single K i d n e y 99mTc-DTPA clearance induced by ACE-inhibition ""n d i f f e r e n t i ation between renovascular and essent ia l hypertension .

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ANTIHYPERTENSIVE EFFICACY OF INTRAVENOUS NICARDIPINE IN HYPERTENSIVE CRISIS.

J. Cl^as. A. Coca*, J. Sobrino, A. De la Sierra*, H.T. Aguilera, B. Gonzalez, G. Waddell, A. Urbano-HArquez. Department of Internal Hedicine. Hospital Clinico y Provincial. School of Medicine. University of Barcelona. SPAIN.

It is generaliy accepted that blood pressure (BP) must be lowered within a few hours in clinical situations of hypertensive urgencies in order to prevent the appearance of end-organ damage. Recent introduction of calcium antagonists and ACE inhibitors has enabled the treattnent of hypertensive crisis. The ail of this study was to asses the antihypertensive effectiveness of the new calcium antagonist Nicardipine (NCP5 in patients with hypertensive crisis. He therefore studied 20 essential hypertensives (11 males, 9 females) aged from EB to 83 years (mean 51) who were admitted at the Emergency Department because of hypertensive crisis. All of them exhibited systolic BP (SBP) values higher than £00 nm Hq and/or diastolic BP (DBP) values higher than 120 mis Hg after 30 minutes of rest. Patients with hypertensive emergencies, eg, hypertensive encephalopathy, intracranial hemorrhage, acute' left ventricular failure, dissecting aortic aneurysm, coronary artery disease and cardiac arrythmia were excluded. The 'study was performed in two steps: a) In the Titration Period NCP was perfused at increasing doses until control of BP was achieved (reduction of DBP greater" than 25 mm Hg, or lowering DBP below 95 mm Hg or SBP below 150 mm Hg). b) In the Infusion Period NCP was perfused for one hour at the same dose that previously controlled BP. Along this period BP, heart rate (HR) and plasma levels of NCP were measured every 15 minutes. In the Titration Period BP decreased from 219 + 20 / 129 ί 13 mm Hg to 169 ± 20 / 95 + 8 mm Hg (p<0.0001), whereas HR increased from 81 ± 12 to 98 ± IB bps (p<0.0001). Dose's required for BP control in this period were 2.5 mg in 2 patients, 5 mg in 13 and 7.5 eg in ^ patients. Perfusion was discontinued in one patient due to the appearance of ventricular arrythmia. At the end of the Infusion Period BP was 166 + 18 / 97 i 10 mm Hg and HR was % ί 18 bpm. Mild side effects were observed in 9 patients: tachycardia higher than 120 bpm in 3, supraventricular arrythmia in 1, polyuria in 3, headache in 2, and flushing in 3 patients. We conclude that NCP is effective in the control of hypertensive crisis with minor side effects. Thus, this drug may be considered as a good alternative to the current therapy for the management of hypertensive crisis.

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CARDIOVASCULAR AND RENAL EFFECTS OF ISO-rANP(l-46) IN COMPARISON WITH IS0-rANP(17-46) AND rANP(99-126). TG Flvnn* and DB Jennings*, Depts. of Biochemistry and Physiology, Queen's Univ., Kingston, Ontario, Canada.

We reported a second a t r i a l peptide which has both cardiovascular and renal a c t i v i t i e s (Am. Soc. Hypertension; Third World Congress of Biologically Active Atrial Peptides, p. 32, 1988) . Sequencing revealed 46 amino acids and a disulfide ring, with 70% homology to rANP(99-126) , between residues 23 and 39. Since cleavage at residue 16 resulted in a peptide similar to rANP(99-126), iso-rANP(17-46) was synthesized for i n i t i a l biological studies. Iso-rANP(17-46) was ac t ive , despite a different carboxyl terminus, but was not as potent as rANP(99-126) in causing hypotension and increasing urinary volume and elec t rolyte excretion. Comparative studies have now been carried out in anesthetized rats on the effects of injections of the complete peptide, iso-rANP(l-46). Iso-rANP(l-46) is equipotent to rANP(99-126) in lowering mean a r t e r i a l pressure and decreasing heart r a t e . Iso-rANP(l-46) also appears to be equipotent to rANP(99-126) in i n c r e a s i n g urine volume and e l e c t r o l y t e excretion. However, unlike rANP(99-126) which had a lesser ef fec t on the kidney at high doses, iso-rANP(l-46) has sustained effec ts on renal excretion over the equivalent high dose range. As well, like iso-rANP(17-46), i t has more potent e f f e c t s on hemoconcentration than rANP(99-126). Supported by Queen's University and the Medical Research Council of Canada.

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CORRELATION BETWEEN HEART RATE AND ARTERIAL PRESSURE: AN INDEX OF THE INTEGRITY OF THE AUTONOMIC NERVOUS SYSTEM. UR Kaesser, C Losem, Ε Grossman, FH Messerli*. Department of Internal Medicine, Section on Hypertensive Diseases, Alton Ochsner Medical Foundation, New Orleans, LA.

Clinical observation indicates that the correlation between heart rate and a r t e r i a l pressure throughout a diurnal cycle differs from one patient to another. In order to identify c l i n i c a l determinants that potentially influence this correlat ion, we studied 47 patients with essential hypertension (off treatment) and 11 normotensive subjects by monitoring blood pressure and heart rate for 24 hours (Accutracker). An average of 120 readings of blood pressure and heart rate were correlated in each patient . The patient population was subdivided into high correlators (r = 0 . 5 - 0 . 7 1 ; η = 14) , intermediate correlators (r = 0 . 2 5 - 0 . 5 ; η = 2 7 ) , and low correlators (r = <0 .25 ; η = 14) . No significant differences in age, sex, race , body surface area, and severity of hypertension were found among the three groups. However, low correlators had a significantly smaller decrease in a r t e r i a l pressure (20 vs 11 mmHg; ρ <0.005) and heart rate (19 vs 11 beats per minute; ρ <0.001) during the night than high corre la tors . A blunted nocturnal drop was previously described in patients with autonomic dysfunction (diabetes mellitus, cardiac t ransplantation, elderly hypertensive p a t i e n t s ) . We therefore conclude that the correlation between heart rate and a r t e r i a l pressure throughout the diurnal cycle is a determinant of the integri ty of the autonomic nervous system.

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THE EFFECT OF FRUCTOSE 1-6 DIPHOSPHATE (FDP) ON 2 2 Na UPTAKE OF RED BLOOD CELLS (RBC) FROM NORMOTENSIVE (NT; AND HYPERTENSIVE (HT) BLACK AND WHITE PERSONS. Langford, Herbert G., M.D., Markov, Angel K., M.D., Holder, Katie, B .S . , University of Mississippi Medical Center, Jackson, Mississippi.

Uptake of 2 2 Na+ by RBC in low Na+ and high K+ medium is more rapid in c e l l s from HT than NT. Since the energy in RBC for ionic transport is derived from glycolysis and FDP increases the energy production via this pathway, we assessed whether FDP will influence the uptake of 2 2 Na+ in RBC from NT and HT blacks and whites by employing the method of Eaton and Mahoney.

Hypertensives had significantly higher flux than normotensives of the same race, but blacks had significantly lower fluxes than whites.

The decrease in uptake af ter FDP was not due to pH, as buffering the medium did not change the FDP e f f e c t , and pH change alone did not change uptake, nor to increased osmolality, as mannitol did not change uptake.

2 2 Na Uptake by RBC Normotensive Hypertensive

White Black White Black n=8 n=9 n=13 n=12

Control 0.31+0.9 0 .21+0.4 0.35+0.11 0 .26+.14 FDP 0.21+0.6 0 .15+0.2 0.25+0.08 0.19+0.01 Signif. p<0.001 p<0.001 p<0.001 p<0.001

We conclude that the elevated 2 2 N a uptake of RBC from white HT is normalized by FDP, and that the uptake by c e l l s from blacks is closer to that from whites af ter FDP. The results raise the possibi l i ty that the high 2 2 N a uptake of HT, corrected by FDP, represents defective function of glycolysis .

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RELATION OF LEFT VENTRICULAR GEOMETRY TO HEMODYNAMIC LOAD IN GOLDBLATT RATS. CL de Simone* M. VolDe? D.C. Wallerson, R.B. Devereux* M. J . F. Camargo , J .H. Laragh'! Cornell Medical Center, New York, NY.

One kidney-one c l ip ( lklc ) and 2 kidney-one c l i p (2klk) Goldblatt hypertension d i f f e r in mechanisms of hypertension, which might be expected to yield different patterns of l e f t ventricular (LV) adaptation. Nevertheless, no evidence exists at this time about these possible differences. Accordingly, LV structure was studied in 21 2klc and 12 lklc Wistar r a t s , 8 weeks af ter surgery, using previously validated echocardiographic measurements. 20 normal Wistar were used as controls . Blood pressure (BP) was 166+49 in 2klc and 170±56 in lklc . Seven 2klc (33%) and 7 lklc (58%) had LV hypertrophy (LVH) (cross sectional area normalized for body weight (CSAI) above 95% normal confidence l i m i t s ) . CSAI was increased only in lklc (p<0.01) , because of increased LV chamber size and cardiac index (both p<0.01). Only in lklc was CSAI closely correlated to BP ( r=0 .82 ; p<0.001) , whereas in 2klc CSAI was strongly related to end-diastolic volume (r=0.74, p<0.0001) . In 2klc BP was related to PRA (r=0.50; p<0.02) and PRA was .higher than in lklc (p<0.01); PRA and a t r i a l nat r iure t ic factor were positively related ( r=0 .58 ; p<0 .006) . These findings sugges t that renin-independent volume overload is present in lklc , which combines with high BP to stimulate eccentric LVH. In 2klk re la t ive wall thickness tends to increase without consistent r ise in LV mass, apparently because reduced volume load par t ia l ly offsets the pressure load stimulus .

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11258| R E L A T I O N S H I P O F A N T I H Y P E R T E N S I V E E F F E C T O F V A S O P R E S S I N ( A V P ) IN S P O N T A N E O U S L Y H Y P E R T E N S I V E R A T S (SHR) TO SODIUM E X C R E T I O N . J R McNeill* and E K Y Chiu Dept of Pharmacol. Univ. of Saskatchewan, Saskatoon, Sask. Canada.

Cessation of a 3 h iv infusion of A V P (20ng/kg/min) is followed by a dramatic and prolonged fall of arterial pressure ( B P ) in SHR but not in W i s t a r - K y o t o rats ( W K Y ) , nor in S H R when an infusion o f phenylephrine replaced the A V P infusion ( A m J Physiol 2 4 9 : H 1 9 3 -H 1 9 7 , 1 9 8 5 ; J Hypertension 5 : 5 9 3 - 5 9 8 , 1 9 8 7 ) . T o determine the relationship of this withdrawal-induced antihypertensive phenomenon ( W A P ) to renal function, we recorded B P ( m m H g ) , urine output (μΐ/kg/min), and sodium ( N a + ) excretion (uEq/kg/min) in conscious 16-2 2 wk-old SHR and W K Y during and after the 3 h iv infusion of A V P . Values are the means ± sem ( n = 7 ) . B P is at the end o f each period.

B P S H R N a + V o l

W K Y B P N a + V o l

AVP control 164±6t - -- 112±2 -AVP:0-180min 195±3*t 21±4*t 94±13*t 143+4* 12±3* 72+6* l-5hr after AVP 134±2*t 1.5+.33* 45±6 108+4 2.0+.62 45±13

SALINE control 156±6f - — 109±2 -AVP:0-180min 161±6t 3.3±.68 50±6 106±2 2.3±.77 53112 l-5hr after AVP I54±5t 4.5±.82 39±8 108+1 2.4+.58 39+8

* p<.05 compared to saline control; +ρ<·05 compared to W K Y B P decreased below pre-infusion basal levels in SHR following the A V P infusion confirming the W A P . Sodium excretion, and to a lesser extent urine output, were increased in both SHR and W K Y during the A V P infusion compared to the saline infusion, and these increases were greater in the SHR. Thus, B P of SHR appears more sensitive to the sodium losses than W K Y . The results suggest that the W A P following an A V P infusion in SHR may be related to a preceding natriuresis that occurred during the infusion of the peptide. (Supported by the Sask Heart Foundation and M R C ) .

[12601 NITRENDIPINE (NTP) IN HYPERTENSION: EFFECT OF TREATMENT FOR ONE YEAR ON LEFT VENTRICULAR (LV) FUNCTION AND NEUROHUMORAL MECHANISMS. TP Giles*, L Roffidal*, A Mazzu*, D Burkholder*, A Quiroz*, G Sander*. Dept. of Medicine, Tulane Medical Center and VA Medical Center, New Orleans, LA.

The effects of NTP (40 mg daily) and hydrochlorothiazide (HCTZ) (50 mg daily), plus an optional sympatholytic on blood pressure (BP,mmHg), heart rate (HR,bpm), M-mode echocardiograms, plasma renin activity (PRA, ng A^/ml/90 min), and norepinephrine (NE,pg/ml) were compared in a 1-year prospective, randomized, parallel trial involving 32 hypertensives (NTP, N=17 ; HCTZ, N=15). NTP monotherapy was successful in 76% of patients while 53% of patients in the HCTZ group required an additional drug for control of BP. Mean values of

BP HR LV FS LAEI PRA NE mass

NTP Group Baseline 161/103 71 95 19 0.55 2.0 396 12 mos. 136*/86* 72 106 35* 0.53 6.7 679*

HCTZ Group Baseline 168/103 71 102 24 0.54 2.8 448 12 mos. 145*/93* 71 106 33 0.57 4.5 640* * ρ <0.05; FS = fractional shortening (%); LAEI=left atrial emptying index; LV mass = gm/m 2

Conclusions: NTP (40 mg daily) is more successful as monotherapy than HCTZ and improves LV systolic function. In these patients with normal baseline LV mass, no changes were observed in LV mass or parameters of LV diastolic function associated with reduction of BP in either treatment group. Favorable changes in LV diastolic function may have been prevented by increased NE.

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24-HOUR BLOOD PRESSURE MONITORING COMPARING SLOW RELEASE VERAPAMIL AND NIFEDIPINE IN THE TREATMENT OT MILD TO MODERATE HYPERTENSION. A. Shamiss, S. M e i s e l , N. Nussinoνitch, T. Rosenthal, Hypertension Unit, Sheba Medical Center, Tel Hashomer, Israel.

The antihypertensive effect of monotherapy with the slow release preparations of the calcium antagonists, nifedipine and verapamil, was compared in mild to moderate essential hypertensive patients using 24-hour blood monitoring. Thirty patients were randomized to either nifedipine 20 mg twice d a i l y (15 patients), or verapamil 240 mg once daily (15 patients), for three months in an open crossover study with a washout period in between. Both drugs caused a reduction in blood pressure over most of the 24-hour period studied: nifedipine from 169+10/107+6 to 140+8/84+7 mmHg (p<0.01), and verapamil from 166+11/107+5 to 145+11/89+8 mmHg (p<0.01). An analysis of activity during the 24-hour monitoring showed that neither nifedipine nor verapamil could combat a rise in blood pressure during eating and t e l e v i s i o n viewing. While nifedipine had a better hypotensive effect than verapamil in moderate hypertensives, the difference was not statistically significant. Side effects were fever with verapamil compared to nifedipine. There were no dropouts from the study.

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PHYSIOLOGIC PLASMA LEVELS OF ATRIAL NATRIURETIC PEPTIDE BLUNT THE ANTINATRIURESIS, ANTIDIURESIS AND STIMULATION OF THE RENIN ANGIOTENSIN SYSTEM CAUSED BY PROLONGED HEAD UP TILT. DJ Grandis, BF Uretsky*, JB Puschett*, L Vassilaros, S Ray. Dept. of Medicine, University of Pittsburgh, PA.

Prolonged (120 min) head up (+60°) tilt (T) decreases urine sodium (Na) excretion (UNaV, mceq/min) and flow (UV, ml/min) and stimulates the renin-angiotensin system in normals. To determine if raising plasma ANP to a level similar to that seen during physiologic stress modifies this response, 7 subjects were studied supine (S), during T, and during recovery (R=S after T) at baseline (B) and with an ANP infusion (.01 mcg/kg/min) during T.

Baseline ANP infusion S Τ R S Τ R

UNaV 260+87 143+62* 220+77* 214+77 183+99* 243+71+ UV 17+3 12+5* 16+3+ 15+3 13+5 16+4 FeNa 1.7+.5 1.0+.3* 1.4+.5+ 1.2+.6 1.2+.5 1.3+.3 GFR 117+22 107+14 120+27 136+40 120+37 150+28 RPF 573 + 96 546 + 99+ 619 + 78// 680 + 87 572 + 181 8 6 0 ^ + ANP 37+31 21+13# 24+11 49+37 179+81* 69+55+ PRA .8+.5 2.5+3* 2.0+2* 1+.5 2.6+2.5 2.0+1.6 ALDO 10+4 16+9* 12+4+ 11+3 9+3 8+3* p<.05 *S vs Τ or R; +TvsR;//B vs ANP(at S,T,or R) . FeNa=fractional Na excretion; GFR, RPF=glomerular filtration rate, renal plasma flow (ml/min); PRA, ALDO=plasma renin activity(ng/ml/hr), aldosterone (pg/ml). Mean arterial pressure decreased in both groups during T. Conclusion: These data demonstrate that increasing plasma ANP to a level seen during physiologic stress may blunt the antinatriuresis, antidiuresis, and ALDO secretion provoked by head-up tilt.

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|1262|

CHRONIC ORTHOSTATIC HYPOTENSION I N THE YOUNG. Μ K i m , R M a n n , Μ Y o g a , Μ K o c h a r * . Z a b l o c k i VA M e d i c a l C e n t e r a n d M e d i c a l C o l l e g e o f W i s c o n s i n , M i l w a u k e e , W i s .

I d i o p a t h i c o r t h o s t a t i c h y p o t e n s i o n ( O H ) a n d S h y - D r a g e r s y n d r o m e a r e u s u a l l y t h e p r o b l e m s o f t h e e l d e r l y . O v e r t h e l a s t 3 y e a r s we h a v e m a n a g e d 3 y o u n g p a t i e n t s w i t h O H . T h e f i r s t i s a 1 6 - y e a r - o l d w h i t e m a l e w h o a t t h e a g e o f 12 y e a r s b e g a n t o e x p e r i e n c e d i z z y s p e l l s t h a t g r a d u a l l y d e v e l o p e d i n t o s y n c o p e o v e r t h e n e x t 18 m o n t h s . H i s b l o o d p r e s s u r e ( B P ) w a s 1 0 0 / 6 5 mmHg s u p i n e a n d 9 0 / 6 0 mmHg u p r i g h t w i t h a c o r r e s p o n d i n g h e a r t r a t e ( H R ) o f 7 6 a n d 1 1 6 / m i n . No o t h e r p h y s i c a l a b n o r m a l i t y w a s n o t e d a n d a l l l a b o r a t o r y t e s t s w e r e normal. T h e s e c o n d p a t i e n t i s a 2 8 - y e a r - o l d w h i t e m a l e w h o d e v e l o p e d s y m p t o m a t i c OH f o l l o w i n g a n i n f e c t i o n w i t h E p s t e i n - B a r r v i r u s . H i s BP w a s 1 0 0 / 7 0 mmHg s u p i n e a n d 5 0 mmHg s y s t o l i c b y p a l p a t i o n o n s t a n d i n g w i t h a c o r r e s p o n d i n g HR o f 1 0 8 a n d 1 2 0 / m i n . H i s p l a s m a r e n i n a n d a l d o s t e r o n e w e r e l o w b u t c a t e c h o l a m i n e s w e r e n o r m a l . T h e t h i r d p a t i e n t i s a 3 3 - y e a r - o l d w h i t e f e m a l e w i t h I g A d e f i c i e n c y , p e p t i c u l c e r , m i t r a l v a l v e p r o l a p s e , T I A s a n d i r o n d e f i c i e n c y a n e m i a w h o d e v e l o p e d s e v e r e s y m p t o m a t i c O H . H e r BP w a s 1 0 0 / 8 0 mmHg s u p i n e a n d 8 0 / 6 0 mmHg u p r i g h t . T h e c o r r e s p o n d i n g HR w a s 7 0 a n d 8 0 / m i n . H e r p l a s m a r e n i n , a l d o s t e r o n e a n d c a t e c h o l a m i n e s w e r e n o r m a l . A l l t h r e e p a t i e n t s w e r e r e c o m m e n d e d a h i g h - s a l t d i e t a n d p r e s c r i b e d l e o t a r d s t o c k i n g s . I n a d d i t i o n , e p h e -d r i n e w a s u s e d i n a l l t h r e e a n d f l u d r o c o r t i s o n e a n d i n d o m e t h a c i n i n t h e f i r s t t w o p a t i e n t s . We c o n c l u d e t h a t c h r o n i c OH c a n a l s o o c c u r i n t h e y o u n g a n d c a n b e t r e a t e d i n a s t e p p e d - c a r e ' m a n n e r .

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EXERCISE A N D BLOOD LIPIDS: EFFECTS OF CHRONIC B-BLOCKADE WITH/{ W I T H O U T ISA. PV Nguyen^ , J C l e r o u x , Μ P e t e r s o n , FHH Leenen . Toronto Western Hosp., Toronto. M o d e r a t e t o s t r e n u o u s i n t e n s i t y

exercise has beneficial effects on blood lipids, (particularly increasing H D L - C ) . The effects of B1+B2, or Bl+B2_blockade +ISA on these changes were assessed in 12 healthy m a l e s in a randomised c r o s s --over study, after 1 w e e k with placebo ( P L A C ) , t i m o l o l l O m g / d ( T I M O ) , o r p i n d o l o l l O m g / d ( P I N D ) . E x e r c i s e endurance on a cycle ergometer at 7 0% V02 max was 73+8 min on PLAC, 4 3+4 on PIND, and 43+5 min on TIMO. Blood lipids at Rest, Exhaustion (Exh) and 15 min Recovery (Rec) we r e : (means+ SEM, mg/dL)

Τ.Cholest. HDL-C Triglyc.

PLAC Rest Exh Rec

132±15 138+12 132±10

46+4 55+8 52 + 4

8 6+24 101+28 97 + 26

TIMO Rest Exh Rec

127+10 156±11 138+10

4 6+4 55+4 49+6

8 6+15 125+19 135±17

PIND Rest Exh Rec

138+13 166+8 139+9

50±4 63+9 56+4

86+15 # 107+18

107+26

Contrary to non-selective B-blockade, B-b l o c k a d e w i t h I S A m a y p o t e n t i a t e (#p<0.05 vs PLAC) the beneficial effects of endurance exercise on lipid p r o f i l e s .

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CONTROL OF HYPERTENSION AMONG D I A B E T I C P A T I E N T S . G S o r o k i n , A S h e t h , Μ K o c h a r * . Z a b l o c k i VA M e d i c a l C e n t e r a n d M e d i c a l C o l l e g e o f W i s c o n s i n , M i l w a u k e e , W i s .

I t i s e s t i m a t e d t h a t m o r e t h a n 2 . 5 m i l l i o n A m e r i c a n s h a v e b o t h h y p e r t e n s i o n a n d d i a b e t e s . T h e u s e o f d i u r e t i c s a n d b e t a b l o c k e r s f o r t r e a t m e n t o f h y p e r t e n s i o n i n t h e s e p a t i e n t s i s s h u n n e d a s t h e y may c a u s e h y p e r l i p i d e m i a a n d h y p e r g l y c e m i a . N e w e r a n t i h y p e r t e n s i v e a g e n t s s u c h a s ACE i n h i b i t o r s a n d c a l c i u m b l o c k e r s a r e r e c o m m e n d e d b y m a n y a u t h o r s . T h e H y p e r t e n s i o n C l i n i c a t t h e Z a b l o c k i VA M e d i c a l C e n t e r h a s u n d e r i t s c a r e a p p r o x i m a t e l y 3 0 0 p a t i e n t s w h o h a v e b o t h d i a b e t e s a n d h y p e r t e n s i o n . We c o n d u c t e d a r e t r o s p e c t i v e s t u d y o f 1 0 0 p a t i e n t s ( 7 5 % w h i t e a n d 25% b l a c k ) w h o w e r e f o l l o w e d u p f o r a 3 - y e a r p e r i o d t o s e e how w e l l d i a b e t e s a n d h y p e r t e n s i o n h a d b e e n c o n t r o l l e d . M e a n a g e i n t h e s e p a t i e n t s w a s 6 4 y e a r s ( S D ± 1 0 ) . I n 8 2 % , h y p e r t e n s i o n w a s c o n t r o l l e d a s d e f i n e d b y a s i t t i n g d i a s t o l i c b l o o d p r e s s u r e c o n s i s t e n t l y £ 9 0 mmHg. I n 67% o f t h e p a t i e n t s , d i a b e t e s w a s c o n t r o l l e d a s d e f i n e d b y a f a s t i n g b l o o d s u g a r c o n s i s t e n t l y <_ 1 6 0 m g / d l . T h e a n t i h y p e r t e n s i v e m e d i c a t i o n s u s e d w e r e : d i u r e t i c s 9 2 % , p o t a s s i u m -s p a r i n g d i u r e t i c s 4 8 % , b e t a b l o c k e r s 6 8 % , a n d o t h e r s 2 0 % . F o r c o n t r o l l i n g d i a b e t e s , i n s u l i n w a s u s e d i n 17% a n d o r a l h y p o g l y c e m i c s i n 44% o f t h e p a t i e n t s . D i e t a n d w e i g h t r e d u c t i o n w a s s u f f i c i e n t t o c o n t r o l d i a b e t e s i n t h e r e m a i n i n g 6% o f p a t i e n t s . T h e s e r u m c r e a t i n i n e , p o t a s s i u m , t r i g l y c e r i d e s , a n d t o t a l c h o l e s t e r o l r e m a i n e d u n c h a n g e d t h r o u g h o u t t h e s t u d y . We c o n c l u d e t h a t i t i s p o s s i b l e t o a t t a i n a s a t i s f a c t o r y c o n t r o l o f b o t h h y p e r t e n s i o n a n d d i a b e t e s w i t h o u t a d v e r s e e f f e c t s o n s e r u m l i p i d s u s i n g p r i m a r i l y t h e d i u r e t i c s a n d b e t a b l o c k e r s .

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INCREASED PROTEIN PHOSPORYLATION AND INTRACELLULAR FREE CALCIUM IN PLATELETS OF HYPERTENSIVE P A T I E N T S . Η . H a l l e r , C . Lindschau,A.Distier.Dpt. Internal Med. Klin.Steglitz,Free University B e r l i n , F R

To further investigate t h e r o l e of second-messenger-systems in EH we s t u died 1)phosphorylation of m y o s i n - l i g h t -chain(20kD) and a specific substrate of proteinkinaseC(47kD) and measured 2) intracellular free calcium [ C a + + ] i in platelets of patients with EH (n=12, mean age 45+6 yrs) and n o r m o t e n s i v e s (n=14,mean age 44+5).Platelets were labelled with 32P and incubated with thrombin (0.1 and 0.25U/ml and the phorbolester TPA 10-7M) for 1,5 and 10 min.Proteins were isolated on SDS-Page. Phosphorylation is expressed as % increase over basal.[Ca++]i was measured by fura2. Results as mean+SEM: *p<0.05 EH v s . NT lOmin: thrombin(0.25U/ml) TPA(10-7M)

20kD 47kD 20kD 47kD EH 156+8* 510+54* 154+10 683+61* NT 116+4 322+29 132+5 491+42 Phosphorylation at 1 and 5 min. was also significantly increased in EH for thrombin and TPA.[Ca++]i was slightly elevated in EH(117+6 vs.104+5nM).There was no correlation between [Ca++]i and 47kD phosphorylation. We conclude l)the activity of the Ca-Calmodulin- and proteinkinase C-pathway is increased in EH.2)increased activity of protein-knase C seems not to be coupled to disturbed calcium regulation in EH.

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INTRACELLULAR FREE CALCIUM AND BLOOD PRESSURE IN SALT-SENSITIVE NORMOTENSIVES DURING H I G H - S A L T DIET. H_.,Haller , A. Sharma,M. Schattenf roh, A.Krib -ben,A.Distier.Dpt.Internal Medicine, K l i n . S t e g l i t z , F r e e U n i v e r s i t y , B e r l i n

Intracellular free calcium[Ca++]i in platelets has been previously shown to be increased in EH.However,the cause of this defect is unknown. We measured therefore platelet [Ca++]i in normotensives with D a positive family history and 2) a proven blood pressure sensitivity to high salt ,and investigated [Ca++]i during a high/low salt diet. Positive (FA+,n=5,24+4yrs)and negative male volunteers(FA-, n=6, 25+5 yrs) w e re cross-over randomized to a low-salt (20mM NaCl/d) and high-salt(250mM NaCl /d) diet of 7 days each.MAP and electrolyte excretion were measured daily. [Ca++]i was determined by fura2 at the end of each period.Results(mean +SEM) §p<0,05 v s . 20mM NaCl; *p<0,05 v s . FA-

20mM NaCl 250mM NaCl FA+ FA- FA+ FA-

MAP (mmHg) 76+4 78+3 83+4§* 78+4 [Ca++li(nM)139+6 147+14 114+8§ 117+7§ [Ca++]i in FA+ was not significantly different from FA-.The increase in MAP during high salt diet is not accompanied by an increase in [Ca++]i. The fall in [Ca++]i in both groups may be influenced by the changes in All or aldo during high salt diet.

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TWENTY-FOUR HOUR AMBULATORY BLOOD PRESSURE MONITORING IN TWIN CHILDREN. BN Garre11* DJ Sava^e*& GR B e r e n s o n * . M e d i f a c t s R e s e a r c h c e n t e r , R o c k v i l l e , M D .

T h e B o g a l u s a H e a r t S t u d y h a s p r o v i d e d o n - g o i n g d a t a o n b l o o d p r e s s u r e p r o f i l e s i n c h i l d r e n f r o m b i r t h t o a g e 2 0 y e a r s i n a d e f i n e d p o p u l a t i o n . A l l BP d a t a h a s b e e n f r o m c a s u a l m e a s u r e m e n t o n l y . We h a v e e v a l u a t e d t h e f i r s t c o h o r t o f t w i n s f r o m t h e s t u d y u s i n g 2 4 - h o u r a m b u l a t o r y BP m o n i t o r i n g . We s t u d i e d 15 p a i r s o f t w i n s w i t h a m e a n a g e o f 1 2 . 0 y e a r s . The?re w e r e 5 f e m a l e p a i r s , 7 m a l e p a i r s a n d 3 M / F p a i r s . A l l r e c o r d i n g s w e r e p e r f o r m e d w i t h a S p a c e l a b s 9 0 2 0 2 r e c o r d e r w i t h r e a d i n g s t a k e n e v e r y 15 m i n u t e s . B l o o d p r e s s u r e w a s a s s e s s e d a s t h e m e a n o f a l l r e a d i n g s f o r 2 4 h o u r s . I n a d d i t i o n , d a t a w a s d i v i d e d i n t o 4 s i x - h o u r t i m e p e r i o d s ( 1 2 M N - 6 A M . 6 A M -1 2 N o o n , 1 2 N o o n - 6 P M , 6 P M - 1 2 M N ) f o r f u r t h e r a n a l y s i s . V a r i a b i l i t y w a s d e f i n e d a s o n e s t a n d a r d d e v i a t i o n o f t h e m e a n s y s t o l i c a n d d i a s t o l i c b l o o d p r e s s u r e i n e a c h t i m e p e r i o d . M e a n 2 4 - h o u r BP f o r t h e g r o u p w a s 1 1 5 . 3 5 / 6 4 . 0 3 m m H g . S y s t o l i c BP i n c r e a s e d w i t h a g e t o a s l i g h t d e g r e e . D i a s t o l i c BP s h o w e d a n o n s p e c i f i c p a t t e r n . T h e r e w a s a s i g n i f i c a n t d i f f e r e n c e i n s y s t o l i c BP i n 1 s e t o f 15 y e a r o l d t w i n s a n d a s i g n i f i c a n t d i f f e r e n c e i n d i a s t o l i c BP i n a 10 y e a r o l d p a i r . F o u r p a i r s o f t w i n s h a d a m e a n d i f f e r e n c e i n s y s t o l i c BP o f lOmmHg o r m o r e . M e a n v a r i a b i l i t y f o r t h e g r o u p w a s 1 2 . 9 / 1 4 . 0 m m H g . T h e r e w a s n o s i g n i f i c a n t d i f f e r e n c e i n v a r i a b i l i t y f o r a n y p a i r o f t w i n s . T h e c i r c a d i a n p a t t e r n o f b l o o d p r e s s u r e w a s d e m o n s t r a t e d i n a l l p a i r s o f t w i n s . T h e r e w a s n o s i g n i f i c a n t d i f f e r e n c e i n BP w h e n d i v i d e d i n t o 6 - h o u r t i m e f r a m e s b e t w e e n a n y o a i r o f t w i n s . I n t h i s s t u d y , a m b u l a t o r y BP m o n i t o r i n g d e m o n s t r a t e d n e a r l y i d e n t i c a l b l o o d p r e s s u r e , b o t h b y p a t t e r n a s w e l l a s a b s o l u t e v a l u e i n t w i n s . S u c h d a t a p r o v i d e s s u p p o r t i v e e v i d e n c e f o r t h e h e r e d i t a r y n a t u r e o f b l o o d p r e s s u r e d e v e l o p m e n t .

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INTERACTIVE EFFECTS OF SODIUM AND CALCIUM ON BLOOD PRESSURE (BP) REACTIVITY IN THE SHR. K . S . S c r o g i n , D.H. H a t t o n * , D.A. McCarron*, Oregon H e a l t h S c i e n c e s U n i v e r s i t y , P o r t l a n d , OR.

S a l t - s e n s i t i v e SHRs show i n c r e a s e d BP as w e l l as enhanced p r e s s o r r e s p o n s e s t o s t r e s s when fed a high sodium d i e t . While supplementary C a + + added t o t h e d i e t has been shown t o reduce sodium-dependent i n c r e a s e s i n BP, i t s e f f e c t on N a + e n hanced p r e s s o r r e s p o n s e s has not been i n v e s t i g a t e d .

To examine t h e e f f e c t s o f C a + + on Na +

p o t e n t i a t e d p r e s s o r r e s p o n s e s , s a l t - s e n s i t i v e SHRs were m a i n t a i n e d on one of f o u r d i e t s v a r y i n g in Na + and C a + + . The d i e t s c o n t a i n e d e i t h e r low o r high Na + ( 0 . 2 9 % o r 3 .15%) combined wi th e i t h e r low or high C a + + ( 0 . 2 % or 2 . 0 % ) . A f t e r e i g h t weeks o f d i e t a r y e x p o s u r e , both u n r e s t r a i n e d and r e s t r a i n e d d i r e c t a r t e r i a l BPs were t a k e n . The f o l l o w i n g day, BP r e s p o n s e s t o 3 . 0 , 0 . 3 , 0 . 1 and 0 . 0 5 ug/Kg doses of n o r e p i n e p h r i n e (NE) and 1 0 0 , 30 and 10 ng doses o f a n g i o t e n s i n I I ( A l l ) were a s s e s s e d a f t e r g a n g l i o n i c b l o c k a d e .

U n r e s t r a i n e d animals mainta ined on the high sodium, low c a l c i u m d i e t had h i g h e r BPs than animals i n t h e o t h e r t h r e e groups ( p < 0 . 0 1 ) . These p r e s s u r e d i f f e r e n c e s were enhanced during s t r e s s ( p < 0 . 0 0 0 1 ) . R e s u l t s from t h e NE dose r e s p o n s e s tudy showed a p a r a l l e l e f f e c t with t h e high Na + low C a + + animals showing g r e a t e r p r e s s o r r e s p o n s e s t o NE a t t h e high doses ( p < 0 . 0 5 ) . P r e l i m i n a r y r e s u l t s i n d i c a t e t h a t t h e r e was no d i f f e r e n c e a c r o s s groups i n r e s p o n s e t o A l l .

^Na/*Ca +Na/tCa tNa/+Ca tNa/tCa U n r e s t r a i n e d BP 160±7 153±4 181±8 156+8 R e s t r a i n e d BP 171±4 154±10 194±4 162111 ΔΒΡ 3ug/Kg NE 9 9 . 5 ± 2 0 9 1 . 4 ± 2 1 138117 1 0 5 . 9 ° 2 7

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AUSCULTATORY VERSUS 0 S C I L L 0 M E T R I C BLOOD PRESSURE MEASUREMENT: I S THERE A D I F F E R E N C E ? BN G a r r e t t * , Β S i I k e & G B r i g d e n , M e d i f a c t s R e s e a r c h C e n t e r , R o c k v i l l e , MD.

A m b u l a t o r y b l o o d p r e s s u r e m e a s u r e m e n t r e l i e s o n t h e u s e o f e i t h e r a u s c u l t a t o r y o r o s c i 1 l o m e t r i c t e c h n i q u e s t o d e t e r m i n e t h e b l o o d p r e s s u r e . W e h a v e s t u d i e d a n e w a m b u l a t o r y BP m o n i t o r i n g d e v i c e t h a t r e c o r d s b o t h m e t h o d s s i m u l t a n e o u s l y t o d e t e r m i n e w h e t h e r t h e r e i s i n c r e a s e d a c c u r a c y w h e n c o m p a r i n g t h e t w o t e c h n i q u e s . W e s t u d i e d 2 4 p a t i e n t s i n b o t h s t a t i c a n d d y n a m i c c o n d i t i o n s u s i n g a N i p p o n - C o l i n 6 3 0 BP m o n i t o r . S t a t i c m e a s u r e m e n t s w e r e m a d e w i t h a H a w k e s l e y R a n d o m - Z e r o s p h y g m o m a n o m e t e r a s w e l l a s a n i n d w e l l i n g b r a c h i a l a r t e r y c a n n u l a o r i n i r a -a o r t i c r o o t c a t h e t e r a s t h e s t a n d a r d o f c o m p a r i s o n . D y n a m i c m e a s u r e m e n t w e r e m a d e w i t h a b i c y c l e e r g o -m e t e r , s u p i n e b i c y c l e o r t r e a d m i l l d e v i c e w i t h a b r a c h i a l a r t e r y c a n n u l a f o r c o m p a r i s o n . F u l l 2 4 -h o u r a m b u l a t o r y BP c o m p a r i s o n w a s m a d e w i t h a b r a c h i a l a r t e r y c a n n u l a . D a t a w a s a s s e s s e d a s t h e m e a n d i f f e r e n c e b e t w e e n t h e r e f e r e n c e s t a n d a r d a n d t h e C o l i n d e v i c e . I n s t a t i c m e a s u r e m e n t , ( A ) w a s - 5 . 8 / - 3 . 0 c o m p a r e d t o i n t r a - a r t e r i a l a n d ( 0 ) w a s - 0 . 7 / - 1 0 . 8 . C o m p a r e d t o R a n d o m - Z e r o , ( A ) w a s - 0 . 8 / 2 . 0 a n d ( 0 ) w a s 4 . 6 / - 5 . 8 . I n b i c y c l e a c t i v i t y , ( A ) w a s 3 . V - 5 . 5 a n d ( 0 ) w a s 2 . 7 / - 3 . 2 c o m p a r e d t o i n t r a a r t e r i a l a n d 8 . 0 / 0 . 5 a n d - 5 . 9 / - 1 2 . 4 r e s p e c t i v e l y c o m p a r e d t o T r e a d m i l l e x e r c i s e . I n e v a l u a t i o n o f f u l l 2 4 - h o u r a m b u l a t o r y r e c o r d i n g , ( A ) w a s 2 . 0 / 1 . 7 a n d ( 0 ) w a s 3 . 3 / - 2 . 4 c o m p a r e d t o b r a c h i a l a r t e r y m e a s u r e m e n t . I n s t a t i c m e a s u r e m e n t , a u s c u l t a t o r y r e c o r d i n g w a s c l o s e r t o t h e s t a n d a r d . T h i s w a s a l s o t r u e i n f u l l 2 4 - h o u r m e a s u r e m e n t a n d b i c y c l e e r g o -m e t e r a c t i v i t y . N e i t h e r t e c h n i q u e w a s v e r y a c c u r a t e d u r i n g t r e a d m i l l e x e r c i s e . I n 2 4 - h o u r a m b u l a t o r y BP d e v i c e s , a u s c u l t a t o r y t e c h n i q u e i s m o r e p r e c i s e .

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Ρ WAVE CONFIGURATION AS AN INDICATOR OF VERY EARLY CARDIOVASCULAR END-ORGAN EFFECTS OF BLOOD PRESSURE WF Graettinger*. DG Cheung*, MA Weber*. VA Medical Center, Long Beach & Univ. of California, Irvine, CA.

We evaluated the relationship of a normal variant bimodal Ρ wave in ECG lead V1 to cardiac structure and function in healthy normotensive adolescents. 2D-guided M-Mode echocardiography, 12 lead ECG, and blood pressure by mercury sphygmomanometer and 2-hour averaged automated monitor were obtained in 40 normotensive (conventional B/P<140/90) adolescents (age 13 yr). Subjects with a normal yet bimodal Ρ wave in lead V1 (BMP) had higher monitor SBP (MSBP), conventional mercury sphygmomanometer SBP (CSBP), LVM, septal thickness (IVS), and stroke volume (SV) than those with unimodal Ρ waves (UMP).

MSBP m m H g

108±12 99±7

CSBP m m H g

110111 103±10

IVS LVM G cm

174+40 .96±.1 144±26 .89±.1

SV c m 3

68±15 57±13

BMP UMP ρ value <.01 =.05 <.01 <.05 <.05

CSBP tended to be higher in the BMP group; this was of borderline statistical significance. LA size was similar in both groups. In the BMP group, LA size was directly related to LVM (r=.63). By multivariate, this correlation coefficient increased to 0.74 with inclusion of HR and to 0.82 with inclusion of CSBP. LA size was unrelated to any parameter in the UMP group. Thus, a BMP in lead V1 while "normal" is associated with slightly higher SBP, greater LVM, thicker ventricular septa and greater stroke volumes. Additionally, a BMP in V1 is predictive of the parameters which influence LA size, especially LVM. While all of these findings are within the traditionally described normal ranges, the bimodal Ρ wave might identify those young individuals who are vulnerable to the early cardiovascular consequences of hypertension.

[1272I PATTERNS OF PERCEIVED STRESS AFFECT DAILY BLOOD PRESSURE VARIABILITY IN NORMAL WORKING WOMEN. GD James», Cardiovascular Center, Cornell Medical Center, New York NY.

The purpose of this study was to examine the relationships between the pattern of perceived stress and daily blood pressure variability in women. The 80 subjects studied were technical and clerical employees of New York Hospital/ Cornell Medical Center who were divided into two groups

depending upon how they perceived stress at work on the day of study: GRP1 (work>home) (N=45, age= 28.7+6.7); GRP2 (work<home)(N=35, age=30.9+8.2). The relationship between blood pressure variability and the pattern of perceived stress was assessed by examining the changes in pressure from work to home to sleep between GRP1 and GRP2 using analysis of variance models.

GRP1 GRP2 Work BP* 121/78+9/8 115/76+9/6 Home BP 116/73+9/7 115/74+11/8 Sleep BP 103/60+7/5 105/64+10/9 Ζ White 84.4 51.5 % Married 24.4 37.1 % with Children 15.6 34.3

Work Sys BP of GRPI>GRP2 Ρ <.05

The results show that women in GRP1 had higher blood pressure at work and lower pressures during sleep than those in GRP2. The differences from sleep to work for both SBP and DBP are greater for GRP1 than GRP2 (p<.05). Women in GRP1 also tended to be single, white and childless. The data suggest that increased perceived stress at work increases blood pressure variability in women.

Supported by NIH Grant HL37054

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CHRONIC I N F U S I O N OF A T R I A L N A T R I U R E T I C P E P T I D E AT P H Y S I O L O G I C A L L E V E L S PREVENTS N a C l - I N D U C E D EXACERBATION OF HYPERTENSION I N N a C l LOADED SPONTANEOUSLY H Y P E R T E N S I V E R A T S . Η J i n , YF C h e n , RH Y a n g , S O p a r i l * . H y p e r t e n s i o n P r o g r a m , U n i v e r s i t y o f A l a b a m a a t B i r m i n g h a m , A L .

We h a v e p r e v i o u s l y s h o w n : 1 ) A c u t e i n f u s i o n o f a t r i a l n a t r i u r e t i c p e p t i d e ( A N P ) p r o d u c e s a n e n h a n c e d d e p r e s s o r r e s p o n s e i n s a l t - s e n s i t i v e s p o n t a n e o u s l y h y p e r t e n s i v e r a t s ( S H R - S ) f e d a h i g h N a C l d i e t c o m p a r e d t o n o r m a l N a C l f e d c o n t r o l s . 2 ) D i e t a r y N a C l l o a d i n g i s a s s o c i a t e d w i t h i n c r e a s e d ( ^ 1 0 0 % ) c i r c u l a t i n g ANP l e v e l s i n WKY r a t s b u t n o t i n S H R - S . T h e c u r r e n t s t u d y t e s t e d t h e h y p o t h e s i s t h a t c h r o n i c i n f u s i o n o f ANP a t a d o s e w h i c h e l e v a t e s p l a s m a ANP t o l e v e l s c o m p a r a b l e t o t h o s e s e e n i n h i g h N a C l f e d WKY r a t s p r e v e n t s t h e N a C l - i n d u c e d e x a c e r b a t i o n o f h y p e r t e n s i o n i n S H R - S . ANP ( 1 - 2 8 , r a t , 0 . 1 y g / h r ) o r v e h i c l e w a s a d m i n i s t e r e d i . v . v i a o s m o t i c m i n i p u m p χ 3 w k s b e g i n n i n g p r i o r t o i n i t i a t i o n o f \7o o r S7o N a C l d i e t s . M e a n a r t e r i a l p r e s s u r e ( M A P ) a n d p l a s m a ANP w e r e m e a s u r e d i n c o n s c i o u s r a t s . R e s u l t s ( m e a n ±SE) a r e :

MSAP(mmHg) P l a s m a A N P ( p g / m l ) 1 % + v e h i c l e ( n = 9 ) 1 6 3 ± 2 7 7 ± 6 8 % + v e h i c l e ( n = 9 ) 1 7 7 ± 2 * 8 5 ± 1 0 1%+ ANP ( n = 9 ) 1 6 3 ± 3 104±9Δ 8%+ ANP ( n = 9 ) 1 6 1 ± 4 119±12Δ * p < 0 . 0 1 c o m p a r e d t o \% + v e h i c l e g r o u p . Δρ<0.05 c o m p a r e d t o t h e r e s p e c t i v e v e h i c l e g r o u p s . T h e d a t a d e m o n s t r a t e t h a t c h r o n i c i n f u s i o n o f ANP a t a d o s e t h a t h a s n o e f f e c t i n SHR-S f e d \% N a C l p r e v e n t s t h e N a C l i n d u c e d e x a c e r b a t i o n o f h y p e r t e n s i o n i n S H R - S .

|1273|

INTRACELLULAR pH (pHi) IN VASCULAR SMOOTH MUSCLE CELLS (VSMC) FROM THE SHR GROWN IN EARLY SUBCULTURE. D.C. Batlle*, ML LaPointe, Northwestern Univ. and Lakeside V.A., Chicago IL.

We have recently shown that resting pHi is lower in lymphocytes obtained from the spontaneously hypertensive rat (SHR) than those obtained in normotensive controls (WKY). This study was undertaken to examine whether this alteration in pHi is also demonstrable in aortic VSMC grown in subculture. Aortic VSMC were obtained from 8 SHR and 7 WKY rats (systolic blood pressure 167±6 and 111±9 mmHg, p<0.001 respectively) and grown on coverslips. Subcultures were obtained by trypsin-ization and passaging the cells onto new cover-slips. pHi was measured in BCECF loaded VSMC which were superfused with a HCO3/CO2 buffered solution (pH 7.40). VSMC were able to maintain a stable pHi, and to fully recover from an acid load (pH a 6.4).

There was no significant difference in VSMC pHi between the SHR and WKY when all the data were pooled (7.35±0.03, n=30 vs 7.32 ±0.03, n=27 respectively) or when the data were further analyzed by passage (Table).

PASSAGE 3 4 5 6 7 SHR 7.32 7.42 7.26 7.31 7.41

±0.06 0.03 0.04 0.09 0.07

WKY 7.33 7.30 7.21 7.43 7.45 ±0.04 0.04 0.07 0.04 0.07

We conclude that potentially important differences in pHi between VSMC from SHR and WKY grown in subculture are not likely to be easily dis-cernable owing to changes in pHi occurring during subpassage and cell transformation in culture.

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|1274|

CONTROL OF STEADY STATE INTRACELLULAR pH (pHi) IN CULTURED VASCULAR SMOOTH MUSCLE CELLS (VSMC). M^ LaPointe and D.C. Batlle*, Northw Univ. and Lakeside VA, Chicago, Illinois.

pHi is a modulator of vascular contraction. This study was undertaken to examine the mechanisms responsible for the maintenance of pHi in VSMC under resting conditions (external pH 7.40). Aortic VSMC grown on coverslips in early subpas-sage in culture were loaded with BCECF and super-fused with either a HEPES or HC0 3/C0 2 buffered solution. Removal of external Na from either solution caused a rapid fall in pHi that was not different between cells assayed in either buffer (ApH 0.34±0.07 and 0.27±0.07 pH units, respectively) . Inhibition of Na+/H+ exchange with a specific amiloride analogue, EIPA, resulted in a marked drop in pHi when added to the HEPES buffer but pHi only fell slightly when EIPA was added to the HC03 buffer (Aj>H 0.25+0.06 and 0.05+0 .02 , respectively). The change in pHi after addition of SITS to the HCO3 buffer was half that elicited by a Na free solution whereas addition of SITS+EIPA decreased pHi to the same degree as a Na free solution (Table).

Na free EIPA SITS SITS+EIPA HCO3 0.27 0.05 0.13 0.26

±0.07 ±0 .02 ±0.04 ±0.06

We conclude that in cultured VSMC studied under resting conditions Na+/H+ exchange actively participates in the regulation of pH^ in a HEPES buffer but is only marginally active in a HCO3 buffer where a SITS-sensitive mechanism is operative as well.

1 2 7 6

ARTERIAL EFFECTS OF ACUTE INHIBITION OF THEREMIN ANGIOTENSIN SYSTEM : A Benetos, Β Pannier, ME Safar* Diagnosis Center, Hopital Broussais, Paris FR This study was aimed to evaluate the arterial effects of acute inhibition of the Renin-Angiotensin system in essential hypertensive patients. Twenty one patients (DBP 95-115 mmHg) were divided in 3 groups. Group I received a continuous IV infusion of Saralazin (ΐμ g/kg/mn). In groups II and III, a continuous IV infusion of the ACE Inhibitor Perindoprilat was administrated at a dose of 1 ^ig/kg/mn or 2.5 μg/]<.g/τπn respectively. Blood Pressure (BP) and Heart Rate (HR) were automatically recorded. Brachial artery hemodynamics were evaluated with a pulsed Doppler velocimeter. All measurements were performed before and at the end of a 30mn continuous IV infusion. Saralazin did not induce any change in BP, HR and brachial artery hemodynamics. In groups II and III, the 2 different doses of Perindoprilat induced an identical BP decrease ( Δ Mean BP -11.3+1.1 mmHg and -10.7+1.6 mmHg respectively), whereas HR remains unchangeable. Brachial artery diameter increases only in group III, from .437+.014 cm to .479+.013 cm (p<0.001). No change was observed in mean blood velocity and blood flow. Plasma ACE activity was inhibited by more than 90 % in both groups II III. PRA, Aj. levels were not modified. We suggest that saralazin failure to decrease BP may be due to the presence of a low renine hypertension in the studied patients or to a partial A^ agonist effect. However in the Perindopilat groups, where a significant BP decrease was observed, the basal PRA, A and ACE was the same as in group I. Despite an identical hypotensive effect and an almost complete plasma ACE inhibition in both Perindoprilat groups, their arterial effect were different. We suggest that higher doses may be necessary in order to inhibit vascular ACE or to stimulate vasodilating systems.

1 2 7 5

IN VITRO CORONARY RESPONSIVENESS TO VASOACTIVE AGENTS IN HYPERTENSION. M.H. Sabouni, G.L. Brown, A.J . Gorman, S. J . Mustafa*. Dept. of Pharmacol. East Carolina Univ., Greenville, NC.

We investigated the effects of hypertension on coronary vascular react ivi ty to s e l e c t ed vasodialator and vasoconstrictor agents. Left anterior descending (LAD) coronary a r t e ries were obtained from one-kidney one-clip hypertensive dogs (MAPS130 mmHg; LVP S150 mm Hg) and from dogs with elevated coronary perfusion pressure induced by chronic ascending aor t ic stenosis (MAP*^ mmHg; LVP 166 mmHg). Ring segments of the LAD 2mm o .d . ) were suspended in organ baths containing Kreb's buffer at 37°C for measurements of isometric tension. LAD a r t e r i e s were also removed from sham-operated dogs (MAP-73 mm Hg), and treated as above. Ach produced concentration-dependent relaxations in KC1 contracted rings from hypertensive as well as sham-operated dogs. There was a significant attenuation in Ach responses obtained from the hypertensive dogs. 2-chloroadenosine and sodium nitroprusside also produced concentration-dependent relaxations in rings from sham-operated dogs. Hypertension caused these concentration-response curves to be shifted to the r ight . PGF2a produced concentration-dependent contractions of the basal tone in rings from both groups of dogs. In comparison, contractions obtained in vessels from the hypertensive models were more profound at a l l concentrations tested. Our results demonstrate attenuations in the relaxing capacities of endothelium-de-pendent and independent vasodialators and augmentation of the contracting effects of PGF2ot in hypertension.

[12771

CHRONIC S T R E S S - I N D U C E D H Y P E R T E N S I O N : A NEW MODEL I N BHR. A - L S i r e n , G F e u e r s t e i n . D e p t . o f N e u r o l o g y , USUHS, B e t h e s d a , MD 20814.

We d e s c r i b e a m o d e l i n w h i c h t w o m i l d e n v i r o n m e n t a l s t r e s s s t i m u l i ( a i r j e t / c o l d w a t e r ) a r e u s e d i n a p a r a d i g m o f c h r o n i c , c o m p o u n d , i n t e r m i t t e n t , v a r i a b l e s t r e s s ( C C I V ) t o p r o d u c e s u s t a i n e d h i g h b l o o d p r e s s u r e i n t h e b o r d e r l i n e h y p e r t e n s i v e r a t ( B H R ) . BHR a n d n o r m o t e n s i v e W i s t a r - K y o t o (WKY) r a t s (4 w e e k s o l d ) w e r e d i v i d e d i n t o 4 g r o u p s ( n=6). One BHR a n d o n e WKY g r o u p s e r v e d a s c o n t r o l s , t h e r e m a i n i n g t w o g r o u p s (BHR/WKY) w e r e e x p o s e d t o s t r e s s s t a r t i n g f r o m 5 w e e k s a g e . T h e r a t s w e r e e x p o s e d d a i l y t o c o l d w a t e r o r a i r j e t s t r e s s i n a l t e r n a t i n g 3-5 d a y s p e r i o d s f o r 11 w e e k s . A s t r e s s f r e e p e r i o d (4 w e e k s ) w a s t h e n f o l l o w e d b y a n o t h e r s t r e s s p e r i o d (4 w e e k s ) . D u r a t i o n o f s t r e s s w a s g r a d u a l l y i n c r e a s e d f r o m 10-20 m i n t o 2h a t v a r i a b l e t i m e p o i n t s i n e a c h d a y . A f t e r 2 w e e k s o f s t r e s s , s y s t o l i c p r e s s u r e ( S A P , b y t a i l p h l e t h y s m o g r a p h y ) i n BHR s t r e s s g r o u p w a s s i g n i f i c a n t l y e l e v a t e d c o m p a r e d t o t h e c o n t r o l BHR (120±2 mmHg v s 110±1 mmHg, p<0.01) o r t o t h e WKY r a t s (103±3 m m H g ) . SAP w a s s i g n i f i c a n t l y e l e v a t e d (20-25 mmHg) i n t h e s t r e s s e d BHR a s c o m p a r e d t o c o n t r o l BHR o r WKY t h r o u g h o u t t h e s t r e s s p e r i o d a n d s t a y e d s i g n i f i c a n t l y e l e v a t e d 2 m o n t h s a f t e r t h e e n d o f t h e s t r e s s e x p o s u r e . No d i f f e r e n c e s b e t w e e n t h e g r o u p s w e r e o b s e r v e d i n h e a r t r a t e , b o d y w e i g h t o r u r i n e s o d i u m c o n t e n t . I n c o n t r a s t t o t h e p r e v i o u s s t r e s s m o d e l s , o u r p a r a d i g m u s e s n o p a i n f u l , a v e r s i v e s t i m u l i . T h u s , t h i s s t r e s s p a r a d i g m m i g h t b e a p e r t i n e n t m o d e l o f h u m a n e n v i r o n m e n t a l s t r e s s .

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1 2 7 8

EFFECT OF THE CALCIUM ANTAGONIST FELODIPINE ON BAROREFLEX-SETPOINT, SYMPATHETIC COUNTERREGULATION, AND CARDIAC BETA-1 RECEPTOR SENSITIVITY. B. Weisser, P. Lieder, B.O. Gobel, H. Vetter, R.Dusing*. Med. Univ.-Poliklinik, Bonn, F.R.G.

The mechanisms responsible for the 'resetting' of the baroreceptor reflex during chronic administration of 1,4 dihydropyridine calcium-antagonists are incompletely understood. The present study investigates the acute and chronic effects of 10 mg per day of felodipine (F) (Hoechst) on arterial blood pressure (BP), heart rate (HR), sympathetic counterregulation, and cardiac beta-1 receptor sensitivity in ten healthy volunteers. BP, HR, and urinary catecholamines were determined during control and on day 1, 4, and 14 of F administration. Dose response curves of i.v. bolus injections of isoproterenol were performed on the same days. F significantly reduced BP from 131 + 6/74 + 3 mmHg to 123 + 6/65 + 2 mmHg on day 1 (p<0.01). BP remained decreased during the entire protocol. The initial increase in HR (62 + 5 to 67 + 4 bpm) remained elevated on day 4 and returned into the control range on day 14 (63 + 4 bpm). Urinary norepinephrine rose significantly with acute F administration (50 + 6 vs. 62 + 12 yug/ 24 h.; p<0.01) and remained increased on day 4. With chronic F administration this value decreased to 55 + 12 yug/24 h. Cardiac beta-1 receptor sensitivity to isoproterenol was not changed at any time of the protocol. Thus, 'resetting' of the baroreflex during chronic F adminstration study is more likely to be caused by a change in sympathetic counterregulation than by a direct influence on cardiac beta receptors controlling the heart rate.

1 2 8 0

ANTIHYPERTENSIVE E F F E C T I V E N E S S OF ZOFENOPRIL VS HYDROCHLO

ROTHIAZIDE ON O F F I C E AND AMBULATORY BLOOD PRESSURES IN

MILD TO MODERATE E S S E N T I A L HYPERTENSION. Y L a c o u r c i e r e * .

H y p e r t e n s i o n U n i t , C . H . U . L . , Q u e b e c , C a n a d a .

T h i s s t u d y e v a l u a t e d t h e e f f e c t s o f z o f e n o p r i l ( Z O ) ,

a new a n g i o t e n s i n c o n v e r t i n g e n z y m e i n h i b i t o r VS h y d r o c h l o

r o t h i a z i d e (HCTZ) u p o n o f f i c e a n d a m b u l a t o r y b l o o d p r e s s u r e s

( A B P ) i n M i l d t o m o d e r a t e h y p e r t e n s i o n ( s i t t i n g d i a s t o l i c

BP 9 5 - 1 1 4 m m H g ) . A f t e r a 4 - w e e k p l a c e b o r u n - i n , s u b j e c t s

w e r e r a n d o m i z e d d o u b l e - b l i n d t o t r e a t m e n t w i t h e i t h e r ZO

3 0 mg ( N : 1 9 ) o r HCTZ 2 5 mg ( N : 2 0 ) o n c e d a i l y o v e r a p e r i o d

o f 1 2 w e e k s . D o s a g e w a s d o u b l e d a f t e r 4 wks f o r p a t i e n t s

w i t h s i t t i n g DBP > 9 0 mmHg. O f f i c e B P , HR a n d s i d e e f f e c t s

w e r e a s s e s s e d a t t h e e n d o f p l a c e b o p e r i o d a n d a f t e r 4 ,

8 a n d 1 2 w e e k t r e a t m e n t a t t h e s a m e t i m e , 2 2 - 2 4 h a f t e r

t h e l a s t d o s i n g . A t t h e e n d o f r u n - i n a n d a c t i v e

t r e a t m e n t s , 1 4 - h o u r ( 8 - 2 2 h ) ABP w a s m e a s u r e d ( I C R , 5 2 0 0

m o n i t o r , S p a c e l a b s ) . T h e t w o r e g i m e s e q u a l l y r e d u c e d o f f i c e

BP ( p < 0 . 0 1 ) w i t h m i n i m a l a d d i t i o n a l e f f e c t s e e n o n

i n c r e a s i n g t h e d o s e . B o t h ZO a n d HCTZ s i g n i f i c a n t l y l o w e r e d

a v e r a g e b a s e l i n e ABP (.p < 0 . 0 0 1 ) . H o w e v e r ZO had a g r e a t e r

e f f i c a c y i n r e d u c i n g BP d u r i n g s o m e w o r k i n g h o u r s . T h e r e

w e r e n o s i g n i f i c a n t c h a n g e s i n HR w i t h b o t h g r o u p s . A d v e r s e

r e a c t i o n s w e r e m i l d a n d t r a n s i e n t w i t h b o t h ZO a n d HCTZ.

C l i n i c a l BP (mmHg) M o n i t o r i n g BP (mmHg)

B A S E L I N E 1 2 WKS BASELINE 1 2WKS

Z 0 F

( 1 9 )

SBP 1 5 1 - 1 4

DBP 9 8 - 3

1 3 7 - 1 8 *

8 9 - 7 *

141 - 1 8

8 9 - 1 1

1 2 5 - 8 * *

8 0 - 1 1 * *

HCTZ S B P 1 5 4 - 1 5 1 3 9 - 1 5 * 1 5 0 - 2 6 1 3 8 - 2 0 *

( 2 0 ) DBP 1 0 0 - 4 8 9 - 6 * 9 4 - 1 3 8 4 - 1 0 *

* p < 0 . 0 1 , * * p < 0 . 0 0 1

I t i s c o n c l u d e d t h a t b o t h Z o a n d HCTZ g i v e n o n c e d a i l y

a t low d o s a g e r e d u c e o f f i c e a n d ABP a n d a r e w e l l t o l e r a t e d .

1 2 7 9

ARTERIAL BLOOD PRESSURE: CORRELATION WITH ERYTHROCYTE COUNT, HEMATOCRIT, AND HEMOGLOBIN CONCENTRATION. B. 0. Gobel. A. Schulte-Gobel, B. Weisser, H. Vetter, R. Dusing*, Med. Univ. Poliklinik, Bonn, F.R.G.

Experimental and clinical hypertension has been associated with various changes in erythrocyte parameters. In the present study, the correlation between arterial blood pressure and red blood cell variables was investigated in 1012 unselected public employees receiving no medication who were admitted to our outpatient clinic for a routine clinical examination. In the entire group, systolic blood pressure averaged 128 + 16 mmHg (SD) (range 90-225 mmHg), while mean diastolic blood pressure was 81 + 10 mmHg (SD) (range 50-145 mmHg). Statistically significant correlations could be demonstrated between systolic and diastolic blood pressure on one side and age, heart rate, body mass index and serum creatinine on the other side. Among the red blood cell variables investigated, no correlation could be shown for arterial blood pressure with red blood cell volume (MCV) and mean corpuscular hemoglobin concentration (MCHC). However, highly significant correlations were observed between systolic and diastolic blood pressure and red blood cell count (r=0.27; p<0.0001), hematocrit (r=0.26; p<0001), and hemoglobin concentration (r=0.28; p<0.0001). Our data thus suggest that erythropoiesis may be stimulated in patients with higher levels of arterial blood pressure. Whether these correlations represent a causal relationship remains unclear. It may be speculated, however, that factors involved in red blood cell formation such as erythropoietin may also participate in the regulation of arterial blood pressure.

1 2 8 1

RELATIONSHIP BETWEEN BLOOD PRESSURE AND MICROALBUMINURIA

IN HYPERTENSIVE T Y P E I I D I A B E T I C S U B J E C T S . Y v e s

L a c o u r c i e r e * a n d A n d r e N a d e a u . H y p e r t e n s i o n a n d D i a b e t e s

R e s e a r c h U n i t s , CHU L a v a l , S t e - F o y , Q u e b e c . C a n a d a .

T h i s s t u d y w a s d e s i g n e d t o a s s e s s t h e c o n t r i b u t i o n o f

d i a b e t e s a n d b l o o d p r e s s u r e ( B P ) o n a l b u m i n u r i n a r y

e x c r e t i o n r a t e i n t y p e I I d i a b e t i c s u b j e c t s w i t h m i l d

t o m o d e r a t e h y p e r t e n s i o n ( s u p i n e d i a s t o l i c B P o f 9 2 -

1 1 0 m m H g ) . S u b j e c t s w i t h m a c r o a l b u m i n u r i a ( > 3 0 0 m g / d a y )

o r d e c r e a s e d r e n a l f u n c t i o n ( s e r u m c r e a t i n i n e > 1 3 5 u m o l / 1 )

w e r e e x c l u d e d . P r e v i o u s a n t i h y p e r t e n s i v e m e d i c a t i o n h a d

b e e n s t o p p e d f o r 4 w e e k s a t t h e t i m e o f s t u d y .

M i c r o a l b u m i n u r i a ( > 1 5 u g / m i n b y R I A , m e a n o f 2 t i m e d

o v e r n i g h t s a m p l e s ) w a s p r e s e n t i n 4 4 ( 4 0 2 ) o f t h e 1 0 9

s u b j e c t s ( 5 8 m a l e s , 5 1 f e m a l e s ) a n d c o m p a r i s o n s w e r e

e s t a b l i s h e d w i t h t h e r e m a i n i n g s u b j e c t s . B o t h g r o u p s

w e r e o f s i m i l a r a g e ( 5 7 ± 1 v s 5 8 ± 1 y e a r s ( m e a n

± S . E . ) ; ρ > 0 . 2 ) . S e r u m c r e a t i n i n e ( 8 4 ± 2 . 8 v s 8 1

± 1 . 8 ; ρ > 0 . 2 ) a n d g l o m e r u l a r f i l t r a t i o n r a t e ( 9 4

+ 3 v s 9 1 ί 2 m l / m i n / 1 . 7 3 m ; ρ > 0 . 5 ) d i d n o t d i f f e r

b e t w e e n g r o u p s . Known d u r a t i o n s o f d i a b e t e s ( 7 ± 1 v s

7 ± 1 y e a r s ; ρ > 0 . 7 ) a n d o f h y p e r t e n s i o n ( 8 ± 1 v s 1 0

± 1 y e a r s ; ρ > 0 . 1 ) w e r e c o m p a r a b l e i n b o t h g r o u p s .

G l y c o s y l a t e d h e m o g l o b i n l e v e l ( H b A ^ ) w a s s l i g h t l y b u t

n o t s t a t i s t i c a l l y h i g h e r i n s u b j e c t s w i t h m i c r o a l b u m i n u r i a

( 9 . 6 ± 0 . 3 v s 9 . 0 ± 0 . 2 $ ; ρ > 0 . 0 5 ) . H o w e v e r , s u p i n e

s y s t o l i c B P ( 1 6 8 ± 2 v s 1 6 2 ± 2 ; ρ < 0 . 0 5 ) a n d d i a s t o l i c

B P ( 9 9 ± 1 v s 9 7 ± 1 ; ρ < 0 . 0 1 ) w e r e s i g n i f i c a n t l y h i g h e r

i n t h e g r o u p w i t h m i c r o a l b u m i n u r i a . M o r e o v e r , t h e l o g

o f a l b u m i n u r i n a r y e x c r e t i o n r a t e i n t h e w h o l e c o h o r t

o f s u b j e c t s w e r e s i g n i f i c a n t l y c o r r e l a t e d ( p < 0 . 0 5 ) w i t h

b o t h s y s t o l i c a n d d i a s t o l i c B P b u t n o t w i t h a n y o f t h e

o t h e r p a r a m e t e r s s t u d i e d . F r o m t h e d a t a o f t h i s

c r o s s - s e c t i o n a l s t u d y , i t w o u l d a p p e a r t h a t t h e p r e s e n c e

o f m i c r o a l b u m i n u r i a i n h y p e r t e n s i v e t y p e I I d i a b e t i c

s u b j e c t s i s m o r e l i n k e d t o t h e i r h i g h B P t h a n t o t h e i r

m e t a b o l i c d i s t u r b a n c e .

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|1282l

F O R E A R M N O R E P I N E P H R I N E D Y N A M I C S D U R I N G L E G R A I S I N G A N D L O W E R

B O D Y N E G A T I V E P R E S S U R E .

J C l e r o u x , C G i a n n a t t a s i o , G G r a s s i , R P e r o n d i , G S e r r a v a l l e ,

Β C a t t a n e o , G Β B o l l a a n d G M a n c i a . C e n t r e - d i F i s i o l o g i a

C l i n i c a & I p e r t e n s i o n e , M i l a n , I t a l y .

T h e r e g i o n a l s p i l l o v e r ( S ) r a t e o f n o r e p i n e p h r i n e ( N E )

h a s b e e n s u g g e s t e d a s a n i n d e x o f l o c a l s y m p a t h e t i c n e r v o u s

a c t i v i t y . Me i n v e s t i g a t e d f o r e a r m N E S r a t e i n 5 h e a l t h y

s u b j e c t s ( 2 9 - 3 y r s , m e a n - S E ) d u r i n g a r e f l e x d e c r e a s e i n

f o r e a r m v a s c u l a r r e s i s t a n c e ( F V R , r a t i o b e t w e e n s p h y g m o n a -

n o m e t r i c m e a n a r t e r i a l p r e s s u r e a n d p l e t h y s m o g r a p h i c f o r e a r m

b l o o d f l o w , F B F ) i n d u c e d b y l e g r a i s i n g ( L R ) a n d r e f l e x

i n c r e a s e s i n F V R b y l o w e r b o d y n e g a t i v e p r e s s u r e ( L B N P )

a t - 7 , - 1 5 , - 2 5 a n d - 4 0 m m H g o f 5 m i n d u r a t i o n , a p p l i e d

a t r a n d o m w i t h e q u a l r e s t p e r i o d s . N E S r a t e ( p g / m i n · 1 O O c c

t i s s u e ) w a s t a k e n a s t h e p r o d u c t o f N E S ( p g / m l , N E v - a +

N E a » F E ) a n d f o r e a r m p l a s m a f l o w ( F P F , c o r r e c t i n g F B F f o r

h e m a t o c r i t ) , w h e r e v - a i n d i c a t e s d e e p v e n o u s - r a d i a l a r t e r y

d i f f e r e n c e a n d F E t h e f r a c t i o n a l e x t r a c t i o n o f e p i n e p h r i n e .

N E S r a t e c o r r e l a t e d i n v e r s e l y w i t h F V R ( r = - 0 . 5 5 ,

ρ < 0 . 0 1 ) a n d p o s i t i v e l y w i t h F B F ( r = 0 . 4 6 , ρ < 0 . 0 1 ) d u r i n g

L R a n d L B N P . T h i s w a s d u e t o t h e g r e a t e r m a g n i t u d e o f c h a n g e

i n F P F w i t h t h e v a r i o u s s t i m u l i a s c o m p a r e d w i t h t h e c h a n g e

i n N E S ( p g / m l ) a n d t o t h e f a c t t h a t t h e s e c h a n g e s w e r e

i n o p p o s i t e d i r e c t i o n s , e g . L R : F P F + 4 4 3 , N E S - 1 4 3 ; L 3 N P

- 2 5 m m H g : F P F - 2 0 3 , N E S + 7 3 . E x p r e s s e d a s c h a n g e s f r o m

b a s a l l e v e l s , N E S r a t e w a s n o t r e l a t e d w i t h F V R ( r = 0 . 1 5 ,

n . s . ) o r F B F ( r = 0 . 4 0 , n . s . ) . I n c o n t r a s t , c h a n g e s i n N E

S ( r = 0 . 6 3 , ρ < 0 . 0 1 ) a n d N E r e l e a s e i n i n t e r s t i t i a l f l u i d

( p g / m l , r = 0 . 8 2 , ρ < 0 . 0 0 1 ) c a l c u l a t e d a s N E S / d - F E ) , a s

w e l l a s v e n o u s N E ( r = 0 . 6 1 , ρ < 0 . 0 1 ) a l l c o r r e l a t e d w i t h

c h a n g e s i n F V R d u r i n g L R a n d L B N P .

S i n c e N E S r a t e i n t h e f o r e a r m f a i l e d t o f o l l o w

s y m p a t h e t i c e f f e c t o r r e s p o n s e , i . e . F V R , t h i s i n d e x d o e s

n o t a p p e a r t o r e f l e c t l o c a l s y m p a t h e t i c n e r v o u s a c t i v i t y

d u r i n g m o d e r a t e r e f l e x a l t e r a t i o n s i n v a s o m o t o r t o n e .

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ISCHEMIC HEART DISEASE (IHD) IN HYP E R T E N S I V E S : H Y P E R T E N S I V E (HHD) OR OBSTRUCTIVE EPICARDIAL CORONARY ARTERY (CAD) DISEASE. AA Carr*, LM Prisant*, JL Houghton. Department of Medicine, Medical College of Georgia, Augusta, GA.

Echocardiographic m e a s u r e s for left v e n t r i c u l a r mass ( L V M ) , h y p ertrophy ( L V H ) , ejection fraction (EF) per 100 g LVM index ( L V M I ) , d i p y r i d a m o l e thallium 201 LV scintigraphy (Th) and coronary arteriography (Cart) w a s pe r f o r m e d in 69 patients w i t h n o n - a c c e l e r a t e d essential hypertension. They were selected on the basis of either chronic or intermittent ECG ischemia, M i n n e s o t a Code ST segment changes 4-1 to 4-4 or Τ wave changes 5-1 to 5-3. Echo LVH was LVMI m e n > 150 g; women > 110 g. Th was negative in 43 (EF/100 g LVMI = 4 7 . 4 % ) . None of these had obstructive CAD by Cart. Th was positive in 26 (EF/100 g LVMI = 3 4 . 9 % ) . O b structive CAD by Cart w a s present in 13. The number and % w i t h LVH and with obstructive CAD was 4, 3 1 % ; for those w i t h Th ischemia and n o o b s t r u c t i o n 10, 77 % ; for those without Th ischemia 24, 56%. Overall for those without obstructive epicardial CAD LVH 61%; with obstruction 3 1 % . These data indicate that in hyper t e n s i v e s w i t h ECG evidence of ischemia Th negative for ischemia excludes the possib i l i t y of obstructive epicardial CAD. The cause of ischemia either by ECG or Th in those without obstructive CAD is pr o b a b l y abnormal intramyocardial coronary blood flow.

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D I E T A R Y E N H A N C E M E N T OF C H O L I N E R E D U C E S B L O O D PRESSURE AND REDUCES VASCULAR R E A C T I V I T Y I N THE SHR R A T . S G r e e n b e r g * a n d FA C u r r o . D e p t . o f P h y s i o l . , U M D N J - N e w J e r s e y M e d i c a l S c h o o l , N e w a r k , N J 0 7 1 0 3 a n d S t . J o s e p h s H o s p i t a l , P a t e r s o n , NJ 0 7 5 0 9

C h o l i n e , i s r e q u i r e d f o r s y n t h e s i s o f p l a t e l e t a c t i v a t i n g f a c t o r a c e t y l c h o l i n e , a n d o t h e r i n t e r m e d i a t e s o f c e l l m e t a b o l i s m . A p a u c i t y o f i n f o r m a t i o n e x i s t s o n t h e e f f e c t s o f d i e t a r y m o d i f i c a t i o n s o f c h o l i n e o n h e m o d y n a m i c s a n d v a s c u l a r r e a c t i v i t y . We e x a m i n e d t h e e f f e c t s o f c h o l i n e d e f i c i e n c y a n d e x c e s s d i e t a r y c h o l i n e o n b l o o d p r e s s u r e , h e a r t r a t e , c a r d i a c h y p e r t r o p h y a n d j _ n v i t r o r e s p o n s e s o f t h e v e i n s f r o m m a l e W i s t e r - K y o t o ( S H R ) r a t s . T h i r t y r a t s / g r o u p w e r e g i v e n a c h o l i n e f r e e d i e t , ( 0 C h ) a n o r m a l c h o l i n e d i e t ( N C h ) a n d a d i e t c o n t a i n i n g f i v e t i m e s n o r m a l c h o l i n e , ( H C h ) f o r e i g h t w e e k s . B l o o d p r e s s u r e s w e r e m o n i t o r e d w e e k l y b y t a i l - c u f f p l e t h y s m o g r a p h y . T h e a n i m a l s w e r e w e i g h e d , k i l l e d a n d t h e h e a r t a n d p o r t a l v e i n r e m o v e d . I n v i t r o c o n t r a c t i o n s t o a n g i o t e n s i n I I , p o t a s s i u m n o r e p i n e p h r i n e , U - 4 6 6 1 9 a n d p r o s t a g l a n d i n s w e r e e v a l u a t e d . OCh r a t s h a d b l o o d p r e s s u r e s 2 0 mm Hg h i g h e r t h a n N C h - S H R . HCh r e d u c e d b l o o d p r e s s u r e b y 4 0 mm H g . T h e v e i n s o f O c h r a t s w e r e m o r e s e n s i t i v e t o e a c h o f t h e a g o n i s t s t h a n t h e v e i n s f r o m N C h - S H R b u t e x h i b i t e d n o r m a l m a x i m a l c o n t r a c t i o n w h e n c o m p a r e d t o N C h - S H R a n d H C h r a t s . NCh r a t s e x h i b i t e d a d e c r e a s e i n s p o n t a n o u s p h a s i c c o n t r a c t i o n s o f t h e v e i n s . T h u s , c h o l i n e a p p e a r s t o m o d i f y p r i m a r i l y m e m b r a n e s e n s i t i v i t y o f s m o o t h m u s c l e . T h e r a p i d o n s e t a n d m a g n i t u d e o f t h e c h a n g e s s u g g e s t t h a t s m a l l c h r o n i c c h a n g e s i n c h o l i n e i n t a k e m a y c o n t r i b u t e t o a l t e r e d v a s c u l a r r e a c t i v i t y a n d p r e s s u r e i n h y p e r t e n s i o n .

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REPEATABILITY OF AUTOMATED AMBULATORY BLOOD PRESSURE MEASUREMENTS. LM Prisant * and AA Carr*. Department of Medicine, Augusta, GA

Seventy-three patients (mean age 46.9 + 12.1 years) with established essential hypertension were entered into a 6 week placebo phase upon discontinuation of medications. An average supine d i a s t o l i c blood pressure (BP) of 95-119 mm Hg during two consecutive v i s i t s qualified the patient for enrollment. Ambulatory blood pressure monitoring was performed with a Pressurometer IV a t 15-minute intervals for a full 24 hour period during the l a s t two placebo v i s i t s a t 7 day intervals . Paired t - t e s t s did not demonstrate any significant difference between the placebo periods for mean systol ic or d ias to l i c PP intervals calculated a t 4-hour, 8-hour, 12-hour, or 24-hour intervals . Only 3 of 48 possible hourly intervals were s ignif icantly di f ferent . Therefore, there was no regression toward the mean with s e r i a l ambulatory blood pressure monitoring. This indicates that for the determination of an antihypertensive drug regimen efficacy only one 24-hour automated ambulatory blood pressure monitoring a t 15 minute intervals is required.

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I N F L U E N C E OF AGE AND BLOOD PRESSURE ON VASCULAR C O M P L I A N C E : GE M c V e i g h , DE B u r n s , Ρ C a r l y l e , Μ W r i g h t , SM F i n k e l s t e i n , J N C o h n * , U n i v e r s i t y o f M i n n e s o t a , M i n n e a p o l i s , MN

P e r i p h e r a l v a s c u l a r c h a r a c t e r i s t i c s c a n be a l t e r e d b y a g e a n d b l o o d p r e s s u r e a l t h o u g h t h e n a t u r e o f t h e s e c h a n g e s r e m a i n p o o r l y d e f i n e d . We t h e r e f o r e u s e d p u l s e c o n t o u r a n a l y s i s ( P C A ) t o e v a l u a t e p r o x i m a l a r t e r i a l c o m p l i a n c e ( C i ) a n d d i s t a l a r t e r i a l c o m p l i a n c e ( C 2 ) i n 2 4 n o r m a l ( m e a n a g e 3 4 y e a r s ) ( N ) a n d 1 1 h y p e r t e n s i v e s u b j e c t s ( m e a n a g e 5 5 y e a r s ) ( H ) . PCA u t i l i z e s c o m p u t e r a n a l y s i s o f t h e b r a c h i a l a r t e r y p r e s s u r e p u l s e m o r p h o l o g y d u r i n g d i a s t o l e a n d r e l a t e s c h a n g e s i n p r e s s u r e w a v e s h a p e t o a m o d i f i e d W i n d k e s s e l m o d e l r e p r e s e n t a t i v e o f t h e c i r c u l a t i o n . M e a n a r t e r i a l p r e s s u r e (MAP) w a s s i g n i f i c a n t l y h i g h e r i n Η a s c o m p a r e d t o Ν ( 1 1 7 ± 3 [ S E M ] v s . 8 5 ± 2 m m H g , ρ < . 0 0 1 ) . C i a n d C2 v a l u e s w e r e r e d u c e d i n Η v s . Ν ( 1 . 4 ± . 2 [ S E M ] v s . 2 . 2 ± . 2 m l / m m H g a n d . 0 2 5 ± . 0 0 5 [ S E M ] v s . . 0 9 9 ± . 0 1 1 m l / m m H g r e s p e c t i v e l y : ρ < . 0 0 5 f o r b o t h ) . C i a n d C2 c o r r e l a t e d s i g n i f i c a n t l y w i t h a g e ( r = - . 6 0 a n d r = - . 6 6 , ρ < . 0 0 1 f o r b o t h ) a n d MAP ( r = - . 5 7 a n d r = - . 5 9 , ρ < . 0 1 f o r b o t h ) . T h u s , C i a n d e s p e c i a l l y C2 c a n d i f f e r e n t i a t e Η f r o m Ν s u b j e c t s . I t w o u l d a p p e a r t h a t a g e a n d i n c r e a s e d a r t e r i a l p r e s s u r e a r e i m p o r t a n t f a c t o r s i n p r o d u c i n g a l e s s c o m p l i a n t v a s c u l a t u r e .

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EFFECTS OF FORCED RUNNING STRESS ON PLASMA CATECHOLAMINES AND CHOLESTEROL: AN INVOLVEMENT OF OPIOID RECEPTORS. HM Rhee*, DF Peterson, SI Koo. Dept. of Pharmacology, Physiology and Biochemistry, Oral Roberts University, School of Medicine, Tulsa, OK.

Different types of stressors such as physical or psychological stresses are known to be key factors that are responsible for sympathetic overdrive with an elevated level of plasma catecholamines. To investigate the role of opioid receptors in physical exercise stress, young adult male Sprague-Dawley rats were forced to run on a treadmill for 3 weeks with a gradual increase in the speed as well as in the duration of running time. The rats that did not run on the day when the blood was withdrawn for catecholamine assay were used as control, in addition to sedentary control rats. Another group of rats was given naloxone ( 1 mg/kg) intraperito-neally 10 min prior to the running. All rats were given 15 g of rat chow daily for cholesterol determination, and the rats were forced to run by giving electric shock when they did not run. The running increased blood pressure and heart rate, even after the treatment with naloxone. Plasma epinephrine in the running rats was 1076.6+299.3 pg/ml plasma. Naloxone ruduced it to 379.1±104.2, while the sedentary control rats had 98.6127.7. Plasma norepinephrine was also increased similarly, although it was not remarkable, compared to plasma epinephrine level. Plasma total cholesterol was increased from the control 51.6+3.0 mg/ 100 ml of plasma to 61 .713.5 (N=19) after forced running. However, naloxone had no effect on neither total cholesterol nor high density lipoprotein plasma concentration, suggesting that opioid receptors are not directly involved in cholesterol metabolism

11287| NALOXONE EFFECTS ON IMMOBILIZATION STRESS AND CATECHOLAMINES CONTENT IN PLASMA AND ADRENAL MEDULLA. HM Rhee*, D Hendrix. Dept. of Pharmacology, Oral Roberts University, School of Medicine, Tulsa, OK.

Psychological stress such as immobilization play a role in etiology of hypertension by an increased sympathetic nervous activity as a result of the stress. To study the role of opioid receptors in the immobilization stress naloxone was used in young male Sprague-Dawley rats(200 to 250 g ) . The rats were surgically implanted arterial and venous catheters and they were subjected to immobilization on wooden boards for 60 min with continuous monitoring blood pressure and heart rate. Naloxone (1 mg/kg) was given intraperito-neally 10 min before the immobilization and control rats had sham operation. At the end of each immobilization 1 ml of blood was obtained to assay plasma catecholamines(Waters' HPLC with E-C detector). Both adrenal medulla were pooled to determine the level of adrenal catecholamines. The immobilization increased systolic and diastolic blood pressures including the heart rate. The immobilization also increased significantly both norepinephrine and dopamine in the plasma with a little effect on epinephrine. This procedure also elevated adrenal dopamine from 0.5+0.04 ug/ g tissue to 1.6+0.34. A pretreatment the animals with naloxone reduced the plasma catechoamine concentrations and adrenal content of epinephrine. The data indicate that psychological stress such as immobilization activates sympathetic nervous system, which was attenuated by opioid receptors, although the precise interactions between the two systems remain to be defined.

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ANGIOTENSIN II AND ATRIAL NATRIURETIC PEPTIDE IN PLASMA AND BRAIN OF 1K1CLIP, 2K2CLIP AND DOCA-SALT HYPERTENSIVE R A T MODELS. H. Wang, M.I. Phillips and B. Kimura. Dept. of Physiology, College of Medicine, University of Florida, Gainesville, F L 32610 U.S.A.

The physiological actions of angiotensin II (All) and atrial natriuretic peptide (ANP) appears to be opposite in many respects. It is not clear, however, if plasma and brain levels of these hormones are counteractive in hypertension. We investigated the levels of All and ANP in male rats to study the changes which occur in different models of hypertension. One kidney was removed and the renal artery of the other clipped (1K1C). In a second group, both kidneys were intact and one was clipped (2K1C). The third group was uninephrectomized and treated with DOCA + 1.0% NaCl. The fourth group was a sham control for the 2K1C and a fifth group was normotensive controls. Weekly measurements of blood pressure were taken and at 4 weeks, trunk blood was removed and brains dissected and frozen. All and ANP were measured by RIA after extraction. The results showed: 1) all groups developed hypertension (p<0.01). 2) plasma All levels were significantly increased in 2K1C and decreased in DOCA-salt and 1K1C. 3) Of the 3 hypertensive groups, only DOCA had an elevated plasma ANP. 4) In brain, the highest levels of All were found in the 2K1C group in the hypothalamus. 5) ANP was highest in all groups in the hypothalamus but there were significantly elevated levels in the cerebellum of 1K1C and 2K1C compared to normotensive and sham controls (p<0.01). DOCA rats had the highest ANP in the cerebral cortex. The results indicate differences in levels of All and ANP in plasma and in brain which are unrelated, except in DOCA salt rats where low plasma All and high plasma ANP occurred.

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|1290| PLASMA ANF OF HYPERTENSIVES IS AFFECTED DIFFERENTLY BY ATENOLOL AND ZOFENOPRIL. F. Elijovich*, C. Laffer and E.L. Schiffrin*. Mount Sinai School of Medicine, New York, NY and Clinical Research Institute of Montreal, Canada. The effects of atenolol (AT) and the converting enzyme inhibitor zofenopril (ZF) on plasma ANF were studied in 20 essential hypertensives. All patients were maintained on placebo for 4 weeks prior to treatment with AT (n=9) or ZF (n=ll). ANF was measured by RIA at the end of the placebo period and after 10 weeks of treatment. Baseline ANF (±3E) , 65±11 pg/ml, war, higher than that of 29 normotensive controls, 41±4 (p<0.05), and correlated significantly with serum creatinine (r=0.87), age (r-0.48) and EKG score, for LVH (r=0.69). AT diminished BP from 170±9/103±2 to 170±8/96+3 mmHg and ZF from 183±7/104±1 to 177±8/98±2 (l-/<0.05 for diastolics). Reductions in BP were not significantly different between the two groups. AT increased ANF by 42±9 (p<0.001) </hilf: ZF produced a non-significant reduction of 19±12. The increase in ANF by AT correlated significantly with serum creatinine (r=0.68), duration of hypertension (r=0.74) and EKG score (r=0.73). Th* reduction in ANF by ZF showed negative correlations with pretreatment ANF (r=-0.7i) and serum creatinine (r=--0.58). Our data suggest that: 1. Pretreatment ANF reflects the magnitude of preexisting cardiac or renal target organ damage. 2. Reduction of BP by beta blockers increases atrial stretch in proportion to the magnitude of this damage. 3. Equivalent reduction of BP by converting enzyme inhibitors decreases atrial stretch, especially in hypertensives with target organ damage.

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N I F E D I P I N E R E D U C E S P L A S M A A T R I A L N A T R I U R E T I C P E P T I D E ( A N P ) I N S E V E R E H Y P E R T E N S I O N . R . A . P h i l l i p s * H . E i s o n * , M. A r d e l j a n , Μ. J o n e s a n d L . R . K r a k o f f * M o u n t S i n a i H o s p i t a l , N e w Y o r k , N Y .

T h e e f f e c t o f n i f e d i p i n e , a s m o n o t h e r a p y , o n p l a s m a A N P , r e n i n ( P R A ) a n d c a r d i a c f u n c t i o n w a s a s s e s s e d i n 1 6 s u b j e c t s w i t h s e v e r e h y p e r t e n s i o n . A f t e r i m m e d i a t e r e d u c t i o n i n p r e s s u r e b y n i f e d i p i n e c a p s u l e s , l o n g t e r m c o n t r o l ( s e a t e d d i a s t o l i c p r e s s u r e < 9 5 mm H g ) w a s a c h i e v e d b y t i t r a t i o n o f n i f e d i p i n e - G I T S , t h e o n c e a d a y c o n t i n u o u s r e l e a s e s y s t e m , 3 0 - 1 5 0 m g / d a y . C a r d i a c o u t p u t ( C O ) , l e f t a t r i a l d i m e n s i o n ( L A ) , e j e c t i o n f r a c t i o n ( E F ) a n d a t r i a l / e a r l y d i a s t o l i c f i l l i n g ( A / E ) w e r e d e t e r m i n e d b y D o p p l e r -e c h o c a r d i o g r a p h y b e f o r e t r e a t m e n t a n d a f t e r t i t r a t i o n . P r e - t r e a t m e n t s y s t o l i c a n d d i a s t o l i c p r e s s u r e s w e r e 1 9 1 + . 8 / 1 1 7 + 7 mm H g ( m e a n + S E ) . B o t h w e r e r e d u c e d ( p < 0 . 0 0 1 ) b y n i f e d i p i n e : - 4 3 + . 6 / - 2 5 ± . 3 mm H g . P l a s m a A N P d e c r e a s e d f r o m U&±10 to 3 6 + 1 0 p g / m l , p < 0 . 0 1 ( - 2 3 + 8 % ) . P R A , C O , L A , E F , a n d A / E w e r e n o t s i g n i f i c a n t l y c h a n g e d . P r e - t r e a t m e n t p l a s m a A N P w a s c o r r e l a t e d w i t h t h e c h a n g e i n s y s t o l i c p r e s s u r e ( r = 0 . 6 0 , p < 0 . 0 2 ) . T h e r e d u c t i o n i n A N P w a s h i g h l y c o r r e l a t e d w i t h p r e t r e a t m e n t p e a k e a r l y ( E ) d i a s t o l i c f i l l i n g v e l o c i t y ( r = 0 . 7 6 , p < 0 . 0 1 ) . S u s t a i n e d r e d u c t i o n o f l e f t v e n t r i c u l a r a f t e r l o a d b y n i f e d i p i n e d i m i n i s h e s t h e s t i m u l u s f o r A N P s e c r e t i o n i n s e v e r e h y p e r t e n s i o n w i t h o u t i n c r e a s i n g r e n i n .

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AMBULATORY MONITORING REVEALS TWO COMPONENTS IN THE PRESSOR RESPONSE TO THE MEDICAL VISIT. C. Laffer and F. Elijovich*. Mount Sinai School of Medicine, New York, NY. The magnitude of the pressor response to the medical visit was assessed by 24 hr BP monitoring in 46 ambulatory hypertensives after 3 weeks on placebo (n=61) or 10 weeks on therapy (n=35). BP readings were divided into: 1) Bedbound or asleep, which were excluded; 2. Initial (INIT) , from the. time the monitor was placed until the patient reached his job or home; 3. Final (FIN), the following day, from the time the patient left his home or job until removal of the monitor; 4. Active (ACT), the remaining time; and 5. INIT+ FIN, i.e., all data surrounding the visit (VIS). Averages of heart rates (HR), and systolic (SYS), diastolic (DIAS), mean (MEAN) and pulse (PP) pressures were calculated in each study. On placebo, VIS SYS (163±2), DIAS (101±1), MEAN (122±1) and PP (61+2) mmHg were higher than ACT SYS (148±2), DIAS (92±1), MEAN (111±2) and PP (56±2), p<0.01. HRs were not different. No difference between INIT and FIN was seen for DIAS, MEAN and HR. FIN SYS (158±3) and PP (58±2) were less than INIT SYS (167±2) and PP (65±2), pi 0.01, but FIN SYS was still higher than ACT SYS, p<0.01. The same patterns were observed in treated groups. We conclude that the pressor response to the medical visit: 1. Has a magnitude of 14±2/10±1 mmHg, (p<0.001). 2. Is due to an autonomic effect on ventricular s'roke volume as suggested by the increased PP but not HR. 3. Is not altered by therapy. 4. Has two components: INIT, previously described as the "white coat syndrome" and FIN, which precedes the encounter with medical staff and has not been previously recognized.

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REDUCED EXCRETION OF MINERALS IN HYPERTENSIVE SUBJECTS FED FAT M O D I F I E D DIETS W I T H FIXED LEVELS OF MINERALS. IM lacono*. RM Dougherty*. USDA, ARS, Western Human Nutrition Research Center, Presidio of San Francisco, CA 94129.

A dietary intervention study was conducted in hypertensive (HT) and normotensive (NT) subjects in which Na, K, Ca, Ρ and Mg were fed at fixed levels through the intervention and swithback periods. In addition, saturated fatty acids and monounsaturated fatty acids were each maintained at 10 percent of total energy (en%) during the same periods and polyunsaturated fatty acids (PUFA) primarily of the n-6 type were fed at either 3 en% or 10 en%. This study was of a switchback design and was conducted on a metabolic unit. All urine was collected for 100 days. Urine volume was reduced and Na, K, Ca and CI were excreted at lower levels in the HT group than in the NT group at either level of PUFA. Slight differences were noted in urinary excretion of Ρ and Mg in the HTs and NTs. At 10 en% PUFA intake, the NT group excreted less Κ and more CI in urine than when they consumed the 3 en% PUFA diet. More urinary Ρ and CI was excreted by the HTs on the 10 en% PUFA diet.

Under the conditions of this experiment, the HTs responded differently than the NTs for the parameters studied. An understanding of the implications of these findings warrants further study.

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THE EFFECT OF FAT MODIFIED DIETS O N BLOOD PRESSURE, MINERAL EXCRETION, AND BLOOD LIPIDS OF MEN W I T H HIGH NORMAL BLOOD PRESSURES. RM Dougherty*. JM lacono*. USDA, ARS, Western Human Nutrition Research Center, San Francisco, CA 94129.

A dietary intervention study was conducted in male subjects with high normal blood pressures on the metabolic unit. The diets were typical of the USA in composition and in choice of food items. Dietary Na, K, Ca, Ρ and Mg were maintained constant. Two levels of fat, 25 percent of total energy (en%) with a polyunsaturated to saturated fatty acid ratio (P/S) of 1.0 and 44 en%, P/S 0.22, were fed in a switchback study with two 40-day intervention periods after a stabilization period of 20-days. Protein was maintained at about 16 en% and carbohydrate was either 61 en% or 42 en%, depending on the amount of fat. Body weights of the subjects were maintained constant by caloric adjustment.

When polyunsaturated fatty acids (PUFA) (mainly n-6) were present at the higher level, 9.2 en% in the 25 en% diet, systolic and diastolic blood pressures were significantly lower than when the subjects consumed the higher fat, lower P/S diet. Urine volume was higher but urinary excretion of Na, P, and Κ was lower when the subjects consumed the 25 en% diet compared to the 44 en% diet. Ca excretion was higher on the 25 en% diet than on the higher fat diet.

Plasma lipids were also influenced by the amount and kind of fat in the diet. Total and HDL-cholesterol were significantly lower when the lower fat, higher P/S diet was consumed (4.3 and 0.93 mmol/L) than when the higher fat, lower P/S diet was consumed (5.3 and 1.2 mmol/L).

In addition to demonstrating the blood pressure and lipid lowering effects of fat modified diets, this study also showed that the amount and quality of fat affected urinary mineral excretion.

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CORTICAL NFURONS WITH ANP-LIKF. IMMUNOREACTIVITY (ANP-UP) MAY CONTROL LOCAL CEREBRAL BLOOD FLOW. J C M c K e r ^ i e * and R.J. Cowie. Dept. of Anatomy, College of Medic ine, Howard U n i v e r s i t y , Washington, D.C

The d i s t r i b u t i o n of ANP-LIR in p e r i k a r y a and f i b e r s of i r o g and ra t b ra i ns has p rev i ous l y been descr ibed but studies have not been conducted on species w i t h more complex co r t i ca l s t r u c t u r e . In the present p r e l i m i n a r y study we have invest igated the d i s t r i b u t i o n of ANP- l . IR in the cor tex of the canine b r a i n by immunoh is tochemis t r y . The b ra i ns of anesthetized dogs (2) we re f i xed by per fus ion w i t h \0% f o r m a l i n , s te reo tax ica l l y blocked and prepared for f rozen sect ioning ( 3 0 ~ 5 0 u ) in e i ther the coronal or sagi t ta l plane. Sections we re incubated in ant ibody against r a t ANF IV and subsequent ly processed by the av id in - b i o t i n -peroxidase complex technique. Subs t i t u t i on of no rma l r a b b i t se rum for p r i m a r y ant ibody was the con t ro l . A N P - L I R was detected in many of the same reg ions , p a r t i c u i a r y hypotha lamic subnucle i and other subcor t i ca l areas, p rev i ous l y descr ibed in f rog and ra t . In add i t ion , scat tered, med ium-s i zed py ram ida l and m u l t i p o l a r neurons possesing ANP-L IR we re observed in many co r t i ca l areas. These neurons were most f requen t l y seen in the depths of s u l c i , adjacent to ce reb ra l vessels en te r i ng f r o m the subarachnoid space. Remarkab l y , the somata we re usua l l y located in the 2nd (and 3 r d ) co r t i ca l l aye rs and pro jected spinous apical den t r i t es towards , and often i n t o , the p i a l - g l i a l in te r face (PGI ) . Other dendr i t i c branches appeared to estab l ish close contact w i t h local microvesse ls . An axon was somet imes observed p ro jec t i ng c e n t r a l l y , g i v i n g - o f f many de l icate, var icose co l la te ra ls some of wh i ch c losely approached blood vessels t r a v e r s i n g the P6I o r i n ne ighbor ing co r t i ca l l aye rs The topography and cy toa rch i t ec tu re of these A N P - L I R ce l ls suggests that they may be sensing, and responding to , local ce reb ra l blood f low. Suppor ted by the Amer i can Heart Associat ion, Nat ion's Capitol A f f i l i a te .

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LABETALOL VS NITROPRUSSIDE IN HYPERTENSION POST CORONARY-BYPASS SURGERY. J S k r o b i c , C C r u i s e , R W e b s t e r , Τ D a v i d , A M a r q u e z - J u l i o * T o r o n t o Western H o s p i t a l , T o r o n t o , Canada. C o r o n a r y a r t e r y b y p a s s g r a f t i n g (CABG) i s a s s o c i a t e d w i t h p o s t o p e r a t i v e high BP f o r which n i t r o p r u s s i d e (NP) i s u s u a l t h e r a p y . L a b e t a l o l (L) may be a s u i t a b l e o p t i o n . C o n s e n t was o b t a i n e d f rom 91 e l e c t i v e CABG p a t i e n t s w i t h no v a l v u l a r d i s e a s e and no b e t a -b l o c k e r c o n t r a i n d i c a t i o n s . I f c r o s s - c l a m p time was < 9 0 m i n and t h e p a t i e n t was s t a b l e f o r 1 hr p o s t s u r g e r y , s t u d y e n t r y was c o n s i d e r e d . I f s y s t o l i c BP (SBP) was >140mmHg o r mean a r t e r i a l p r e s s u r e >90mmHg, r a n d o m i z a t i o n t o NP o r L i n f u s i o n w a s d o n e f o l l o w i n g b a s e l i n e hemodynamics. Repeat hemodynamics were r e c o r d e d when BP c o n t r o l was a c h i e v e d . R e s u l t s w e r e a s s e s s e d w i t h a n a l y s i s o f c o v a r i a n c e f o r r e p e a t e d measures and s t u d e n t s t t e s t . H i g h BP o c c u r r e d i n 4 0 p a t i e n t s , b a s e l i n e p a r a m e t e r s w e r e s i m i l a r i n a l l . N P l o w e r e d d i a s t o l i c BP ( D B P ) , i n c r e a s e d h e a r t r a t e ( p < 0 . 0 0 5 ) : d e c r e a s e d c e n t r a l v e n o u s a n d pulmonary c a p i l l a r y wedge p r e s s u r e s (CVP, PCWP) ( p < 0 . 0 5 ) and d i d n o t c h a n g e c a r d i a c i n d e x ( C I ) . L d e c r e a s e d HR ( p < 0 . 0 0 5 ) : d e c r e a s e d CI , r a i s e d CVP and P C W P ( p < 0 . 0 5 ) : m a i n t a i n e d DBP. SBP d e c r e a s e d by >20mmHg w i t h both drugs ( p < 0 . 0 0 5 ) . To m a i n t a i n BP c o n t r o l f o r t h e n e x t 24 h r s , t h e NP g r o u p needed a 3 f o l d g r e a t e r dose of NP. The r e s u l t s s u g g e s t t h a t i n post -CABG h y p e r t e n s i o n L c a n be s a f e , e f f e c t i v e and may f a v o r d e t e r m i n a n t s of the m y o c a r d i a l 02 s u p p l y / d e m a n d r a t i o . The l a t t e r p o i n t r e q u i r e s more s tudy .

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ALTERED MOLAR VASOPRESSIN ( A V P ) AND A T R I A L NATRIURETIC FACTOR ( A N F ) CONCENTRATIONS FOLLOWING THE FONTAN PROCEDURE ( F P ) IN CONGENITAL HEART D I S E A S E JM S t e w a r t " , GA Z e b a l l o s , A C h a n g , Κ M u r d i s o n , Κ S e l i g m a n , B J C l a r k e , PK W o o l f , BG F i s h , WI N o r w o o d , MH G e w i t z . New Y o r k M e d i c a l C o l l e g e V a l h a l l a , NY a n d C h i l d r e n ' s H o s p i t a l o f P h i l a d e l p h i a , P h i l a , P a .

A r g i n i n e v a s o p r e s s i n ( A V P ) a n d a t r i a l n a t r i u r e t i c f a c t o r ( A N F ) a r e v a s o r e g u l a t o r y p e p t i d e s w i t h a n t a g o n i s t i c e f f e c t s w h i c h m a y r e s u l t f r o m t h e i r e f f e c t s o n cGMP s y n t h e s i s . T h e y a r e p r e s e n t i n p l a s m a i n n e a r l y e q u i m o l a r c o n c e n t r a t i o n s ( [ ] ) a n d h a v e i n t e r d e p e n d e n t r e l e a s e m e c h a n i s m s . S u c c e s s f u l F o n t a n P r o c e d u r e ( F P ) a c u t e l y r a i s e s r i g h t a t r i a l p r e s s u r e , b u t p a t i e n t s u r v i v a l i s o f t e n c o m p l i c a t e d b y d i s o r d e r e d f l u i d b a l a n c e . T h e r e f o r e , we a s s e s s e d p l a s m a [ A V P ] a n d [ A N F ] s i m u l t a n e o u s l y b y R I A p r i o r t o , d u r i n g a n d p o s t F P i n 1 4 c h i l d r e n ( 2 - 1 0 y ) . [ A V P ] i n c r e a s e d ( p < . 0 1 ) o n c a r d i o p u l m o n a r y b y p a s s ( C P B ) b u t d e c r e a s e d f o l l o w i n g a n a s t o m o s i s w h i l e [ A N F ] w a s i n c r e a s i n g ( p < . 0 5 ) . When [ A N F ] w a s m a x i m u m ( d a y s 3 -1 0 ) , [ A V P ] d e c r e a s e d t o l e s s t h a n p r e o p l e v e l s ( p < . 0 5 ) . I n c r e a s e d [ A N F ] m a y i n h i b i t [ A V P ] r e l e a s e i n F P . L o w e r [ A V P ] / [ A N F ] m a y s t i m u l a t e cGMP a c c u m u l a t i o n t h e r e b y m o d i f y i n g v a s c u l a r t o n e a n d f l u i d r e t e n t i o n i n s o m e o f t h e s e p a t i e n t s .

preop Anesth CPB OffCPB POD1 POD2 POD3-10 [ANF](pM/l) 26+8 21+5 29+7 76+19 47+8 71+24 83+13 [AVP](pM/l) 18+4 36+12 109+21 113+25 68+20 47+16 8+3 [ANF]/[AVP] 1 . 4 0 . 6 0 . 3 0 . 7 0 . 7 1 . 5 1 0 . 4

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11300| USE OF ENALAPRIL IN PATIENTS WITH CAPTOPRIL ASSOCIATED DRUG REACTIONS. Ρ La B e l l e , PV R o d e l , MSDRL, West P o i n t , PA

I n t h e E n a l a p r i l (E) H y p e r t e n s i o n (HTN) Compassionate Use Program, 278 p a t i e n t s ( p t s ) were t r e a t e d w i t h Ε who had 386 adverse d rug r e a c t i o n s (ADR) on p r i o r C a p t o p r i l ( C ) . The p r i o r doses o f C were known f o r 218 ADR's ( i n 138 p t s ) . The p r i o r C doses and mean maximum d a i l y doses o f Ε used f o r HTN c o n t r o l were ( m g / d a y ) : No .o f p t s

ADR C Mean Dose Ε Mean Dose ADR conL. (No. o f p t s ) (med ian ; range ) (med ian ; range) on b

Rash(82) 151 ( 1 0 0 ; 1 2 . 5 - 6 0 0 ) 21 .6 ( 2 0 ; 2 . 5 - 1 2 0 ) 2 Dysyeus ia (42 ) 116 ( 1 0 0 ; 1 8 . 7 5 - 3 0 0 ) 25 .4 ( 2 0 ; 2 . 5 - 1 2 0 ) 1 H e m a t o l o g y ( 2 9 ) * 101 ( 1 0 0 ; 6 . 2 5 - 3 0 0 ) 21 .3 ( 1 5 ; 2 . 5 - 6 0 ) 3 * * P r o t e i n u r i a ( 2 1 ) 172 ( 1 5 0 ; 3 7 . 5 - 3 0 0 ) 20 .2 ( 2 0 ; 5 - 4 0 ) ϋ Angioedema(3) 104 ( 1 5 0 ; 1 2 . 5 - 1 5 0 ) 11.7 ( 1 0 ; 5 - 2 5 ) 0 0 t h e r ( 4 2 ) 62 ( 1 0 0 ; 1 2 . 5 - 4 5 0 ) 27 .2 ( 1 5 ; 5 - 8 0 ) 3 * Hematology - l e u c o p e n i a ( 1 4 ) , n e u t r o p e n i a ( 9 ) , t h r o m b o c y t o

p e n i a ( 2 ) , pancy topen ia ( 2 ) , a g r a n u l o c y t o s i s ( 1 ) ** l e u c o p e n i a ( 2 ) , n e u t r o p e n i a ( 1 ) Of t h e 218 ADR on C o n l y 9 c o n t i n u e d o r r e c u r r e d on h . A l t h o u g h no case o f angioedema o c c u r r e d on Ε i n t h i s s t u d y , t h e use o f o t h e r ACE i n h i b i t o r s (ACEI) a f t e r angioedema on an ACEI i s n o t recommended.

For these 138 p t s f o r whom t h e p r i o r C dose was known, 79% o f t he 77 p t s who had ADR on C < 150 mg/day and 58% o f t h e 61 p t s who had ADR on C > 150 mg/day r e q u i r e d Γ- < 20 mg/day f o r HTN c o n t r o l .

S i x t y (60 ) o f t h e 138 p t s had p r e e x i s t i n g r e n a l i n s u f f i c i e n c y ( R I , serum c r e a t i n i n e > 1.6 m g / d l , c o n s i d e r e d h i g h r i s k f o r ADR). The C dose wh ich had b e e n a s s o c i a t e d w i t h t h e ADR and t he c o r r e s p o n d i n g Ε dose f o r Η FN c o n t r o l was i d e n t i f i e d i n t hese 60 p t s ( m g / d a y ) : No. o f p t s i n C Dose Ε Dose C Dose Range Range Mean Median Range Mean Median

5 6 . 2 5 - 2 5 11.2 12.5 2 . 5 - 3 0 10.5 5 9 25-50 4 4 . 4 50 2 . 5 - 4 0 13.1 10

17 75 -112 .5 8 3 . 1 75 2 . 5 - 6 0 21 .5 20 29 150-600 236 .2 150 2 . 5 - 8 0 19.9 l b Of t hese 60 p t s w i t h R I , 71% o f t he 31 p t s who had ADR on

C < 150 mg/day and 72% o f t h e 29 p t s who had ADR on C > 150 mg/day r e q u i r e d Ε < 20 mg/day f o r HTN c o n t r o l .

Most p t s w i t h ADR on C, i n c l u d i n g h i g h r i s k p t s w i t h R I , were s u c c s s f u l l y t r e a t e d w i t h Ε f o r HTN, u s u a l l y r e q u i r i n g b < 20 mg/day . Very few (4.2%) C a s s o c i a t e d ADR c o n t i n u e d o r r e c u r r e d on E.

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SECRETORY ACTIVITY OF ATRIAL TISSUE IS PRESERVED BY APROTININ (Ap) λ GA Zeballos, C Hoegler, MH Gewitz, JM Stewart". New York. Medical College, Valhalla, NY

Tissue proteases may play a triple role in ANF secretion in vitro by: 1) degrading cell membrane, 2) converting prohormone to the active peptide, and 3) degrading the active peptide. To investigate the effects of protease inhibition on ANF released from unstretched atria, we super-fused quiescent atrial appendage strips with high and low dose Ap. Ap inhibits peptide proteolysis and preserves membrane integrity. Strips were incubated for three consecutive 20 min periods in oxygenated Krebs-Henseleit solution at 37°C: A) without Ap; B) with 67 KlU/ml Ap; C) with 400 KlU/ml Ap. At the end of each period, the solution was replaced and ANF measured (ANF in ng/min/gww) by radioimmunoassay.

No Ap Ap (67 KlU/ml) Ap (400 KlU/ml)

0-20min 13.0+0.7 11.1+1.0 17.6+1.8

20-40min 4.6+2.8 6.0+1.7 9.5+1.4

40-60min 2.0+1.2 3.9+0.9 12.2+1.6

These data indicate that 400 KlU/ml Ap enhances ANF content (p<.05) in each time period. ANF decreased with time in the absence of AP and with 67 KlU/ml Ap but not with 400 KlU/ml (40-60 min vs 0-20 min, p<.05). The data suggest that Ap protects atrial myocytes from cellular proteases while preventing proteolysis of active ANF thereby preserving secretory activity.

113011 EFFECT OF AGE, RACE AND DEGREE OF HYPERTENSION IN PATIENTS WITH MILD TO MODERATE HYPERTENSION TREATED WITH FELODIPINE, HYDROCHLOROTHIAZIDE OR ATENOLOL *D .A . S h a p i r o , *M.C. Dun lay , * G . I . Holmes, TK-E. L i p s c h u t z , JM . Hesney, and *J.D. I r v i n , *Depar tments o f C l i n i c a l Research , ( C a r d i o v a s c u l a r ) and Τ B i o s t a t i s t i c s , Merck, Sharp and Dohme Research L a b o r a t o r i e s , West P o i n t , PA 19486.

The a n t i h y p e r t e n s i v e e f f i c a c y o f f e l o d i p i n e , a d i h y d r o p y r i d i n e c a l c i u m a n t a g o n i s t , was e v a l u a t e d w i t h r e s p e c t t o age , race and degree o f h y p e r t e n s i o n i n two s i m i l a r l y d e s i g n e d , d o u b l e - b l i n d , p a r a l l e l g r o u p , p lacebo (Pbo) c o n t r o l l e d s t u d i e s . F e l o d i p i n e ( F e l ) 5-10mg b i d was compared w i t h h y d r o c h l o r o t h i a z i d e (HCTZ) 25-50mg once d a i l y i n m i l d l y (DBP 90-105mmHg) h y p e r t e n s i v e p a t i e n t s ( n = 2 5 6 ) :

ELDERLY YOUNG (-*65YR) (<65YR) BLACK NONBLACK MILD MODERATE

0% % p a t i e n t s * 17% 83% 34% 66% 100% Fel : - 1 2 * - 1 0 * * , + ν -7@ - 1 1 * * , + J ν - 1 0 * HCTZ: -9(s> - 6 ( 9 - 8 * - 6 - 7 * Pbo : - 5 - 4 - 3 - 5 - 4

I n a second s t u d y , Fel (5-10mg b i d ) was compared t o a t e n o l o l (A ten ) (50-100mg once d a i l y ) i n m i l d (DBP 95-105 mmHg) t o m o d e r a t e l y (DBP 106-115 mmHg) h y p e r t e n s i v e p a t i e n t s ( n = 2 3 3 ) :

% p a t i e n t s 16% 84% 22% 78% 76% 24% Fel : _ 1 2 * * - 1 0 * * - 1 0 * * - 10 _ g * * - 1 4 * ' A t e n : _ g * * - 1 0 * * -9(3 - 10 - 1 1 - 8 Pbo : - 2 - 4 - 3 - 4 - 3 - 6

* , * * p^ 0 . 0 5 , 0 . 0 1 , r e s p e c t i v e l y ; compared t o p lacebo @ 0 . 0 5 i p < 0 . 1 0 , compared t o p lacebo

++ p i O . 0 1 ; compared t o HCTZ o r a t e n o l o l

These subgroup ana lyses were no t p r i m a r y o b j e c t i v e s o f t he s t u d i e s . F e l o d i p i n e appeared t o be s i g n i f i c a n t l y more e f f e c t i v e than HCTZ i n m i l d l y and a t e n o l o l i n mode ra te l y h y p e r t e n s i v e p a t i e n t s . A l t h o u g h t he number o f p a t i e n t s i n each group was o f t e n s m a l l , f e l o d i p i n e appeared t o be s l i g h t l y more e f f e c t i v e than e i t h e r o f t he o t h e r a c t i v e agents i n the e l d e r l y . A l l a c t i v e agents appeared t o be e f f e c t i v e i n b lack p a t i e n t s , however , f e l o d i p i n e appeared s i g n i f i c a n t l y more e f f e c t i v e i n nonb lack p a t i e n t s w i t h m i l d h y p e r t e n s i o n i n the HCTZ s t u d y .

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1 3 0 2

INVOLVEMENT OF AN UNKNOWN HUMORAL AGENT IN DOCA-SALT HYPERTENSION. M.D. A s h e n , J . M . Hamlyn . D e p a r t m e n t o f P h y s i o l o g y , U n i v e r s i t y o f M a r y l a n d , B a l t i m o r e , MD.

A r t e r i a l p r e s s u r e (AP) i s r e g u l a t e d by neurohumoral (NH) and c a r d i a c (C) f a c t o r s and v a s c u l a r s t r u c t u r e (VS) . To a s s e s s i n v i v o c o n t r i b u t i o n o f known NH a n d C f a c t o r s t o AP, d i r e c t m e a n a r t e r i a l p r e s s u r e (DMAP) was m e a s u r e d b e f o r e and d u r i n g a c u t e n e u r o h u m o r a l and c a r d i a c b l o c k a d e (NHCB) d u r i n g p r e ( d a y 5) and d e v e l o p m e n t a l ( d a y 12 and 3 0 ) s t a g e s o f DOCA-salt h y p e r t e n s i o n (HT). S t r u c t u r a l c o n t r i b u t i o n t o AP was a s s e s s e d i n v i v o by m a x i m a l v a s o d i l a t i o n w i t h NHCB and n i t r o p r u s s i d e (NP) a n d i n s i t u by p e r f u s i o n - f i x a t i o n (PF) o f r e s i s t a n c e v e s s e l s . NHCB was a c h i e v e d by c o m b i n e d i n f u s i o n o f m a x i m a l l y e f f e c t i v e d o s e s o f h e x a m e t h o n i u m , m e t h s c ο ρ ο 1 a m i n e , c a p t o p r i l , d(CH 2 ) 5 T y r ( M e ) AVP and a t e n o l o l t o c h r o n i c a l l y c a n n u l a t e d , c o n s c i o u s r a t s . I n s i t u VS was a s s e s s e d by m e d i a a r e a measurements i n PF v e s s e l s and was n o t d i f f e r e n t b e t w e e n DOCA and sham. B a s e l i n e DMAP was e l e v a t e d i n DOCA r a t s o n d a y 1 2 ( 1 3 3 + . 6 v s 1 0 5 ± _ 3 mmHg s h a m ; P < 0 . 0 5 ) and d a y 30 ( 1 5 9 + 6 v s 1 1 1 + 3 mmHg s h a m ; P < 0 . 0 5 ) . During NHCB, DMAP was e l e v a t e d i n DOCA r a t s on d a y 5 , 12 and 30 ( P < 0 . 0 5 ) . DMAP d i f f e r e n c e b e t w e e n DOCA a n d s h a m w i t h NHCB w a s a b o l i s h e d by a d d i t i o n o f NP. We c o n c l u d e t h a t t h e e l e v a t e d DMAP o f DOCA a n i m a l s d u r i n g NHCB i s due t o an unknown h u m o r a l a g e n t whose a c t i o n s a r e i n t e r r u p t e d by NP.

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PROTEIN KINASE C AND PLATELET REACTIVITY IN SPONTANEOUSLY HYPERTENSIVE RATS. S . K0UT0UZ0V, I . LIMON, P. MEYER, P. MARCHE* Dept P h a r m a c o l o g y , Necker H o s p i t a l 7501b P a r i s f - rance . I t i s through t h e g e n e r a t i o n o f t h e second messeng e r s i n o s i t o l t r i p h o s p h a t e ( I P 3 ) and d i a c y l g l y c e ro l (DG) t h a t p h o s p h o l i p a s e C (PLase C) a c t s in c o n c e r t with p r o t e i n k i n a s e C (PKC) t o c o n t r o l t h e c e l l u l a r p h y s i o l o g i c a l r e s p o n s e s . S i n c e p l a t e l e t r e a c t i v i t y t o thrombin i s enhanced in s p o n t a n e o u s l y h y p e r t e n s i v e r a t s (SHR) when compared t o c o n t r o l s (WKY), we i n v e s t i g a t e d w h e t h e r , in SHR, t h e PKC pathway could be i n v o l v e d in such p l a t e l e t hyp e r r e a c t i v i t y . PKC a c t i v i t y was determined in 32p_ p r e l a b e l e d washed p l a t e l e t s from SHR and WKY by measur ing t h e a g o n i s t - i n d u c e d 32p l a b e l i n g o f t h e 47 and 20 kDa p r o t e i n s (P47 and P 2 0 , t h e endogenous PKC s u b s t r a t e s in t h e p l a t e l e t ) a f t e r SDS-gel e l e c t r o p h o r e s i s . In u n s t i m u l a t e d p l a t e l e t s no d i f f e r e n c e could be d e t e c t e d between SHR and WKY in t h e 32p l a b e l i n g o f any p r o t e i n . L i k e w i s e , t h e i n c r e a s e in 32ρ l a b e l i n g o f P47 and P20 f o l l o w i n g a c t i v a t i o n by phorbol e s t e r or by d i - o c t a n o y l g l y c e r o l , was s i m i l a r in SHR and WKY. By c o n t r a s t , a f t e r thrombin ( 0 . 0 5 - 0 . 3 U/ml) s t i m u l a t i o n t h e 3 2 P l a b e l i n g o f P47 and P20 were s i g n i f i c a n t l y i n c r e a sed in SHR vs WKY. The EC50 v a l u e s o f thrombin f o r 3 2 P - P 4 7 and 3 2 P - P 2 0 were 25 and 30 %, r e s p e c t i v e l y lower in SHR than in WKY. These r e s u l t s i n d i c a t e t h a t t h e i n t r i n s i c p l a t e l e t PKC a c t i v i t y i s s i m i l a r in SHR and WKY. T h e r e f o r e t h e enhanced throm-b i n - e l i c i t e d PKC a c t i v i t y in SHR, i s l i k e l y t h e r e s u l t o f an i n c r e a s e d PLase C-induced DG format i o n in t h i s r a t s u b s t r a i n . Our f i n d i n g t h a t EC50 v a l u e o f thrombin f o r PLase C a c t i v i t y ( a s r e f l e c t e d by 3 2 p _ p h o s p h a t i d i c a c i d f o r m a t i o n ) was 30 % lower in SHR vs WKY, s u p p o r t s such an h y p o t h e s i s . T h u s , our data prov ide e v i d e n c e f o r a h y p e r s e n s i t i v i t y o f PLase C and c o n s e q u e n t a l t e r a t i o n s in p h o s p h o i n o s i t i d e - r e l a t e d e v e n t s t h a t l i k e l y p a r t i c i p a t e t o t h e enhanced p l a t e l e t r e s p o n s e s o b s e r v e d in pr imary h y p e r t e n s i o n .

113031 PLATELET Ca 2 + HANDLING AND MEMBRANE STRUCTURE IN ESSENTIAL HYPERTENSION K.H. LE QUAN SANG, T . M0NTENAY-GARESTIER0, M.A. DEVYNCK INSERM U / , Phar -m a c o l o g i e CHU Necker and °INSERM U201 Museum. Pr imary h y p e r t e n s i o n has been r e p e a t e d l y found t o be a s s o c i a t e d with v a r i o u s a l t e r a t i o n s in c e l l C a 2 + h a n d l i n g . The i n c r e a s e d c y t o s o l i c f r e e C a 2 + c o n c e n t r a t i o n ( [ C a 2 + ] - j ) o b s e r v e d in p l a t e l e t s has been proposed t o r e f l e c t a s i m i l a r i n c r e a s e in v a s c u l a r smooth musc le c e l l s . The p r e c i s e o r i g i n o f such an i n c r e a s e i s unknown. In t h e p r e s e n t s t u d y , we have i n v e s t i g a t e d a p o s s i b l e a l t e r a t i o n o f membrane s t r u c t u r e , a n a l y z e d by changes in t h e m o b i l i t y o f f l u o r e s c e n t probes : DPH ( d i p h e n y l -h e x a t r i e n e ) and TMA-DPH ( t r i m e t h y l a m i n o d i p h e n y l h e -x a t r i e n e ) embedded r e s p e c t i v e l y in t h e l i p i d b i -l a y e r s and a t t h e l i p i d - w a t e r i n t e r f a c e . [ C a 2 + ] •j was de termined in p a r a l l e l by t h e Quin-2 f l u o r e s c e n t c h e l a t o r . The c h a r a c t e r i s t i c s o f t w e n t y - f o u r age and s e x - m a t c h e d u n t r e a t e d h y p e r t e n s i v e and n o r m o t e n s i v e s u b j e c t s a r e g iven in t h e t a b l e (mean + SEM).

EHT Sex 7men, 4~women Age ( y e a r s ) 3 6 . 1 + 3 . 7 PAs mmHg) 149 + 4 PAd (mmHg) 9 8 + 4 r (DPH) 0 . 1 6 0 + 0 . 0 0 3 0 . 1 5 8 r (TMA-DPH) 0 . 2 5 8 + 0 . 0 0 3 0 . 2 7 0 [ C a 2 + ] - j ( n M ) 207 + 9 F l u o r e s c e n c e a n i s o t f o p y o f TMA-DPH (rTMA-DPH) a t 37°C in washed p l a t e l e t s , u n s t i m u l a t e d ex v i v o , was s i g n i f i c a n t l y d e c r e a s e d in h y p e r t e n s i v e p a t i e n t s , i n d i c a t i n g a lowered m i c r o v i s c o s i t y a t t h e o u t e r p a r t o f c e l l membrane. rTMA-DPH was i n v e r s e l y c o r r e l a t e d with d i a s t o l i c blood p r e s s u r e ( r = - 0 . 4 5 0 , p = 0 . 0 2 6 ) and [ C a 2 + ] - j ( r = - 0 . 5 6 0 , ρ = 0 . 0 0 6 ) . T h i s c o r r e l a t i o n remained v a l i d a t c o n s t a n t blood p r e s s u r e and age ( r = - 0 . 5 3 6 , ρ = 0 . 0 1 and r = - 0 . 5 6 5 , p = 0 . 0 0 5 ) . T h i s s u g g e s t s t h a t s t r u c t u r a l membrane a l t e r a t i o n s may p a r t i c i p a t e in t h e v a r i o u s f u n c t i o nal a b n o r m a l i t i e s d e m o n s t r a t e d in p l a t e l e t s from h y p e r t e n s i v e p a t i e n t s .

9men, 4women 3 5 . 3 + 2 . 8

122 + 4 7 5 + 3

0 . 0 0 4 0 . 0 0 2

175

0 . 0 0 1 0 . 0 0 1

0 . 0 0 5 0 . 0 2

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ENHANCED GROWTH OF SHR VS WKY AORTIC FIBROBLASTS S . DURANT, E. MILLANVOYE, P. MEYER - INSERM U7, Dept o f P h a r m a c o l o g y , Hopi ta l N e c k e r , 161 rue de S e v r e s , 75015 P a r i s , F r a n c e

The e f f e c t o f h y p e r t e n s i o n on t h e a r t e r i a l a d -v e n t i t i a has been i g n o r e d t o t h e b e n e f i t o f t h e m e d i a . T h u s , e x p e r i m e n t s were performed on advent i t i a l f i b r o b l a s t s o b t a i n e d from t h e a o r t a o f n o r m o t e n s i v e W i s t a r Kyoto (WKY) and s p o n t a n e o u s l y hyp e r t e n s i v e (SHR) r a t s , u s u a l l y 12 w e e k - o l d . 1 ) K i n e t i c s t u d i e s r e a l i z e d in minimal e s s e n t i a l medium supplemented by 10 % n e o n a t a l bov ine serum demonst r a t e t h a t from day 2 (48 h a f t e r p l a t i n g ) t o day 8 ( s a t u r a t i o n d e n s i t y ) t h e growth o f SHR f i b r o b l a s t s i s 1 . 5 - f o l d i n c r e a s e d as compared t o WKY. 2 ) R a i s i n g t h e serum c o n t e n t o f t h e medium from 1 t o 20 % shows t h a t a ) SHR as wel l as WKY f i b r o b l a s t s r e q u i r e t h e p r e s e n c e o f serum growth f a c t o r s t o p r o l i f e r a t e , b) a t a l l serum c o n c e n t r a * t i o n s t e s t e d , SHR c e l l s grow f a s t e r than WKY. 3) Enhanced growth was noted s i m i l a r l y in SHR c e l l s o b t a i n e d from young (5 w e e k - o l d ) and a d u l t (12 w e e k - o l d ) r a t s . 4 ) C o n d i t i o n e d medium from SHR c u l t u r e s does not s t i m u l a t e t h e growth o f WKY c e l l s , r u l i n g out t h e h y p o t h e s i s o f o v e r s e c r e t i o n o f a u t o c r i n e growth f a c t o r s . In c o n c l u s i o n , t h e s e r e s u l t s r e p r e s e n t t h e f i r s t d e m o n s t r a t i o n o f an enhanced growth o f v a s c u l a r SHR f i b r o b l a s t s . They s t r o n g l y s u g g e s t t h a t t h e a d v e n t i t i a may p a r t i c i p a t e in t h e development o f t h e v a s c u l a r m o d i f i c a t i o n s o f h y p e r t e n s i o n and in t h e chemica l p r o c e s s e s l e a d i n g to a t h e r o s c l e r o s i s . In a d d i t i o n , t h e p r e s e n t i n v e s t i g a t i o n shows t h a t a r t e r i a l f i b r o b l a s t s o f SHR, s i m i l a r l y t o m y o c y t e s , e x h i b i t an i n t r i n s i c a b n o r m a l i t y r e s p o n s i b l e f o r enhanced r e s p o n s i v e n e s s t o growth f a c t o r s .

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11306| INCIDENCE AND SIGNIFICANCE OF SILENT ST CHANGES DURING AMBULATORY MONITORING IN ASYMPTOMATIC HYPERTENSIVES. J . Szlachcic, Β. 0 'Kelly, JF Tubau*, K. Daiss, BM. Massie*. VA Medical Center and University of California, San Francisco, CA

Ambulatory ECG monitoring (AECG) is becoming increasingly popular in the assessment of s i lent coronary artery disease (CAD). However, i t s applicabil i ty to the hypertensive population is uncertain because of the presumed high frequency of false positive r e s u l t s .

Therefore, we prospectively examined the incidence and severity of ST abnormalities by 48 hour AECG in 80 asymptomatic hypertensive patients (PTS) while off therapy. All PTS underwent exercise ECG (ETT) with Thallium scintigraphy (TL). Thirteen (16%) had AECG with >lmm ST depression lasting >lmin compared to baseline. These were subdivided into groups; Gpl had both ETT and TL positive and Gp2 had one or both tes ts negative. Gpl had significantly greater severity and frequency of ST changes during AECG and a l l 3 PTS who underwent angiography had significant CAD.

No Total Time-ST Longest episodes duration integral episode

(min) (mm-min) (min) Gpl(n=7) 5 .7±0 .8 270±84 320±72 94±17 Gp2(n=6) 2 .010 .4 70+20 90±35 42±7

p< 0.002 0.05 0.02 0.02 Only one Gp2 PT (1 out of 7 in the study with

LVH and s t ra in) had ST changes that overlapped with those of Gpl. Thus, in this asymptomatic population the incidence of AECG abnormalities is low (16%) but the severity of ST changes by AECG predicts s i lent CAD as suggested by concordant positive ETT and TL t e s t s .

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THE ROLE OF CALCIUM IN THE RELEASE OF ATRIAL NATRIURETIC PEPTIDE IN VITRO. A.Jardine, B.Leckie, JMC Connell; MRC Blood Pressure Unit, Western Infirmary, Glasgow Gil 6NT.

We have investigated the role of Ca 2 + in the release of Atrial Natriuretic Peptide (ANP) in the isolated superfused rat atrium. Atria were suspended between a pacing electrode and a tension transducer under 0.5g resting tension and paced at 2Hz. The superfusate, a HEPES buffered physiological solution at 37°C, was collected and rat ANP measured by radioimmunoassay (RIA). After a 45 minute equilibration period in 2mM C a 2 + , basal collections were made over a 15 minute period. In group (a) Ca 2 + was maintained at 2mM for the following 60 minutes; in the other groups the superfusate was changed to contain contain either (b) OmM Ca 2 + or (c) 1 0 _ & M Verapamil for 30 minutes, or (d) 5mM EGTA for 5 minutes before returning to 2mM C a 2 + for the remainder of the experiment. The results are given in the following table (% basal, mean ±SE, n=8). TIME: Basal 1-15 16-30 31-45 46-60 (mins) (a) 100 106(6) 77(7) 87(8) 73(4) (b) 100 70(7) 58(9) 65(11) 69(9) (c) 100 86(10) 67(11) 66(13) 62(9) (d) 100 76(8) 76(8) 70(6) 77(20)

There was a gradual decline in the release of ANP in 2mM C a 2 + , but a significant initial reduction with OmM C a 2 f , EGTA, or Verapamil, paralleled by a fall in developed tension. Restoration of 2mM C a 2 + halted the decline in ANP release, suggesting that the release mechanism is calcium dependent, possibly involving a stretch sensitive channel.

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RENAL EFFECTS OF THE ATRIOPEPTIDASE INHIBITOR UK 69,578 IN NORMAL MAN. AG Jardine, JMC Connell, DB Northridge, S. Dilley, B. Leckie, AF Lever. MRC Blood Pressure Unit, Western Infirmary, Glasgow, Scotland.

UK 69,578 (UK69) is a compound developed by Pfizer Central Research (UK) which elevates endogenous plasma levels of atrial natriuretic peptide (ANP) by inhibition of the atriopeptidase EC 3.4.24.11. Eight normal volunteers taking a fixed Na diet received 2mg/Kg i.v. UK 69 or placebo on separate days in a randomised manner. Subjects were water loaded and urine volume replaced by drinking water. Glomerular filtration rate (GFR) and renal plasma flow (ERPF) were measured, by Inulin and PAH clearance respectively, for 4 hours and urinary electrolyte excretion for 12 hours post dosing. Plasma ANP concentration increased from 21.8±2.7 pg/ml (mean±SE) to a peak level of 45.8±6.2 two hours after UK69 and was unchanged after placebo (25.8±6.0(basal) vs. 21.9±2.9(2 hrs)). Urinary Na excretion was increased by UK69 from 91.7±13.7 to 133.6±5.3 mmoles/12 hours (P<0.01). There was an upward trend in both GFR and ERPF during the protocol. At two hours post dose, when ANP was maximally elevated, ERPF was not significantly different between the active and placebo groups (153±13% vs 137±13%, % basal values) but both GFR ( 177±7% vs. 138±5%, % basal values, P<0.05) and fractional Na excretion (1.61±0.21% vs 0.95±0.10%, P<0.01) were significantly increased.

UK 69 produces a natriuresis by increasing GFR and fractional Na excretion, and it is likely that this occurs as a consequence of elevated plasma ANP.

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ELEVATION OF PLASMA ATRIAL NATRIURETIC FACTOR BY AN ATRIOPEPTIDASE INHIBITOR HAS BENEFICIAL ACUTE EFFECTS IN MILD HEART FAILURE. DB Northridge, A Jardine, IN Findlay, SG Dilly J M C Connell and HJ Dargie. Department of Cardiology, Western Infirmary, Glasgow. UK 69 578 (Pfizer Central Research) is an inhibitor of atriopeptidase, the enzyme responsible for the degradation of atrial natriuretic factor (ANF). I n animals and normal volunteers it causes a rise in plasma ANF with an associated diuresis and natriuresis. We examined the acute effects of UK 69 578 in six patients with mild chronic heart failure [mean (range) peak oxygen consumption during maximal treadmill exercise 20.4 (16.0-24.9) ml kg _ T min - 1 ] . UK 69 578 was administered as an intravenous infusion over 20 minutes, in a placebo controlled, cross-over study. Mean baseline plasma ANF was elevated at 84 (53) pg/ml (normal <50) , and rose further to a peak of 275 (93) pg/ml, 1 hour after UK 69 578 (p<0.05). Plasma ANF did not change following placebo. Eight hour urinary sodium excretion rose from 39 mmol after placebo to 70 mmol after UK 69 578 (p<0.05), but there was no significant rise in potassium excretion. There was no change in heart rate, blood pressure, echocardiographic left ventricular dimensions or Doppler measurements of aortic blood flow. However, invasive measurements using a Swan Ganz catheter demonstrated significant falls in mean right atrial and pulmonary artery wedge pressures of 3 1 % and 26% respectively following UK 69 578. There was no change in cardiac output. Thus inhibition of atriopeptidase results in significant elevation of plasma ANF, with associated diuresis, natriuresis and venodilatation. Atriopeptidase inhibitors may therefore have a future therapeutic role in mild heart failure.

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DOUBLE-BLIND COMPARISON OF ONCE DAILY BENAZEPRIL, HYDROCHLOROTHIAZIDE AND PLACEBO IN MILD TO MODERATE HYPERTENSION. T. Faaan*. K. Head, J. DeSilva*. J. Whalen*, Departments of Medicine and Pharmacology, University of Arizona College of Medicine, Tucson, Arizona.

BenazepriUHCL (BZ) is a novel, non-sulfhydryl converting enzyme inhibitor which was discovered by Ciba-Geigy. Three hundred thirty-four patients, with essential hypertension and sitting diastolic blood pressure (SDBP) of 95-114 mmHg after 2-4 weeks of placebo (P), were randomized to receive P, BZ alone, hydrochlorothiazide (HCTZ) alone, or combinations of various doses of BZ + HCTZ once daily for 6 weeks. Blood pressure was measured at baseline (week 0, hour 0), every 2 weeks at 24 hours after the dose (hour 0), and 2 hours post dose at Weeks 0 and 4. Shown below, for 170 patients receiving P, BZ 20 mg, HCTZ 25 mg or BZ 20 mg + HCTZ 25 mg, are baseline sitting systolic blood pressure (SSBP)/SDBP, change from baseline in mmHg, all adverse experiences (AE) regardless of apparent relationship to the drug, and dropouts due to AE.

Ρ BZ H C T Z B Z / H C T Z

(η = 40) (n = 42) (n = 45) (n = 43)

Baseline 1 5 3 / 1 0 3 1 5 3 / 1 0 4 1 5 4 / 1 0 2 1 5 5 / 1 0 3

W k 0, Hr 2 -7/-5 -14*/-12* - 7 / 7 -137-9* W k 2, Hr 0 0/-4 -107-9* -7*/-6 -227-13* W k 4, Hr 0 - 7 / - 7 - 9 / - 9 -12/-9 -217-15* W k 4 , Hr2 -5/-7 -157-14* -167-11 -307-20* W k 6, Hr 0 -6/-6 - 1 0 / - 1 0 * -137-8 -217-13* Endpoint -2/-4 -107-10* -127-7 -227-14* Any AE 13(33%) 21(50%) 23(51%) 26 (61%)

AE Dropout 2(5%) 0(0%) 1(2%) 3(7%) *, change f rom baseline ρ < 0.05 c o m p a r e d to change on P.

BZ 20 mg once daily clinically and statistically significantly lowered SSBP and SDBP at most times, while HCTZ 25 mg lowered only SSBP. The combination of BZ 20 mg and HCTZ 25 mg once daily significantly lowered SSBP and SDBP at all time points. Benazepril 20 mg once daily is an effective and well tolerated drug with antihypertensive effects additive to those of hydrochlorothiazide.

1 3 1 1

THE OVER-EXPRESSION OF c - F O S AND c -MYC ONCOGENES OBSERVED I N AORTIC SMOOTH MUSCLE CELLS FROM SHR I S NOT OBLIGATORY L I N K E D TO ENHANCED P R O L I F E R A T I O N Μ B A U D O U I N - L E G R O S , J L PAQUET, G B R U E N E L L E , Ρ MEYER - INSERM U 7 , P h a r m a c o l o g i e , Hop N e c k e r , 1 6 1 r u e d e S e v r e s , 7 5 0 1 5 P A R I S , FRANCE. A o r t i c s m o o t h m u s c l e c e l l s f r o m SHR a o r t a i s o l a t e d b y e n z y m a t i c d i g e s t i o n p r o l i f e r a t e m u c h m o r e r a p i d l y a n d a r e 2 . 5 t o 3 t i m e s m o r e n u m e r o u s a t c o n f l u e n c y t h a n c o n t r o l c e l l s f r o m WKY r a t s c u l t u r e d i n t h e same c o n d i t i o n s i n t h e p r e s e n c e o f 1 0 % f e t a l c a l f s e r u m ( F C S ) . S u b c o n f l u e n t c u l t u r e s f r o m b o t h s t r a i n s w e r e m a d e q u i e s c e n t b y s e r u m d e p r i v a t i o n t h e n r e - a c t i v a t e d b y a d m i n i s t r a t i o n o f e i t h e r FCS o r . v a s o - a c t i n g d r u g s ( a n g i o t e n s i n I I , s e r o t o n i n ) . FCS s t i m u l a t e s b o t h t h e p r o l i f e r a t i o n (DNA c o n t e n t ) , t h e p r o d u c t i o n o f i n o s i t o l p h o s p h a t e s f r o m p r e - i n c o r p o r a t e d ^ - m y o i n o s i t o l , a n d t h e e x p r e s s i o n o f t h e o n c o g e n e s c - f o s a n d c - m y c ( N o r t h e r n B l o t o f t o t a l R N A ) . A l l t h e s e p a r a m e t e r s a r e t w i c e m o r e i n t e n s i v e l y e n h a n c e d i n c u l t u r e s f r o m SHR t h a n i n c o n t r o l o n e s . When a n g i o t e n s i n I I a n d s e r o t o n i n a r e a d d e d t o t h e same c u l t u r e s t h e y a l s o i n d u c e PLC a c t i v a t i o n a n d t h e e x p r e s s i o n o f c - f o s a n d c - m y c , w h i c h a r e b o t h h i g h e r i n SHR c u l t u r e s t h a n i n c o n t r o l o n e s . H o w e v e r , i n t h e same c o n d i t i o n s , t h e s e v a -s o a c t i n g d r u g s d o n o t e x h i b i t a n y m i t o g e n i c a c t i o n i n e i t h e r t y p e o f c e l l s i n t h e a b s e n c e o f s e r u m , c - f o s a n d c - m y c e x p r e s s i o n t h e r e f o r e a p p e a r t o be l i n k e d t o PLC a c t i v a t i o n i n VSMC m e a n w h i l e t h e c o o p e r a t i v i t y o f o t h e r g e n e ( s ) m a y b e r e q u i r e d , i n t h e s e c e l l s , f o r i n d u c t i o n o f p r o l i f e r a t i o n . As PLC h y p e r r e a c t i v i t y , t h e e n h a n c e m e n t o f t h i s ( t h e s e ) o t h e r g e n e ( s ) e x p r e s s i o n m a y b e i n v o l v e d i n t h e i n c r e a s e d c e l l u l a r p r o l i f e r a t i o n o b s e r v e d i n SHR.

1 3 1 2

SODIUM REGULATION I N THE A F F I N I T Y OF RENAL ALPHA2 ADRENOCEPTORS FOR A D R E N A L I N E I N SABRA H Y P E R T E N S I VE ( S B H ) AND NORMOTENSIVE ( S B N ) RATS W. Q I N G , J . P . DAUSSE. a n d D . B E N - ISHAY D e p t o f P h a r m a c o l o g y , INSERM U 7 , H o p i t a l N e c k e r , P a r i s , F r a n c e . S o d i u m i o n s d i m i n i s h e d t h e a f f i n i t y o f o f a l p h a 2 -a n d a l p h a i - a d r e n o c e p t o r s f o r a d r e n a l i n e . I n a d d i t i o n , t h e d i e t a r y s o d i u m i n t a k e was a b l e t o m o d u l a t e s y m p a t h e t i c a c t i v i t y . T h e a i m o f t h e p r e s e n t s t u d y w a s t o i n v e s t i g a t e t h e i n v i t r o e f f e c t o f s o d i u m o n t h e a f f i n i t y o f r e n a l a l p h a } - a n d a l p h a 2 ~ a d r e n o c e p t o r s f o r a d r e n a l i n e o f s a l t -s e n s i t i v e ( S B H ) a n d s a l t - r e s i s t a n t ( S B N ) S a b r a r a t s . S o d i u m i o n s m a r k e d l y d e c r e a s e d a l p h a 2 ~ a d r e n o -c e p t o r a f f i n i t y f o r a d r e n a l i n e i n SBH b u t n o t i n SBN r a t s . U n d e r t h e s e c o n d i t i o n s , a d r e n a l i n e a f f i n i t y f o r a l p h a ] _ - a d r e n o c e p t o r w a s u n c h a n g e d . I f t h e s e d a t a w e r e t r u e i n v i v o , t h e s o d i u m i o n , b y a c t i n g a s a n i n h i b i t o r , c o u l d m o d i f y t h e e f f e c t s o f a g o n i s t s o n r e n a l , a l p h a 2 - a d r e n o c e p t o r s o f SBH r a t s . C o n v e r s e l y , t h e a b s e n c e o f s o d i u m r e g u l a t i o n o f a l p h a 2 - a d r e n o c e p t o r a f f i n i t y f o r a d r e n a l i n e i n SBN r a t s m i g h t r e p r e s e n t a g e n e t i c a l l y m e d i a t e d c h a n g e r e s p o n s i b l e f o r t h e r e s i s t a n c e t o t h e d e v e l o p m e n t o f s a l t - i n d u c e d h y p e r t e n s i o n .

11313|

S K I N F I B R O B L A S T HYPERRESPONSIVENESS TO GROWTH FACTORS I N HYPERTENSION P . G U I C H E N E Y , J . L . PAQUET a n d P . MEYER INSERM U 7 , P h a r m a c o l o g y , H o p i t a l N e c k e r , 1 6 1 r u e d e S e v r e s , 7 5 0 1 5 P A R I S .

S k i n f i b r o b l a s t s i s o l a t e d f r o m n e w b o r n s p o n t a n e o u s l y h y p e r t e n s i v e r a t s ( S H R ) a n d W i s t a r - K y o t o n o r m o t e n s i v e r a t (WKY) b y e n z y m a t i c d i g e s t i o n w e r e g r o w n i n MEM w i t h 1 0 % f e t a l c a l f s e r u m . C e l l p r o l i f e r a t i o n w a s a s s e s s e d b y t h e m e a s u r e o f c e l l DNA c o n t e n t d u r i n g t h e e x p o n e n t i a l g r o w i n g p h a s e . T h e g r o w t h r a t e w a s h i g h e r i n c e l l s f r o m SHR t h a n f r o m WKY i n 10 % s e r u m m e d i u m . T h e m e a n g e n e r a t i o n t i m e a v e r a g e d 2 5 . 5 1 . 4 h f o r SHR a n d 3 2 . 0 +_ 2 . 5 h ( n = 9 ) . T h e c e l l g r o w t h w a s i n h i b i t e d b y c o n t a c t b u t t h e l e v e l o f i n h i b i t i o n o c c u -r e d a t h i g h e r c e l l d e n s i t y i n t h e c a s e o f SHR. 2 4 h o u r s a f t e r a d d i t i o n o f v a s o p r e s s i n ( 0 . 1 μ Μ ) , s e r o t o n i n ( 1 μ Μ ) , a n g i o t e n s i n I I ( 0 . 5 μΜ) o r b r a d y k i n i n ( 1 a n d 3 μΜ) t o q u i e s c e n t c e l l s i n p r e s e n c e o f 0 . 5 % s e r u m no i n c o r p o r a t i o n o f 3 H - t h y m i d i n e i n t h e c e l l s w a s o b s e r v e d . I n c o n t r a s t , s e r u m ( 5 , 1 0 , 15 %) a n d i n s u l i n ( 1 μ g / m l ) i n d u c e d a m a r k e d s t i m u l a t i o n o f 3 H - t h y m i d i n e i n c o r p o r a t i o n a n d t h e c e l l r e s p o n s e w a s s i g n i f i c a n t l y h i g h e r i n SHR t h a n i n WKY. S e r u m , b r a d y k i n i n a n d v a s o p r e s s i n b u t n o t i n s u l i n i n d u c e d p h o s p h a t i d y l i n o s i t o l t u r n o v e r i n t h e s e c e l l s . S e r u m ( 1 0 , 15 %) a n d b r a d y -k i n i n e ( 1 μΜ) i n d u c e d h i g h e r i n o s i t o l p h o s p h a t e f o r m a t i o n i n SHR c e l l s l a b e l l e d w i t h ^ - m y o i n o s i t o l t h a n i n WKY c e l l s . I n c o n c l u s i o n , s k i n f i b r o b l a s t s i s o l a t e d f r o m n e w b o r n SHR s h o w e d h y p e r r e s p o n s i v e n e s s t o g r o w t h f a c t o r s a s i t h a s b e e n s h o w n i n v a s c u l a r s m o o t h m u s c l e c e l l s i n h y p e r t e n s i o n . T h e r e f o r e , t h e y m a y b e o f g r e a t i n t e r e s t f o r c l i n i c a l s t u d i e s .

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1 3 1 4

THE ROLE OF SPECIF IC GRANULES I N VENTRICULUS ON ATRIAL NATRIURETIC PEPTIDE (ANP) SECRETION I N ACUTE HEART F A I L U R E . K i y o t a k a S a t o h * , T a k a s h i M a s u d a , K e n j i A n d o , N o b u h i r o H a s e g a w a , R y u i c h i K i k a w a d a and F u m i a k i M a r u m o * K i t a s a t o U n i v e r s i t y , S c h o o l o f M e d i c i n e , K a n a g a w a , J a p a n .

To e x a m i n e t h e r o l e o f s p e c i f i c g r a n u l e s i n a t r i d a n d v e n t r i c l e s on ANP s e c r e t i o n , t h e ANP c o n t e n t and i t s m o l e c u l a r f o r m s i n t h e p l a s m a , l e f t a t r i u m ( L A ) a n d l e f t v e n t r i c l e ( L V ) w e r e o b s e r v e d i n 11 c a n i n e s d u r i n g a n d a f t e r r e v e r s i b l e m i t r a l r e g u r g i t a t i o n ( M R ) . A b a s k e t c a t h e t e r was i n s e r t e d i n t h e LA v i a t h e p u l m o n a r y v e i n a n d f i x e d a t t h e m i t r a l v a l v e . A c u t e MR was b r o u g h t a b o u t by e x t e n d i n g t h e t i p b a s k e t w i r e , and r e c o v e r y was a s s u r e d by c l o s i n g t h e b a s k e t . D u r i n g t h i s p r o c e d u r e , b l o o d s a m p l e s , s m a l l p i e c e s o f LA a p p e n d a g e and LV w e r e o b t a i n e d a n d e x a m i n e d f o r t h e i r ANP c o n t e n t a n d i t s m o l e c u l a r f o r m .

R e s u l t s : b e f o r e d u r i n g f o l l o w i n g LAP(MmmHg) 7 . 3 + 2 2 23 4 ± 7 . 0 10 7 ± 3 . 4 P l a s m a ANP

( p g / m l ) 4 7 . 4 ± 23 0 148 8 ± 9 3 . 2 5 1 9 ± 3 2 . 4 LA ANP

( n g / m g P . ) 1 0 3 . 1 ± 4 5 . 7 67 1 ± 4 6 . 1 43 6 ± 2 9 . 8 LV ANP

( n g / m g P . ) 1 .356 ± 0 . 6 0 4 0 . 5 9 4 ± 0 . 4 0 5 0 . 4 2 2 ± 0 . 1 2 5

P l a s m a ANP l e v e l was f o u n d t o i n c r e a s e , b u t LA and LV t i s s u e ANP c o n t e n t d e c r e a s e d u r i n g MR. P l a s m a ANP c o n c e n t r a t i o n was s i g n i f i c a n t l y c o r r e l a t e d t o LA p r e s s u r e ( r = 0 . 7 7 ~ 0 . 9 8 ) i n e a c h d o g . The m a i n ANP m o l e c u l a r f o r m i n p l a s m a was a l p h a - A N P , and i n t i s s u e , gamma-ANP.

We c o n c l u d e : The c h a n g e o f ANP c o n t e n t i n LA a n d LV t i s s u e i s p o s s i b l y d u e t o d i m i n i s h e d ANP i n t h e a t r i u m a n d v e n t r i c u i u s . S p e c i f i c g r a n u l e s i n a t r i a and v e n t r i c u l u s may h a v e a p a r t on ANP s e c r e t i o n i n a c u t e h e a r t f a i l u r e .

1 3 1 6

B R A I N SECRETION OF A T R I A L N A T R I U R E T I C P E P T I D E ( A N P ) I N MAN. N . T e r a n , G . P a r r a , B . R o d r i g u e z -I t u r b e a n d J . G u t k o w s k a . H o s p i t a l U n i v e r s i t a r i o , M a r a c a i b o , V e n e z u e l a

E x t r a - a t r i a l ANP p r o d u c t i o n i s d i f f i c u l t t o d e m o n s t r a t e i n v i v o b e c a u s e t h e h i g h e s t c o n c e n t r a t i o n s o f p l a s m a i m m u n o r e a c t i v e ANP ( i - A N P ) a r e f o u n d i n r i g h t h e a r t s a m p l e s . We s t u d i e d c o n c e n t r a t i o n g r a d i e n t s o f p l a s m a i - A N P d u r i n g s u r g e r y w i t h c a r d i o p u l m o n a r y b y p a s s ( C P B ) i n w h i c h h e a r t a n d l u n g s a r e e x c l u d e d f r o m c i r c u l a t i o n . P l a s m a s a m p l e s w e r e o b t a i n e d s i m u l t a n e o u s l y f r o m t h e i n t e r n a l j u g u l a r v e i n ( U V ) , r a d i a l a r t e r y ( R A ) a n d a n t e c u b i t a l v e i n ( A C V ) i n 10 p a t i e n t s u n d e r g o i n g c o r o n a r y b y p a s s s u r g e r y a n d 3 p a t i e n t s w h o h a d v a l v e r e p l a c e m e n t w i t h c o m p l e t e C P B . L e v e l s ( f m o l / m l ) o f i - A N P i n t h e I J V w e r e ( m e a n + SEM) 9 . 9 + 2 . 1 a n d i n c r e a s e d t o 1 4 . 6 + 2 . 7 aricT 1 6 . 4 + 3 . 9 a f t e r 15 a n d 45 m i n o f C P B , r e s p e c t i v e l y . C o n c e n t r a t i o n g r a d i e n t s I JV - RA c h a n g e d f r o m - 5 . 3 +_ 1 . 9 b e f o r e CPB t o 7 . 7 + 2 . 2 d u r i n g CPB ( P < 0 . 0 0 1 ) . L e v e l s o f i - A N P i n ACV w e r e s t e a d y a t 4 . 8 t o 4 . 1 + 0 . 8 ( f m o l / m l ) . S t r u c t u r a l a n a l y s i s d o n e i n s a m p T e s o f o n e p a t i e n t t a k e n f r o m ACV b e f o r e s u r g e r y a n d f r o m U V d u r i n g C P B , s h o w e d s i m i l a r p e a k s a f t e r p u r i f i c a t i o n by H P L C , s u g g e s t i n g t h a t p r o h o r m o n e p r o c e s s i n g e n z y m e s i n b r a i n a n d h e a r t a r e l i k e l y i d e n t i c a l . ANP l i k e m a t e r i a l f r o m U V a n d ACV d i s p l a c e d i n c o m p a r a b l e m a n n e r 1 2 5 I - A N P b o u n d t o r a t g l o m e r u l a r r e c e p t o r s i n a d o s e - d e p e n d e n t m a n n e r , s u g g e s t i n g t h a t b r a i n a n d h e a r t ANP h a v e s i m i l a r b i o l o g i c a l a c t i v i t y .

O u r s t u d y s h o w s c o m p e n s a t o r y b r a i n s e c r e t i o n o f a c t i v e ANP i n v i v o , w h i c h u n d e r l i n e s t h e p h y s i o l o g i c a l r e l e v a n c e o f t h i s h o r m o n e .

1 3 1 5

A T R I A L N A T R I U R E T I C P E P T I D E ( A N P ) AND P R O T E I N I N T A K E I N I N S U L I N - D E P E N D E N T D I A B E T I C S . C . M a r i n , G . P a r r a , J . H e r r e r a , B . R o d r i g u e z - I t u r b e , J . G u t k o w s k a . H o s p i t a l U n i v e r s i t a r i o , M a r a c a i b o , V e n e z u e l a .

E l e v a t e d l e v e l s o f p l a s m a i m m u n o r e a c t i v e ANP ( i - A N P ) a n d i n c r e a s e d d i e t a r y p r o t e i n i n t a k e h a v e b e e n r e p o r t e d i n i n s u l i n - d e p e n d e n t d i a b e t i c s . We s t u d i e d p l a s m a i - A N P i n 2 2 i n s u l i n - d e p e n d e n t d i a b e t i c s , a g e 4 t o 3 1 y e a r s , a n d i n 2 0 c o n t r o l c h i l d r e n o f c o m p a r a b l e a g e , b e f o r e a n d 9 0 m i n a f t e r a m e a t m e a l . We f o u n d s i m i l a r f a s t i n g ANP l e v e l s ( f m o l / m i n ) i n d i a b e t i c s ( 3 . 2 9 _+ SE 0 . 5 1 ) a n d c o n t r o l s ( 3 . 7 5 _+ 0 . 7 9 ) a n d s i g n i f i c a n t ( P < 0 . 0 1 ) p o s t p r a n d i a l i n c r e m e n t s i n ANF c o n c e n t r a t i o n s t h a t w e r e n o t d i f f e r e n t i n d i a b e t i c s ( 6 . 3 6 + 1 . 0 ) a n d c o n t r o l s ( 5 . 5 2 + 0 . 8 7 ) . E i g h t p a t i e n t s w e r e s t u d i e d on a d i e t p r o v i d i n g 2 . 5 3 _+ 0 . 6 4 g p r o t e i n . k g - * . d a y _ 1 ( H P D ) a n d a g a i n a f t e r 3 m o n t h s on a d i e t o f 0 . 6 g p r o t e i n . k g ~ l . d a y 1 ( L P D ) . R e s u l t s ( m e a n j f SE) w e r e as f o l l o w s :

ANF ( f m o l / m l ) F a s t i n g 9 0 ' p o s t m e a l P_

HPD 4 . 1 6 + 0 . 8 7 8 . 2 5 + 1 . 5 6 < 0 . 0 1 LPD 2 . 4 0 + 0 . 4 4 2 . 8 5 + 0 . 8 2 NS

Ρ Ρ < 0 . 0 2 Ρ < 0 . 0 5

O u r r e s u l t s i n d i c a t e t h a t f a s t i n g a n d p r o t e i n -s t i m u l a t e d p l a s m a i - A N P l e v e l s a r e n o t d i f f e r e n t i n d i a b e t i c s a n d c o n t r o l s . T h r e e m o n t h s o f p r o t e i n r e s t r i c t e d d i e t i s a s s o c i a t e d w i t h d e c r e a s e d l e v e l s o f t h i s h o r m o n e .

1 3 1 7

CAPTOPRIL (C) 50 mg + A LOW DOSE OF HYDROCHLOROTHIAZIDE (H) (15 mg) IN HYPERTENSIVE DIABETIC SUBJECTS. A.Sant ucci*, R.Buoninconti#, R.De Cesaris@, GF Botta~, C.Giarrizzo, C. Ferri '·, F. Balsano. University of Rome, # University of Naples, & University of Bari, Fondazione Andrea Cesalpino, Squibb SpA, Rome,Italy.

To mantain the good antihypertensive efficacy of C + H, due to their synergistic effect, and to minimize the metabolic problems related to Η in hypertensive diabetic patients (HD), we evaluated the fixed combination of C 50 mg + a low dose of Η (15 mg) versus a standard dose of Η (25 m g ) . 30 HD, aged 43-66, were randomly, double blindly, assigned to be treated with C + Η (19) or Η (11) for 3 months, in o.d. regimen. Blood pressure was recorded at the baseline and 24+3 hours after last dosing every 4 weeks for a 3 months period. On the same times the most important metabolic parameters have been evaluated. R e s u l t s : analysis of the percentage decrements is:

C + Η Η

1 month 3 month 1 month 3 month SBP - 9 . 5 % - 1 4 % * - 1 1 % - 9 . 5 % * DBP - 1 3 % - 1 6 % * - 1 2 % - 1 0 . 4 % *

C + Η showed to have a better a n t i h y p e r tensive effect in HD as compared vs. Η without create any metabolic inpairment.

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1318 SAFETY EVALUATION OF A FIXED COMBINATION OF CAPTOPRIL (C) 50 mg + A LOW DOSE OF HYDROCHLOROTHIAZIDE (H) 15 mg, IN HYPERTENSIVE DIABETIC PATIENTS (HD). A. Santucci*, G. Botta, G. De Mattia, 0. Laurenti, C. Giarrizzo, C.Ferritt, F.Balsano. University of Rome, Institute I Clinica Medica, # Fondazione Andrea Cesalpino, Rome, Italy.

The fixed combination of C+H has been proved to be highly efficacious in h y p e r tensives showing a protective action on metabolic profile because of the p o s sibility of C to balance the ipoK+ due to H. To evaluate the efficacy and the t o l e -rability of C 50 mg + Η 15 mg, 137 HD (93.4*/- type I I ) , aged 29-71, duration of hypertension 5.7+4.3 yrs and diabetes 7.6+6.2 yrs, have been treated for 3 months with the fixed combination C+H in O.D.regimen. The treatment achieved a good BP control (Θ6.1% after 1 month and 9 4 . 7 % after 3 months of DBPs<95 m m H g ) . The table shows the modification of some of the monitored p a r a m e t e r s :

BASELINE 1 MONTH 3 MONTHS P< Glucose 149. 3 143. 9 143. 9 n. s HbAlc 7. 4 7. 2 6. 9 n. s Na+ 141.5 140. 3 140. 1 n. s K+ 4. 3 4. 3 4. 23 n. s Cho1 est ero1 229. 9 222. 3 220. 7 . 001 Tryg1icerides 17Θ 156 15Θ . 05 Total proteinuria resulted improved during the treatment. In conclusion our data show that C + Η is effective and safety in HD.

1319 ATRIAL NATRIURETIC FACTOR (ANF) IN YOUNG NORMOTENSIVE SUBJECTS WITH OR W / 0 FAMILY HISTORY OF HYPERTENSION AND IN YOUNG HYPERTENSIVE PATIENTS. A.Santucci*. C. Ferri#, I.Cammare 11a,S.Valentino,S.Tan iE, A. Musca"". Un i vers i t y of Rome"La Sapienza", Istituto I Clinica Medica,~ II Semeiotica Medica, # Fondazione Andrea Cesalpino, & Ospedale Militare Principale.Rome,Italy

Although ANF plays an important role in sodium homeostasis, its behaviour in young normotensives having a family history of hypertension (NHTF) has never been evaluated. We studied 26 essential hypertensives (HT) (mean age: 2 2 . 5 + 2 ) , 21 normotensives (NOR) (mean age: 22.3+1.9) and 13 NHTF (mean age : 22+1.Θ) under normal Na+ intake (120 m E q / d i e ) . Blood samples for plasma ANF, renin activity and aldosterone (ALD) evaluation (by the RIA method) were taken after a night bed sleep (A) and again after 1 hour of deambulation (B). Resulting data showed that ANF in HT (A = 44.5+19.4 pg/ml, Β = 24.1+11.6 pg/ml) was at higher level than in NOR (A= 3Θ.3+19.4 pg/ml, Β = 19.9+10.6 pg/ml) and NHTF (A 41.4+ 1 6 . 3 pg/ml, Β = 22.3+9.9 p g / m l ) . ANF was inversely correlated with ALD in all groups, but only in Β situation (p(0.001 in HT, p<0.05 in NOR and N H T F ) . ANF plasma levels were higher in NHTF than in NOR in both A (Delta% +7.4) and Β situations (Delta% + 1 0 ) , suggesting a likely increase of ANF in NHTF.

1320 LONG-TERM ENALAPRIL TREATMENT IN ELDERLY HYPERTENSION. V^Marigliangtt, M . C a c -ciafesta, G. Traisi, C. Fe r r i , G . P i c c i -ri 1 Ι Ο , Α . Α Γ iania),E. Bagagl ini<i), F. F e r -retti3.Universita "La Sapienza"1stituto I Clinica Medica,ttCattedra di Geriatria <i)Istituto Geriatrico Villa del le Quer — ce ( N e m i ) , Rome Italy.

ACE—inhibitors are known to be e f f e c tive and safety in the long-term therapy of essential hypertension. The aim of this study was to evaluate the long-term efficacy of enalapril (E) in elderly essential hypertensive p a tients. 4 0 pts (mean a g e : 7 4 . 1 ) a f f e c ted by mild to moderate essential h y p e rtension were treated with Ε ( 1 0 m g / d a i l y ) . S ide—effects were assessed at the baseline and every month by clinical and biochemical examination over a period of IB m o n t h s . On the same times blood pressure were recorded at 9 . 0 0 a.m., after 2 4 hours from the last Ε administration. 3 6 pts responded to Ε therapy at month 4 , while after 1 8 m o n t h s 3 0 pts were still in good blood pressure c o n t r o l . Resulting data are given below:

BASELINE 1 8 M O N T H S SBP 1 7 7 ± 1 1 . 3 mmHg 1 4 7 ± 8 . 3 mmHg * DBP 1 0 4 ± 9 . 7 mmHg 8 4 ± 7 . 2 mmHg * * = p < 0 . 0 0 1 Major side-effects = Ο p t s .

Our data suggest that Ε is effe c t i v e and safety in the long—term treatment of elderly essential h y p e r t e n s i v e s .

1321 HEMODYNAMIC A L T E R A T I O N S BY RECOMBINANT HUMAN E R Y T H R O P O I E T I N A D M I N I S T R A T I O N IN HEMOUIALYZED P A T I E N T S WITH NORMAL CARDIAC F U N C T I O N . Τ Takamoto* , Κ S a t o * , Τ Masuda, F Marumo*. Dept . o f M e d i c i n e , Tokyo Medical and Dental U n i v . , T o k y o , and Dept . o f M e d i c i n e , K i t a s a t o U n i v . , School o f M e d i c i n e , Kanagawa, Japan

Hemodynamic e f f e c t s o f r e c o m b i n a n t human e r y t h r o p o i e t i n ( r -hEPO) a d m i n i s t r a t i o n were s t u d i e d in 15 c h r o n i c hemodialyzed p a t i e n t s (mean a g e : 4 2 y r s . ) with normal c a r d i a c f u n c t i o n . B e f o r e and a f t e r t h e r-hEPO t h e r a p y , 1)M-mode and Doppler e c h o c a r d i o g r a p h i c s t u d i e s , 2 )measurements o f c i r c u l a t i n g blood volume by r a d i o - i o d i n a t e d serum a l b u m i n , 3) measurements o f a t r i a l n a t r i u r e t i c p e p t i d e (ANP) plasma c o n c e n t r a t i o n were c a r r i e d o u t . A f t e r t h e s i x weeks o f r-hEPO t h e r a p y , h e m a t o c r i t i n c r e a s e d from 20 t o 33%, and hemoglobin i n c r e a s e d 6.6 t o 9.7 g / d l . C a r d i a c i n d i c e s e s t i m a t e d as f o l l o w s :

B a s e l i n e A f t e r r-hEPO s y s t o l i c ' BP(mmHg) 128 + 11 136 + 28 NS d i a s t o l i c BP(mmHg) 72 Τ 15 80 Τ 17 NS h e a r t r a t e 72 Τ 11 67 Τ 11 NS LVW t h i c k n e s s (mm) 8 . 6 τ 1.3 9.8 τ 1.9 ρ<0 01 LV d i a s t . d i m . (mm) 52 τ 5 49 τ 4 ρ<0 05 e j e c t . f r a c t i o n (%) 70 τ 7 71 τ 8 NS c a r d i a c output(1/m) 6.2 τ 1.6 5.3 τ 1.2 ρ<0 05 LV wal1 s t r e s s 61 τ 17 49 τ 20 ρ<0 05 AO mean v e l . ( m / s ) 0.8 τ 0.1 0.6 τ 0.1 ρ<0 05 blood volume 97 τ 12 110 τ 18 NS ANP ( p g / m l ) 121 τ 83 85 τ 64 ρ<0 01

The r-hEPO t h e r a p y r e s t o r e d t h e s e v e r e uremic anemia with t h e r e c o v e r y from compensat ing h y p e r dynamic c a r d i a c f u n c t i o n . C i r c u l a t i n g b lood volume did not change $ however , plasma ANP c o n c e n t r a t i o n was d e c r e a s e d s e c o n d a r y t o p r e l o a d r e d u c t i o n .

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COMPARISON OF THE EFFECT CF ESSENTIAL HYPERTENSION (E.H.) ON RENAL FUNCTION DECLINE TJM BLACK VERSUS WHITE SUBJECTS. SJ Rosansky*, DR Hoover, LA King, JJ Gibson, WJBD VA Hospital and University of S.C. Departments of Medicine, S t a t i s t i c s and Preventive Medicine. Hypertensive nephropathy as a cause of renal failure is 7 times more common in blacks compared to whites. As part of a study looking at the effect of E.H. on renal function we compared the decline in renal function in black versus white E.H. and non-E.H.-control subjects (C). Subjects were obtained from a retrospective chart review of a male veteran population discharged with a diagnosis of E.H. An E.H. subject qualified if he had a normal urinalysis and qualifying blood pressure (>_ 105 dias tol ic or _> 180 systolic and _> 100 diastolic), within 3 years of a normal serum creatinine (SO). C did not have an E.H. discharge diagnosis and had all recorded blood pressures between 1973-1981 (entry period) less than 160/95. Diabetics were excluded from the study. E.H. subjects were significantly more obese than non-E.H. subjects (82.3 kg versus 71.3 kg, ρ < .001). This trend appeared to be more marked in black E.H. subjects compared to black C 81.2 kg versus 68.4 kg. Time averaged blood pressure using an average measurement for each quarter of each year during average followup of 9 years was significantly higher in the E.H. vs C (148/95 versus 127/80, ρ < .001). SO. rose faster and estimated creatinine clearances (CCr) decline faster in black E.H. versus black C. This pattern was not seen in white E.H. or white C.

Δ 0(mg5&/yr) Δ CCr (ml/min/ (per 1.73 m2) Ν ρ value

.10

NS

Conclusion: E.H. may be a more significant risk factor for renal function decline in blacks than in whites.

Black E.H. .04 -3.5 23 Black Control .01 -1.5 33 Wiite E.H. .006 -1.8 26 Wiite Control .003 -1.2 37

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CHARACTERIZATION OF THE RENAL MICROVASCULAR EFFECTS OF ENDOTHELIN. R. L o u t z e n h i s e r * . K. Hayashi , M. E p s t e i n * , C. Horton . Nephrol . S e c t . , V.A. Med. C t r , and Univ. Miami, Miami, FL

The r e n a l hemodynamic and m i c r o v a s c u l a r e f f e c t s o f t h e n o v e l v a s o c o n s t r i c t o r p e p t i d e e n d o t h e l i n (ENDO) were a s s e s s e d in i s o l a t e d p e r f u s e d r a t k i d n e y s . At 3 nM, ENDO reduced r e n a l p e r f u s a t e f low (RPF) by 95±4% (ED50 0 . 1 4 ± 0 . 0 4 nM, n = 4 ) . C h a r a c t e r i z a t i o n o f t h e tempora l p r o f i l e o f ENDO-induced v a s o c o n s t r i c t i o n r e v e a l e d t h a t t r a n s i e n t exposure t o t h e p e p t i d e r e s u l t e d in prolonged v a s o c o n s t r i c t i o n ( i . e . 30% r e c o v e r y a f t e r 1 5 . 8 ± 1 . 5 min v s 1 . 3 ± 0 . 3 min f o r a n g i o t e n s i n I I , n = 4 ) . At 0 . 3 nM, ENDO r e d u c e d g l o m e r u l a r f i l t r a t i o n r a t e (GFR) from 0 . 5 8 ± 0 . 0 4 t o 0 . 0 9 ± 0 . 0 5 ml/min/g ( n = 6 ) . The a d d i t i o n o f n i f e d i p i n e ( 1 . 0 μΜ, NIF) r e s t o r e d GFR t o 0 . 4 3 ± 0 . 1 2 m l / m i n / g . Complementary s t u d i e s were conducted in i s o l a t e d p e r f u s e d h y d r o n e p h r o t i c kidneys t o d e l i n e a t e a c t i o n s o f ENDO on a f f e r e n t (AA) and e f f e r e n t (EA) a r t e r i o l e s . ENDO e l i c i t e d dose-dependent v a s o c o n s t r i c t i o n o f t h e AA (μπι, n = 5 ) : ΓENDOΊ 0 0 . 0 0 1 0 . 0 1 0 . 0 3 0 . 1 0 . 3 1 . 0 (nM) AA 17±1 17±1 16±1 1 6 ± 1 1 4 ± 1 12±1 1 1 ± 1 At 0 . 3 nM, ENDO p r e f e r e n t i a l l y v a s o c o n s t r i c t e d t h e AA, r e d u c i n g AA and EA d i a m e t e r s by 41±4% and 13±4%, r e s p e c t i v e l y . ENDO-induced v a s o c o n s t r i c t i o n o f t h e AA was r e v e r s e d by NIF (μπι, n = 6 ) :

b a s a l ENDO ENDO + NIF [μΜ] LP_JJ L i . 0 ] LiPJ

AA 18±1 11±1 13±1 1 5 ± 1 17±1 EA 16±1 14±1 14±1 1 4 ± 1 14±1

In c o n t r a s t , a t r i a l n a t r i u r e t i c p e p t i d e (ANP, 100 nM) r e v e r s e d AA v a s o c o n s t r i c t i o n by o n l y 26±8% ( 1 7 ± 1 μπι, 9±1 μπι, 11±1 μπι; b a s a l , ENDO, and ENDO+ANP, r e s p e c t i v e l y n = 5 ) . Thus, ENDO i s a p o t e n t r e n a l v a s o c o n s t r i c t o r , t h a t r e d u c e s GFR by s e l e c t i v e l y c o n s t r i c t i n g t h e AA. Although t h e s u s t a i n e d a c t i o n s o f ENDO m i l i t a t e a g a i n s t a p h y s i o l o g i c r o l e f o r t h e p e p t i d e i n t h e k i d n e y , our f i n d i n g s i n d i c a t e t h a t c i r c u l a t i n g ENDO c o u l d e x e r t a d v e r s e r e n a l e f f e c t s . The a b i l i t y o f NIF t o r e v e r s e t h e s e a c t i o n s s u g g e s t s t h e u t i l i t y o f c a l c i u m a n t a g o n i s t s in r e s t o r i n g normal r e n a l f u n c t i o n in t h e p r e s e n c e o f ENDO.

1 3 2 3

AN ESTIMATION OF ARTERIAL DIAMETER AND VOLUME IN SYSTEMIC AND REGIONAL CIRCULATIONS IN ESSENTIAL HYPERTENSION. ME Safar, B. Pannier, St Laurent, R. Asmar, GM London, Diagnosis Center, Broussais H o s p i t a l , Paris.

Using non invasive technics (pulsed Doppler, echography or a combination of b o t h ) , arterial diameter (cm) was measured in the brachial artery ( B A ) , the common carotid artery ( C C A ) , the terminal abdominal aorta (Abd A o ) , the aortic arch (AoA) and the sigmoind valve (Sv) in a population of subjects with sustained essential hypertension (HT) in comparison with age and sex-matched normal subjects ( N T ) . In both populations age was between 20 and 60 years. Mean values + 1 standard error of the mean were :

BA CCA AbdAo AoA Sv NT 0 . 5 + 0 . 0 1 0 . 7 + 0 . 2 1 . 4 + 0 . 0 5 2 . 5 + 0 . 1 0 3 + 0 . 1 2 HT 0 . 5 + 0 . 0 1 0 . 7 + 0 . 2 1 . 6 + 0 . 0 5 3 + 0 . 1 0 3r+0.13 Pvalue < 0 . 0 0 1 NS < 0 . 0 0 1 < 0 . 0 1 NS

In NT, the AoA diameter was positively and significantly (r = 0 . 6 6 ; ρ < 0 . 0 1 ) correlated with body surface area ( B S A ) . No significant correlation was observed in HT,but at any level of BSA, AoA diameter was higher in HT than in NT. The study provides evidence that (i) the response of the large arteries to increased blood pressure may differ significantly according to the circulation involved, and, (ii) contrasting with the usual observation of decreased total intravascular volume in hypertension, intra-arterial blood volume is markedly increased.

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PHARMACOLOGICAL ANALYSIS OF THE ENHANCED PRESSOR RESPONSE TO CENTRAL CHOLINERGIC STIMULATION IN HYPERTENSIVE RATS. JJ Buccafusco* and AC Hays. Dept. Pharmacology and Toxicology and Veterans Administration Medical Center, Augusta, GA.

At least 3 regions of the CNS in rats are capable of generating a hypertensive response to cholinergic stimulation, the hypothalamus, medulla and thoracic spinal cord. I.v. administration of indirect agonists (physostigmine, PHY), but not direct agonists (arecoline, AREC) produce an exaggerated pressor response in spontaneously hypertensive (SHR) rats, results consistent with altered acetylcholine (ACh) release rather than enhanced receptor sensitivity. The purpose of this study was to characterize the participation of each brain region in the generation of enhanced pressor responses to cholinergic agonists. Rats were prepared with chronic implants in the lateral cerebral ventricle (LV), the cisterna magna (IC) or spinal intrathecal space (IT). PHY and AREC were employed for LV and IC injections, and neostigmine and carbachol (indirect/direct agonists) for IT injections. Blood pressure was recorded through previously implanted aortic catheters in freely-moving SHR and normotensive (WKY) rats. As expected, i.v. injection of PHY, but not AREC evoked an exaggerated pressor response in SHR. Surprisingly, both arecoline and physostigmine evoked enhanced pressor responses in SHR following LV or IC injection as did both neostigmine and carbachol following IT injection. IC injection provided the greatest enhancement of pressor responses in SHR. In order to reconcile the enhanced responses obtained from central injection of the direct agonists, at least for the IT injections, rats were administered hemicholinium-3 IT or IC to deplete regional ACh levels. Depletion of medullary, but not spinal ACh resulted in a blockade of the carbachol-in-duced pressor response. Thus, the enhanced pressor response to direct receptor stimulation in the spinal cord (and perhaps the forebrain) may be due to activation of medullary cholinergic pressor centers. Supt: HL30046; Veterans Admin.

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F E L O D I P I N E O N C E D A I L Y C O M P A R E D W I T H N I F E D I P I N E

T W I C E D A I L Y I N H Y P E R T E N S I V E S T R E A T E D W I T H

M E T O P R O L O L . W . A . L i t t l e r , M . W . B a i g , D . C h e e ,

M . G a l e a , G . J a c k s o n , A . C . F . K e n m u r e , H . M a n s y ,

E . J . P e r r i n s , P . D . I . R i c h a r d s o n , S . J . B . T i m e r i c k ,

J . W e s t , R . W i l k i n s o n . A UK m u l t i c e n t r e h o s p i t a l

g r o u p .

T h i s w a s a r a n d o m i s e d , d o u b 1 e - b 1 i η d , p a r a l l e l -

g r o u p s t u d y i n 1 0 0 p a t i e n t s a g e d 2 0 - 7 0 . P a t i e n t s

w h o s e s e a t e d d i a s t o l i c p h a s e V b l o o d p r e s s u r e

( d B P ) w a s 1 0 0 t o 1 1 5 m m H g w h i l e t a k i n g m e t o p r o l o l

s u s t a i n e d r e l e a s e 2 0 0 mg o m , r e c e i v e d e i t h e r

f e l o d i p i n e e x t e n d e d r e l e a s e ( E R ) l O m g om ( n = 5 1 ) o r

n i f e d i p i n e r e t a r d ( R ) 2 0 m g b d ( n = 4 9 ) i n a d d i t i o n

t o m e t o p r o l o l f o r 8 w e e k s . A f t e r 2 o r 4 w e e k s

t r e a t m e n t , t h e d o s e o f f e l o d i p i n e o r n i f e d i p i n e

w a s d o u b l e d i f s e a t e d d B P w a s g r e a t e r t h a n 9 5 m m H g .

A t t h e e n d o f t h e s t u d y , f e l o d i p i n e ER 2 4 h o u r s

p o s t - d o s e r e d u c e d p a t i e n t s ' m e a n s e a t e d d B P b y

1 7 mmHg ( f r o m 1 0 7 _+ 6 m m H g , m e a n +_ S D ) a n d

n i f e d i p i n e R 1 2 h o u r s p o s t - d o s e r e d u c e d m e a n

s e a t e d d B P b y 9 mmHg ( f r o m 1 0 4 + 5 m m H g ) , p < 0 . 0 0 1

f o r d i f f e r e n c e b e t w e e n g r o u p s . T h e p r o p o r t i o n s

o f p a t i e n t s c l a s s i f i e d a s r e s p o n d e r s ( s e a t e d d Β Ρ £

9 5 mmHg o r a r e d u c t i o n i n s e a t e d d B P o f a t l e a s t

1 0 m m H g ) w e r e : f e l o d i p i n e 89% ( η = 4 6 ) , n i f e d i p i n e

5 8% ( n = 4 5 ) , ρ = 0 . 0 0 0 6 f o r d i f f e r e n c e b e t w e e n

g r o u p s .

T h e t y p e a n d f r e q u e n c y o f a d v e r s e e v e n t s w a s

t h e s a m e f o r b o t h t r e a t m e n t s . T h e m o s t c o m m o n

a d v e r s e e v e n t s w e r e h e a d a c h e , f l u s h i n g a n d a n k l e

o e d e m a .

F e l d o i p i n e ER o n c e d a i l y w a s s u p e r i o r t o

n i f e d i p i n e R t w i c e d a i l y i n c o n t r o l l i n g b l o o d

p r e s s u r e i n h y p e r t e n s i v e p a t i e n t s . T h e t w o

t r e a t m e n t s w e r e e q u a l l y w e l l t o l e r a t e d .

1 3 2 8

HEMODYNAMICS OF SEASONAL ADAPTATION. J . L . I z z o J r . , P . S . L a r r a b e e , E. S a n d e r , M.C. Kai l a y . D e p t s . o f M e d i c i n e , S t a t e U n i v e r s i t y o f New York a t B u f f a l o and U n i v e r s i t y o f R o c h e s t e r , rtew York .

We s t u d i e d 4 groups o f s u b j e c t s [ n = 2 7 , with 7 n o r m o t e n s i v e s ( N T ) , 3 NT with h i s t o r y o f h y p e r t e n s i o n ( H T ) , 11 i n t e r m i t t e n t HT, 6 mi ld s u s t a i n e d HT] t o i n v e s t i g a t e s e a s o n a l changes in supi'.ie and u p r i g h t hemodynamics. S u b j e c t e n t r y was s t a g g e r e d in summer ( J u l - A u g ) , f a l l ( 0 : t -Nov) , w i n t e r ( J a n - F e b ) or s p r i n g (Apr-May)* C a r d i a c o u t p u t (CO) was measure. ! by a c e t y l e n e r e b r e a t h i n g and BP by c u f f ; : y s t ^ m i c v a s c u l a r r e s i s t a n c e (SVR) and s t r o K e volume (SV) were c a l c u l a t e d . Plasma n o r e p i n e p h r i n e (PNE) c i d hemodynamic v a r i a b l e s were compared a c r o s s s e a s o n s by ANOVA. In t h e s u p i n e p o s i t i o n , t h e r e was a t r e n d toward w i n t e r peaks o f UP, PNE, and SVR with c o r r e s p o n d i n g n a d i r s o f CO and SV. No s i g n i f i c a n t s e a s o n a l t r e n d s were seen in u o r i n h t s y s t o l i c ( 1 1 6 - 1 1 9 mmHg) or d i a s t o l i c BP ( C i - 0 5 mmHg) o r h e a r t r a t e ( 7 7 - 3 1 b / .min) . However, much l a r g e r u p r i g h t s e a s o n a l hemodynamic t r e n d s wer» seen ( n = 2 7 ) :

Summer F a l l Winter S p r i ;_irj p__ C0(L/min) 5 . 0 4 . 8 4 . 0 4 . 7 " . 0 0 3 SV(ml) 68 60 50 63 . 0 2 SVR(U) 1560 1660 2000 1670 . 0 0 5 PNE(pg/ml) 450 469 571 536 . 0 5

No s i g n i f i c a n t p a t t e r n d i f f e r e n c e s w-re seen among t h e 4 g r o u p s . U p r i g h t PNE c o r r e l a t e d i n v e r s e l y with u p r i g h t CO and SV ( p < . 0 2 e . c h ) .

We c o n c l u d e t h a t m a j o r ( 2 0 - 3 0 % ) s e a s o n a l hemodynamic a d a p t a t i o n s o c c u r in n o r m o t e n s i v e s and h y p e r t e n s i v e s in t h e Northern USA. Winter s y m p a t h e t i c nervous a c t i v a t i o n and v a s o c o n s t r i c t i o n a r e matched by d e c r e a s e d c a r d i a c o u t p u t .

1 3 2 7

2 4 - H O U R A N T I H Y P E R T E N S I V E E F F E C T O F FELODIPINE ONCE DAILY GIVEN AS MONOTHERAPY TO 102 ELDERLY PATIENTS. A DOUBLE-BLIND STUDY VS PLACEBO. J Hosle and A W Mulder for the Binational MC Study Qroup (UK and NL), The Surgery, Glasgow, Scotland and Catharina Ziekenhujs, Eindhoven, Holland. Felodipine (PlendiH is an antihypertensive calcium antagonist which selectively reduces the contractile activity of the resistance vessels. A total of 102 elderly (ages 64-82 years) hypertensive patients with a diastolic blood pressure (DBP) >100 mm Hg were randomised to felodipine (F) extended release (ER) 5 mg once daily (n=49) or placebo (P, n»52). If, after 2 weeks, the DBP was >95 mm Hg, the dose was doubled and the treatment continued for another 2 weeks. Blood pressure (BP), heart rate (HR) and body weight were measured 24 hours after dose intake. Adverse events (ADE) were reported spontaneously and by open questioning. Routine laboratory investigations were performed before and at the end of the study. After 2 weeks' treatment F 5 mg daily resulted in a BP fall of 12/12 mm Hg (baseline 177/105 mm Hg) compared with 4/8 mm Hg on PTbaseline 180/106). The difference in change was statistically significant for SBP (p=0.01). The dose was then increased in 41 % of the F group and in 50 % of the Ρ group. At the end of the study, BP was reduced by 14/13 mm Hg on F and by 4/8 mm Hg on P. The fall was significantly greater on F than on Ρ both for SBP (p=0.005) and DBP (p=0.007). The proportion of responders (DBP <95 mm Hg or fall in DBP >10 mm Hg) was 75 % on F and 42~% on Ρ (p=0.0008). HR and body weight remained unchanged. No clinically significant changes occurred in any of the laboratory variables. Reported ADE were few and of similar magnitude in both groups, headache and ankle swelling being the most frequent. Six patients were withdrawn from the study, 4 because of ADE (3 on F). In this large group of 102 elderly patients, felodipine ER tablets 5 to 10 mg once daily, given as monotherapy, was effective and well tolerated in the treatment of hypertension.

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SEASONAL COMPONENT OF "OFFICE HYPERTENSION". J . L . I z z o J r . , E. S a n d e r , P . S . L a r r a b o e . D e p t s . o f M e d i c i n e , S t a t e U n i v e r s i t y o f New Yor>. a t B u f f a l o and U n i v e r s i t y o f R o c h e s t e r , "lew York .

The d i a g n o s i s o f h y p e r t e n s i o n (HT) could be confounded by s h o r t - t e r m o r l o n g - t e r m BP v a r i a b i l i t y . We i n v e s t i g a t e d t h e e f f e c t s o f s e a s o n a l v a r i a t i o n in 4 groups o f 27 s u b j e c t s , i n c l u d i n g 7 n o r m o t e n s i v e s ( N T ) , 3 NT with h i s t o r y o f HT, 11 i n t e r m i t t e n t HT, and 6 s u s t a i w e d mi ld HT. E n t r y was s t a g g e r e d dur ing summer ( J u l - A u g ) , f a l l ( O c t - N o v ) , w i n t e r ( J a n - F e b ) o r s p r i n g (Apr-May) . Each s u b j e c t had s u p i n e and u p r i g h t BP ( c u f f ) and HR d e t e r m i n a t i o n s a f t e r 5 min in t h e c l i n i c and 30 min l a t e r in t h e c l i n i c a l l a b . Each s u b j e c t a l s o wore an ambula tory BP m o n i t o r ( S p a c e l a b s ) f o r 24 h o u r s . C l i n i c s u p i n e d i a s t o l i c (D) BP (mean + SD) was h i g h e r in w i n t e r (84 + 9 ) than summer (79 + 10 mmHg), wi th i n t e r m e d i a t e f a l l and s p r i n g v a l u e s ( n = 2 7 , p < . 0 5 ) and s i m i l a r p a t t e r n s a c r o s s g r o u p s . Nir.e o f 27 s u b j e c t s had w i n t e r c l i n i c DBP i n c r e a s e s > 6 mmHg. Supine l a b BP was 6 mmHg lower than c l i n i c ( p < < . 0 0 1 ) w i t h o u t s i g n i f i c a n t winter-suΊϊΐντ ::iean d i f f e r e n c e s , but 8 / 2 7 s u b j e c t s had w i n t e r sup in l a b DBP i n c r e a s e s ^ 6 mmHg. In c o n t r a s t , mean waking a m b u l a t o r y w i n t e r DBP was not d i f f e r e n t from summer. S e a s o n a l changes in c l i n i c s u p i n e s y s t o l i c BP (3 mmHg) and u p r i g h t HR (6 b / m i n 3 p<.

0 5 ) a l s o were o b s e r v e d . We c o n c l u d e t h a t t h e p r e v a l e n c e o f o f f i c e

h y p e r t e n s i o n i n c r e a s e s in w i n t e r , confounding t h e d i a g n o s i s o f h igh-normal or e l e v a t e d BP. These f i n d i n g s u n d e r s c o r e t h e p i t f a l l s o f a r b i t r a r y t;P c u t o f f p o i n t s , d i f f i c u l t i e s in o b t a i n i n g c o n s i s t e n t BP v a l u e s , and need f o r time-- o r p l a c e b o - c o n t r o l l e d drug t r i a l s .

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[13301 ARE LV MASS AND DIASTOLIC FILLING RELATED TO AEROBIC CAPACITY IN MEN WITH MILD HYPERTENSION? M.B. Effron. S.A. Valenti, M.H. Kelemen, andKJ. Stewart. Johns Hopkins School of Medicine at Francis Scott Key Medical Center, Baltimore, M.D.

To examine the relationships among indices of LV mass, LV diastolic filling, and aerobic capacity in patients with mild hypertension, we studied 51 men, without evidence of ischemic or valvular heart disease, with diastolic blood pressures between 90-105 mm Hg off medications for at least 4 weeks. LV mass index (LVMI) was determined by 2D guided M-mode echocardiogram. Peak velocities of early diastolic filling (E) and late diastolic filling (A) were determined by Doppler. Aerobic capacity was measured as maximal oxygen uptake ( M V 0 2 ) during Bruce treadmill testing.

Parameter MeantSD r + v s M V 0 2 r+vsage

M V 0 2 (ml/kg/min) 30.7±5.0 Age (years) 45.0±8.0 - 0.33* PeakE/A 1.1210.4 0.27 -0.34* LVMI(g/cm2) 127.0+20.0 0.20 0.29* * p<0.05 + univariate correlation

These data indicate that age is a significant correlate of LV mass and diastolic filling. However, only age was predicitive of aerobic capacity. We conclude that aerobic capacity in men with mild hypertension is determined primarily by non- cardiac factors.

11332| LONG-TERM SUCCESS OF A HYPERTENSION SUPPORT GROUP. M.L. Binstock* and K.L. Franklin, University of Conecticut School of Medicine, Farmington, CT, and Saint Francis Hospital and Medical Center, Hartford, CT.

Compliance is th<2 major problem in the control of high blood pressure. Support groups are an effective short-term adherence strategy; therefore, the long-term value of a hypertensive support group was studied.

Employees at an aerospace corporation were screened for high blood pressure. Those with elevated readings were referred for follow-up care and invited to join a worksite support group. Forty-six people participated m 60-minute sessions which met bimonthly for three years. Compliance strategies were emphasized. All employees were screened initially, after one year and after three years. A compliance questionnaire was also administered.

There was a significant reduction in blood pressure for support group members (initial blooc pressure, 149/95 mmHg; one year, 134/84 mmHg; three year, 133/81 mmHg). The support group was well received and participation remained high. A questionnaire suggested that employees who attended meetings were knowledgeable about hypertension, and 95% took their medications as directed over 8u% of the time. Eighty-six percent kept their appointments with their physician over 80% of the time.

This suggests Lhat support groups can be maintained, and that members comply with medication and appointments. In addition, blood pressure remains well controlled.

113311 RESPONSE TO THE COLD PRESSOR TEST—ΪΝ NORMOTENSLVES AND HYPERTENSIVES. : A. Benetos. R. Asmar, ME Safar * Diagnosis Center, Hopital Broussais, Paris FR. Blood Pressure (BP) and Heart rate (HR) responses to the Cold Pressor Test (CPT) were studied in 73 patients with essential hypertension (HT) aged 26 to 67 years and 49 controls (NT) aged 27 to 67 years. After 15 minutes of bed rest, the subjects were asked to immerse their left hand to juste above the wrist for 90 seconds in ice water (4°-5° C ) . BP and HR were automatically recorded every minute before, during (30" and 90" of the CPT), and for 5 ? after the the test. Peak BP and^jHR changes, when occured, were observed at the 90 second of the CPT. Patients were classified as responders when they increase of at least 16 mmHg SBP or 12 mmHg DBP. 47 out of 73 (64 %) HT were responders to the CPT, increasing MBP by 18,6 £ 1 . 4 mmHg (m + SEM). In NT subjects 23 out of 49 (47 %) were responders ( Δ Μ Ρ Β = 16.3 + 1.3 mmHg). A negative relationship was observed in NT but not in HT patients between MBP changes during the CPT and the age (p<0.001) or the basal MBP (p<0.01). There was no relationship between BP response and the presence or not of family history of hypertension. A positive correlation was found in HT patients between basal level of active renine (A.R. ) in the upright position, and MBP changes during the CPT (p<0.001). Mean plasma A.R. was 24.2 ± 3.5 pg/ml in responders VS 37.5 ± 2.9 pg/ml in non responders (p<0.001). In HT but no in NT patients, BP changes were associated with a simultaneous increase of HR (p<0.01 between Δ MBP andAHR). These results suggest : 1- BP elevation during the CPT is a very common reaction in young NT more especially as basal MBP is lower. Therefore it is unlike that the CPT can be used as a predictor test of futur hypertension in this population. 2- In hypertensives the lack of BP increase during the CPT makes unlike the presence of a high renine hypertension.

1333 LOW AMOUNTS OF ENDOTHELIN IN THE CIRCULATION OF HEALTHY PERSONS AT REST AND AT PHYSICAL STRESS Ε Hartter;" DH Petzl, W Schuller, W Woloszczuk Clin, of Occupat. Medicine, Univ. of Vienna & L. Boltzmann-Inst. f. Klin. Endokr., Vienna,Austria

Estimations of endogenous levels of endothelin (ET), a powerful vasoconstrictor-peptide, might be crucial for elucidation of its physiology. We have developed a RIA for measurment of ET. EDTA-blood samples (ice-bath) were processed to EDTA-plasma (PL). Following extraction of endothelin-like im= munoreactivity (ET-ir) from PL by Sep-Pak C18 cart ridges (Waters, Milford,MA) we determined ET-ir by competitive RIA with delayed addition of tracer (TR) and second-antibody precipitation of antigen bound (125-I-ET, porcine was from ANAWA, Wangen, Switzerland;rabbit-anti porcine ET and synthetic ET were from Peninsula,Belmont,CA; immunoprecipi= tating reagent was from SORIN/Biomedica, Saluggia, Italy). TR bound at zero dose (Bo) was 20%, non specific binding was 4% of total TR added.Sensiti= vity of the assay was 0.2 pg/tube. Within-and bet= ween assay precision within the range of 20% and 80% binding relative to Bo were 10% and 16% res= pectively. No decay of ET-ir was observed at pro= longed (3h) ice-cooling of EDTA-blood samples. In blood of alltogether 24 healthy persons (age: 38+13 years) we could clearly find ET-ir, ranging from 0.3-1.7 pg/ml in amount (x+SD=1.0+0.4 pg/ml). Physiological enhancement of blood pressure by bi= cycle-ergometry did not raise PL-levels of ET-ir in healthy persons. We summarise: 1) ET-ir is present in low amounts in circulating blood. 2) A rise in blood pressure by the stimulus of physical stress is not associa= ted by an enhanced systemic release of ET-ir into circulation.

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CYCLIC GMP DEPENDENT MODULATION OF RELEASE OF NOREPINEPHRINE FROM ADRENERGIC NERVES INNERVATING CANINE ARTERIES AND V E I N S . S G r e e n b e r q * , FPJ D i e c k e , Κ Peevy and TP Tanaka. Dept. o f P h y s i o l . , UMDNJ-New Jersey Medical School , Newark, NJ 07103 and D e p t . o f P e d i a t r i c s , U n i v . So . A l a b a m a , Mobi le Alabama, 36688.

Previous s tud ies showed t h a t the r e l e a s e of norep inephr ine (NE) from adrenerg ic nerve endings i n n e r v a t i n g vascu la r smooth muscle (VSM) i s i n h i b i t e d by substances which r a i s e c y c l i c 3 ' , 5 ' -guanosine monophosphate (cGMP) and enhanced by s u b s t a n c e s which e l e v a t e c y c l i c AMP (cAMP) i n n e r v e s . T h i s p o s t u l a t e was t e s t e d i n i s o l a t e d c a n i n e pu lmonary and m e s e n t e r i c a r t e r i e s and v e i n s u s i n g t h e t e c h n i q u e o f s u p e r f u s i o n and measurement o f t h e e f f l u x o f r a d i o l a b e l e d NE dur ing transmural nerve s t i m u l a t i o n a t 0 . 5 , 1 , 2 , 4 , 8 , 16 and 32 Hz f o r 10 m i n . S t i m u l a t i o n o f adeny la te cyc lase w i t h f o r s k o l i n , p r o s t a c y c l i n and i l o p r o s t , and i n h i b i t i o n o f Type I I I cAMP phosphodiesterase w i t h neural s p e c i f i c r o l i p r a m and muscle s p e c i f i c m i l r i n o n e and i s o b u t y l m e t h y l -xanth ine (IBMX) d id not enhance the c o n t r a c t i o n s to nerve s t i m u l a t i o n nor the e f f l u x o f NE from adrenerg ic nerves i n n e r v a t i n g the blood v e s s e l s . E l e v a t i o n s i n cGMP by the guany la te cyc lase a c t i va tors S I N - 1 , n i t r o g l y c e r i n , sodium n i t r o p r u s s i d e and n i c o r a n d i l and i n h i b i t i o n of cGMP phosphod i e s t e r a s e w i t h M&B-22948 and v e r o p h y l l i n i n h i b i t e d t h e r e s p o n s e s t o n e r v e s t i m u l a t i o n i n concent ra t ions which were less e f f e c t i v e a g a i n s t NE, w h i l e i n h i b i t i n g t h e e f f l u x o f NE where t e s t e d . These data support the conclusion t h a t i n t r a n e u r o n a l cGMP i s an i n h i b i t o r y modulator of NE re lease from adrenerg ic nerves .

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MECHANISMS OF SYMPATHICOTONIC ORTHOSTATIC HYPOTENSION. D.H.P. S t r e e t e n * , G.H. Anderson, J r . * , J.W. M i l l e r , F.D. Thomas. Dept. o f Med . , SUNY Health Science Center , Syracuse, N.Y.

In p a t i e n t s wi th sympathicotonic o r t h o s t a t i c hypotension, we have reported t h a t (1 ) an i n f l a t e d MAST su i t overcame the o r t h o s t a t i c BP and Ρ abnormal i t ies suggesting excessive g r a v i t a t i o n a l pooling which was conf i rmed, a f t e r y y m T c -pertechnetate l abe l ing of red c e l l s , by e x t e r n a l s c i n t i l l a t i o n counting supine and s tand ing ; (2) reduced venous r e t u r n caused by p o o l i n g , decreased o r t h o s t a t i c cardiac f i l l i n g , shown by e n d - d i a s t o l i c s c i n t i l l a t i o n counting over l e f t v e n t r i c l e ; (3 ) o r t h o s t a t i c increases i n plasma norepinephrine (NE) were excess ive , presumably t r iggered by low-pressure cardiac r e c e p t o r s , and associated w i th o r t h o s t a t i c t achycard ia . We have now studied vascular responsiveness to NE in 8 pa t i en ts and 10 healthy c o n t r o l s : (1 ) s tep-wise increasing ra tes of I .V . NE in fus ion r a i s e d s y s t o l i c and d i a s t o l i c B.P. equa l ly in p a t i e n t s and c o n t r o l s , i n d i c a t i n g normal myocardial and a r t e r i o l a r responses; (2) p l a t e l e t a2~adrenerg-ic receptors showed normal densi ty and a f f i n i t y f o r ^H-yohimbine, ind ica t ing absence of a g lobal receptor d e f e c t ; (3 ) venous responsiveness t o norepinephrine infused at 1 ,4 , 16,64 and 256 ng/min was measured by Linear Var iab le D i f f e r e n t i a l Transformer. I t was normal in hand veins but excessive ( i n 5 of 8 p a t i e n t s ) i n foot ve ins s i m i l a r to the excessive venous responsiveness of both hand and foot veins in 3 subjects w i th autonomic f a i l u r e . Conclusion: Autonomic denervat ion ( f u n c t i o n a l or anatomic) of lower limb veins may be the mechanism of excessive o r t h o s t a t i c pooling in some of these p a t i e n t s .

1 3 3 5 HYPOTENSIVE PROPERTIES OF ANTIBODIES DIRECTED AGAINST HF, A PRESSOR AGENT ISOLATED FROM SH RATS. DG Todd. W Kopp, WD McCumbee , V Reichenbecher, GL Wright . Dept. of Physiology, Marshall Univ. School of Medicine, Huntington, WV.

Hypertensive factor (HF), a compound shown to influence tissue calcium metabolism and induce prolonged blood pressure elevation has been recently isolated from the erythrocytes of spontaneously hypertensive (SH) rats and tentatively identified as a peptide. In the present study, we investigated the biological properties of anti-HF antibodies directed against this peptide. Partially purified antibody preparations significantly decreased HF stimulation of lanthanum-resistant calcium uptake in aortic tissue in vi_tro. Infusion of the antibody preparation into the SH rat resulted in a rapid decline (54 torr) in mean blood pressure. The blood pressure of normotensive rats fell following infusion of the antibody preparation, but to a lesser extent (34 torr) than observed in SH rats. In contrast, infusion of the serum immunoglobulin preparations from control (unimmunized and ovalbumin immunized) rabbits had no significant effect on the blood pressure of SH or normotensive rats. The systolic blood pressure of SH rats was reduced for at least 72h following a single injection of the antibody preparation; whereas, the blood pressure of normotensive rats had returned to normal levels within 24h following antibody injection. Finally, it was found that injections of small volumes of anti-HF antibody solution attenuated the pressor response to norepinephrine in the SH but not the normotensive rat. The results indicate that antibodies raised against HF antagonize the stimulation of calcium uptake by the peptide and lower blood pressure to a greater degree in SH than normotensive rats. Moreover, the data suggest that the hypotensive effect of anti-HF antibodies may be mediated through an attenuation of the vascular responsiveness to constrictor agents.

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RELATIONSHIP BETWEEN PLASMA ATRIAL NATRIURETIC HORMONE (ANH) AND SERUM POTASSIUM (K) DURING CHRONIC DIURETIC THERAPY (Rx) IN ESSENTIAL HYPERTENSION (EH). J . G i l s d o r f , G.H.Anderson* ,Jr , G. L ighty , N. Blakeman, C. Hare, D.H.P. S t r e e t e n * Dept. of Medicine, SUNY-HSC, Syracuse, NY.

We prev iously reported the e f f e c t of Rx in pts wi th EH upon plasma ANH (AJH 1988, 1 , No .3 , Part 2 .141A) . We now repor t on e f f e c t of Rx on K, plasma aldosterone (PA) and r e l a t i o n s h i p t o ANH. 28 pts wi th EH o f f medicat ion > 1 week had blood drawn f o r ANH and K. Then Rxed on hydrochlorot h i a z i d e (HCTZ) 50 mg qd, and returned 1 month l a t e r f o r repeat measurements. I n 14 pts HCTZ increased ANH ( i n i t i a l ANH 11 .6±2 .0 pg/ml) and i n 11 pts reduced ANH ( i n i t i a l ANH 31 .3±9 .6 p g / m l ) . The t a b l e fo r these 2 groups show: Rx Δ i n ANH (AANH), ANH a f t e r HCTZ (RxANH), i n i t i a l Κ ( I n i -K ) , Κ a f t e r HCTZ (Rx -K) , the Δ Κ induced by HCTZ (Δ K ) , and PA a f t e r HCTZ (Rx-PA) . (Data mean ± SE). ANH ΔANH Rx-ANH I n i - K Rx-K Δ Κ Rx-PA

(pg /ml ) (pg /ml ) (mEq/L)(mEq/L)(mEq/L)(ng/%) Rise 8 . 1 19.7 4 .0 3.4 - 0 . 6 17.0

±1.5 ± 2 . 0 ± 0 . 1 ± 0 . 1 ± 0 . 1 ± 1 . 6 Fa l l - 2 0 . 9 * 1 0 . 3 * 4 .0 3 . 8 * - 0 . 2 * 14.4

±7 .8 ±2 .5 ± 0 . 1 ± 0 . 1 ± 0 . 1 ± 2 . 6 ( *p< .01 cf ANH r i s e ; nonpaired Τ t e s t )

Both groups had s i m i l a r , s i g n i f i c a n t (P< .05) f a l l s in weight and BP. There was a s i g n i f i c a n t (P a t l eas t < .05) c o r r e l a t i o n betweenΔK and Δ ANH ( r = - . 5 3 ) , Ini-ANH ( r = . 7 0 ) , and Rx-PA ( r = - . 5 4 ) . By m u l t i p l e l i n e a r regression Κ was most r e l a t e d t o Ini-ANH not Rx-Aldo. Thus: Since i n f u s i o n of ANH is known to cause both a k a l i u r e s i s and n a t r i u r e s i s , r e s u l t s suggest t h a t ANH plays an important r o l e in causing d i u r e t i c induced hypokalemia.

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PREDICTORS OF SODIUM SENSITIVITY IN MILD HYPERTENSION. MS P e c k e r , * GD J a m e s * JE S e a l e y * S J a c k s o n , Β D i f a b i o , L C a r r o l l , S O r l i c , Μ B l a k e , Μ Alderman*TG P i c k e r i n g * Ρ S c h n a l l , SA A t l a s * JH L a r a g h * C o r n e l l U. Medical C o l l e g e , New York, N.Y.

We examined c o r r e l a t e s of sodium s e n s i t i v i t y in 42 working s u b j e c t s with u n c o m p l i c a t e d , mild i d i o p a t h i c h y p e r t e n s i o n , d i a s t o l i c p r e s s u r e 9 0 - 1 0 5 mmHg. S u b j e c t s fo l lowed high (H,>225 m e q / d ) , medium (M,100-160 meq/d) and low (L ,<40meq/d) sodium d i e t s over c o n s e c u t i v e 4 week p e r i o d s . D i e t s were o t h e r w i s e s i m i l a r . Blood p r e s s u r e , 24 hour u r i n e and blood t e s t s were measured during the 4 t h week of each p e r i o d . 18 s u b j e c t s were sodium s e n s i t i v e (SS, >10 mmHg i n c r e a s e in d i a s t o l i c p r e s s u r e on Η compared with L) , and 20 s u b j e c t s were sodium i n s e n s i t i v e ( S I , <5 mmHg i n c r e a s e in d i a s t o l i c p r e s s u r e on Η compared with L ) . 8 of 12 women and only 10 of 30 men were SS. In t h e s e s u b j e c t s with predominant ly normal r e n i n v a l u e s , n e i t h e r PRA, u r i n a r y a l d o s t e r o n e , weight c h a n g e s , age nor r a c e c l e a r l y d i s t i n g u i s h e d SS from S I . The t a b l e shows mean v a l u e s on the d i e t s :

Low Medium High BP SS 1 2 7 / 8 3 1 4 1 / 9 2 * 1 4 9 / 9 9 * , # (mmHg) S I 1 3 0 / 8 9 1 3 8 / 9 1 1 4 1 / 8 9 UNaV SS 23 139 * 315 * r # (meq/d) S I 25 137 * 284 ANF SS 8 . 8 1 3 . 7 * , $ 1 8 . 2 * (pM) S I 8 . 0 9 . 2 1 3 . 4 P r o r e n i n SS 2 1 . 9 $ 1 5 . 4 1 2 . 8 * , $ ( n g / m l / h r ) S I 3 3 . 9 2 2 . 6 * 1 9 . 2 *

* p < . 0 5 vs low, # p< . 0 5 vs medium; $ p < . 0 5 vs S I While on M, 10 of 11 s u b j e c t s with ANF l e s s than 10 fmol/ml were S I . P r o r e n i n was s i g n i f i c a n t l y lower in SS on a l l d i e t s . T h e r e f o r e , ANF and p r o r e n i n may be u s e f u l i n d i c a t o r s of SS. Supported by H L - 3 5 8 8 6 .

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C H A R A C T E R I Z A T I O N O F H O M O G E N O U S B O V I N E A T R I A L G R A N U L E S E R I N E P R O T E I N A S E P . M . W y p i i a n d R . B . H a r r i s * , D e p t . B i o c h e m . a n d M o l e c . B i o p h y s . , V i r g i n i a C o m m o n w e a l t h U n i v . , R i c h m o n d , V A .

W e p r e v i o u s l y i d e n t i f i e d a s e r i n e p r o t e i n a s e a s s o c i a t e d w i t h b o v i n e a t r i a l s e c r e t o r y g r a n u l e s w h i c h r e c o g n i z e s t h e s e q u e n c e G l y - P r o - A r g - S e r - L e u - A r g -A r g c o n t a i n e d i n p r o - a t r i a l n a t r i u r e t i c f a c t o r ( p r o A N F ) a n d f l & i v e s t h e A r g 9 8 - S e r " b o n d t o y i e l d t h e S e r 9 - T y r 1 ^ " n a t r i u r e t i c p e p t i d e . W e n o w r e p o r t t h e p u r i f i c a t i o n o f t h i s e n z y m e t o h o m o g e n e i t y as j u d g e d b y e l e c t r o p h o r e t i c a n d N - t e r m i n a l s e q u e n c e c r i t e r i a . T h e e n z y m e w a s p u r i f i e d f r o m i s o l a t e d a t r i a l g r a n u l e s f o l l o w i n g a p r o c e d u r e w h i c h i n c l u d e s a n i o n e x c h a n g e a n d p r e p a r a t i v e g e l f i l t r a t i o n c h r o m a t o g r a p h i e s , F P L C w e a k a n i o n e x c h a n g e c h r o m a t o g r a p h y , a n d a n a l y t i c a l g e l f i l t r a t i o n . T h e r e is a d i s c r e p a n c y b e t w e e n t h e a p p a r e n t m o l e c u l a r w e i g h t d e t e r m i n e d b y S D S - P A G E ( - 7 5 , 0 0 0 ) a n d g e l f i l t r a t i o n ( - 4 0 0 , 0 0 0 ) . T h e d i s c r e p a n c y m a y be d u e t o a s s o c i a t i o n o f e n z y m e m o n o m e r s o r t o g l y c o s y l a t i o n . T h e p u r i f i e d e n z y m e h a s a s p e c i f i c a c t i v i t y o f 6 u n i t s / m g ( B z - G - P - R - 2 - N a p h t h y l a m i d e s u b s t r a t e ) a n d is 2 0 0 0 - f o l d p u r i f i e d c o m p a r e d t o t h e h o m o g e n a t e p r e p a r e d f r o m i s o l a t e d g r a n u l e s . T h e r e is a 2 . 5 - f o l d i n c r e a s e i n a c t i v i t y i n 1 - 5 m M C a C ^ b u t a t h i g h e r i o n i c s t r e n g t h ( d u e t o C a C I ^ , N a C l o r o t h e r a g e n t s ) t h e e n z y m e is c o m p l e t e l y i n h i b i t e d . E G T A o r E D T A a l s o c o m p l e t e l y i n h i b i t t h e e n z y m e . O u r r e s u l t s s u g g e s t t h a t t h e e n z y m e is a n e u t r a l p H , c a l c i u m -d e p e n d e n t s e r i n e p r o t e i n a s e . I t is p r e s e n t w i t h i n a t r i a l g r a n u l e s b u t r e m a i n s i n a c t i v e i n t h e u n f a v o r a b l e i n t r a -g r a n u l a r e n v i r o n m e n t . P r o c e s s i n g o f p r o - A N F t o t h e a c t i v e n a t r i u r e t i c p e p t i d e s p r o b a b l y o c c u r s d u r i n g s e c r e t i o n .

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A T R I A L NATRIURETIC FACTOR (ANF) RELEASE FROM THE ISOLATED, PERFUSED CANINE LEFT LOWER LUNG LOBE (L L L ) . JE Hall and R Burnstein. Department of P e d i a t r i c s , State University of New York, Stony Brook, NY . To test the hypothesis that the lung stores A N F , we studied pulmonary vein l evels of ANF in the L L L . Animal s of e i ther sex were anesthetized with p e n t o b a r bital (approximately 30 m g / k g ) , v e n t i l a t ed, and anticoagulated with 10,000 units of sodium heparin. The LLL w a s removed through a left thoracotomy, and au t o l o gous blood collected via a femoral artery catheter. The LLL was then p u m p -perfused with blood at a constant 5 m l / gm/mi n . Blood w a s collected in an EDTA tube, and the ANF level measured by radioimmunoassay (Peninsula Laboratories) after extraction of the peptide w i t h a C18 SEP-COLUMN. Samples were taken 1) from the blood before perfusion of the LL L , and 2) immediately after perfusion of the L L L . ANF levels (pgm/ml; mean + SEM) were (n=5 l o b e s ) :

Before After 12.9 + 6.5 28.3 + 9.8

Perfusion of the isolated LLL produced a significant increase (paired t-test; ρ < 0.05) in blood ANF levels consistent with w a s h - o u t of ANF from storage sites in the LLL .

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THE "ΚΗΠΕ COAT/'-INDUCED BLOOD PRESSURE RISE: A PREDICTOR OF MYOCARDIAL INFARCTION AMCNG HYPERltNSIVES. Alderman Mi,* Ooi WL. Madhavan S, Cohen H. Albert Einstein College of Medicine, Bronx, NY.

Many persons have higher blood pressure (BP) when measured by a physician (MD), but the relationship of this response t o cardiovascular disease (CVD) occurrence i s uncertain, lb determine, among hypertensives, the difference between the BP taken by a nurse (RN) and MD, in that order, and i t s relation t o CVD, the "MD minus RN1' BP (ΔΒΡ) was determined in 1,737 previously untreated patients (sustained, pre-treatment RN EP > 160 and/or 95 mmHg). Patients stratified by textiles of Δ diastolic BP ( I : <-3, U : -2 t o 3, and I I I : >4 mmHg) were similar fcy baseline body mass index (BMI), serum cholesterol, EK3 finding, history of CVD, pretreatment and attained in-treatment BPs, but fer t i le I I I had more smokers, ware more likely to be < 5 5 years of age, male and black. Over 4.2 years (mean treatment followup), myocardial infarction (MI) morbidity and mortality per 1,000 patient-years were, respectively: t e r t i l e 1= 3.2, 11= 3.7, m = 7.6 (relative risk= 2.4, H I vs. I + H , p<0.05), vhereas stroke incidence and non-CVD mortality were indistinguishable between ter t i les . Similar findings emerged when stratification was by/i systolic BP.

In a Cox Prqpcrtional Hazards model, controlling for smoking, BMI, cholesterol, prior CVD, EFG, and initial RN or MD BP, only age, sex and A diastolic BP were predictive (p<0.03) of MI and total CVD. Thus, a likely physiological stress response identifies a subgroup of hypertensives who, despite successful therapy, are at increased risk of ME.

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IN VIVO VISUALIZATION OF SYMPATHETIC INNERVATION AND FUNCTION BY POSITRON EMISSION TOMOGRAPHY US. Goldstein. G Eisenhofer, R Miletich, R Finn, KL Kirk, J Bacher, PC Chang, and IJ Kopin. Hypertension-Endocrine Branch, NHLBI, NIH, Bethesda, MD.

We used positron emission tomographic (PET) scanning after systemic intravenous administration of [ 1 8 F ] -fluorodopamine to assess sympathetic neuroanatomy and function in anesthetized dogs. The heart avidly removed and concentrated circulating flurodopamine, providing striking PET images of the left ventricle. The y-intercept for the relationship between the log of the myocardial radioactivity concentration and time decreased by about 5-fold during neuronal uptake blockade, demonstrating that the heart is extraordinarily dependent on neuronal uptake for removal of circulating catecholamines. Reserpinization abolished cardiac positron emission after injection of [18F]-6-fluorodopamine, proving that the normal PET image of the heart resulted from radioactive labelling of the storage vesicles. The turnover rate of cardiac radioactivity therefore would be directly related to the turnover rate of the vesicles. In dogs with unilateral superior cervical ganglionectomies, less positron emission was noted from salivary glands of the ganglionectomized than of the intact side, confirming that the technique visualized sympathetic nerve endings. By analysis of radioactivity time-activity curves for the gall bladder and ureters or bladder, the PET technique also was used to examine the excretion of fluorodopamine metabolites. PET imaging after injection of fluorodopamine provides a new means to delineate sympathetic neuroanatomy, quantify Uptake-1 activity and regional norepinephrine turnover, and follow the renal and hepatic excretion of catecholamines and catecholamine metabolites.

|1344| AGE RELATED EVALUATION OF THE CA 2* DISTRIBUTION IN AORTIC TISSUE OF SPONTANEOUSLY HYPERTENSIVE AND NORMOTENSIVE RATS. C S p i e k e r *, W Zidek, DB ν B a s s e w i t z , D Heck, KH Rahn. Med. Univ. P o l i k l i n i k Munster , FRG. D i s t u r b a n c e s in the metabol ism of c a l c i u m have been i m p l i c a t e d in the p a t h o g e n e s i s of e s s e n t i a l h y p e r t e n s i o n . In the p r e s e n t s t u d y , p a r t i c l e - i n d u c e d X - r a y e m i s s i o n (PIXE) was used to ge t i n f o r m a t i o n on the s p a t i a l d i s t r i b u t i o n of C a 2 * in a o r t a s of s p o n t a n e o u s l y h y p e r t e n s i v e r a t s (SHR) and n o r m o t e n s i v e c o n t r o l s aged 1 week, 4 weeks and 12 weeks. To d i f f e r e n t i a t e changes in C a 2 * metabol ism in h y p e r t e n s i v e a r t e r i e s from s e c o n d a r y phenomena due t o the a r t e r i o s c l e r o s i s , the a n i m a l s have been e x a mined in t h e e a r l i e s t s t a g e of h y p e r t e n s i o n . I t was found t h a t the C a 2 * c o n t e n t was not e l e v a t e d in t h e a o r t i c smooth muscle of SHR aged 1 week ( n = l l ) as compar e d t o n o r m o t e n s i v e c o n t r o l s ( n = 1 0 ) ( 1 8 8 , 9 ^ 9 0 , 1 ;ug C a 2 * / g t i s s u e v s . 2 5 9 , l * - 7 0 , 2 μ g C a 2 * / g . The C a 2 * c o n t e n t was r a i s e d ( p < 0 , 0 5 ) in the a o r t i c smooth musc l e of SHR aged 4 weeks ( n = 1 3 ) as compared to 12 WKY r a t s (4 weeks) ( 725 , 2 *-1 30 , 9 jig C a 2 * / g t i s s u e v s . 4 4 1 , 0 - 2 1 1 , 1 ug C a 2 * / g and in 17 SHR ( 3 months) as compared t o 13 WKY r a t s r e s p e c t i v e l y ( 3 3 9 0 , 1 ^ 7 2 9 , 9 ug C a 2 * / g t i s s u e vs. 1 6 3 2 , 1 * 5 6 9 , 5 jig C a 2 * / g The r e s u l t s c o n f i r m t h e a g e - r e l a t e d i n c r e a s e in the a r t e r i a l C a 2 * c o n t e n t in n o r m o t e n s i v e r a t s and d e m o n s t r a t e a d d i t i o n a l l y t h a t t h i s a g e - r e l a t e d r i s e in a r t e r i a l C a 2 * c o n t e n t i s a c c e l e r a t e d in SHR.

I1343| CIRCADIAN BLOOD PRESSURE PROFILES OF PATIENTS RECEIVING A SINGLE DOSE OF A CONVERTING ENZYME INHIBITOR (RAMIPRIL). C S p i e k e r *, Η V e t t e r , W Zidek , KH Rahn. Med. Univ . P o l i k l i n i k Munster & Bonn, FRG. R a m i p r i l i s a new c o n v e r t i n g enzyme i n h i b i t o r . I t s p r o l o n g e d d u r a t i o n of a c t i o n makes i t s u i t a b l e f o r a once d a i l y admin i s t r a t i o n . T h e r e f o r e in t h i s s t u d y t h e e f f e c t of a s i n g l e dose of r a m i p r i l on t h e 24 hours blood p r e s s u r e p r o f i l e s was compared with t h a t of p l a c e b o in p a t i e n t s with e s s e n t i a l h y p e r t e n s i o n . This was a randomized , double b l i n d s t u d y of out p a t i e n t s . The s t u d y was done in a c c o r d a n c e to l o c a l l a w s . 10 e s s e n t i a l h y p e r t e n s i v e s (BP 1 6 8 , 3 * 1 9 , 2 / 1 0 1 , 4 * 1 0 , 8 ) were i n c l u d e d i n t o the t r i a l . The p a t i e n t s had no a n t i h y p e r t e n s i v e m e d i c a t i o n s p r i o r t o t h e s t u d y . 24 hours blood p r e s s u r e r e g i s t r a t i o n ( Squipp-Kranzbi ihler ) was c a r r i e d out 2 4 h o u r s b e f o r e , 24 hours a f t e r and 48 hours a f t e r t h e p a t i e n t s r e c e i v e d t h e m e d i c a t i o n a c c o r d i n g to the double b l i n d s t u d y r e g i m e . R e s u l t s : The blood p r e s s u r e in the group r e c e i v i n g r a m i p r i l d e c r e a s e d a f t e r 24 hours t o 147 , 0*7 , 5 / 9 7 , 0*4 , 1 ( p < 0 , 0 5 ) v s . 1 6 0 , 2 * 1 5 , 3 / 1 0 0 , 5 * 1 1 , 1 ( n . s . ) in t h e p l a c e b o g r o u p . A f t e r 48 hours t h e blood p r e s s u r e of the r a m i p r i l group was 1 5 8 , 2 * 1 2 , 1 / 9 7 , 8 * 8 , 2 v s . 162 , 3*-l 1 , 9 / 1 3 , 1 mm Hg in t h e p l a c e b o group ( N . S . ) . The d a t a show a s u f f i c i e n t d e c r e a s e of blood p r e s s u r e a f t e r a d m i n i s t r a t i o n of 5 mg r a m i p r i l d u r i n g 24 h o u r s , whereas no e f f i c i e n t blood p r e s s u r e l o w e r i n g e f f e c t c o u l d be r e g i s t e r e d a f t e r 48 h o u r s .

113451 THE COSINOR METHOD - A COMPUTER AIDED MODEL TO DIFFERENTIATE ESSENTIAL FROM SECONDARY HYPERTENSION. C S p i e k e r * . CM S t a -s c h e n , W Zidek, KH Rahn. Med. Univ . P o l i k l i n i k , Munster & S c h i f f . Med. I n s t . M., K i e l , FRG. N o n i n v a s i v e a m b u l a t o r y c i r c a d i a n blood p r e s s u r e r e g i s t r a t i o n i s meanwhile acknowledged as a s u i t a b l e t e c h n i q u e f o r blood p r e s s u r e m o n i t o r i n g . In t h i s s t u d y a c o m p u t e r a i d e d model , a c c o r d i n g t o t h e c o -s i n o r method, was used to q u a n t i f y the c i r c a d i a n blood p r e s s u r e p e r i o d i c i t y and was e x p r e s s e d as a c o e f f i c i e n t of p e r i o d i c i t y in %. The c o s i n o r method i s c o n s i dered as an e f f i c i e n t method f o r rhythm d e t e c t i o n ( H a l b e r g e t a l . 1 9 7 2 ) . In 20 e s s e n t i a l h y p e r t e n s i v e s (BP 1 7 9 , 3 ^ 9 , 0 / 1 0 5 , 6 -- 1 0 , 8 mm Hg) , 16 s e c o n d a r y h y p e r t e n s i v e s (BP 1 $ 9 , 2 M 2 , 8 / 1 1 5 , 7 ^ 6 , 1 mm Hg) and 12 n o r m o t e n s i v e s , n o n i n v a s i v e 24 h blood p r e s s u r e m o n i t o r i n g ( S q u i b b - K r a n z b i i h l e r ) was p e r f o r m e d . The c o e f f i c i e n t f o r s y s t o l i c blood p r e s s u r e was h i g h e r in e s s e n t i a l h y p e r t e n s i v e s and n o r m o t e n s i v e s than in s e c o n d a r y h y p e r t e n s i v e s ( 4 2 , 9 * 1 8 , 0 and 4 3 , 0 ^ 1 6 , 7 v s . 2 8 . 2 - ^ 1 7 , 7 ; p < 0 , 0 5 ) . The c i r c a d i a n p e r i o d i c i t y of d i a s o l i c p r e s s u r e showed no s i g n i f i c a n t d i f f e r e n c e s . D e s p i t e the l a r g e o v e r l a p , c o e f f i c i e n t s of p e r i o d i c i t y below 20% f o r s y s t o l i c p r e s s u r e may s u g g e s t s e c o n d a r y h y p e r t e n s i o n . F u r t h e r more t h e a n a l y s i s of c i r c a d i a n blood p r e s s u r e p a t t e r n u s i n g t h e c o s i n o r method may be h e l p f u l as a n o n i n v a s i v e t e c h n i q u e t o d i f f e r e n t i a t e between e s s e n t i a l and s e c o n d a r y h y p e r t e n s i o n .

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IN VITRO AND IN VIVO EFFECTS OF ENDOGENOUS DIGITALIS-LIKE SUBSTANCE. M.Ikeda, T.Morise, S.Okamoto, I.Miyamori*, R.Takeda*, 2nd Dept. of I n t . Medicine, Sch of Medicine, Kanazawa Univ, Kanazawa, Japan.

The mode of inhibition and in vivo biologi c a l e f f e c t s of the p a r t i a l l y purified endogenous d i g i t a l i s - l i k e substance (DLS) on Na-K-ATPase were studied in Wistar r a t s . Active p r i n c i p l e s were determined by inhibi t ion of canine Na-K-ATPase a c t i v i t y , displacement of Η ouabain from i t s binding s i t e and c r o s s - r e a c t i v i t y w i t h s p e c i f i c digoxin ant ibody. DLS were extracted from human urine by a combination of SEP-PAK C-jo adsorption chromatography and two steps of high performance l iquid chromatography ( s i l i c a - g e l and DIOR columns ) . DLS dose-dependent l y i n h i b i t e d renal and myocardial Na-K-ATPase a c t i v i t y and the dose-response curves were c losely similar to that of ouabain. Lineweaver-Burk plot analysis showed a non-competitive inhibition with respect t o ATP. DLS (equivalent t o 10 5M ouabain) increased urine volume, u r i nary Na excretion and mean blood pressure 60 , 75 and 10% respectively, in comparison with saline infusion. Na-K-ATPase a c t i v i t i e s ( 1 0 6moles Pi/mg protein/h) were s ignif icant ly suppressed, from 236 t o 172 in the kidney and from 11 .5 t o 9 .0 in the myocardium. These data suggest that 1)DLS exhibits a potent i n h i b i t o r y e f f e c t on Na-K-ATPase l ike ouabain, 2)DLS inhibits Na-K-ATPase n o n - c o m p e t e t i v e mode and 3)DLS p o s s e s s e s d iure t i c , n a t r i u r e t i c and pressor properties in vivo.

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CARDIOVASCULAR, RENAL AND HORMONAL EFFECTS OF ENDOTHELIN (ET) IN RABBITS: EFFECTS OF ET ANTIBODY. I .Miyamori* , T.Matsubara, Y . I t o , H.Koshida, R . T a k e d a * . 2nd D e p t . of M e d i c i n e , S c h . o f Medicine, Kanazawa Univ, Kanazawa, Japan.

The e f f e c t s of endothelin (ET), a potent vaso-constrict ing peptide synthesized in the endothelium, on a r t e r i a l BP, renal blood flow (RBF) and plasma aldosterone were studied by bolus in jec t ion of porcine ET (Peptide I n s t i t u t e , 100-1000 pmol/Kg, iv) in rabbits . BP and heart rate were monitored continuously through the indwelling c a n n u l a p l a c e d in t h e femoral a r t e r y . ET produced a s ignificant increase in BP (10% above the control) by lOOOpmol of ET and a significant decrease in plasma a ldosterone (22% f a l l from t h e p r e - i n f u s i o n l e v e l ) by subpressor dose (lOOpmol, iv) of ET in conscious rabbits . In a s e p a r a t e experiment , RBF decreased by 20% a t 500-1000prnol of ET in anesthetized rabbits . To t e s t the role of endogenous ET in blood stream f o r the c o n t r o l of BP and BRF, ET antibody r a i s e d a g a i n s t rabbi t ( IC =1.3pmol/ml a t 10 dilution) was infused a t graded concentrat ions , maximum dose being 2ml a t 2000 dilution. The antibody did not change the systemic BP, but i t caused a s l ight increase in RBF. The same dose of ET antibody inhibited the r i s e in a r t e r i a l BP induced by exogenous ET. The present r e s u l t s d e m o n s t r a t e t h a t ET p o s e s s e s a vasoconstr ic t ing a c t i o n and d e c r e a s e s RBF in vivo, and suggest that ET may contribute t o the control of BP by regulating the local vascular t o n e and t h r o u g h t h e changes in the renal hemodynamics.

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EVIDENCE A G A I N S T A ROLE OF INSULIN IN THE MAINTENANCE OF HYPERTENSION IN S P O N T A N E OUSLY HYPERTENSIVE R A T S . Ν T s u t s u , Y T a k a t a , Κ N u n o i , S Sadoshima, Μ F u j i s h i m a . 2 n d Dept. Intern. M e d . , Kyushu Univ., F u k u o k a , Japan.

To investigate a possible role of insulin in the maintenance of h y p e r t e n sion in spontaneously hypertensive rats ( S H R ) , mean blood pressure (MBP) , heart rate (HR) and plasma insulin and glucose before and after the intravenous glucose load (1 g/kg) were examined in conscious and unrestrained SHR and normotensive wistar kyoto rats (WKY) of adult age with a continuous recording of MBP and HR. Basal plasma glucose were identical between the two g r o u p s , but its insulin and the w e i g h t s were significantly lower in SHR than in W K Y . H o w e v e r , the a s s o c i a t ion of MBP with plasma insulin was not significant when the weigts and basal plasma glucose w e r e -adjusted using partial correlation. In either SHR or W K Y , basal plasma insulin did not c o r r e lated with basal MBP. A l t h o u g h the plasma insulin at 5 and 10 min after the glucose load profoundly increased to 13 and 9 fold in SHR (p < 0.001) and 7 and 8 fold in WKY ( ρ < 0.001) from their respective basal insulin l e v e l s , MBP and HR in either SHR C>r WKY remained unchanged throughout the time course of this study.

Our results suggest that insulin m i g h t not play a role in the maintenance of hypertension in SHR

1 3 4 9

AMBULATORY BLOOD PRESSURE MONITORING IN C L I N I C A L T R I A L S . A . C o a t s , J . C o n w a y , P . S l e i g h t . C a r d i a c D e p t . J o h n R a d c l i f f e H o s p i t a l , O x f o r d , E n g l a n d . T h e a c c u r a c y a n d p o w e r o f c l i n i c a l t r i a l s a r e c r i t i c a l l y d e p e n d e n t u p o n t h e r e p r o d u c i b i l i t y o f BP e s t i m a t e s . W i t h d i r e c t i n t r a - a r t e r i a l r e c o r d i n g s t h e i n t r i n s i c v a r i a b i l i t y o f s y s t o l i c BP ( a s m e a s u r e d b y t h e SD o f d a y t i m e r e a d i n g s ) i n 1 4 2 p a t i e n t s w a s 1 6 . 9 mmHg. I n d i r e c t d a y t i m e BP m o n i t o r i n g c a n o n l y m e a s u r e a s m a l l p r o p o r t i o n o f b e a t s , a n d h e n c e c a n o n l y a p p r o a c h t h i s l e v e l o f r e p r o d u c i b i l i t y . We h a v e i n v e s t i g a t e d t h e r e q u i r e m e n t s t o a c h i e v e a d e q u a t e l e v e l s o f r e p r o d u c i b i l i t y f r o m i n d i r e c t m o n i t o r i n g a t 3 0 m i n i n t e r v a l s d u r i n g t h e d a y i n 7 5 p a t i e n t s . R e p r o d u c i b i l i t y o f d i a s t o l i c BP a s g i v e n b y SDD ( t h e SD o f t h e d i f f e r e n c e s b e t w e e n m e a s u r e m e n t s o n d i f f e r e n t o c c a s i o n s ) w a s o b t a i n e d f r o m 2 r e c o r d i n g s m a d e 1 m o n t h a p a r t . SDD v a r i e d w i t h t h e n u m b e r o f BP r e a d i n g s p e r d a y a n d t h i s p r o f o u n d l y a f f e c t e d t h e n u m b e r o f s u b j e c t s r e q u i r e d i n a t r i a l . To r e l i a b l y ( p o w e r 0 . 9 ) m e a s u r e a 5 mmHg d i a s t o l i c d r u g r e s p o n s e f o r p a r a l l e l o r c r o s s - o v e r t r i a l s b y t h e m e t h o d s o f B l a n d a n d o f H i l l s & A r m i t a g e r e s p e c t i v e l y t h e f o l l o w i n g n u m b e r s (N) a r e n e e d e d : N o . o f r e a d i n g s SDD Ν ( p a r a l l e l ) Ν ( c r o s s - o v e r )

1 1 4 3 2 6 0 8 2 2 1 0 4 1 8 0 4 4 4 8 9 1 3 0 3 2 8 8 1 1 1 0 2 7 2 4 + 6 3 6 5 1 6 o p t i m i z i n g t h e r e p r o d u c i b i l i t y c

e s t i m a t e s a m b u l a t o r y B P m o n i t o r i n g c a n s u b s t a n t i a l l y r e d u c e t r i a l n u m b e r s . H o w e v e r t o a c h i e v e t h i s , r e a d i n g s m u s t b e m a d e o v e r t h e w h o l e w a k i n g d a y .

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[13501 VARIABILITY OF URINARY CALCIUM EXCRETION IN F R E E -LIVING INDIVIDUALS A . S i a n i , N . G i o r g i o n e , R.Iacone & P.Strazzullo. Institute of Internal Medicine,2nd Medical School, University of N a p l e s , Italy.

A large intraindividual variability in urinary Na and Κ excretion has been reported, to the extent that several urine collections are needed to a d e quately characterise Na and Κ urinary excretion. There is no data, to our kn o w l e d g e , with regard to 24h Ca excretion variability. We studied the va r i a b i l i t y of 24h urinary Ca excre tion in a sample of 43 Neapolitan free-living indi^ viduals w i t h mild BP elevation (M/F=22/21,age 46+ 10/50+8 yrs,SBP 145+7/147+9 mmHg,DBP 90+8/88+5 mm Hg).Five 24h urine specimens were collected by each individual w i t h i n a one mo n t h period. Intra-and interindividual v a r i a n c e s were calculated acco rding to Liu et al(Am J E p i d e m i o l , 1 9 7 9 ) . The e s t i mated ratio of intra- to interindividual variabili ty was 0.52 for men and 1.30 for women. Based on these numbers, 2 collections are needed to characterise Ca excretion in m e n and 5 in'womenv

Our data suggest a sex-related difference in uri nary Ca excretion; in particular, a significantly lower number of urine collections is needed for an. adequate characterisation of Ca excretion in men.

113511 SERUM A N D TISSU T A L CALCIUM IN GENE T I C A L L Y HYPERTENSIVE RATS OF THE MILAN STRAIN. M. C i r i l l o * . Inst. of Internal M e d i c i n e , 2nd M e d i c a l School,Univ. of N a p l e s , N a p l e s , Italy.

Genetically h y p e r t e n s i v e rats of the M i l a n strain (MHS) have higher urinary calcium (Ca) than n o r m o tensive control (MNS) rats despite of lower Ca bal a n c e . T h e present study investigated the Ca content in extracellular fluid and in different tissues of 8 m a l e two-month old M H S and 8 matched MNS rats. The serum concentration of total and ionized Ca, of albumin were measured on blood samples taken from carotid artery in anaerobiosis.The right femur,the right k i dney,the heart v e n t r i c l e s and a sample of abdominal skeletal m u s c l e were also taken , rapidly stripped of the attached soft tissue and wet ashed in hydrochloric acid to m e a s u r e Ca and protein content.

In comparison to M N S , M H S had not significantly different serum total and ionized Ca while their serum bound Ca (given by total m i n u s ionized C a ) was higher (p<.01) despite of normal serum albumin.Kidney and skeletal m u s c l e Ca content was slightly reduced(p= n.s.) i n M H S . T h e cardiac content of Ca and protein was h i g h e r in M H S : w h e n cardiac Ca was factored by cardiac protein no difference was found b e t w e e n M H S and M N S .

The results indicate that:i)MHS have normal Ca content in serum and soft tissues,the high cardiac Ca being infact secondary to cardiac h y p e r t r o p h y ; i i ) in keeping w i t h previous evidence of renal h y p e r c a l c i u -r i a a n d o f reduced Ca b a l a n c e , the bone Ca,which is the largest endogenous Ca p o o l , is reduced in M H S .

|1352|

REDUCED C A L C I U M BINDING CAPACITY IS AN INTRINSIC ABNORMALITY OF RED BLOOD CELL MEMBRANE IN SHR. M.Cirillo*,F.Cirillo,O.Russo.Inst. of Internal Medicine, 2nd Medical School_,Upiv. of N a p l e s , Italy.

Reduced calcium binding capacity is a widespread and primary abnormality in SHR. In red blood cell (RBC) membrane it is detectable only inmembrane homogenate consisting of sealed inside-out v e s i c l e s (I0V). T h e formation of sealed I0V implies the removal of c y t o -skeleton (CS) protein from RBC m e m b r a n e : the present study d e a l s with the Ca binding capacity of RBC m e m brane homogenates w i t h normal (MB+CS) and reduced (MB-CS) C S content in SHR and normotensive WKY r a t s .

In all m e m b r a n e homogenates SDS polyacrilamide slab gel electrophoresis was used to analyze the C S content,while previously reported m e t h o d s were u s e d for determination of pr o t e i n and cholesterol content, acetylcholinesterase activity (ACE) and Ca binding c a p a c i t y in the presence of submicromolar free Ca c o n c e n t r a t i o n s .

In M B - C S of both SHR and WKY,Ca binding capacity w a s higher than in MB+CS (p<.01) because of increased number and aff inity for Ca of binding sites;no sealed IOV was d e t e c t a b l e , ACE being similar before and a f t e r addition of Triton X 1 00. In comparison to WKY rats, MB-CS of SHR showed reduced number of Ca binding sites (p<.01 ) and normal affinity for Ca ions;no difference was observed between the strains using M B + C S . Similar data were found using 1 uM Ca ionophore (A231 8 7 ) . The results show-that CS affects m e m b r a n e Ca binding but that the reduced Ca binding capacity of SHR is due to an intrinsic membrane disorder.

|1353[

MEMBRANE CALCIUM BINDING IN HUMAN HYPERTENSION. M. C i r i l l o * & M . Laurenzi,on behalf of the Gubbio Study Collaborative Group. Inst. of Internal M e d i c i n e 2nd M e d i c a l School,Naples,Italy - Center for Epidemiological R e s e a r c h , M e r c k Sharp & D o h m e Italy.

Reduced membrane calcium (Ca) binding capacity is a primary and widespread abnormality in h y p e r tensive rats.The present study deals with the red blood cell (RBC) membrane Ca binding capacity of comparable groups consisting of never treated h y p e r tensives (untrHPT,n=12),patients on pharmacological treatment for hypertension (trHPT,n=12) and healthy normotensives (NT,n=12) screened in the course of an epidemiological study (Gubbio Study);only non obese 30-60 year old individuals were entered in the Ca binding analysis.RBC membrane Ca binding capacity was measured in vitro using submicromolar free Ca concentrations as previously described.

Independently of free Ca untrHPT membranes bound significantly less Cathan NT (p<. 04) ; trHPT had Ca binding capacity similar to that of untrHPT and significantly lower than that of NT at 40 nmol/L free Ca (p < . 0 2 ) .

The results indicate that, independently of treatment, human hypertension is associated w i t h an altered cell membrane Ca handling w h i c h could be important from a pathogenetic point of view.

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113541 RELATION BETWEEN HEMATOCRIT AND DIASTOLIC PRESSURE M. C i r i l l o * & M. L a u r e n z i , on b e h a l f of the Gubbio Study C o l l a b o r a t i v e G r o u p . I n s t , of I n t e r n a l Medicine 2nd Medical S c h o o l , N a p l e s , I t a l y - Center f o r E p i d e m i o l o g i c a l R e s e a r c h , M e r c k Sharp & Do hme I t a l y .

B a s e l i n e d a t a from a l o n g i t u d i n a l p o p u l a t i o n study on h y p e r t e n s i o n ( n = 5 , 3 7 6 ; r e s p o n s e r a t e = 8 4 % ) were used t o i n v e s t i g a t e among a d u l t p a r t i c i p a n t s (>_ 20 y e a r o l d ) the r e l a t i o n of h e m a t o c r i t (HCT) and i t s d e t e r m i n a n t s - red blood c e l l (RBC) count and RBC v o l u m e - w i t h d i a s t o l i c p r e s s u r e (DBP) c o n t r o l l i n g f o r s e x , age ,smoking h a b i t , a l c o h o l i n t a k e and body-mass i n d e x .

U n t r e a t e d h y p e r t e n s i v e s - def ined as having a DBP f a l l i n g in the h i g h e s t 20% f o r the s p e c i f i c s e x - and a g e - g r o u p - and p a r t i c i p a n t s t r e a t e d f o r h y p e r t e n s i o n had h i g h e r HCT than n o r m o t e n s i v e s (NT) independ e n t l y of confounders ( p < . 0 0 1 ) : among males t h i s was p r i m a r i l y due t o g r e a t e r RBC volume ( p < . 0 0 1 ) , a m o n g f e m a l e s t o g r e a t e r RBC count ( p < . 0 0 1 ) ; w h i t e blood c e l l and p l a t e l e t c o u n t s were comparable in h y p e r t e n s i v e s and N T . P o s i t i v e independent a s s o c i a t i o n s were found between HCT and DBP, and between HCT and p r e v a l e n c e of high DBP ( p < . 0 0 1 ) .

The r e s u l t s s u g g e s t t h a t HCT may c o n t r i b u t e t o DBP r e g u l a t i o n and t o the development of high DBP.

1 3 5 6

C O N T R A S T I N G R E N A L SODIUM HANDLING A F T E R A C U T E C A P T O P R I L ( C A ) A D M I N I S T R A T I O N IN N O R M O T E N S I V E I N S U L I N - D E P E N D E N T D I A B E T I C S (IDD) AND C O N T R O L S ( C ) . T . Hannedouche, A. Delgado, A. Gnionsahe, B. Lacour*, J.P. Griinfeld. Departement de Nephrologie et INSERM U90, Hopital Necker,Paris, France.

In 15 newly diagnosed normotensive EDD and 8 C, we compared before (b) and after acute sublingual 75 mg captopril administration the following parameters : glomerular filtration rate (GFR), renal vascular resistance (RVR), fractional sodium excretion (FE^a) and fractional proximal reabsorption of sodium ( F P R N 3 ) assessed from inulin, PAH, and lithium clearances. Results (mean ± SD) are :

GFR RVR F E N a F P R N a

(ml/min 1.73m2)(dym.sec/cm5) (xl03)

b 123±17 6,516 ± 623 16 ± 6 0.71 ± 0.04 C a 110 ± 15* 5,963 ± 7 3 5 22 ± 7 * * 0.67 ± 0.04*

b 149 ±22++ 5,852 ± 1,670 15 ± 2 0.79 ±0 .04+++ IDD a 136 ± 2 7 + + 5,426 ± 7 3 5 * 17 ± 6 0.78 ± 0.06*+++

* p>0.005, ** p>0.001 Ca vs b; + p>0.05, ++ p>0.01, +++ p>0.001 IDD vs respective C. Acute Ca administration slightly decreased GFR and RVR in C and in IDD. Ca increased FE]sjain C mainly due to decreased FPRN a. We conclude : 1) Ca induced a renal vasodilation in both C and IDD, probably related to predominant effect on postglomerular resistance, 2) Ca induced natiuretic effect in C but not in IDD, probably due to minimal reduction in angiotensin-dependent component of FPRNa.

113551 ROLES OF ANGIOTENSIN II (All) AND THROMBOXANE (Tx) IN 2K-1C RAT HYPERTENSION. W . II . Folger, C.S. Wilcox*, W. J. Welch, R. Cannizzaro. Div. of Nephrology and Hypertension, University of Florida, Gainesville, FL. Both the All and Tx systems are

stimulated in renovascular hypertension. Thu s , we examined their interaction in rats 2-3 weeks post-clip after pretreatment (pre-Rx) with a vehicle (V) or TSI (CGS-12,970; 50 mg/kg IP) for 3 days. After anesthesia animals received an IV infusion (Inf) of V, TSI or a Tx receptor antagonist (SQ-29,548; 8 m g / k g / h r ) . Thereafter, they received graded intravenous injections (Inj.) of ACEI (CGS-14,831; maximum dose LOO mg/kg) or its vehicle. Results for TxB excretion (pg/min) and change in MAP (mmHg) produced by the infusions and injections appear below (* ρ < 0 . 05) : Gp # Pre-Rx Inf Inj TxB Δ MAP 1 (9) V V V 38± 10 - 1 3 ± 4 2 (8) TSI TSI V 1 4±2* - 1 4±5 3 (9) V V ACEI 30±8 -36±4* 4 (L0) TSI TSI ACEI 8 ± 1 * -33+6* 5 (7) V SQ V 29±9 - 1 4 ± 6 Compared to V, only TSI lowered T x B 2

excretion but only ACEI lowered BP. The ACEI dose-response curve was unaltered by concurrent dosing with T S I . Conclusions: in the early phase of 2K-1C renovascular hypertension: 1) BP is strongly A l l -dependent, but independent of Tx; 2) there is no interaction between ACEI and TSI .

1 3 5 7

EFFECT OF NON-CHLORIDE SODIUM SALT ON BLOOD PRESSURE IN NORMOTENSIVE SUBJECTS

A . M . f i h a r m a f f i . S c h a t t e n f r o h , A . K r i b b e n , A . D i s t l e r . D e p t . o f M e d i c i n e ,

Klinikum S t e g l i t z , B e r l i n ( W ) , FRG

To t e s t t h e e f f e c t o f NaCl and a non-c h l o r i d e N a - s a l t ( N a - c i t r a t e , NaCt) on b l o o d p r e s s u r e i n p r e v i o u s l y c h a r a c t e r i z e d s a l t - s e n s i t i v e ( S S , n = 7 ) and s a l t - r e s i s t a n t ( S R , n = 8 ) n o r m o t e n s i v e s u b j e c t s , we a d m i n i s t e r e d 2 2 0 mmol Na e i t h e r a s NaCl o r a s NaCt f o r 1 week e a c h i n a p l a c e b o - c o n t r o l l e d s i n g l e -b l i n d c r o s s o v e r s t u d y .

In SS, NaCl i n c r e a s e d MABP by 5 . 6 ί 0 . 9 mmHg ( p < 0 . 0 0 2 ) , w h i l e MABP i n SR was n o t a f f e c t e d . NaCt f a i l e d t o r a i s e MABP i n e i t h e r SS o r SR. NaCl i n c r e a s e d mean u r i n a r y c a l c i u m e x c r e t i o n (UCaV) i n a l l s u b j e c t s from 3 . 5 ± 1 . 1 mmol/d t o 4 . 5 ± 0 . 9 ( p < 0 . 0 1 ) . With NaCt, UCaV d e c r e a s e d t o lower t h a n b a s a l l e v e l s ( 2 . 1 ± 0 . 4 , p < 0 . 0 1 ) . The e x c r e t i o n and plasma v a l u e s o f o t h e r e l e c t r o l y t e s w e r e u n c h a n g e d .

We c o n c l u d e t h a t : ( 1 ) NaCl r a i s e s BP i n SS w h i l e NaCt does n o t . ( 2 ) NaCl i n c r e a s e s UCaV i n b o t h SS and SR w h i l e NaCt does n o t . The e f f e c t o f NaCl on BP may t h e r e f o r e i n v o l v e an i n f l u e n c e on C a - h o m e o s t a s i s .

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1 3 5 8

INFLUENCE OF NON-CHLORIDE SODIUM SALT ON REPONSE TO ANGIOTENSIN I I (ANG I I )

INFUSION IN NORMOTENSIVE MEN

A.M.Sharma,S .Schat tenfroh, A . K r i b b e n , V . B a h r , W . O e l k e r s , A . D i s t l e r .

D e p t . o f M e d i c i n e , K l i n i k u m S t e g l i t z , B e r l i n ( W ) , FRG

To t e s t t h e r e l a t i o n s h i p between Ang I I , a l d o s t e r o n e ( A L D ) , r e n a l plasma f l o w ( R P F ) , and BP i n p r e v i o u s l y c h a r a c t e r i zed s a l t - s e n s i t i v e ( S S , n = 7 ) and s a l t -r e s i s t a n t ( S R , n = 8 ) n o r m o t e n s i v e s u b j e c t s i n g e s t i n g e i t h e r NaCl o r N a - c i t r a t e ( N a C t ) , we p e r f o r m e d Ang I I i n f u s i o n s ( 2 , 4 , 8 n g / k g / m i n ) a f t e r a d m i n i s t e r i n g 220 mmol Na e i t h e r a s NaCl o r NaCt f o r 1 week e a c h i n a p l a c e b o - c o n t r o l l e d s i n g l e b l i n d c r o s s o v e r s t u d y . Changes i n MABP (mmHg), A L D ( n m o l / l ) and R P F ( = C 1 P A H ? m l / m i n ) were m e a s u r e d . Mean v a l u e s a r e b e l o w : PARAMETER SS SR

NaCl NaCt P i NaCJ NaCt P i Δ MABP 1 8 . 9 * 2 0 . 6 * 1 4 . 0 1 4 . 8 1 0 . 7 1 0 . 3 Δ ALD 0 . 5 6 0 . 5 4 1 . 0 6 0 . 6 9 0 . 7 8 0 . 9 9 Δ RPF - 5 7 8 * - 4 9 0 * - 4 1 7 - 3 3 1 - 2 6 8 - 2 9 1

* p < 0 . 0 1 SS v s . SR We c o n c l u d e t h a t : ( 1 ) SS r e a c t t o Ang I I w i t h a g r e a t e r r i s e i n MABP and a g r e a t e r d e c r e a s e i n RPF t h a n SR, w h i l e c h a n g e s i n ALD a r e n o t d i f f e r e n t . ( 2 ) These c h a n g e s a r e t h e same w i t h NaCl and NaCt.

|1360| OPIOID MODULATION IN REGULATION OF CARDIOVASCULAR FUNCTION AND VASOPRESSIN SECRETION IN CONSCIOUS RATS. T. Yamada, K. Nakao*, H. I toh , Y. S a i t o , M. Mukoyama, H. Arai , K. Hosoda, G. Shirakami, S. Suga, N. Morii , A. Sugawara, S* Shiono, H. Imura. Second Division, Department of Medicine, Kyoto University School of Medicine, Kyoto 606, Japan.

Accumulating evidence suggests that endogenous opioid peptides are involved in the cardiovascular function and vasopressin (AVP) s e c r e t i o n . We previously reported that intracerebroventricular ( icv) injection of leumorphin, a /C-agonist derived from proenkephalin Β (neoendorphin/dynorphin precursor), decreases blood pressure and inhibits water intake and AVP secretion in' conscious, unres t r a i n e d r a t s . In t h i s study, we have examined the e f f e c t s of opioid a n t a g o n i s t , naloxone, on cardiovascular function and AVP secretion.

Male Wistar r a t s , weighing 240-280 g, were prepared with l e f t l a t e r a l v e n t r i c u l a r cannula, r i g h t jugular vein c a t h e t e r and r i g h t femoral artery catheter. All experiments were carried out under conscious and freely moving conditions.

I n t r a v e n o u s ( i v ) i n j e c t i o n of n a l o x o n e (0 .5 mg/kg) did not a l t e r basal blood pressure , but significantly increased basal AVP s e c r e t i o n . Naloxone i n j e c t i o n did not a f f e c t the pressor response induced by i cv i n j e c t i o n of Ang I I (100 n g ) , but prolonged the AVP s e c r e t i o n . However, naloxone s i g n i f i c a n t l y potent ia ted the pressor response and the AVP secretion induced by icv injection of carbachol (10 ng).

These r e s u l t s suggest that endogenous opioid peptides e x e r t an i n h i b i t o r y contro l of AVP s e c r e t i o n under both b a s a l and s t i m u l a t e d condit ions and play an important r o l e in the regulation of cardiovascular function in ra ts .

1 3 5 9

CHARACTERIZATION OF HUMAN ATRIAL NATRIURETIC POLYPEPTIDE (ANP) EXPRESSED IN C0S-7 CELLS FROM cDNA. K. Hosoda, K. Nakao*, H. A r a i , H. I t o h ; M. Mukoyama, A. Sugawara, T. Yamada, G. Shirakami, N. Morii , S. Shiono, N. Kitamura, H. Imura. 2nd Div., Dept. of Med., Kyoto Univ. Sch. of Medicine, Kyoto 606 , I n s t i t u t e for Liver Research, Kansai Medical Univ., Moriguchi 570, Japan.

Three d i s t i n c t molecular forms of ANP, γ-, β-, and α-human ANP (γ-, β-, and α-hANP) were isolated from the human atr ium. Recently , the possible coupling between the p o s t t a n s l a t i o n a l processing of ANP precursor , γ-hANP, and the s e c r e t o r y pathways, regulated and c o n s t i t u t i v e s e c r e t i o n s , is postulated. In the present paper, to elucidate biosynthesis and secretion of ANP in c e l l s solely with constitutive secretion, we introduced SV40-PBR322 expression vector containing human ANP cDNA into COS-7 c e l l s by transfection with the calcium phosphate precitation method. Northern blot analysis revealed a single band of hANP messenger RNA with the expected s i z e . Using two RIAs for Y-hANP[l-25] and for a-hANP (γ-hANPC99-126]), both y-hANP[ 1 - 2 5 ] - l i k e i m m u n o r e a c t i v i t y ( - L I ) and α-hANP-LI were detec ted in the c e l l e x t r a c t s and the c u l t u r e medium. Gel permeation s tudies coupled with these two RIAs of the the c e l l extracts showed that the main peak was γ-hANP and that α-hANP was detected as a minor peak. In the culture medium, γ-hANP-derived peptides consisted of three components, γ-hANP, N-terminal fragment of γ-hANP, and a-hANP. β-hANP was not detec ted either in the ce l l extract or in the medium.

These r e s u l t s i n d i c a t e that COS c e l l s t r a n s -fected with ANPcDNA secrete both γ-hANP and a-hANP Via the constitutive pathway.

[13611 EXPRESSION OF BRAIN NATRIURETIC PEPTIDE (BNP)-GENE IN HEART. K. Hosoda, K. Nakao*, H. A r a i , Y. S a i t o , H. I t o h , T. Yamada, M. Mukoyama, G. Shirakami, S. Suga, N. Minamino, K. Kangawa, H. Matsuo, H. Imura. Second Division, Department of Medicine, Kyoto Universi ty School of Medicine, Kyoto 606, Department of Biochemistry , Miyazaki Medical College, Miyazaki 889-16, Japan.

BNP is a new natr iuret ic peptide isolated from the porcine brain and has a s t r i k i n g homology in amino acid sequence with a t r i a l n a t r i u r e t i c peptide (ANP). In the present study, we inves t i gated expression of the BNP-gene in the porcine heart, since ANP is not only a cardiac hormone but also is recognized as a neuropeptide.

BNPcDNA was cloned from a cDNA l i b r a r y of the porcine atrium by hybridizat ion with an o l i g o nucleotide mixture representing the cDNA sequences predicted from N-terminus of porcine BNP. A Xhol-Notl fragment of BNPcDNA was labeled by random-primer method and used as a probe for Northern blot a n a l y s i s . Hearts were removed from p i g s , quickly frozen in liquid nitrogen at the slaughter house, and stored at -70°C u n t i l use. Total RNA was e x t r a c t e d using Acid-Guanidium Phenol Chloroform method. Forty pg of total RNA of each t i s s u e was denatured in g l y o x a l , loaded on an agarose gel, fractionated electrophoretically, and blot ted on a nylon membrane. A s ingle band of approximately 0.8 kb, which was the expected size , was detected in r ight and l e f t a t r i a . The rank order of the BNPmRNA level in the porcine heart was consistent with that of the tissue BNP concent ra t ion .

These r e s u l t s demonstrate that BNP gene i s expressed in the heart and suggest that BNP works as a cardiac hormone alone on in concert with ANP.

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113621 DIFFERENCE IN REGULATION OF ATRIAL NATRIURETIC POLYPEPTIDE (ANP)-GENE EXPRESSION BETWEEN ATRIUM AND VENTRICLE. H. Arai , K. Nakao*, Y. S a i t o , T. Yamada, H. I t o h , S. Shiono, M. Mukoyama, K. Hosoda, G. Shirakami, S. Suga, A. Sugawara, N. Morii , H. Imura. Second Divis ion, Department of Medicine, Kyoto Univers i ty School of Medicine, Kyoto 606, Japan.

We have reported that the expression of the ANP gene i s augmented in v e n t r i c l e s of SHR and SHR-stroke prone (SHR-SP) at the stage of established hypertension and v e n t r i c u l a r hypertrophy. In order to elucidate the difference in regulation of ANP-gene e x p r e s s i o n between the a t r i u m and v e n t r i c l e , we compared ANPmRNA l e v e l s in the atrium and ventricle of 11-week-old SHR-SP after nifedipine administration or water deprivation.

After the nifedipine administration for 5 weeks (from 6th to 11th week of age) , s y s t o l i c blood pressure (196 ± 6 mmHg, mean ± SE) and the r a t i o of v e n t r i c u l a r weight/body weight (3.82 ± 0.05%) were reduced compared with those of control SHR-SP (259 ± 9 mmHg, 4.40 ± 0.04%, p<0.01). The ANPmRNA level in the lef t ventricle of nifedipine-treated SHR-SP was approximately three times lower than that of control SHR-SP. There was no significant change in the a t r i a l ANPmRNA level.

After 3 days of water deprivation, no s i g n i f i cant change was observed in the v e n t r i c u l a r ANPmRNA level , although the a t r i a l ANPmRNA level in water -depr ivated r a t s was reduced to half of the control level.

These r e s u l t s i n d i c a t e that the expression of the ANP gene in the v e n t r i c l e i s c l o s e l y a s s o c i ated with hypertension and ventricular hypertrophy and that the regulation of the ANP-gene expression in the ventricle differs from that in the atrium.

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APPLICATION OF MONOCLONAL ANTIBODIES AGAINST ATRIAL NATRIURETIC POLYPEPTIDE (ANP) DIRECT SANDWICH ENZYME IMMUNOASSAYS FOR PLASMA α-, β- AND γ-ANP. Μ. Mukoyama, Κ. Nakao*, Τ. Yamada, Η. I t o h , Υ. S a i t o , Η. Arai , Κ. Hosoda, G. Shirakami, S. Suga, A. Sugawara, S. Hashida, E. Ishikawa, H. Imura. 2nd Div., Dept. of Med., Kyoto Univ. Sch. of Medicine, Kyoto 606, Dept. of Biochemistry , Miyazaki Medical College, Miyazaki 889-16, Japan.

Human c a r d i o c y t e s produce a family of a t r i a l natr iuret ic polypeptide (ANP) including γ-hANP, a-hANP, β-hANP and N-terminal fragment "N-peptide". We prepared f i v e monoclonal antibodies against d i f f e r e n t par ts of γ-hANP by fusion of a mouse myeloma c e l l l ine X63-Ag8.653 with spleen c e l l s from BALB/c mice immunized with α-hANP (y-hANP[99-1 2 6 ] ) , a-ANP[ 17 -28 ] (γ-ΑΝΡ[ 115-126]) , y-hANP[l-25] or y-hANP[75-98]. Three of. these are d i r e c t e d against α-hANP sequence: the N-terminal half of the ring structure, the N-terminal sequence, and the C-terminal sequence, respectively, of α-hANP. The fourth antibody is directed against y-hANP[l-2 5 ] , and the f i f t h against y-hANP[ 7 5 - 9 8 ] . All of them had high a f f i n i t i e s for t h e i r r e s p e c t i v e antigens (Ka = 1 0 1 0 - 1 0 1 1 M ~ 1 ) . Using these a n t i bodies in combination, we established specific and highly s e n s i t i v e sandwich enzyme immunoassays (EIAs) for ANP (peroxidase method). In the EIA f o r α-hANP, we could measure 0.01 fmol/ tube (0 .6 pg/ml plasma) of α-hANP without e x t r a c t i o n . EIAs for β- and γ-hANP were also highly sensitive (0.01 f m o l / t u b e ) , and we could d e t e c t plasma β- and/or γ-hANP in some c a s e s . These r e s u l t s i n d i c a t e that monoclonal a n t i b o d i e s a g a i n s t different parts of γ-hANP provide useful tools to investigate physiological and pathophysiological significance of γ-ΑΝΡ-derived peptides.

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PREPARATION OF POLYCLONAL AND MONOCLONAL ANTIBODIES FOR ENDOTHELIN APPLICATION FOR SPECIFIC RADIOIMMUNOASSAY Y. S a i t o , K. Nakao*^ T. Yamada, H. I toh , M. Mukoyama, H. Arai , K. Hosoda, G. Shirakami, S. Suga, H. Imura. Second Division, Department of Medicine, Kyoto University School of Medicine, Kyoto 606, Japan.

Analaysis of endothelin gene have revealed three d i s t i n c t molecular forms of endothelin, endothelin I, II and III(ET I, ET I I , and ET I I I ) . ET I and ET I I I correspond to the sequences of porcine and human ET and r a t ET, r e s p e c t i v e l y , identified previously. In order to elucidate the significance of ET in cardiovascular disorders, we have prepared polyclonal and monoclonal antibodies for ET and set up s p e c i f i c radioimmunoassays (RIAs) for ET. Two kinds of antisera (ET-M9, ET-M10) were prepared by immunizing BALB/c mice with synthetic ET I conjugated to bovine thyroglobulin using the carbodiimide coupling procedure. Radio-i o d i n a t i o n of ET I was c a r r i e d out by the chloramine Τ method. The f i n a l d i l u t i o n of both a n t i s e r a was 1 : 1 0 , 0 0 0 . In the RIA with ET-M9, values of I C - ^Q and I C ^ Q were 1.5 pg and 12 pg per tube, r e s p e c t i v e l y and, in the RIA with ET-M10, those were 1.0 pg and 8 pg per tube, respectively. Cross-reactivity with ET I I I in the RIA with ET-M9 was 50% on a molar basis and was 100% in the RIA with ET-M10. Neither RIA with ET-M9 nor ET-M10 recognized ET I [17 -21 ] . In addition, monoclonal antibody (KY-ET-I) was developed by fusion of mouse myeloma ce l l s with spleen ce l l s from immunized mice.

These r e s u l t s i n d i c a t e that these antibodies for ET become useful tools to investigate s i g n i f i cance of ET.

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PREPARATION AND CHARACTERIZATION OF MONOCLONAL ANTIBODIES TO ARGININE VASOPRESSIN. T.Yamada, K. Nakao*, M. Mukoyama, A. Sugawara, H. I t o h , Y. S a i t o , H. Arai , K. Hosoda, G. Shirakami, S. Suga, N. Morii , S. Shiono, H. Imura. 2nd Div., Dept. of Med., Kyoto Univ. Sch. of Med., Kyoto 606, Japan.

Monoclonal antibodies to arginine vasopressin (AVP) have been produced by fusion of a non-producing mouse myeloma c e l l l i n e , X63-Ag8.653, with spleen ce l l s from BALB/c mice immunized with s y n t h e t i c AVP conjugated to bovine thyroglobulin using the carbodiimide coupling procedure. Fusion was performed with 50 % polyethylene g l y c o l . Antibody-producing hybridomas were cloned by the limiting dilution technique, which resulted in the establishment of three d i s t i n c t monoclonal a n t i bodies, KY-AVP-I, KY-AVP-II and KY-AVP-III.

KY-AVP-I, I I and I I I belong to the I g G ^ I g G 2 a

and IgG^ s u b c l a s s , r e s p e c t i v e l y . All of them have high a f f i n i t i e s for AVP. Using these monoclonal antibodies, we have established the radioimmunoassay (RIA) for AVP. The RIA with KY-AVP-I showed c r o s s - r e a c t i v i t i e s of 0.3 % with oxytocin (OT) and 67 % with lysine vasopressin (LVP). Values of IC-^Q and I C ^ Q were 10 pg and 100 pg per tube. The RIA with KY-AVP-II had c r o s s - r e a c t i v i t ies of 1 % with OT and 100 % with LVP. Values of I C - ^Q and I C ^ Q were 2 pg and 12 pg per tube. In the RIA with KY-AVP-III, there was no c r o s s -reaction with OT and LVP. Values of I C 1 Q and I C ^ Q in t h i s RIA were 0.5 pg and 6 pg per tube. These antibodies were also a v a i l a b l e for immunohisto-chemistry and for neutralization experiment.

These r e s u l t s i n d i c a t e that monoclonal a n t i bodies to AVP provide useful t o o l s to e l u c i d a t e physiological and pathophysiological s i g n i f i c a n c e of AVP.

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DOES REPETETIVE MYOCARDIAL ISCHAEMIA DURING CORONARY ANGIOPLASTY STIMULATE ANF RELEASE?

R Dietz, Ε Will, Μ Haass. Dept. of Cardiology, University of Heidelberg, FRG.

A stimulated ANF release during myocardial ischaemia could represent a cardioprotective mechanism because of a cardiac unloading effect. In 14 patients who underwent coronary angioplasty of a single stenosis, plasma ANF concentrations were determined and pulmonary artery pressures were recorded during the procedure. Basal values were compared with those following periods of 3Q and 60 sec of coronary occlusion. The procedure was repeated after administration of diltiazem (2 mg i.e.) in order to evaluate the possible inhibition of stimulated ANF release by calcium antagonists. In the total group there were no changes in ANF plasma concentrations following short lasting regional ischaemia. In a subgroup of 8 patients characterized by a. rise in pulmonary artery pressure » 5 mmHg above basal values ANF concentrations rose progressively (from 156+30 to 18U34 pg/ml) . In contrast ANF values were not af fected in the remaining 6 patients who did not show a significant rise in pulmonary artery pressure. For all patients a significant linear relationship existed between pulmonary artery pressure and ANF values (r= 0.53, p«0.0l) . In conclusion, short lasting re gional myocardial ischaemia itself does not represent a sufficient stimulus for a stimulated ANF release,- under these conditions no inhibitory effect of the calcium antagonist diltiazem on ANF release could be established.

PARATHYROID HORMONE (PTH) AND CARDIOVASCULAR EFFECTS OF DIHYDROPIRIDINES (DHP) . G.M.LONDON, P.SASSANO, M.E.SAFAR.Centre de Diagnostic. Hopital Broussais, PARIS,FRANCE.

In vitro studies Remonstrated that parathormone augments calcium entry into heart cells, increasing their beating rates and impairing their energy production, storage and utilization. Clinical and experimental studies showed that hyperparathyroidism (HPTH) in end-stage renal failure (ESRF) is associated with an increased blood pressure (BP), heart rate (HR) and myocardial oxygen consumption (MV02). We studied in 20 hypertensive ESRF patients the influence of parathyroid activity on cardiovascular response to DHP derivatives (Nicardipine-NI,90 mg per day for 4 weeks). Before the treatment HPTH was estimated on the basis of serum PTH, and bone histomorphometry (number of osteoclasts -NO, and osteoclastic resorption sur-faces-ORS). NI induced a significant decrease in systolic (SAP) and diastolic (DAP) arterial pressure, but did not change significantly the HR or MV02 (SAPxHR product). Changes in SAP and QDAP were correlated to baseline serum PTH (p=0.001), to NO (p=0.008), and to ORS (p=0.002). Furthermore the significant decrease in blood pressure was observed only in patients with histologically evident HPTH (ORS 1%) (198/106 + 22/11 to 163/85 + 16/11 mmHg;p 0.01). In this subset, Ni treatment induced a significant decrease in HR (p 0.05) and MV02 (from 16410+2460 to 13506+1035; ρ 0.02). Our data are the firts to show that blood pressure response to DHP in ESRF is related to parathyroid activity as judged from serum PTH and bone histomorphometry. In ESRF with secondary HPTH the DHP derivatives normalize blood pressure and significantly decrease myocardial oxygen consumption.

11368| ATRIAL NATRIURETIC PEPTIDE-mRNA IN PATIENTS WITH LEFT-SIDED VALVULAR HEART DISEASE

Μ Haass, ThA Fischer, J Hanze, W Saggau, RE. Lang, R Dietz.

Dept. of Cardiology, Pharmacology and Cardiac Surgery, University of Heidelberg, Heidelberg, FRG

The regulation of atrial natriuretic peptide (ANP) synthesis within cardiac atrial myocytes was investigated in patients with chronically elevated plasma ANP concentrations. In 8 patients with left-sided valvular heart disease undergoing cardiac surgery for valve replacement hemodynamic data were obtained during cardiac catheterization and venous plasma samples for ANP (measured by RIA) were withdrawn prior to surgery. Tissue probes for determination of tissue ANP levels (measured by RIA) and ANP-mRNA (determined by Northern blotting) were taken from the right atrium after thoracotomy. Both plasma ANP (r=.74, p«.05) and ANP-mRNA (r=.87, p«.0l) were positively correlated with mean pulmonary artery pressure. ANP-mRNA was also related to plasma ANP (r=.62 ( p«.04). However, no correlation was obtained between ANP-mRNA or plasma ANP concentrations and tissue ANP levels. We conclude, that central hemodynamics determine not only release of ANP from the heart but also ANP synthesis in cardiac atrial myocytes. Furthermore, ANP synthesis was found to be independent of atrial tissue ANP levels.

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R E G I O N A L AND S U B C E L L U L A R DISTRIBUTION OF CLONIDINE-DISPLACING SUBSTANCE IN BRAIN. MP Meeley*. LK Char, Ρ Emsberger*, DJ Reis*. Division of Neurobiology, Cornell University Medical College, New York, NY. Clonidine-displacing substance (CDS) is a low-molecular-weight substance in brain defined by displacement of 3H-p-aminoclonidine ( 3H-PAC) binding to brain membranes. CDS also elicits contraction of rat gastric fundus (GF). We sought to determine whether CDS is (a) differentially distributed among brain regions, and (b) contained in a subcellular fraction enriched with synaptosomes. Regional distribution of CDS was determined by 3 H-PAC radioreceptor assay (Ernsberger et al., Brain Res 441 : 309, 1988). Methanol extracts of 8 dissected regions of fresh bovine brain were prepared (Meeley et al., Life Sci 38: 1119, 1986); the amount of extract giving 50% inhibition of InM 3 H-PAC binding was defined as lUnit of CDS. CDS was heterogeneously distributed in brain. Highest levels were obtained in hypothalamus > brainstem (dorsomedial and ventrolateral) > midbrain (4-26Unit/g wet wt). Frontal cortex and striatum also contained measurable levels of CDS (~4Unit/g), whereas the vermis of cerebellum and corpus callosum gave values which were not significant compared to nonspecific binding (<2Unit/g). Subcellular distribution of CDS, specifically within nerve terminals, was also determined. A P 2 fraction of brain was osmotically shocked with 7.5vol water, and the soluble fraction further purified in parallel with brain supernatants (Meeley et al., Neurosci Lett 84: 84, 1988). CDS was present in P 2 fractions, as measured by 3 H-PAC radioreceptor assay (1 and 3Unit/g brain for P 2 and supernatant, respectively) and by GF bioassay (lUnit elicited 38 + 4% standard maximal contraction, compared to 41 + 5 % for supernatant). We conclude that CDS is heterogeneously distributed in brain, and that bioactive CDS is released from a synaptosome-enriched fraction of bovine brain by osmotic shock, suggesting it is present in nerve terminals. Hence, CDS may be a novel neurotransmitter or modulator which participates in central regulation of arterial pressure.

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A D R E N A L C H R O M A F F I N C E L L S E X P R E S S CLONIDINE-SPECIFIC I M I D A Z O L E R E C E P T O R S W H I C H B I N D A N E N D O G E N O U S C L O N I D I N E - D I S P L A C I N G S U B S T A N C E . P. Ernsberger*, G. Feinland, MJ. Evinger, M.P. Meeley*, DJ. Reis* Division of Neurobiology, Cornell University Medical College, New York, NY 10021

Clonidine binds not only to a2-adrenergic receptors but also to imidazole sites which are distinct from adrenergic and histaminergic receptors and are localized in medulla oblongata (Ernsberger et al., Eur J Pharmacol 134:1 '87) and in kidney (Ernsberger et al., Am. J Hypertension 1:30A '88). Since clonidine inhibits catecholamine release from adrenal chromaffin cells by a non-adrenergic mechanism .(Powis & Baker, Mol Pharmacol 29:134 '86), we sought to determine whether bovine chromaffin cells express clonidine-specific imidazole sites. Chromaffin cells were isolated by enzymatic digestion and differential sedimentation. Membranes (P2 fraction) were incubated (40 min, 25°C) with the high-affinity clonidine analog 3H-/?-aminoclonidine (3H-PAC) prior to vacuum filtration. Phentolamine (10 μΜ) defined nonspecific binding. Specific high-affinity 3H-PAC sites were abundant in chromaffin cell membranes (Bmax = 3 ± 1 pmol/mg protein; KD = 9 ± 2 nM). Adrenergic agents with imidazole rings, e.g. PAC and phentolamine, completely and potently inhibited 3H-PAC binding, whereas non-imidazoles such as epinephrine, phenylephrine, and SKF-86466 were inactive (IC50 > 1 mM). Imidazoles lacking adrenergic potency, such as cimetidine and imidazole-4-acetic acid, exhibited high affinity for 3H-PAC sites (IC50 < ΙΟμΜ). Brain extracts containing clonidine-displacing substance (CDS), the putative natural ligand for imidazole receptors, inhibited 3H-PAC binding with high affinity (K, = 0.21 ± 0.04 Units). We conclude that clonidine binds to imidazole but not cc2-adrenergic receptors in adrenal chromaffin cells. These sites may mediate the adrenal medullary actions of clonidine and CDS may be their endogenous ligand.

11373| BRAIN NATRIURETIC PEPTIDE (BNP) AND ATRIAL NATRIURETIC PEPTIDE (ANP) SYSTEMS FOR DUAL INHIBITORY PEPTIDERGIC MECHANISM IN CENTRAL CARDIOVASCULAR CONTROL. K. Nakao*, H. I t o h , T. Yamada, G. Shirakami, Y. S a i t o , M. Mukoyama, H. Arai , K. Hosoda, S. Suga, N. Minamino, K. Kangawa, H. Matsuo, H. Imura. Second Division, Department of Medicine, Kyoto Univers i ty School of Medicine, Kyoto 606 and Department of Biochemistry, Miyazaki Medical College, Miyazaki 889-16, Japan.

BNP i s a novel n a t r i u r e t i c peptide i s o l a t e d from the pig b r a i n and has a high sequence homology to ANP. In order to e l u c i d a t e the possible physiological significance of BNP in the c e n t r a l control of body fluid and cardiovascular funct ion , we have i n v e s t i g a t e d the regional d i s t r i b u t i o n of BNP in the .bra in using s p e c i f i c radioimmunoassay (RIA) for porcine BNP, and the effects of intracerebroventricular ( icv) injection of BNP in conscious , unrestrained r a t s . Our RIA detected immunoreactive BNP in the porcine and canine bra ins , but no immunoreactivity in r a t , human or monkey brain. The regional distribution of BNP in the brain differed from that of immunoreactive ANP, suggesting the existence of the BNP neuronal system d i s t i n c t from the ANP neuronal system.

The i cv i n j e c t i o n of BNP in conscious , unres t r a i n e d r a t s at tenuated water i n t a k e , pressor response and vasopressin secretion induced by the i cv i n j e c t i o n of angiotensin I I , with potencies comparable to those of ANP.

These r e s u l t s suggest the presence of a dual inhibitory mechanism of BNP and ANP in the central control of fluid and electrolyte balance and blood pressure.

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INCREASED PLASMA N E U R O P E P T I D E Y AND CARDIOVASCULAR RESPONSES TO STRESS IN MALE RATS. Z. Z u k o w s k a - G r o j e c , C A . Vaz, G.H. Shen, P.A. Capraro, D.S. Goldstein and H.R. Keiser. Department of Physiology & Biophysics, Georgetown University Medical Center, Washington, D.C.

The greater prevalence of ischemic heart disease and hypertension in males than in females may be related to exaggerated cardiovascular and sympafho-adrenomedullary (SA) responses to stress. Weight-matched, sexually mature male and female rats with indwelling catheters were subjected to stress of handling + novelty (H+N) or COLD (4°C water on cage floor). At rest there were no sex differences in blood pressure and plasma levels of neuropeptide Υ (NPY-immunoreactivity, -ir, RIA) - a putative sympathetic co-transmitter and a vasoconstrictor - whereas resting plasma levels of norepinephrine (NE), epinephrine (EPI) and 3,4-dihydroxyphenylglycol (DHPG, a NE metabolite) were higher in females (by 80, 83, and 108%) - suggesting higher SA activity. H+N stress increased blood pressure, heart rate, and plasma NE and DHPG only in males. Pressor, tachycardic, and plasma NE responses of males to COLD exceeded those of females (by 10, 15, and 70%), whereas increments in plasma EPI and DHPG were similar - indicating that greater sympafho-neural activation and relatively lesser NE inactivation in males may both contribute to their enhanced cardiovascular stress responses. During recovery from stress males had a 2-fold increase in plasma NPY-ir associated with protracted hypertensive response, whereas females had neither of them. Thus, females appear to have higher SA activity at rest but decreased cardiovascular and SA responses to stress. Since NPY causes potent and prolonged vasoconstriction (especially in coronary, cerebral and splanchnic vascular beds), greater release of NPY during stress in males may contribute to their increased risk of myocardial ischemia, stroke and hypertension.

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BRAIN NATRIURETIC PEPTIDE (BNP) IS A NOVEL CARDIAC HORMONE. Y. S a i t o , K. Nakao*, T. Yamada, H. I t o h , M. Mukoyama, H. Arai , K. Hosoda, G. Shirakami, K. Nishino, N. Minamino, K. Kangawa, H. Matsuo, H. Imura. 2nd Div., Dept. of Medicine, Kyoto Univ., Sch. of Medicine, Kyoto, Dept. of Biochemistry , Miyazaki Medical College, Miyazaki, Japan.

BNP i s a 26-amino acid peptide i s o l a t e d from the porcine brain and has a high sequence homology to α - a t r i a l n a t r i u r e t i c peptide (α-ANP). In the present study, to elucidate whether or not BNP is synthesized in and secreted into circulation from the h e a r t , we have measured l e v e l s of BNP-like immunoreactivity (-LI) in extract of the porcine h e a r t , in perfusate from the i s o l a t e d porcine heart and in porcine plasma using radioimmunoassay. BNP-LI was detected in the extract of the atr ium, though no d e t e c t a b l e amount of BNP-LI (more than 1 ng/g) was present in the v e n t r i c l e . The BNP-LI level in the porcine atrium was 148.7± 23.3 ng/g. BNP-LI was also detected in the perf u s a t e from the hear t . Basal s e c r e t o r y r a t e of BNP was 3.18±0.76 ng/min. Moreover, BNP-LI was detected in porcine plasma at the concentration of 4 .2±1 .3 pg/ml. Gel f i l t r a t i o n studies showed that BNP i s present in the atrium as a large molecule and is secre ted into the c i r c u l a t i o n as a small molecule. The percentage of BNP-LI to ANP-LI was almost the same among the ext rac t , the perfusate and the plasma ( 2 - 3 p e r c e n t ) . BNP-LI was a l s o present in the e x t r a c t and perfusate from the canine heart as well as from the porcine heart.

These results indicate that BNP is synthesized in and i s secre ted into the c i r c u l a t i o n from the heart and suggest that BNP plays an important role in fluid-volume and c a r d i o v a s c u l a r homeostasis alone or together with ANP.

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EVIDENCE FOR DETERRENT ACTION OF ENDOGENOUS ATRIAL NATRIURETIC POLYPEPTIDE (ANP) IN HYPERTENSION EFFECTS OF ANP MONOCLONAL ANTIBODY IN SHR AND DOCA-SALT RATS. H. I t o h , K. Nakao*, M. Mukoyama, T. Yamada, Y. S a i t o , S. Shiono, H. Arai , K.Hosoda, G. Shirakami, S. Suga, H. Imura. 2nd Div., Dept. of Med., Kyoto Univ. Sch. of Med., Kyoto 606 Japan

To e l u c i d a t e the pathophysiological r o l e of augmented secretion of ANP in the development of hypertension, we examined the effect of both acute and chronic administrations of monoclonal antibody against ANP (MoAb-ANP) in SHR-stroke prone (SHRSP) and DOCA-salt r a t s . Weekly intravenous administrations of MoAb-ANP significantly elevated blood pressure of SHR-SP, compared with c o n t r o l SHR-SP (182 ± 2 mmHg for MoAb-ANP vs. 162 ± 2 mmHg for c o n t r o l , 7-week-old, p<0.05), while MoAb-ANP i n j e c t i o n s had no e f f e c t on blood pressure of normotensive Wistar Kyoto ra ts . Chronic blockade of c i r c u l a t i n g ANP r e s u l t e d in the s i g n i f i c a n t shortening of the l i f e - s p a n of SHR-SP by about 2 weeks. The intravenous bolus a d m i n i s t r a t i o n of MoAb-ANP caused the significant elevation of basal mean blood pressure of SHR-SP by 13 ± 2 mmHg with the concomitant reduction of the elevated plasma c y c l i c GMP level (13 ± 1 pmol/ml before the inject ion; 8.1 ± 0.2 pmol/ml after the injection, p<0.05) . Chronic r e p e t i t i v e i n j e c t i o n s of MoAb-ANP also significantly accelerated the development of hypertension in DOCA-salt r a t s (189 ± 5 mmHg for MoAb-ANP vs. 173 ± 4 mmHg for control, 4 weeks a f t e r the t r e a t m e n t , p<0.05) a s s o c i a t e d with the reduced plasma cycl ic GMP level (4 ± 2 pmol/ml for MoAb-ANP vs. 12 ± 2 pmol/ml for control, p<0.05).

These r e s u l t s s u g g e s t t h a t augmented ANP secretion in hypertension could represent an ant i hypertensive deterrent mechanism.

|1377| THE VENTRICLE IS A MAJOR SECRETORY ORGAN OF ATRIAL NATRIURETIC POLYPEPTIDE (ANP) IN SPONTANEOUSLY HYPERTENSIVE RATS-STROKE PRONE (SHR-SP). G. Shirakami, K. Nakao*, Y. S a i t o , A. Sugawara, T. Yamada, H. I toh , M. Mukoyama, H. Arai , K. Hosoda, N. Morii , S. Shiono, K. Mori, H. Imura. Departments of Medicine and Anesthesiology, Kyoto University School of Medicine, Kyoto 606, Japan.

Plasma ANP concentrations are elevated in SHR and i t s s u b s t r a i n , SHR-SP, and ANPmRNA and ANP levels in their ventricles are markedly increased compared with those in contro l WKY. In order to c lar i fy whether or not the ventricle secretes ANP, we studied ANP s e c r e t i o n from i s o l a t e d perfused hearts of adult male WKY, SHR and SHR-SP (24-30W) by Langendorff method. After the whole heart was perfused for 90 min, the atrium was s u r g i c a l l y removed. The e f f l u e n t s from the perfused whole heart and from the v e n t r i c l e were c o l l e c t e d and ANP l e v e l s were measured by RIA. The ANP s e c r e tory r a t e s from the whole hear ts of WKY, SHR and SHR-SP were 1.99 ± 0.4, 2.34 ± 0.2 and 3.05 ± 0.2 ng/min (mean ± S.E.), respectively, and decreased to 0.08 ± 0 .02, 0.27 ± 0.06 and 2.06 ± 0.27 ng/min 30 min a f t e r the a t r i a l r e m o v a l . The ANP secretory rates of the ventricle were, therefore, 4.4 ± 0 .9 , 11.5 ± 2.5 and 68.2 ± 7.3% of those of whole hear ts in these 3 s t r a i n s . In the gel f i l t r a t i o n study, the major secretory form of ANP from whole hearts and ventricles of the 3 strains was a low molecular weight form of ANP, α-rat ANP.

These results demonstrate that the ventricle is a s i g n i f i c a n t s o u r c e of c i r c u l a t i n g ANP, especially in SHR-SP, at the stage of established hypertension and v e n t r i c u l a r hypertrophy and suggest the pathophysiological importance of ventr icular ANP.

[13761

PREPARATION AND APPLICATION OF MONOCLONAL ANTIBODIES FOR BRAIN NATRIURETIC PEPTIDE (BNP). H. I t o h , K. Nakao*, M. Mukoyama, Y. S a i t o , T. Yamada, G, Shirakami, H. Arai , K. Hosoda, S. Suga, H. Imura. 2nd Div., Dept. of Medicine, Kyoto Univ. Sch. of Medicine, Kyoto 606, Japan.

Two monoclonal antibodies (MoAbs) for BNP, KY-BNP-I and KY-BNP-II, have been produced by fusion of a nonproducing mouse myeloma c e l l l i n e , X63-Ag8.653, with spleen c e l l s from BALB/c mice immunized with synthetic porcine BNP conjugated to bovine thyroglobulin . Analysis by a sca tchard p l o t d e m o n s t r a t e d t h a t both MoAbs f o r BNP possessed high a f f i n i t y for BNP. with Ka of 4.0 χ 10 9 Μ"1 (KY-BNP-I) and 2.0 χ 1 0 1 0 M"1 (KY-BNP-II). With these MoAbs, s p e c i f i c radioimmunoassays (RIAs) for BNP have been e s t a b l i s h e d . The l e a s t d e t e c t a b l e q u a n t i t i e s of BNP were as l i t t l e as 5 pg/tube (KY-BNP-I) and 1 pg/tube (KY-BNP-II). These RIAs exhibited c r o s s - r e a c t i v i t i e s of 55% (KY-BNP-I) and 33% (KY-BNP-II) with BNP-32, another form of endogenous BNP in the porcine brain. Cross-react ivi t ies of α-human and rat ANPs were less than 0.001 %. These RIAs detected BNP-l ike immunoreactivity not only in the porcine brain but also in the canine brain , with the highest concentra t ion in the medulla oblongata, one of the c r u c i a l regions for c e n t r a l c a r d i o vascular control. The intravenous pretreatment of purified MoAb[KY-BNP-II] almost completely blocked the hypotensive a c t i o n of the intravenous in jec t i o n of BNP in r a t s , wi th the c o n c o m i t a n t suppression of BNP-induced i n c r e a s e of plasma cycl ic GMP level. These results indicate that our MoAbs for BNP will serve as a useful tool for the elucidation of the pathophysiological significance of BNP.

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DEVELOPMENT OF MONOCLONAL ANTIBODIES AGAINST RECEPTORS FOR ATRIAL NATRIURETIC PEPTIDE (ANP). S. Suga, K. Nakao*, M. Mukoyama, T. Yamada, H. I toh , Y. S a i t o , H. Arai , K. Hosoda, G. Shirakami, H. Imura. Second Division, Department of Medicine, Kyoto Univers i ty School of Medicine, Kyoto 606, Japan.

In order to e l u c i d a t e h e t e r o g e n e i t y , t i s s u e speci f ic i ty and signal t ransduct ion of r e c e p t o r s for a t r i a l n a t r i u r e t i c peptide (ANP), we have developed monoclonal antibodies for ANP receptors. Monoclonal antibodies have been produced by fusion of a mouse myeloma c e l l l ine X63-Ag8.653 with spleen ce l l s from BALB/c mice immunized with 140 K-Da dimetric receptors for ANP purified from the bovine lung. Hybridoma grew in n e a r l y 90% ( 5 2 0 / 5 7 6 ) of the w e l l s . Culture media were screened for t h e i r a b i l i t y either to precipitate

I-ANP-receptor complexes or to i n h i b i t the binding of ANP to r e c e p t o r s . A n t i - r e c e p t o r antibody-producing c e l l s were recognized in 8% ( 4 2 / 5 2 0 ) of these w e l l s . After the primary secreening , seven monoclonal ant ibodies with d i f f e r e n t s p e c i f i c i t i e s were obtained. Five of them i m m u n o p r e c i p i t a t e d I - A N P - r e c e p t o r complexes and the remaining two inhibi ted the binding of ANP to r e c e p t o r s . These c e l l s were cloned and grown as a s c i t i c tumor. Ascit ic fluids contained monoclonal antibodies with high t i t e r s (precipitators 1 : 1 0 6 " 7 ; inhibitors 1 : 1 0 4 " 5 ) .

These monoclonal antibodies for ANP r e c e p t o r s become powerful tools to elucidate the heterogenei t y and s ignal t ransduct ion of ANP r e c e p t o r s and to establish the model of ANP receptor disease.

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113791 CHRONOBIOLOGICAL INVESTIGATION OF CIRCADIAN RHYTHMS FOR TOTAL RENIN AND ACTIVE RENIN CONCENTRATIONS IN CLINICALLY HEALTHY YOUNG SUBJECTS. Τ Kawasaki*, Ρ Cugini, Κ Uezono* and Κ Itoh. Institute of Health Science, Kyushu Univ., Kasuga, Fukuoka, Japan.

This study has been performed in order to assess the circadian rhythmicity of the renin-angiotensin-aldosterone system by measuring the time-qualified changes of total renin (TRC) and active renin concentrations(ARC). The study has been extended to plasma renin activity (PRA) and plasma aldosterone concentration (PAC) for a confirmation of previous findings.

Clinically healthy 6 male and 6 female subjects, 20 to 25 years of age, volunteered for this study. Time-qualified data series have been analysed by means of chronobiological procedures in order to derive rhythmometric parameters, to compute the AESOR, a parameter that estimates the area underlying periodic oscillation, and to correlate the sinusoidal curves.

Significant circadian rhythms were validated for TRC, ARC, PRA and PAC. The periodic oscillations were seen to be significantly correlated, indicating that TRC, ARC, PRA and PAC fluctuate in phase during the 24-hour span.

The AESOR for TRC was found to be 8 times greater than that for ARC, suggesting that the inactive renin accounts for more than 80% of the total renin 24-hour periodic secretion. No sex-related differences were observed.

Accordingly, the above-mentioned conclusion can be applied to young subjects without relating to gender.

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ALTERATIONS IN THE CENTRAL ANF-SYSTEM OF RATS WITH ONE-KIDNEY, ONE-CLIP AND TWO-KIDNEY, ONE-CLIP RENAL HYPERTENSION Udo Bahner, Helmut Geiger, Miklos Palkovits*, Detlev Ganten** and August Heidland University of Wurzburg, Dept. of Medicine, D-8700 Wurzburg, *Semmelweis University, Med. School, H-1450 Budapest, **Uni-versity of Heidelberg, Dept. of Pharmacology, D-6900 Heidelberg

Atrial natriuretic peptides (ANF) in the brain are involved in the regulation of blood pressure (B.P.) and electrolyte and fluid homeostasis (EFH). To investigate a possible role of the central ANF-system in renal hypertension we have measured the concentration of ANF by radioimmunoassay in 18 selected brain areas of the volume-dependent 1K1C - and the renin-dependent 2K1C - renal hypertension and their controls (1K-C resp. 2K-C).

The most important results are summarized in the table:

Brain areas 1K-C 1K1C 2K-C 2K1C OVLT 83 20** 107 39** Preoptic periv. nucl. 360 460* 350 134*** Supraoptic nucl. 20 55* 32 65* Paraventric. nucl. 145 226*** 154 174 Med. eminence 171 359*** 154 92** Locus coeruleus 69 122** 81 82 NTS 74 20** 54 53

Values are pg ANF/mg protein.*= ρ 0.05,**=p 0.01,***= ρ 0.001

The alterations of ANF-concentration in various brain areas known to be involved in BP- and EFH-regulation strengthen the idea that ANF is an important modulator in these physiological mechanisms. The fact that ANF is changed in the opposite direction in 1K1C- and 2KlC-hypertensive rats indicates a certain correlation with the renin-angiotensin system.

[13801

EFFECTS OF TENNIS TRAINING ON BLOOD PRESSURE AND OTHER RELATED VARIABLES IN BORDERLINE HYPERTENSIVES. K. Uezono*, T. Kawasaki*, M. Tokunaga and K. Hashimoto. Inst, of Health Science, Kyushu Univ., Kasuga, Fukuoka, Japan.

We reported the effects of light sports training on blood pressure(BP) and other related variables in borderline hypertensives. (AJH 1: 30A, 1988) In this study tennis training was applied and effects on those variables were assessed in 10 normotensive (NT) and 8 borderline hypertensive (BHT) subjects.

Eighteen subjects, 11 men and 7 women, 63.3 ±9.4 (mean i SD) years of age, had 90-min tennis classes twice a week for 3 months.

After 3 months, they showed better flexibility. Their body weight did not change, skinfold at back and percent body fat significantly decreased. Vital capacity increased slightly and significantly. BP did not change significantly (NT: 126± 13/77±8mmHg-> 133 1 15/73 f 5 mmHg; BHT: 144+ 3/81 + 7mmHg > 141 t 13/77 l 13 mmHg). Hemoglobin Al and Ale (p<0.001), LDL cholesterol and apolipo-AH decreased markedly. HDL cholesterol and plasma Cortisol (p<0.01) increased significantly in all subjects after 3 months. Anxiety scores estimated by Spielberger 1s inventory and so on, showed significant decrease (p<0.01).

Systematic and regular tennis training at mild intensity had no accident, and significant improvements were shown in physical, biochemical, hormonal and psychological parameters, as previously reported. By having fun, light sports including tennis are good events to keep subject's motivation to continue exercise, which is usually difficult to do.

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CONTRAST M E D I A INDUCED ACUTE RENAL F A I L U R E (CARF)—PROTECTIVE A C T I O N OF A T R I A L N A T R I U R E T I C P E P T I D E ( A N P ) K. S c h a f f e r h a n s , U. B a h n e r , H. G e i g e r , E . P . L a n d w e h r * , J . S t r o h m e i e r , A . H e i d l a n d U n i v e r s i t y o f W u r z b u r g , D e p t . o f N e p h r o l o g y a n d * D e p t . o f R a d i o l o g y , F R G - 8 7 0 0 W u r z b u r g

T h e p r e s e n t s t u d y w a s d e s i g n e d t o i n v e s t i g a t e t h e p r o t e c t i v e a c t i o n o f ANP i n C A R F . I n t h i s s t u d y we u s e d f e m a l e S p r a g u e - D a w l e y r a t s . A f t e r r e m o v a l o f t h e r i g h t k i d n e y a n d c l a m p i n g o f t h e l e f t r e n a l a r t e r y o v e r a p e r i o d o f 20 m i n u t e s i n f u s i o n s t u d i e s w e r e p e r f o r m e d . I o p a m i d o l e ( I O P ) a n d ANP w a s i n f u s e d i n t r a v e n o u s l y a t 2 g p e r h o u r (90 m i n u t e s ) a n d 10 ug / k g b . w . / h (60 m i n u t e s ) , r e s p e c t i v e l y . I n g r o u p 1 r a t s r e c e i v e d IOP s o l e l y ( c o n t r o l s , C O ) , i n g r o u p 2 a n d 3 ANP w a s i n f u s e d a f t e r o r b e f o r e t h e t o x i c i n s u l t . GFR, u r i n a r y f l o w ( V ) , e l e c t r o l y t e e x c r e t i o n , r e n a l b l o o d f l o w a n d a r t e r i a l b l o o d p r e s s u r e w a s m e a s u r e d .

IOP i n d u c e d a n o n - o l i g u r i c C A R F . A f t e r t h e t o x i c i n s u l t ANP i n f u s i o n i n d u c e d a n i n c r e a s e o f GFR i n g r o u p 2. I n g r o u p 3 GFR e x c e e d e d b a s a l v a l u e s a n d r e m a i n e d e l e v a t e d o v e r t h e w h o l e p e r i o d o f t h e e x p e r i m e n t , i n s p i t e o f IOP i n f u s i o n .

IOP h a s b e e n c i t e d t o i m p a i r e r e n a l f u n c t i o n a n d d e c r e a s e s r e n a l b l o o d f l o w . T h i s may b e , a t l e a s t i n p a r t , m e d i a t e d by a c t i v a t i o n o f i n t r a r e n a l r e n i n - a n g i o t e n s i n - s y s t e m . ANP a n t a g o n i z e s - the a c t i o n o f a n g i o t e n s i n I I a n d n o r e p i n e p h r i n e on r e n a l v a s c u l a t u r e a n d g l o m e r u l a r c e l l s , i n c r e a s e s t h e g l o m e r u l a r s u r f a c e a r e a a v a i l a b l e f o r u l t r a f i l t r a t i o n a n d h e n c e i n c r e a s e s K f . T h e s e a c t i o n s may c o n t r i b u t e t o t h e p r o t e c t i v e e f f e c t o f ANP i n t h e e a r l y C A R F .

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INCREASED β-ENDORPHINERGIC ACTIVITY IN PATIENTS WITH BORDERLINE HYPERTENSION IS INDEPENDENT OF SYNPATHETIC NERVOUS SYSTEM ACTIVITY K. Kraft, M. Godde, R. Kolloch, K.O.StLrnpe, Medizinische Polikl inik, Universitat Bonn, FRG

In young patients with essential hypertension plasma concentrat ions of β-endorphin l ike act ivi ty (β-end) are reduced as compared to age-matched normotensive (N) subjects. Chronic treatment with the central et2-receptor agonist clonidine (C) normalizes β-end and blood pressure (BP). In the present study plasma concentrations of β-end were measured in 11 patients with borderline hypertension (BH) (24-32 years of age; diastol i c BP 90-94 mn Hg) and in 13 age-matched Ν subjects. After 2 h of recumbency and after 9 min submax. bicycle exercise as well as in the 10th and 80th min of the subsequent resting period β-end, plasma noradrenaline (NA) and plasma renin a c t i vity (PRA) as well as BP and heart rate were determined. In the BH patients β-end was significantly higher than in the Ν af ter 2 h rest ( 2 3 . 8 + 1 . 5 vs. 12.6 + 2.7 pg/ml; p<0.01) and at a l l times af ter exercise. Also NA, PRA and heart rate (HR) were increased in the BH patients. Clonidine (150 pg bid for 2 weeks) did not af fect the β-end concentration in the BH patients, but reduced NA and PRA. The reduction in BP and HR at rest was greater in BH than in N. I t is concluded that the elevated plasma β-end in BH is not influenced by endogenous or pharmacologically induced changes of sympathetic nervous system act iv i ty , β-end could be a marker to separate BH from Ν subjects or patients with established hypertension. A higher central β-end act ivi ty may counteract the high sympathe t i c tone in BH by i t s hypotensive e f f e c t and contribute to the decrease in BP following C.

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FLAVODILOL IN ESSENTIAL HYPERTENSION: IMPORTANCE OF INTRA-ARTERIAL BLOOD PRESSURE MEASUREilEtlTS. Simian Vardan. M.D., H. Smulyan, M.D., S. Mookherjee, M.D., VA Medical Center and SUNY HSC, Syracuse, NY.

Ten patients with mild essential hypertension (HTN) received 6 weeks therapy with Flavodilol, a new anti-HTN agent comprising of a beta blocker-like side chain attached to the vasodilator fla-vone nucleus. The control average intra-arterial (IA) systolic blood pressure (BP) and that recorded externally by cuff method (cuff) were 153.0 ± 6.09 SE vs. 149.2 ±3.62mmHg;(p-NS). The IA diastolic BP, however, was lower by about 20mmHg compared to the cuff BP (80.3 ± 2.68 vs. 100.8 ± 1.55 mmHg; P<0.001). Following 6 weeks of Flavodilol therapy up to 500mg daily, IA BP values, heart rate, cardiac index, systemic vascular resistance, mean systolic ejection rate, plasma renin activity, aldosterone and urinary metanephrines did not change. The cuff BP however fell (systolic to 141.1± 3.11 mmHg; P<0.05 and the diastolic to 93.4 ± 2.02; P<0.01). Bias on the part of unblinded observers might explain this discrepancy between cuff and IABP following therapy. Had we relied on the cuff BP alone, Flavodilol with only mild symptomatic side effects would have been considered an effective and safe anti-HTN agent. Our data underscores the importance of IABP recordings in an open-label study evaluating newly developed anti-HTN drugs prior to a large scale population trial. Furthermore, the control IA diastolic BP < 90 mmHg may not necessarily indicate normo-tension particularly when diastolic BP by cuff is higher. Therefore to better delineate the definition of essential HTN IABP measurements in a large population is needed.

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ANTIHYPERTENSIVE EFFECT AND TOLERABILITY OF FELODIPINE EXTENDED RELEASE (ER) TABLETS IN COMPARISON WITH FELODIPINE PLAIN TABLETS (PT) AND PLACEBO IN HYPERTENSIVES ON A DIURETIC. S.G. Carruthers (Representing the Canadian Study Group) Victoria Gen. Hospital & Dalhousie Univ., Halifax, Nova Scotia.

Felodipine (F), a new dihydropyridine calcium antagonist, lowers BP by selectively reducing vascular tone in resistance arterioles. An extended release (ER) F tablet was developed to provide BP control after once daily administration.

After a 4 wk run-in period, 148 hypertensive patients (DBP >95mm Hg), 95 M, 53 F, mean age 52.2±I0 yrs, from 16 centres were randomized to one of three parallel groups. Each group received, in addition to hydrochlorothiazide (Hydrodiuril), 25 mg o.d., either FER 5 mg o.d.(n=50), FPT 2.5 mg b.i.d. (n=50) or placebo in a double blind manner. Every 2 wk, if seated DBP>90mmHg, the F dose was doubled. All recordings of BP and heart rate (HR) were made at the end of the dosing interval over 6 wks. The mean starting BP for all 3 groups was similar (FER and FPT 150/101, placebo 150/100 mmHg). The mean seated BP reduction after 6 wks treatment compared to randomization values were 15/11, 16/12, and 10/7 mmHg for the FER, FPT, and placebo groups, respectively. There was no statistical difference between FER and FPT groups (p>0.2). Both preparations were more effective in reducing BP than placebo (seated DBP, p<0.01). No difference in HR was noted. There were 14 withdrawals [FERn=4, FPTn=6), 8 for adverse experiences (FERn=3, FPTn=4), mostly vasodilatory in nature. In conclusion, the antihypertensive effect of FER o.d., and FPT b.i .d. , were similar, and both were well tolerated.

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BINDING OF ISO-ANP IN THE RAT. SC Pang-, Z-J Zhou, DB Jennings-, TG Flynn*. Departments of Anatomy, Physiology and Biochemistry, Queen's University at Kingston, Ontario, Canada K7L 3N6.

We have recently discovered a second, amino acid sequence-distinct, natr iuret ic peptide from rat a t r i a . Because this peptide e l i c i ted a diuretic and nat r iure t i c , and cardiovascular response similar to ANP when infused into assay r a t s , we called i t iso-ANP. The present study was designed to determine the binding of iso-ANP in various organs of the r a t . Rats were anaesthetised and then infused with 1 2 5 1- label led iso-rANP in bolus. At 2 or 10 min. they were perfused f i r s t with phosphate buffered saline (PBS) and then with 4% paraformaldehyde in PBS. Organs were excised and processed for either gamma counting or autoradiography at the LM level . Binding was considered to be specif ic i f the labels were completely displaced with a concomitant infusion of excess amount of i s o -rANP. I t was found that the binding of iso-rANP was the highest in the kidney, and with 32% displacement by "cold" peptide. Autoradiography showed that iso-rANP binded to various segments of the nephron, but only those labels in the glomerulus were completely displaced. Binding of iso-rANP to the right ventricle and lung were highly speci f ic , up to 89% of these were displaced. These results indicate that tissue binding s i t e s for iso-rANP are similar to those for ANP. The physiological significance of i s o -rANP and i t s functional relationship with ANP and other natr iuret ic peptides remain to be determined.

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|1387| PHYSICAL ACTIVITY AND CARDIOVASCULAR RESPONSES TO ADRENERGIC STIMULATION. LA Ferrara, G Mainenti, ML Fasano, Τ Marotta, R Borrelli, Μ Mancini. Institute of Internal Medicine and Metabolic Diseases. University of Naples, Naples, Italy. The role of the physical activity on blood pressure (BP) and heart rate (HR) at rest and during stimulation of the sympathetic nervous system by mental stress and isometric exercise has been evaluated in 162 llyr old children divided in two groups of physical activity (group 1= sedentary; group 2= physically active) by using a Saltin modified questionnaire. Family history of arterial hypertension was also investigated. Resting BP, measured four times at 3 week intervals, was slightly higher in group 1 (107/75 +_ 11/11 versus 105/73 + 11/11 mmHg) as well as HR (91 + 11 versus 87 _+ 12 beats/min, ρ 0.02). During a 270 sec. mental test, systolic and diastolic BP increased by 6/12% in group 2 and more markedly in group 1 (7/15%); during a 120 sec. isometric exercise, BP increased by 23/45% in group 1 and 20/40% in group 2. These responses were independent of sex, body weight and family history of hypertension. The results of this study indicate that physical training influences BP not only at rest but also during sympathetic stimulation.

11389| RELATIONSHIP BETWEEN ACTIVE AND INACTIVE RENIN AND FETAL GROWTH IN WOMEN WITH HIGH RISK PREGNANCIES Morganti A, Ferraris P, Quorso P, Ambroso GC*, Co-mo G*, Sala C, Pulazzini E. Centro Fisiol. Clinics e Ipertensione and *Div. di Nefrologia, Ospedale Maggiore, Milano, Italy

To examine the relationship between the prore-nin-renin system and fetal growth, we measured plasma active and inactive (activated with immobilized trypsin) renin (AR and IR, ng/ml/h) in 29 women with hystory of complicated pregnancies collecting samples from the 3th week (w) until delivery at 4w intervals. In 23 women who delivered infants (I) of normal weight for the gestational age (NGA, 2929+93 g) after 37.2+0.5 w, supine AR was 2.7+0.2 at the 8th w, increased to 7.0+1.1 (p< 0.02) at the 23th w and declined thereafter where--as IR was 84+13 at the 8th w and decreased to 74+ 8 at the 28th w (ns). In 3 women the pregnancy was interrupted at the 28th w because of signs of fetal distress when I were small (SGA) while the. remaining 3 women delivered SGA I (1593+71 g) after 32.7+1.0 w. In these 6 women AR was 1.9+0.5 at the 8th w and failed to increase (1.8+0.5 at the 28th w) whereas IR was 53+16 at the 3th w and remained unchanged. These differences in renins between women with NGA and SGA I were significant (p<0.05). All the women studied remained normotensive. throughout gestation. Thus, low AR and IR are associated with growth retardation and both these events cannot be related to elevation in blood pressure.

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EFFECT OF SODIUM/STRESS INTERACTION ON BP LEVELS. Ν Poulter*, Μ Shipley, C Bulpitt, II Markowe, Μ Marmot. Dept of Community Medicine, University College & Middlesex School of Medicine, London,UK

Data from the Whitehall Department of the Environment study were analysed to investigate the hypothesis that psychological stress affects physiological mechanirms controlling sodium (Na) balance such that in the face of excess Na intake blood pressure (BP) elevation is induced. 363 randomly selected male civil servants who were not taking antihypertensive medication answered questions relating to tension, skills and expectations, from which a stress score was derived. After 5 minuter lying, pulse rates & BPs were recorded by standardised observers. Approximately 6 weeks later, subjects collected a 24 hour urine specimen which was analysed for electrolyte content. Subjects were divided into 9 subgroups by tertiles of Na excretion and tertilcs of the stress score. Those in the subgroup with highest, values for both variables had the highest mean SBP h DBP (adjusted for ape, alcohol intake and BUI) of the 9 subgroups.

SBP fx DBP were not related to Na excretion nor to the stress score alone but DBP was sign!f:i.cau.tly related to an interaction term between urinary i-ia excretion & stress scor* (p : :0.035). SBP was not related to t'.ie interaction term (p=C.4).

The regression slopes of adjusted S & DBP on stress scores within each fertile of Na excretion were different (significantly so for DBP: p<0.wl) and were positive only in the highest Na fertile, suggesting the impact of stress on the induction of elevated arterial pressure may be confined to those with relatively high Na intakes. These data support the hypothesis under investigation.

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ENHANCED RELEASE OF ATRIAL NATRIURETIC FACTOR (ANF) DURING BETA ADRENERGIC BLOCKADE IN MAN C.Sala,L.Terzoli, G.Bolla, A.Morganti, A.Zanchetti Clinica.Medica Generale e Terapia Medica, Universita di Milano and Centro Fisiologia Clinica e Ipertensione, Ospedale Maggiore, Milano, Italy

In spite of the alterations of renal hemodynamics observed during chronic treatment, beta-blockers decrease blood pressure without inducing sodium retention. To investigate whether this may be due to a compensatory increase of ANF, we measured systolic blood pressure (SBP,mmHg), heart rate (HR,b/min), ANF (pmol/L,in extracted plasma) and plasma norepinephrine (NE,pg/ml) at rest and after exercise on a cycloergometer (120 Watt for 15 min) in 7 patients with borderline hypertension before and after treatment with nadolol (N, 80 mg/ day for 7 days). Results are shown as means+SE; p<0.05 or less, between before Ν vs after N.

Rest Before Ν After Ν

SBP HR ANF NE

127+4.2 77.1+2.4 11.2+1.6 318+49

118+8.0 60.3+2.6* 19.1+3.9* 450+76*

Exercise Before Ν After Ν 181+10 161+13 154+7.8 109+8.6*

24.2+4.2 100+19* 1177+153 1213+188

Our data show that after Ν the secretion of ANF is increased particularly during physical exercise; this effect, possibly due to increased atrial distension, might contribute to maintain sodium homeostasis during treatment with beta-blockers.

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ANGIOTENSIN II (AII)-INDUCED ANF RELEASE IN VIVO AND IN VITRO. Μ Volpe*, MJF Camargo*, SA Atlas*, RE Sosa, FB Mueller*. JE Sealey*, JH Laragh*. Cornell Univ. Medical College, New York, NY.

We evaluated the role of hemodynamic factors in mediating ANF secretion induced by graded All infusion (1-10 ng/kg/min) in 8 anesthetized dogs during maintained volume expansion (VE) and converting enzyme inhibition (CEI). Arterial ANF (fmol/ml) and right atrial (RAP), pulmonary wedge (PWP) and mean blood (MBP) pressures (mm Hg) were:

ANF RAP PWP MBP Control 19± 2 3. 9±.4 8.5±1 142±5 VE+CEI 34± 6* 6. 31.911 12 ll 1 1 140±2 All 1 39±11 6. 4±.8 12 ±1 141±3

2.5 55±20* 6. 0±.7 12 ±1 149±2* 5 69±20* 5. 9±.5 11 ±1 154±3*

10 80±23* 5. 8±.4 12 ±1 159±4* Recovery 52±15 6. 4±.8 11 ±1 140±6

^P<0.05 vs Control ; *P<0 05 vs VE+CEI During VE, ANF increased in parallel with RAP and PWP. But All increased ANF further without changing either RAP or PWP. This response was not correlated with the increase in MBP, and was not observed in 4 control dogs receiving vehicle alone.

We also tested the effect of All on ANF release by superfused rat atrial minces (200 mg tissue per column) after 200 min pre-equilibration. Basal release (53±9 fmol/min) was increased by 1, 10 and 100 nil All (peak responses 129±18, 176±46 and 210± 66 % of control at 15 min). The response was highly variable (range 112 to 390% with 100 nM All), for reasons which remain to be determined. Taken together, these findings suggest, nonetheless, that All can modulate ANF secretion by a direct effect on the atria, i.e. independent of changes in intramural atrial pressure.

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β -HUMAN ATRIAL NATRIURETIC PEPTIDE (ANP) IN CONGEST IVE HEART FAILURE (CHF). Κ / I n d o t Μ S h i c h i r i , Κ S a t oh and F Mar υ mo, K i t a s a t o Β i n c h e m . L a b s . , S a g a m i h a r a , J a p a n .

To e l u c i d a t e c i r c u l a t i n g and e x c r e t i n g f o r m s o f Λ Ν Γ in h e a l t h and in CHF, p l a s m a and u r i n e s a m p l e s o b t a i n e d f r o m 33 p a t i e n t s w i t h CHF a s w e l l a s 15 h e a l t h y v o l u n t e e r s w e r e s t u d i e d . T h e r e was no s i g n i f i c a n t d i f f e r e n c e in ANP l e v e l b e t w e e n h e a l t h y v o l u n t e e r s and m i l d CHF p a t i e n t s i N e w Y o r k H e a r t A s s o c i a t i o n [ N Y H A ] c l a s s 1 1 ) 1 4 9 . 4 + 1 9 . 3 v s 4 7 . 0 + 9 . 5 p g / m l ) . H o w e v e r , a s CHF a d v a n c e d , ANP b e c a m e m a r k e d l y i n c r e a s e d ( c l a s s I I , 1 3 0 . 9 + 4 3 . 0 ; I I I 3 3 9 . 1 + 2 0 4 . 8 ; IV 4 2 3 . 4 + 2 1 3 . 8 p g / m l ) .

R e v e r s e p h a s e h i g h p e r f o r m a n c e l i q u i d c h r o m a t o g r a p h y , g e l p e r m e a t i o n c h r o m a t o g r a p h y a n d s u b s e q u e n t r a d i o i m m u n o a s s a y f o r ANP r e v e a l e d t h a t c i r c u l a t i n g c o m p o n e n t s o f ANP c o n s i s t e d o f α ANP w i t h o r w i t h o u t β ANP a n d / o r χ ANP in CHF, w h i l e a ANP a l o n e o r a ANP a n d χ ANP i n h e a l t h y v o l u n t e e r s , and t h a t e x c r e t i n g f o r m s w e r e e i t h e r « ANP a l o n e o r α a n d β ANP in CHF, and o n l y r /ANP in h e a l t h y v o l u n t e e r s , χ -ANP was n o t d e t e c t e d in u r i n e o f a n y s a m p l e s e x a m i n e d . A l t h o u g h i n c r e a s e o f t o t a l ANP was d u e t o a l l c i r c u l a t i n g c o m p o n e n t s in CHF, p e r c e n t a g e o f β ANP e x c e e d e d t h a t o f o t h e r f o r m s in s e v e r e CHF (NYHA c l a s s I I I and I V ) . S u c c e s s f u l t r e a t m e n t o f CHF r e s u l t e d in r e d u c t i o n o f ANP and d i s a p p e a r a n c e o r r e d u c t i o n o f β ANP in a l m o s t a l l p a t i e n t s e x a m i n e d . χ ANP was n o t d e t e c t e d f r o m u r i n e o f

n e i t h e r h e a l t h y p e r s o n s n o r CHF p a t i e n t s .

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IHREE TYPES OF AUSCULTATORY GAPS (AG) DURING BLOOD PRESSURE (BP) MEASUREMENT. SG Blank, JE West, FB Mueller*, MS Pecker*, W Perry, TG Pickering*. Cornell Med. Coll. & AT&T Bell Labs.

The mechanisms of AG (loss and reappearance of Korotkoff (K) sounds during cuff pressure (CP) deflation in the absence of cardiac arrhythmias) are poorly understood. The wideband external pulse recorded from a transducer under a BP cuff during a BP measurement has three components. KI is an inaudible, low frequency (f ) signal present when CP is above systol ic (SP). K2 is an audible high f component which appears at SP and disappears at dias tol ic (DP), and corresponds to the Κ sound. K3 is a large amplitude, inaudible, low f component which appears between SP and DP and pers is ts below DP.

Three types of AG (GI, G2, G3) were identified in 60 hypertensive patients ( p t s ) . Thirteen pts exhibited a GI gap, which occurs when CP is just below SP, and is characterized by the presence of KI and K2, with intermittent disappearance of K2. GI can be explained by a phasic decrease of SP, with loss of Κ sound when SP is below CP. Seven pts exhibited a G2 gap, which occurs when CP is just above DP, and is characterized by the presence of ΚΙ, K2, and K3, with intermittent disappearance of K2. G2 can be explained by a phasic increase of DP, with loss of Κ sound when DP is above CP. G3 was seen in 3 p ts , and is not characterized by the disappearance and reappearance of K2, but is associated with an underdeveloped K2. G3 is not associated with a phasic variation of a r t e r i a l pressure, and must be explained by local phenomena occurring under the BP cuff .

In summary, three types of AG have been identic fied during BP measurement.

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TBIAZ3D&-INDOCED HYPERLIPIDEMIA IS NOT CAUSED BY HYPOKALEMIA/ RP Ames*, St. Luke' s-Roosevelt Hospital/ New York/ NY.

The mechanism of thiazide-induced hyperlipidemia is unknown/ but the lipid changes correlate with the glucose intolerance of diuretic therapy. The glucose intolerance of thiazides is attributed to potassium (K) depletion. To test whether hypokalemia plays a role in the dyslipidemia of diuretics/ I examined the effects on lipids of a combination diuretic tablet which contains equal milligram doses of hydrochlorothiazide and spironolactone. Fasting glucose (G), triglycerides (Tg), total cholesterol (TC)/ and high density lipoprotein cholesterol (HDL) were measured in 44 patients with mild or moderate hypertension during unblinded treatment. Baseline measurements were obtained during a drug-free interval of at least 3 weeks duration before starting or after stopping the diuretic treatment. No other antihypertensive or 1 ipid-altering drugs were used in this study. The average treatment period was 3 months and the mean dose was 50 mg of each drug. Results included (*p<05/ +p^ 0 . 0 1 / #p«:0.001 vs baseline):

TC Tg HDL G Κ Ratio _ ... mg/dl meg/1 TC/HDL

Baseline: 230 126 52 106 4 . 3 4 . 6 Diuretic 245# 189+ 51 119* 4 . 3 5 . 2 * During therapy weight decreased from 182 to 179* pounds/ systolic blood pressure (BP) decreased from 161 to 139# mm Hg and diastolic BP from 100 to 89# mmHg. Conclusions: 1) Maintaining normal serum Κ does not prevent diuretic-induced elevations in TC, Tg or G. 2) The glucose and lipid disturbance caused by thiazides is not due to hypokalemia.

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KETANSERIN IN THE TREATMENT OF DIABETIC PATIENTS WITH HYPERTENSION OR PERIPHERAL VASCULAR DISEASE M. Janssens. J. Symoens, Janssen Research Foundation, Beerse, Belgium

Data were evaluated from 30 studies with a total of 940 diabetic patients, of whom 548 received ketanserin, while 392 received a reference drug. The indication for treatment was mainly essential hypertension or peripheral vascular disease. More than half of the patients participated in the PACK-trial, a placebo-controlled study in claudicants. Most of the studies were chronic, ketanserin doses ranging from 20 mg b.i.d. to 40 mg t.i.d. No clinically relevant effects were observed on the variables of diabetic treatment, i.e. fasting and postprandial blood glucose, 24-hour urine glucose, C-peptide, hemoglobin and glucose tolerance tests. In the studies in essential hypertension, on average, systolic blood pressure decreased from 165 to 152 mmHg, while diastolic blood pressure fell from 96 to 88 mmHg. In the studies in peripheral vascular disease, blood flow was increased with ketanserin. In patients with diabetic foot ulcers, wound healing was significantly improved with ketanserin compared to placebo. In the PACK-trial, a beneficial effect of ketanserin on trophic changes was observed. Overall, the incidence of side-effects with ketanserin was low, with 12 % of the patients having some complaints. In conclusion, ketanserin effectively reduces blood pressure and improves the peripheral circulation in patients with diabetes and hypertension or peripheral vascular disease respectively, without interfering with diabetic control.

[13971 RELATIONSHIP BETWEEN BLOOD PRESSURE CONTROL, HEMATOCRIT LEVELS AND RENAL FUNCTION. A.K. Mandal.* R.J. Markert, and R.D. Bell, Depts of Med and Physiol, VA Med Cent and Wright State Univ, Dayton, OH 45428 and Chicago Coll Osteopath Med, Downers Grove, IL 60515

We have shown that reduction in blood pressure (BP) is accompanied by a significant decrease in hematocrit (Hct) (J Lab Clin Med 111:63, 1988). This study reports relationship between BP control, Hct levels and renal function in 97 hypertensive patients. Data on Systolic (S) and Diastolic (D) BP, Hct, Serum creatinine (Scr) and hydrochlorothiazide (H) dose at entry and 5 years thereafter were analyzed. Of 97 patients, 60 entered in 1974 (GR I) and 37 in 1980 (GR II). 97% received Η ranging from 100 mg in GR I to 50 mg in GR II. Pearson correlation coefficients and correlation matrix were computed to examine the relationship among these variables and paired t-test was used to determine the change over time. In both groups SBP and DBP decreased significantly (P<.001). BP between entry and 5 years later were 140 + 14 and 94 + 7 vs 131 + 17 and 8 5 + 9 , and 139 + 16 and 8 8 + 9 , vs 138 + 17 and 8 5 + 9 , in GR I and GR II, respectively. In GR I, Scr did not change; whereas in GR II, Scr decreased (1.29 vs 1.24 mg%) significantly (P<004). In GR II only, Hct decreased (48.06 vs 44.65%) significantly (P<.001). Significant (P<.05) positive correlations were found between BP and Scr and DBP and Η dosage. In conclusion, this analysis indicates 1) Change in DBP which accompanies high Η dose is beneficial in renal preservation; 2) Hct decrease may be related to renal function improvement.

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E N A L A P R I L IK PATIENTS W I T H CHRONIC C O N G E S TIVE HEART FAILURE.MFC M a r a n h a o * , A Sbissa, Μ B a t l c L n . i , F M A l b a n e s e , A M Martins-Evangelic Hospital Sch.Med.Curitiba,PR B r a z i l .

F o r t y - e i g h t patients(PTS) with chronic congestive heart failure (CHF) were treated w i t h e n a l a p r i l m a l e a t e ( E ) . T h e r e w e r e 28 m a les and Γ0 females,aged from 23-80 years (mean=55).The cases were associated w i t h : cardiomyopathy(26),ischemic heart disease (17) and"miscellaneous"(5).According to NYHA,16 PTS(33%)were functional class I I ; 28 PTS(58,3%) were class III;4 PTS(8,4%) were class IV.All PTS received oral Ε (.10·-40mg.once a day)for 10 weeks , c o n c o m i t a n t l y w i t h digitalis and diuretics , after 2. \-eekn of w a s h - o u t in an open non-comparative b a sis. The PTS were seen clinically every 2 w e e k s , a n d laboratory tests,ECG.x-rayc and ECHO w e r e performed in the begin and end the study.Subjective improvement was e v a luated both by PTS and p h y s i c i a n s , a n d in the end of the trial,38 PTS(79,2%)were class II;Γ P T S ( 1 8 , 8 % j w e r e class III;and 1 patient w a s class IV(2,0%).Among the 39 PTS in class II,19(50%)were upgraded from class III and 3 PTS(7,9%)from class IV. Objective changes ir. the clinico.l, ECHO a n d h e a r t size w a s seen,specially in the e j e c tion f r a c t i o n ( E F ) a n d in t h e percentual shorthniixc (A%) a n d i n t h e cardiothcracic index(CI) ( p < 0 . 0 1 ) . In sumnary,it appears that enalapril n a l e a t e is an effective a n giotensin concerting enzyme(ACE)inhibitor for the m a n a g e m e n t of PTS in chronic CHF.

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TRANSFER OF HYPERTENSIVE PATIENTS FROM PRAZOSIN TO TERAZOSIN THERAPY. MJ Klepper, AR Laddu, RR Luther, CJ Maurath, R Achari. Abbott Laboratories, Abbott Park, IL.

In a single-blind study, we evaluated the efficacy and safety of transferring hypertensive patients with diastolic blood pressure (DBP) of 95-114 mm Hg from twice-daily prazosin (P) treatment to once-daily treatment with terazosin (T), a new, selective, alpha-1 adrenoreceptor antagonist. Sixteen patients on maintenance doses of Ρ (2, 5 or 10 mg BID) were transferred to a similar total daily dose of Τ ( 5 , 10 or 20 mg QD) and maintained on Τ treatment for a period of 8 weeks. Systolic blood pressure (SBP) and DBP were measured at the end of Ρ treatment (baseline) and every two weeks during the Τ treatment period. The mean values (N=16) at baseline and at the end of treatment with Τ were as follows: Treatment Ν SBP/DBP (mm Hg) Prazosin T6~ Supine 140.3/87.7 (Baseline) Standing 133 .9 /88 .5

Terazosin 16 Supine 136 .9 /87 .1 Standing 132.3/86.2

Blood pressure (BP) at the end of Τ treatment showed no loss of antihypertensive effect. In fact, Τ treatment produced a further decrease in BP; the average decreases from baseline were 3.4/0.6 mm Hg and 1 .6/2 .3 mm Hg for supine and standing SBP/DBP, respectively. BPs measured every two weeks during the Τ treatment period also demonstrated that the BP control was maintained throughout this period. The most common adverse experience was mild to moderate dizziness associated with the highest dose of T. This study demonstrates that patients maintained on twice-daily Ρ therapy can be effectively transferred to once-daily Τ therapy at equivalent total daily doses to maintain adequate control of BP.

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[13991 AUTOGRAPHIC LOCALISATION OF THE BINDING OF PORCINE BRAIN NATRIURETIC PEPTIDE [BNP] AND DES [18-22] ATRIAL NATRIURETIC PEPTIDE(4-23) "NH2 (C-ANP4-23) IN RAT BRAIN. J.Brown*, A Czarnecki. Physiological Lab., Univ. of Cambridge and Dept. of Medicine, Royal Postgraduate Medical School, London, England. Intracerebroventricular (ICV) injections of BNP and of rat α-ANP similarly attenuate the dipsogenic effects of ICV angiotensin II in the rat. High affinity binding sites for ANP occur in the subfornical organ (SFO), a nucleus necessary for the dipsogenic effects of ICV angiotensin II. The full binding specificity of these sites is not known. BNP shows some structural affinity to ANP and, therefore, may share common binding sites. Additionally, C-ANP4-23 distinguishes a subgroup of ANP receptors involved in clearing circulating ANP in extracarebreal tissues. We have investigated this in the brain by autoradiographic competition binding studies in 15 μιιι frozen serial sections of 18 rats. Section? were preincubated in buffer and then exposed to 200 pM of rat a-ANP. Non-specific binding was determined in the presence of 1 μΜ unlabelled rat α-ANP. Binding isotherms were determined in successive sections from individual brains using 1 pM - ΙμΜ unlabelled rat α-ANP or BNP or C-ANP4-23. Sections were then exposed to LK8 Ultrofilm and regional optical densities of autoradiograms were measured by computerised microdensitometry. Unlabelled BNP completely displaced all but the nonspecific binding of [125I] α-ANP in the brain, including binding to the SFO, area postrema, choroid plexus and arachanoid. C-ANP4-23 competed mainly for binding sites on arachanoid. The IC50 for displacement in SFO w a s 10-8.830 + 0 . 2 2 Μ by BNP and 10-8·βι + O . M Μ for ANP. In choroid plexus these IC50 were 10-»·" ί °•» Μ for BNP and 10 -8 76 + 0.16 « f0 r

ANP. Thus, BNP can compete at all ANP receptors in the brain. BNP and ANP have similar affinities for binding sites in SFO and choroid plexus. In the SFO, this may explain the similar actions of BNP and ANP on the dipsogenic effect of ICV angiotensin II; endogenous BNP may be an important ligand at brain receptors previously thought specific for atrial natriuretic peptides. Binding sites for C-ANP4-23 in other organs clear bound peptide; these sites on arachanoid may also be able to clear BNP and α-ANP.

114031 A DOUBLE-BLIND, FORCED TITRATION STUDY COMPARING A NOVEL A.C.E. INHIBITOR, CGS-16617, AND PLACEBO IN MILD TO MODERATE HYPERTENSION. J . de Suva*. R. Glazer*. G. Lewis, L. Ivankoe, L. Ribeiro*, CIBA-GEIGY Corp., Summit, NJ. CGS-16617 is a new, long acting, non-sulfhydryl angiotensin converting enzyme (A.C.E.) inhibitor. We compared progressively increasing once daily (od) doses of CGS-16617 (20, 40, and 80 mg) to placebo. Of f i f t y - nine patients ( p t s . ) with a si t t ing diastol ic blood pressure (SDBP) > 95 and < 114 mmHg af ter four weeks of placebo, forty were randomized to CGS-16617 treatment and 19 to placebo. Those pts. randomized to CGS-16617 treatment group were scheduled to receive 20 mg od during the f i r s t week, 40 mg od during the second week, and 80 mg during the final 2 weeks of double-blind Rx. SDBP was measured at the end of the dosing interval and safety evaluations were performed weekly for 4 weeks. The table shows change in SDBP (mmHg) af ter each week of double-blind Rx.

WEEK OF DOUBLE-BLIND Rx Rx 1 2 3 4 ENDPT Placebo - 3 . 4 - 3 . 0 - 4 . 6 - 3 . 7 - 3 . 0 CGS-16617 - 7 . 7 * -11 .6** - 1 1 . 3 * * - 1 1 . 8 * * -11.3**

* ρ < .05 * * ρ < .001 vs. placebo

Adverse experiences were reported in 21% of the pts . in the placebo group and 10% in the CGS-16617 group. None of these experiences were classif ied as serious. CGS-16617 administered od appears to be an effective and well tolerated antihypertensive agent.

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IS THERE A PERICARDIAL RESTRICTION ON THE CARDIAC SECRECTION OF ATRIAL NATRIURETIC FACTOR (ANF)? C H a l l and J S a n d e r u d . I n s t , f o r S u r g . R e s . Oslo Norway.

The p u r p o s e o f t h i s s t u d y was to i n v e s t i g a t e w h e t h e r t h e o p e n i n g o f the p e r i c a r d i u m c a n i n f l u e n c e t h e cardiac s e c r e t i o n o f (ANF). The s t u d y was p e r formed on two g r o u p s (A and B) o f a n a e s t h e t i z e d , m e c h a n i c a l l y v e n t i l a t e d p i g s . In group A a m i d l i n e t h o r a c o t o m y was p e r f o r m e d and i m m u n o r e a c t i v e ANF was measured i m m e d i a t e l y b e f o r e and 5 min a f t e r a Y - s h a p e d wide o p e n i n g o f the p e r i c a r d i u m . I n g r o u p Β an o c c l u d e r was p l a c e d around t h e d e s c e n d i n g aorta t h r o u g h a l e f t s i d e d t h o r a c o t o m y . Plasma ANF was measured b e f o r e and a f t e r a 5 min p e r i o d o f a s t a n d a r d i z e d a o r t i c s t e n o s i s , f i r s t l y w i t h an i n t a c t p e r i c a r d i u m , s e c o n d l y a f t e r t h e p e r i c a r d i u m had been opened. In g r o u p A p e r i c a r d i o t o m y was accompanied by a 57 p e r c e n t i n c r e a s e in a r t e r i a l ANF c o n c e n t r a t i o n ( ( f r o m 55±24 pmol l - 1 t o 8 6 ± 6 2 pmol l - 1 ) ( l e a n i S D , N = l l , p < 0 . 0 5 ) ) . In g r o u p Β the i n c r e a s e i n a r t e r i a l ANF was 1 8 5 1 1 9 9 pmol l - 1

a f t e r s t e n o s i s w i t h an i n t a c t p e r i - c a r -dium w h i l e t h e c o r r e s p o n d i n g i n c r e a s e a f t e r s t e n o s i s w i t h an open p e r i c a r d i u m was 3 6 2 ± 3 2 3 pmol l - 1 (mean±SD, N-5, p < 0 . 0 5 ) . These r e s u l t s s u p p o r t the hy p o t h e s i s t h a t t h e p e r i c a r d i u m may r e s t r i c t a t r i a l d i l a t a t i o n i n t h o r a c o t o m i z e d pigs and t h a t t h e opening o f t h e p e r i c a r d i u m i n c r e a s e t h e ANF r e s p o n s e t o a t r i a l i n t r a c a v i t a r y p r e s s u r e i n c r e a s e .

[14041 LOW DOSE I N F U S I O N OF αί-h ANF I N NORMAL MAN: R I S K S AND CONSEQUENCES: N E _ _ B r u u n , Μ Damk jaer N i e l s e n , Ρ S k 0 t t , J G i e s e . D e p t . o f C l i n i c a l P h y s i o l o g y , G l o s t r u p H o s p i t a l , G l o s t r u p a n d H v i d f l r e H o s p i t a l , K l a m p e n b o r g , D e n m a r k .

To i n v e s t i g a t e t h e e f f e c t s o f a 2 - and 4 f o l d i n c r e a s e i n plasma ANF c o n c e n t r a t i o n , 3 and 12 ng χ k g " 1 χ m in " - 1 a-hANF was s tepw i se i n f u s e d i n t o normal sup ine v o l u n t e e r s on a 18o mmol/24h d i e t a r y sodium i n t a k e . A 9o min c o n t r o l p e r i o d was f o l l o w e d by two 2-hour i n f u s i o n p e r i o d s w i t h u r i n e c o l l e c t i o n s i n t h e l a s t 9o min o f each p e r i o d . Due t o f a i n t n e s s and c o l d swea t i ng i n t he f i r s t s u b j e c t and severe h y p o t e n s i o n ( 6 0 / 4 9 ) i n t h e second v o l u n t e e r t he h i g h i n f u s i o n dose was subsequen t l y reduced t o 6 ng χ k g " 1 χ m i n " 1 ( c a u s i n g a 3 - f o l d i n c r e a s e i n t h e b a s a l A N F - l e v e l ) . N e v e r t h e l e s s , adverse r e a c t i o n s such as o r t h o s t a t i c h y p o t e n s i o n w i t h b r a d y c a r d i a and changes i n t h e ECG ( e c t o p i c a t r i a l p a c i n g and d i p h a s i c T-wa-ves ) occured i n t h r e e o f t h e nex t f o u r s u b j e c t s . A l l adverse r e a c t i o n s emerged a t t h e v e r y end o f t h e 4 -hou r i n f u s i o n p e r i o d . I n t he t h r e e l a s t s u b j e c t s 5oo ml i s o t o n i c NaCl was i n f u s e d over 5 min a t t he end o f t h e l a s t u r i n e c o l l e c t i o n p e r i o d ( a f t e r t h e f i n a l b l o o d s a m p l i n g ) . I n these s u b j e c t s no adverse r e a c t i o n s were o b s e r v e d . Frequent b i o c h e m i c a l measurements demons t ra ted p a r a l l e l i n c r e a s e s i n plasma ANF and cGMP c o n c e n t r a t i o n s . Hema toc r i t i n c r e a s e d p r o g r e s s i v e l y w h i l e a n a t r i u r e t i c response (27%) was o n l y found a t t h e l o w e s t i n f u s i o n l e v e l . Minor i n c r e a s e s i n plasma c a t e c h o l amine c o n c e n t r a t i o n s were observed w h i l e t h e r e n i n - a n g i o t e n s i n I I - a l d o s t e r o n e system was p r o g r e s s i v e l y supp ressed . D i u r e s i s d i d n o t change.

Our r e s u l t s demons t ra te t h a t i n c r e a s e s o f plasma ANF c o n c e n t r a t i o n even w i t h i n t h e p h y s i o l o g i c a l range cause d i s t i n c t hemodynamic and b i o c h e m i c a l e f f e c t s . However, l o n g - t e r m ANF i n f u s i o n i m p l i e s a s e r i o u s e lement o f r i s k n e c e s s i t a t i n g c l o s e m o n i t o r i n g .

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THE EFFECT OF SODIUM, AS THE CHLORIDE OR THE BICARBONATE SALT, ON BLOOD PRESSURE I N NORMAL AND MILDLY HYPERTENSIVE BLACK AND WHITE SUBJECTS. FC L u f t , WB Zemel , JR Sowers, NS F i n e b e r g , MH Weinberger . I n d i a n a U n i v e r s i t y Med C t r . , I n d p l s . I N & Wayne S t . U n i v . Sch. o f M e d . , D e t r o i t , M I .

Prev ious work has shown t h a t Na i n c r e a s e s o n l y as t h e C I s a l t i n an imal h y p e r t e n s i o n and i n man. To t e s t t h e c l i n i c a l r e v e l v a n c e o f t h a t e f f e c t , we p e r f o r m e d e x p e r i m e n t s i n n o r m a l and h y p e r t e n s i v e b l a c k and w h i t e s u b j e c t s . Ten (5 w h i t e and 5 b l a c k ) normal (NBP) and 10 (5 w h i t e and 5 b l a c k ) h y p e r t e n s i v e (HBP) s u b j e c t s n o t i n g e s t i n g m e d i c a t i o n were g i v e n a f i x e d 60 mmol/d NaCl d i e t (K 70 mmol /d, Ca 600 mg/d) f o r 5 days. They were t h e n ass igned , i n random o r d e r under p l a c e b o - c o n t r o l l e d , d o u b l e - b l i n d , c r o s s - o v e r c o n d i t i o n s , t o e i t h e r NaH00 3 o r NaCL (60 mmol/d) g i v e n i n t h e form o f m i n e r a l w a t e r ( S t a a t l . Fachingen) o r equimolar amounts o f NaCl c o n t r o l s o l n , f o r 7 days . A l l u r i n e was c o l l e c t e d . Blood p ressure (BP) was t a k e n by machine. BP on days 5 and 12 (mean + SD) i s below:

NBP HBP NaCl 110+6 111+10 125+12 127+12

67+6 68+6 76+6 78+5 NaHC0 3 110+6 111+10 128+6 *123+9 *P<0 .05 67+6 66+9 78+8 77+7 Renin and a l d o s t e r o n e e f f e c t s o f Na were n o t d i f f e r e n t . Cumulat ive Na and Mg b a lan c e was n o t d i f f e r e n t . However, NaCl caused an i n c r e a s e i n UCaV and UKV w h i l e NaHC0 3 d i d n o t . UCaV was g r e a t e r i n HBP t h a n NBP, b u t l e s s i n b l a c k s t h a n w h i t e s ( P < 0 . 0 5 ) . We conclude t h a t Na as a non-C l s a l t does n o t u n f a v o r a b l y a f f e c t BP i n NBP o r HBP. The d i f f e r e n c e s i n NaCl and non-C l Na s a l t s may i n v o l v e e f f e c t s on Ca homeostasis .

1 4 0 7

CONTRASTING EFFECTS OF TWO CALCIUM A N T A G O N I S T S ( C A ) O N PLASMA VOLUME AND PROTEIN E X T R A V A S A T I O N . J P V a l e n t i n , JM H a l i m i . J R i b s t e i n * . A M i m r a n * . D e p t . o f M e d i c i n e . CHU. M o n t p e l l i e r F r a n c e .

P e r i p h e r a l e d e m a w i t h o u t f l u i d r e t e n t i o n i s a c o m m o n s i d e e f f e c t o f t r e a t m e n t w i t h CA. To e x p l o r e t h e p o s s i b i l i t y t h a t CA m a y a l t e r d i f f e r e n t l y f l u i d p a r t i t i o n b e t w e e n v a s c u l a r and i n t e r s t i t i a l c o m p a r t m e n t s , w e s t u d i e d t h e e f f e c t s o f d i l t i a z e m (D) and n i c a r d i p i n e (N) i n a n e p h r i c a n e s t h e t i z e d r a t s on c h a n g e s i n h e m a t o c r i t ( H t ) and p l a s m a p r o t e i n c o n c e n t r a t i o n ( P t ) . A f t e r a 4 0 - m i n i n f u s i o n o f Ν and D (1 and 100 u g / k g / m i n r e s p e c t i v e l y ) , BP d e c r e a s e d by 2 1 and 19%, and Ht i n c r e a s e d by 6 .1±0 .2 and 1.5±0.1% r e s p e c t i v e l y . T h e c a l c u l a t e d l o s s o f p l a s m a v o l u m e w a s 10.3% a f t e r N ic as c o m p a r e d t o o n l y 2.6% a f t e r D, t h i s l a t e r e f f e c t w a s n o t d i f f e r e n t f r o m t h a t i n d u c e d by v e h i c l e ( V ) . P t d i d n o t c h a n g e s i g n i f i c a n t l y i n D and V r a t s and i n c r e a s e d by o n l y 3 .7±0.2% i n Ν r a t s . In a s e c o n d s e t o f e x p e r i m e n t s , p r o t e i n e x t r a v a s a t i o n w a s s t u d i e d u s i n g Evans b l u e (EB) dye as a m a r k e r . T h e d r u g -i n d u c e d e x t r a v a s a t i o n o f E B - a l b u m i n i n s k e l e t a l and c a r d i a c m u s c l e s w a s s i g n i f i c a n t l y i n c r e a s e d f o l l o w i n g N, as c o m p a r e d t o D o r V. No c h a n g e w a s o b s e r v e d i n b r a i n , i n t e s t i n e , l i v e r and s k i n a f t e r b o t h CA. T h i s s u g g e s t s t h a t 2 s t r u c t u r a l l y d i f f e r e n t c a l c i u m a n t a g o n i s t s a t e q u i - h y p o t e n s i v e d o s e s m a y e x e r t d i f f e r e n t e f f e c t s on e x t r a c e l l u l a r f l u i d p a r t i t i o n .

1 4 0 6

TREATMENT OF M I L D HYPERTENSION WITN AN I O N - E X CHANGING SEAWEED P R E P A R A T I O N . Μ A u r e l l * , Μ K r o t -kiewski, G H o l m , G G r i m b y a n d T T z c z e o a n i k . D e D a r t m e n t of NeDhrology, R e h a b i l i t a t i o n a n d M e d i cine , S a h l g r e n ' s H o s D i t a l , U n i v e r s i t y o f G o t e b o r g , G o t e b o r g , S w e d e n .

S i x t y - t w o middle-aged otherwise healthy D a t i e n t s with w e l l Droved b u t Dreviously untreated mild h y D e r t e n s i o n h a v e received a sod ium -adsorbing a n d Dotassiurn-releasing s e a w e e d D r e D a r a t i o n ( S e a w e e d f i b e r - S F ) 4 g t . i . d . T h e m e a n blood Dressure ( M B P ) evaluated i n t h e double-blind c r o s s o v e r m a n n e r with f o u r w e e k s f a m i l i a r i z a t i o n a n d w a s h o u t D e r i o d s s h o w e d , both a t r e s t a n d during s u b m a x i m a l e x e r c i s e , a s i g n i f i c a n t l y h i g h e r d e c r e a s e o f b l o o d Dressure af ter four w e e k s o n SF than af ter a n i d e n t i c a l Der iod o f Dlacebo t r e a t m e n t . T h e MBP decrease w a s s ignificantly higher i n s o d i u m - s e n s i t ive than i n s o d i u m i n s e n s i t i v e Datients ( 1 1 . 6 v s 5 . 7 mmHg, d < 0 . 0 0 1 ) a n d also significantly correlat e d with t h e i n c r e a s e i n Dlasma renin a c t i v i t y ( P R A ) o n s e a w e e d treatment ( d < 0 . 0 1 ) . No c h a n g e s o f Dlasma sodium a n d Dotassium c o n c e n t r a t i o n s w e r e o b s e r v e d . U r i n a r y sodium e x c r e t i o n d e c r e a s e d a n d u r i n a r y Dotass ium e x c r e t i o n i n c r e a s e d ( d < 0 . 0 5 ) o n s e a w e e d treatment a n d t h e urinary sodium/DOtassium r a t i o d e c r e a s e d ( d < 0 . 0 1 ) . A s judged from t h e Dositive correlations b e t w e e n the decrease o f MBP a n d t h e decrease o f urinary s o d i u m , increase o f urinary Dotassium, decrease i n the sodium/DOtassium urinary excretion rat io and the i n c r e a s e o f P R A , the d e c r e a s e o f MBP w a s most Drobably deDendent o n the i n t e s t i n a l absorDtion o f sodium and release o f Dotassium from the s e a w e e d DreDaration.

[ 1 4 0 8 |

SODIUM INTAKE IS A DETERMINANT OF LEFT VENTRICULAR MASS IN UNTREATED ESSENTIAL HYPERTENSIVES. G du C a i l a r . J R i b s t e i n * , A M i m r a n * . Dep t . o f M e d i c i n e . CHU. M o n t p e l l i e r . F r a n c e

Many f a c t o r s have been i m p l i c a t e d i n t h e p a t h o g e n e s i s o f m y o c a r d i a l h y p e r t r o p h y . In t h e p r e s e n t s t u d y , w e a s s e s s e d t h e i n f l u e n c e o f d i e t a r y s o d i u m on t h e d e g r e e o f l e f t v e n t r i c u l a r h y p e r t r o p h y ( L V H ) i n 4 1 p a t i e n t s aged 3 8 ± 1 0 ( m ± s d ) w i t h m i l d e s s e n t i a l h y p e r t e n s i o n ( c a s u a l b l o o d p r e s s u r e 1 4 9 ± 1 7 / 9 1 ± 1 1 m m H g ) . P a t i e n t s had n e v e r been g i v e n a n t i h y p e r t e n s i v e d r u g s b e f o r e , and i n g e s t e d ad l i b i t u m s o d i u m i n t a k e . B o t h p o s t e r i o r w a l l t h i c k n e s s ( P W T ) and l e f t v e n t r i c u l a r m a s s ( L V M ) , and n o t e n d - d i a s t o l i c d i a m e t e r o r LV f r a c t i o n a l s h o r t e n i n g , as m e a s u r e d by M - m o d e e c h o c a r d i o g r a p h y , w e r e d i r e c t l y c o r r e l a t e d w i t h u r i n a r y s o d i u m e x c r e t i o n r a t e (UNa, m m o l / 2 4 h ; r = 0 . 4 7 and 0 . 4 6 ; p < 0 . 0 2 ) . In a s t e p w i s e m u l t i p l e r e g r e s s i o n a n a l y s i s , UNa w a s a s s o c i a t e d w i t h LVM i n d e p e n d e n t l y o f s e x , age , body m a s s i n d e x and b l o o d p r e s s u r e . No c o r r e l a t i o n w a s f o u n d b e t w e e n LVM and p l a s m a r e n i n a c t i v i t y , w h i l s t a p o s i t i v e one e x i s t e d b e t w e e n PWT and h e m a t o c r i t ( r = 0 . 4 2 ; p < 0 . 0 0 7 ) . In u n t r e a t e d h y p e r t e n s i v e s , d i e t a r y s o d i u m m a y t h u s p l a y an i n d e p e n d e n t r o l e i n m o d u l a t i n g l e f t v e n t r i c u l a r m a s s , p o s s i b l y t h r o u g h e x p a n s i o n o f v o l u m e o r a c t i v a t i o n o f t h e a d r e n e r g i c s y s t e m .

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114091 E N D O G E N O U S A N G I O T E N S I N I I M O D U L A T E S T H E

E F F E C T OF A T R I O P E P T I N ON F L U I D P A R T I T I O N .

J P V a l e n t i n , J R i b s t e i n * . A M i m r a n * . D e p t . o f

M e d i c i n e . C H U . M o n t p e l l i e r F r a n c e .

A N P o p p o s e s t h e e f f e c t s o f t h e r e n i n

s y s t e m a t d i f f e r e n t l e v e l s , a n d i n d u c e s a

f l u i d s h i f t o u t o f t h e i n t r a v a s c u l a r

c o m p a r t m e n t . T h e i n f l u e n c e o f s o d i u m i n t a k e

( L S : l o w v s H S : h i g h s o d i u m f o r 4 w e e k s ) a n d

a n g i o t e n s i n - c o n v e r t i n g e n z y m e i n h i b i t i o n

( L S - C E I : c a p t o p r i l g i v e n f o r 2 w e e k s t o LS

r a t s ) o n t h e e f f e c t s o f A N P i n f u s i o n ( 0 . 1

M g / k g / m i n f o r 3 0 m i n ) w a s a s s e s s e d i n

b i n e p h r e c t o m i z e d a n e s t h e t i z e d r a t s b y

m e a s u r i n g c h a n g e s i n b l o o d p r e s s u r e ( B P ) a n d

h e m a t o c r i t ( H t ) . D u r i n g A N P i n f u s i o n , B P

d e c r e a s e d b y 5 ± 1 . 6 % i n HS a n d 3 . 5 ± 0 . 9 % i n L S

r a t s ; t h i s r e s p o n s e w a s s i m i l a r i n t h e L S -

CEI g r o u p . A N P - i n d u c e d i n c r e a s e i n H t w a s

m o r e m a r k e d i n HS t h a n i n L S r a t s ( 8 . 1 ± 0 . 1

v s 5 . 8 ± 0 . 3 % , p < 0 . 0 0 1 ) , b u t w a s a b o l i s h e d b y

CEI p r e t r e a t m e n t . I n f u s i o n o f A l l a t a

s u b p r e s s o r d o s e ( 2 . 5 n g / k g / m i n ) r e s t o r e d t h e

r e s p o n s e o f H t t o A N P i n L S - C E I r a t s . T h e s e

r e s u l t s i n d i c a t e t h a t A l l m o d u l a t e s t h e

e f f e c t o f A N P o n f l u i d p a r t i t i o n , b u t n o t o n

a r t e r i a l p r e s s u r e , p o s s i b l y b e c a u s e o f

o p p o s i n g i n f l u e n c e s o f A N P a n d A l l o n p r e -

a n d p o s t c a p i l l a r y r e s i s t a n c e s .

1 4 1 1

CHRONIC EFFECTS OF EXCESS SUCROSE INGESTION ON 3 STRAINS OF RAT. M.Zein*. J .L .Areas* and H.G.Preuss* George town University, Wash ing ton ,D.C.20007 Because dietary intake of sucrose may part ic ipate in age-re lated hyper tension, w e placed SHR, W K Y and regular Wistar on 5 diets. The basel ine diet (I) der ived equal calor ies f rom sucrose , proteins and fats. T w o other diets (11,111) der ived the majori ty of calor ies f rom sucrose with decreases in calor ies f rom proteins or fats. The last two diets (IV,V) were relatively low in sucrose with a higher percentage of the total calor ies f rom proteins and fats respect ively. The rats were p laced on their respect ive diet at age 3 month . They have now been on these diets a total of 9 months. The response is dif ferent among strains. In SHR, the hypertensive rats, the diets highest in sucrose calor ies (11,111) caused a markedly increased BP with in 2 weeks in contrast to Diet I, IV and V. This d i f ference, approx 20-30 m m Hg. , has held over 9 months . Dif ferently, the regular Wistar rats, the normotens ive rats, consuming diets II and III are only showing signif icant d i f ferences (approximate ly 10 m m Hg) after 9 months. The response of W K Y , normotens ive rats wi th a family history, is intermediate but shows a clearcut elevat ion of BP in W K Y consuming diets II and III. This di f ference is becoming greater with t ime (20 m m at 9 months) . Consistent changes in body weights are lacking. F rom the many urinary and b lood parameters examined , our data suggest the increased BP is due to changes in ca techo lamine metabo l ism, vo lume expans ion and the presence of a natr iuret ic factor. W e conc lude that excess ingest ion of sucrose can cause e levat ions in BP which var ies among rat strains. Our results are consis tent wi th excess sucrose ingest ion playing s o m e role in age-re la ted hyper tens ion.

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COMPARATIVE STUDY OF THE EFFECTS OF PERINDOPRIL ( P . ) AND CAPTOPRIL ( C . ) ON PLASMA L IPID PROFILE AND GLUCOSE METABOLISM P .L . H a l i n i , P. F o l i n o , E. S t r o c c h i , E. A m b r o s i o n i * C a t t e d r a e S e r v i z i d i Farmaco log ia C l i n i c a - U n i v e r s i t y o f BOLOGNA ( ITALY) The aim o f t h i s 3-month doub le b l i n d s t udy was t o assess t he e f f e c t s o f two A C E - I : P. and C. on plasma l i p i d p r o f i l e and g lucose m e t a b o l i s m . A f t e r a 1-month p lacebo p e r i o d 29 p t s (8 F; age 29-65 y r s ) w i t h e s s e n t i a l h y p e r t e n s i o n ( 1 6 2 / 1 0 3 + 2 / 1 mmHg) r e c e i v e d randomly P. 4 -8 mg od o r C. 25-50 mg t d f o r 3 months . H y d r o c h l o r o t h i a z i d e 25 mg od was added a t 2nd month i n 8 and 10 p t s o f t he P. and C. g r o u p s , r e s p e c t i v e l y . The mean r e d u c t i o n i n sup ine BP va lues was s i g n i f i c a n t i n bo th groups ( P : - 1 2 / 1 3 + 3 / 2 mmHg ; C: - 9 / 1 0 + 3 / 2 mmHg), and no t s i g n i f i c a n t l y d i f f e r e n t between t he two g r o u p s . However, t he percen tage o f p t s w i t h a sup ine DBP o f 90 mmHg o r l e s s was g r e a t e r i n t he P. group than i n t he C group (71% vs 40%; p < . 0 0 1 ) . Except f o r a s i g n i f i c a n t i n c r e a s e i n ApoB i n t he C g r o u p , t h e r e was no s i g n i f i c a n t change i n t he va lues (mean+SEM) o f m e t a b o l i c p a r a m e t e r s :

P. g roup(n=14) C. g roup(n=15) basal f i n a l basal f i n a l

To t -Cho i (mg/dL) 229+12 235+13 215+5 220+6 HDL-C (mg/dL) 47+3 47+3 44+_5 41+2 Apo-A l (mg/dL) 168+11 166+10 154+9 154+8 Apo-B (mg/dL) 139+10 140+9 128+6 132+6* Glucose (mmol /L) 5 .3+0 .4 5 .5+0 .2 5 . 2 + 0 . 1 5 . 1 + 0 . 1 I n s u l i n (uU/mL) 6 .7+0 .6 7 .0+0 .5 8 .3+0 .5 7 . 6 + 0 . 4 C-pept ide(mU/mL) 1 .7+0.2 1.8+0.2 1 .8+0 .1 1 .9+0.1

Our r e s u l t s demons t ra te t h a t t he a n t i h y p e r t e n s i v e a c t i o n o f bo th P. and C , a l s o i n comb ina t i on w i t h a d i u r e t i c , i s n o t a s s o c i a t e d w i t h adverse e f f e c t s on plasma l i p i d p r o f i l e and g lucose m e t a b o l i s m .

1 4 1 2

EARLtf BP RESPONSE IN RABBITS AFTER U^T2JEPHRT3CTOKY ( W D : . J.Areas*-, flt·,Zein*, Η Q Preucs*. Georgetov.Ti University Medical Center, l - o g t , of Medicirie, W& s h i n g t G n , D.C. 20007

Raised BP in rabbit is believed to have ::enal origins. Grclli-.ian (AJP 142:, 666, 1544) reported that uni in rabbits led tc hypertension and concluded that this spo3:e against the liberation c:. a pressor substance by the ischemic or damped k i d ney as being causative. However, Flasher and Drury (AJP 158:''.38,1949) , were unable to corroborate this. ITe follo\T2c DP in 7 rabbits early after uni and 4 rabbits after a sham procedure. Over 10 days BP increased from baseline average of C3 to .97 nm Hg in the uni rabbits (p<.01). In contrast, BP did not change after sham. BUM and creatinine rose from 15 to 24 mg/dl (pC.01) and from 0.9 to 1.4 mg/dl (p^.Ol) respectively, v;hile no significant changes were seen in serum Na (143/14C), Κ (4.3/ 4.5), CI 104/104), C02 (21.3/22/5), anion gap (17.7/19.6), Wg (2.3/2.5) & calcium (13.3/13.4). Ijeasurement o:: serun insulin levels and digoxin-like substances showed no significant changes, but renin activity rose from 11.4 to 49.9 ng/'ml/h, hovjever, there was no significant correlation between the rise in LP and renin activity. Iieasurement of serum renotropic activity after uni also shoved a significant elevation above baseline 97.6% (p<.001). The LP of rabbits after operation correlated significantly with renotropic activity (r=.71, p<.001). \ l e conclude that BP rises after uni in rabbits and because of the strong correlation found that a specific regulator of renal growth, renotropin plays an iinrortant role in the BP elevation after uni.

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1 4 1 3

THE EFFECT OF ABNORMAL LIVER FUNCTION ON THE EFFICACY AND SAFETY OF ENALAPRIL IN THE TREATMENT OF HYPERTENSION. C A . Brown. J . E . Rush, T . J . Cook, Merck Sharp & Dohme Research L a b o r a t o r i e s , West P o i n t , PA.

E n a l a p r i l (EN) i s a p rod rug wh ich undergoes e s t e r h y d r o l y s i s , p r i m a r i l y i n the l i v e r , t o the a c t i v e m e t a b o l i t e e n a l a p r i l a t . To de te rm ine whether t he presence o f abnormal l i v e r f u n c t i o n (ALF) a l t e r s t he e f f e c t s o f e n a l a p r i l i n t he t r e a t m e n t o f h y p e r t e n s i o n (HTN), we ana lyzed t he e f f i c a c y d a t a f rom a d o u b l e -b l i n d , c o n t r o l l e d , m u l t i c l i n i c HTN s tudy a c c o r d i n g t o the p a t i e n t s ' AST and serum b i l i r u b i n l e v e l s a t base l i n e (ALF n=48, normal l i v e r f u n c t i o n [NLF] n=222) . T o t a l serum b i l i r u b i n was 29% and AST was 49% h i g h e r than t he upper l i m i t o f t he normal range f o r the ALF g r o u p . T o t a l serum b i l i r u b i n was 58% and AST was 61% o f t he upper l i m i t o f t he normal range f o r t he NLF g r o u p . P a t i e n t s were t r e a t e d w i t h EN 10-40 mg a lone d a i l y f o r up t o 12 weeks. S i m i l a r decreases i n s y s t o l i c (SBP) and d i a s t o l i c (DBP) were observed between the subgroups as p resen ted i n t he t a b l e be low.

Mean Changes i n Blood Pressure (mmHg)

Week 6 Week 12

ALF - 1 3 . 1 - 1 0 . 0 - 1 6 . 3 - 1 2 . 8 NLF - 1 8 . 2 - 1 1 . 4 - 2 2 . 0 - 1 3 . 2

These da ta show t h a t EN i s e q u a l l y e f f i c a c i o u s i n t h e t r e a t m e n t o f HTN i n p a t i e n t s w i t h normal and i m p a i r e d l i v e r f u n c t i o n .

|1415[

CENTRAL DEPRESSOR MECHANISMS OF CALCIUM i K. T a k e d a * . H . I t h o . M . H i r a t a , S . K a w a s a k i . J . H a y a s h i , Y . N a k a m u r a , S . S a s a k i a n d M . N a k a g a w a . 2nd D e p t . o f M e d . , K y o t o P r e f e c t u r a l U n i v . o f Med. K y o t o , J a p a n . j To d e t e r m i n e w h e t h e r c a l c i u m i n d u c e v a s o d e p r e s s o r , e f f e c t c e n t r a l l y , C a C 1 2 w a s i n j e c t e d i η t r a c e b r o v e n t r i c u 1 a 11y in a w a k e n o r m o t e n s i v e a n d s p o n t a n e o u s l y h y p e r t e n s i v e r a t s . C a n n u l a w e r e in-J s e r t e d i n t o f e m o r a l a r t e r y t o r e c o r d t h e b l o o d p r e s s u r e and s t a i n l e s s c a n u l l a was i m p l a n t e d i n t o r i g h t c e r e b r a l v e n t r i c l e . Ca e l i c i t e d d o s e J

d e p e n d e n t l y v a s o d e p r e s s o r r e s p o n s e s . (50mM - l l ± 2 , i 1 0 0 m M - 2 1 ± 6 , 150mM - 2 7 + 3 mmHg) . D i l t i a z e m i η-j h i b i t e d s i g n i f i c a n t l y d e p r e s s o r r e s p o n s e s i n d u c e d b y lOOmM C a C 1 2 ( - 1 6 ± 3 v s - 2 + 1 , Ρ < 0 . 0 1 ) . ! I n t r a v e n o u s i n j e c t i o n s o f lOOmM C a C 1 2 d i d n o t ! e l i c i t any c h a n g e s o f b l o o d p r e s s u r e s . V a s o d e p r e s - j s o r r e s p o n s e s i n d u c e d by i . e . v . i n j e c t i o n s o f ! lOOmM C a C 1 2 w e r e s i g n i f i c a n t l y l a r g e r in SHR t h a n i n WKY ( - 2 2 + 3 % v s - 1 1 + 6 , Ρ < 0 . 0 5 ) . P r e s s o i ] r e s p o n s e s t o i . e . v. a n g i o t e n s i n Π w e r e a t t e n u a t e d , a f t e r i . c . v . i η j e c t i o n s o f CaC12 in WKY, b u t n o t in SHR (WKY : 2 3 ± 3 v s 1 0 ± 2 % . P < 0 . 0 5 . S 1 1 R : 2 7 ± 5 v s 20 + 5%, n. s . ) . T h e s e f i n d i n g s s u g g e s t t h a t c a l c i u m h a s v a s o d e p r e s s o r e f f e c t s c e n t r a l l y a n d i n h i b i t c e n t r a l a n g i o t e n s i n p r e s s o r s y s t e m , a n d t h i s m e c h a n i s m s o f c a l c i u m i s a l t e r e d in SHR.

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PLASMA DIGITALIS-LIKE ACTIVITY IN ONE-KIDNEY,ONE CLIP (1K1C) AND TWO-KIDNEY, ONE CLIP (2K1C) HYPERTENSION. A.L. Rauch*. W.G. Campbell, J r . , and V.M. Buckalew, J r . Bowman Gray Sch. of Med., Winston-Salem, NC & Emory Univ., Atlanta, GA.

Reduced renal function is a key factor in the development of many models of hypertension. To determine the potential role of a competitive and reversible ligand of the Na,K ATPase molecule in the association of renal function and hypertension, the plasma levels of this ligand were determined in 1K1C and 2K1C hypertensive rabbits and their respective controls (lKlCc and 2KlCc). Ligand levels were quantitated with a radioreceptor assay using erythrocyte ghosts and t r i t i a t e d ouabain, and the result were expressed as pmoles of d i g i t a l i s - l i k e ac t ivi ty /ml . Additionally, plasma phospholipid levels were determined with a spectophotometric assay for phosphate af ter separation by thin layer chromatography. After 2 weeks, the d is to l i c blood pressure (mmHg) was increased in the 1K1C group compared to the lKlCc group (64+2 vs 84+3, p<0.001) and in the 2K1C group compared to the 2KlCc group (67+3 vs 82+3, p<0 .001) . The ligand levels were decreased in the 1K1C group compared to the lKlCc (20+2 vs 43+ 10, p<0.005) and increased in the 2K1C group compared to the 2KlCc group (21+5 vs 9+3, p<0 .05) ; however, the ligand levels of the 1K1C group were increased compared to the 2KlCc group (p<0.05) . Plasma phospholipids (phosphatidylcholine, lysophosphatidyl-choline, sphingomyelin) levels were unchanged. These results suggest that reduction of renal function is physiological stimulus for increasing the levels of a c i rculat ing ligand to the Na,K ATPase molecule.

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DECREASED HYPOTHALAMIC AND MEDULLARY GABA TURNOVER IN SPONTANEOUSLY HYPERTENSIVE RATS S. S a s a k i * , H. I t o h , M . H i r a t a , T . N a k a t a , S . K a w a s a k i , J . H a y a s h i , M . O g u r o , K . T a k e d a ? M . N a k a g a w a . 2 n d D e p t . o f M e d . , K y o t o P r e f e c t u r a l U n i v . o f M e d . , K y o t o , J a p a n

To d e t e r m i n e w h e t h e r G a m m a - a m i n o b u t y r i c a c i d (GABA) n e u r o n a c t i v i t i e s i n t h e c e n t r a l n e r v o u s s y s t e m w o u l d be a l t e r e d i n h y p e r t e n s i o n , c e n t r a l GABA c o n t e n t and GABA t u r n o v e r r a t e w e r e m e a s u r e d i n s p o n t a n e o u s l y h y p e r t e n s i v e r a t s (SHR) and t h e i r n o r m o t e n s i v e c o t r o l s ( W K Y ) . When GABA c o n c e n t r a t i o n s i n c e r e b r o - s p i n a 1 f l u i d ( C S F ) w e r e m e a s u r e d w i t h a h i g h p e r f o r m a n c e l i q u i d c h r o m a t o g r a p h y , we f o u n d t h a t CSF GABA c o n c e n t r a t i o n s w e r e l o w e r i n S H R t h a n i n W K Y . S i n c e h y p o t h a l a m u s a n d m e d u l l a o b l o n g a t a a r e s u g g e s t e d a s t h e p o s s i b l e a c t i v e s i t e s o f t h i s s y s t e m , b a s a l GABA c o n t e n t s a n d i n v i v o GABA t u r n o v e r r a t e s o f bGth h y p o t h a l a m u s a n d m e d u l l a o b l o n g a t a w e r e m e a s u r e d f o r t h e s e c o n d s t u d y . In v i v o GABA t u r n o v e r r a t e s w e r e e s t i m a t e d by GABA a c c u m u l a t i o n a f t e r i n j e c t i o n o f a m i n o o x y a c e t i c a c i d ( Α 0 Α Α ) , a s e l e c t i v e i n h i b i t o r o f GABA d e g r a d i n g s y s t e m . B a s a l GABA c o n t e n t s n o t o n l y i n t h e m e d u l l a o b l o n g a t a b u t a l s o i n t h e h y p o t h a l a m u s w e r e a l m o s t t h e same b e t w e e n SHR and WKY. On t h e c o n t r a r y , GABA t u r n o v e r r a t e s o f SHR w e r e s i g n i f i c a n t l y l o w e r t h a n t h o s e o f WKY b o t h i n t h e h y p o t h a l a m u s and in t h e m e d u l l a . S i n c e GABA h a s b e e n known t o be an i n h i b i t o r y n e u r o t r a n s m i t t e r i n t h e c e n t r a l n e r v o u s s y s t e m a n d t o c o n t r o l a u t o n o m i c a n d c a r d i o v a s c u l a r a c t i v i t i e s , o u r f i n d i n g s s u g g e s t t h a t t h e d e c r e a s e d c e n t r a l GABA-e r g i c a c t i v i t i e s i n d u c e s y m p a t h e t i c h y p e r a c t i v i t y t o c o n t r i b u t e t h e b l o o d p r e s s u r e e l e v a t i o n i n SHR.

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THE ROLE OF CENTRA L a 2 - A D R Ε Ν 0 R Ε C Ε Ρ TO R S IN T H E CENTRAL RESETTING OF BAROREFLEX IN SHR J. Η ay a s h i. K . T a k e d a * , H . I t h o , Μ. H i r a t a , S.Kawasaki, M . O g u r o , Y . N a k a m u r a and M . N a k a g a w a . 2nd D e p t . of M e d . , K y o t o P r e f e c t u r a l Univ. of Med., Kyoto, Japan.

To d e t e r m i n e whether a 2 - a d r e n o r e c e p t o r in the brain can involve in the central alteration of baroreflex in SHR, central c u t t i n g end of a o r t i c d e p r e s s o r nerves were electrically stimulated in SHR w i t h or w i t h o u t i.v. a d m i n i s t r a t i o n s of c l o n i d i n e . ADN s t i m u l a t i o n s elicited frequency - J d e p e n d e n t l y d e p r e s s o r and s y m ρ a t h o - i η h i b i t ο r yl r e s p o n s e s in WKY and SHR. These r e s p o n s e s were! significantly smaller in SHR than those in WKY.: I.v. i n j e c t i o n s of c l o n i d i n e lowered the bloodj pressure in SHR and WKY. In SHR, c l o n i d i n e i m - j proved depressor and sympatho-inhibitory responses' to ADN stimulations and the d i f f e r e n c e s between SHR and WKY were disappeared. However, clonidine did not affect those r e s p o n s e s to ADN stimulation in WKY. T h e s e f i n d i n g s s u g g e s t t h a t c e n t r a l α 2 -a d r e n o r e c e p t o r s could c o n t r i b u t e to the central attenuation of baroreflex via ADN in SHR. Table 1.Depressor Responses to ADN Stimulations

η 2. 5 5 20 Hz

WKY 10 1 8 ± 1 2 6 ± 2 3 9 + 2

SHR 7 1 1 ± 2* 1 9 ± 2** 3 0 ± 2*

SHR+Clo 8 1 5 ± 2 2 1 ± 2 3 9 ± 2

M e a n + S E M % changes from basal blood pressure.

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N I F E D I P I N E A T T E N U A T E A U G M E N T E D PRESSOR RESPONSES TO EXERCISE IN BORDERLINE HYPERTENSION. ' K. Takeda*, S.Sasaki, II. Itho, M. Hirata, S.Kawasakij, J.Hayashi, Y.Nakamura and M.Nakagawa. 2nd Dept. of Med., Kyoto Prefect, of Med., Kyot'o Japan. j

To determine whether nifedipine can block exagi-gerated pressor r e s p o n s e s to dynamic exercise ijn borderline hypertensives (BHT), pressor r e s p o n s e s during ergometer exercise were measured before and after sublingual administrations of n i f e d i p i n e ijn n o r m o tens i ve (NT) and b o r d e r l i n e h y p e r t e n s i v e ^ (BUT). 11 NT and 12 BHT were examined. Ergo-mete:r exercise were loaded for every three min. from 5XJ to 125 Watt by 25 watt step up. Forty min. aftejr first exercise, nifedipine (lOmg) was adm i η i s tere;d subl i ngu 1 a 1 y. 20 min later, e r g o m e t r i c exercisle was repeated. Blood p r e s s u r e s were m e a s u r e d bjy auscultation, heart rate was counted by ECG an!d cardiac output was measured by UCG methods. ι B e f o r e n i f e d i p i n e a d m i n i s t r a t i o n s , p r e s s o!r responses in diastolic pressure were si gn i f i can t ljy larger in BHT than in NT. Tachycardic and cardiaic output increased responses were identical in botjh groups. Norepinephrine increases were also larger in BHT than in NT. Nifedipine inhibited the aug 1-mented pressor r e s p o n s e s in diastolic pressures}. Nifedipine did not affect cardiac output in both NT and BHT. Nifedipine did not reduce exaggerated norepinephrine increases in BHT, but augmented the increases of NE during exercise in NT. ! These f i n d i n g s suggest that BHT has exaggerated responses during exercise, which is i n h i b i t e d by nifedipine. !

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T R A N S E C T I O N OF A O R T I C D E P R E S S O R NERVE FAILS TQ ELEVATE BLOOD PRESSURE IN SHR j K. T a k e d a * . J . H a y a s h i . H . I t h o , Μ . Η i r a t a ,1 S . K a w a s a k i , M . O g u r o , Y. Nakamura, M.Nakagawa. 2nd Dept. of Med., Kyoto P r e f e c t u r a l Univ. of Med. J Kyoto, Japan.

We reported central attenuation of baroreflex via aortic depressor nerve (ADN) in 2nd ASH meet-; ing. In p r e s e n t s t u d y , to e l u c i d a t e w h e t h e r b a r o r e f l e x via ADN c o u l d c o n t r i b u t e to t h e development of hypertension in SHR, Systolic blood p r e s s u r e were m e a s u r e d in SHR and WKY w i t h ο i without ADN t r a n s e c t i o n s . In WKY, systolic blood pressure was significantly elevated one day after ADN t r a n s e c t i o n s (120 + 3 vs 146 + 4 mmHg. P < 0 . 0 1 ) a n c i continued for seven days. However, blood pressures in ADN t r a n s e c t e d SHR w e r e s a m e as in sham 4 operated SHR during observations period (160 + 4 vs1

164+3 m m H g , n . s . ) . 7th day, all rats were anesthetized with urethane. Femoral artery and venoui were c a n u l a t e d and splanchnic nerve activity was recorded. B r a d y c a r d i c and s y m ρ at ho - i η h i b i t ο r ) r e s p o n s e s d u r i n g the elevation of blood pressure^ by phenylephrine were significantly smaller in ADN transected WKY than those in sham-operated WKY. Ir SHR, ADN t r a n s e c t i o n s did not a t t e n u a t e the b r a d y c a r d i c and s y m p a t h o - i n h i b i t o r y r e s p o n s e s . P r e s s o r r e s p o n s e s to e l e c t r i c a l s t i m u l a t i o n of posterior hypothalamus were also attenuated by ADN transections in WKY, while this a t t e n u a t i o n was not seen in SHR. T h e s e f i n d i n g s s u g g e s t that baroreflex via ADN could not act to c o u n t e r the d e v e l o p m e n t of h y p e r t e n s i o n in SHR, in other w o r d s , a t t e n u a t i o n of b a r o r e f l e x can p a r t l y develop the hypertension.

1 4 2 0

PVN LESIONS ATTENUATE THE DEVELOPMENT OF HYPERTENh SION WITH SYMPATHETIC NERVOUS INHIBITION IN SHR j K.Takeda*, T.Nakata, H.Itho, M.Hirata, S. Kawasaki} J.Hayashi, S.Sasaki and M.Nakagawa. j 2nd Dept. of Med., Kyoto Prefect, of Med., Kyoto; Japan. ί

To d e t e r m i n e whether p a r a v e n t r i c u l a r n u c l e u s (PVN) can be involved in the development of hyperj-tension in SHR and s y m p a t h e t i c n e r v o u s system| blood pressures were measured in PVN lesioned SHR and WKY , a d d i t i o n a l l y , cardiovascular responses to ganglionic blocker and v a s o p r e s s i n a n t a g o n i s t were examined. Lesions were produced electrical 1^ in five week olds rats. The development of hypery-tension in SHR was inhibited in PVN lesioned SHR from 5 to 8 week olds, while PVN lesions did not reduce blood p r e s s u r e p r o m i n e n t l y . 8 weeks old! b l o o d p r e s s u r e s w e r e r e c o r d e d d i r e c t l y f r o m femoral artery in awake rats. Mean blood p r e s s u r 3 was also lowered in lesioned SHR (13 2 db 5 vs 112 ± 5 mmHg, Ρ < 0. 0 5 ) , while mean blood p r e s s u r e ii lesioned WKY was not different from sham-opera tea WKY ( 1 1 0 + 4 vs 1 1 2 ± 5 m m H g ) . D e p r e s s o r r e s p o n s e ; to i. v. hexamethonium (25mg/kg) were significantly larger in sham-operated SHR than in lesioned SHR (-41± 4% vs -28 ± 3%. P<0.05) dPVAVP injections did not reduce blood pressure in all groups. j

8 weeks old, rats were moved in the metabolic cagi and collected urine for twenty four hours. AVP excretions were not modified by PVN lesions in SHR and WKY. Norepinephrine e x c r e t i o n s were sig - r n i f i c a n t l y reduced in lesioned SHR than in shamj operated SHR. These findings suggest that PVN can c o n t r i b u t e to d e v e l o p the h y p e r t e n s i o n in younj; SHR with sympathetic inhibitions.

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11421| AUGMENTED D E P R E S S O R AND SΥ ΜΡ ΑΤ Η0 - I Ν Η I Β I Τ 0 R ί RESPONSES TO BROMOCRIPTIN IN SHR M. O g u r o , K. T a k e d a * , Η. 11 ho , M . H i r a t a , S . K a w a s a k i , J . H a y a s h i , Y . N a k a m u r a , S . S a s a k i and M . N a k a g a w a . 2nd D e p t . o f M e d . , K y o t o P r e f e c t . U n i v . o f M e d . , K y o t o , J a p a n .

B r o m o c r i p t i n e ( B R ) , D A 2 - r e c e p t o r a g o n i s t , h a s d e p r e s s o r r e s p o n s e s . T o d e t e r m i n e w h e t h e r ! b r o m o c r i p t i n e h a s a u g m e n t e d d e p r e s s o r r e s p o n s e s i n SHR o r n o t , i f s o , w h e t h e r s y m p a t h e t i c n e r v o u s s y s t e m c a n c o n t r i b u t e t o d e p r e s s o r r e s p o n s e s , ! b r o m o c r i p t i n e w a s i n t r a v e n o u s l y i n j e c t e d i n SH^ a n d WKY. BR e l i c i t e d d o s e - d e p e n d e n 1 1 y v a s o d e p r e s - j s o r r e s p o n s e s in u r e t h a n e a n e s t h e t i z e d n o r m o t e n - ] s i v e W i s t a r r a t s . H e a r t . r a t e w a s a l s o r e d u c e d . ; M e t o c l o p r a m i d e a n d d o m p e r i d o n e i n h i b i t e d s i g - j n i f i c a n t l y v a s o d e p r e s s o r r e s p o n s e s . S y m p a t h e t i c n e r v e a c t i v i t y r e c o r d e d f rom s p l a n c h n i c n e r v e was n o t a l t e r e d by b r o m o c r i p t i n e i n j e c t i o n s . V a s o d e p r e s s o r r e s p o n s e s by i . v. i η j e c t i o n s o f BR ( 21 μ g) w e r e s i g n i f i c a n t l y l a r g e r i n SHR t h a n i n WKY ( 1 0 m i n : - 3 9 ± 2 v s - 2 9 + 2 % , Ρ < 0 . 0 5j ) . P l a s m a n o r e p i n e p h r i n e was s i g n i f i c a n t l y r e d u c e c ^ in WKY and SHR a f t e r b r o m o c r i p t i n e i n j e c t i o n s . Thej r e d u c t i o n o f n o r e p i n e p h r i n e w a s s i g n i f i c a n t l y ! l a r g e r i n SHR t h a n i n WKY ( - 4 4 ± 5 v s - 2 3 ± 6 %, Ρ < 0 . 0 5 ) . E p i n e p h r i n e s w e r e s i g n i f i c a n t l y e l e v a t e d a f t e r BR i n j e c t i o n s , t h e s e r e s p o n s e s w e r e n o t d i f f e r e n t b e t w e e n SHR and WKY.

T h e s e f i n d i n g s s u g g e s t t h a t b r o m o c r i p t i n e l o w e r e d b l o o d p r e s s u r e m a i n l y by p r e - s y n a p t i c i n h i b i t i o n o f n o r e p i n e p h r i n e r e l e a s e , a n d i n SHR, DA2 r e c e p t o r s y s t e m i s a l t e r e d .

114231 ENHANCED N O R E P I N E P H R I N E R E L E A S E IN HYPOTHALAMUS FROM LOCUS CERULEUS IN SHR. S . K a w a s a k i , K. T a k e d a * , H . I t h o , M . H i r a t a , J . H a y a s h i , M . O g u r o , Y . N a k a m u r a , S . S a s a k i a n d M . N a k a g a w a . 2nd D e p t . o f M e d . . K y o t o P r e f e c t u r a l U n i v . o f M e d . , K y o t o , J a p a n .

To e l u c i d a t e w h e t h e r l o c u s c e r u l e u s ( L C ) p r o j e c t s f u n c t i o n a l l y t o p o s t e r i o r h y p o t h a l a m u s and c a n c o n t r i b u t e t o t h e d e v e l o p m e n t o f h y p e r t e n s i o n i n SHR, n o r e p i n e p h r i n e was m e a s u r e d i n p o s t e r i o r h y p o t h a l a m u s by b r a i n d i a l y s i s b e f o r e a n d a f t e r i n j e c t i o n s o f L - g l u t a m e t e ( G l u ) i n t o LC. Glu e l i c i t e d p r o l o n g e d t h e e l e v a t i o n ο f b l o o d p r e s s u r e i n b o t h SHR a n d WKY. P r e s s o r e f f e c t s w e r e s i g n i f i c a n t l y l a r g e r in SHR t h a n in WKY ( + 1 7 . 8 ± 2 . 0 % v s + 8 . 4 ± 1 . 3 % : Ρ < 0 . 0 5 ) . E x t r a c e l l u l a r n o r e p i n e p h r i n e (NE) in t h e p o s t e r i o r h y p o t h a l a m u s was i n c r e a s e d a f t e r LC s t i m u l a t i o n . I n c r e a s e s o f NE was s i g n i f i c a n t l y l a r g e r i n SHR t h a n i n WKY ( + + 7 7 . 4 ± 3 4 . 0 % v s + 2 1 . 8 + 1 5 . 6 %, P < 0 . 0 1 ) . The i n j e c t i o n s o f 60HDA ( 4 m g / μ 1 ) i n t o p o s t e r i o r h y p o t h a l a m u s l o w e r e d t h e b l o o d p r e s s u r e i n SHR ( ( S H R : 1 7 1 + 1 v s 1 4 8 ± 5 , P < 0 . 0 1 . WKY: 1 2 4 ± 4 v s 1 1 4 ±

|2 mmHg, NS. ) a n d a t t e n u a t e d s i g n i f i c a n t l y p r e s s o r r e s p o n s e s t o G l u i n j e c t i o n s i n t o LC i n S H R ( SHR: v e h 2 2 . 4 ± 3 . 6 v s 6 0 Η DA 1 0 . 4 + 2 . 1 %, P < 0 . 0 1 , WKY:Veh 1 6 . 1 ± 2 . 6 v s 60HDA 1 2 . 0 ± 2 . 4 % , N S ) . T h e s e f i n d i n g s s u g g e s t t h a t LC p r o j e c t s f u n c t i o n a l l y t o p o s t e r i o r h y p o t h a l a m u s a n d t h i s p r o j e c t i o n s c a n c o n t r i b u t e t o t h e d e v e l o p m e n t o f h y p e r t e n s i o n in SHR.

1422 ALTERED NORADRENERGIC P R O J E C T I O N TO HYPOTHALAMUS VIA BAROREFLEX IN SHR. S . K a w a s a k i , K . T a k e d a * , Η . I t h o , M . H i r a t a , J . H a y a s h i , M . O g u r o , Y . N a k a m u r a . S . S a s a k i and M . N a k a g a w a . 2 n d D e p t . o f M e d . , K y o t o P r e f e c t u r a l U n i v . o f M e d . , K y o t o , J a p a n .

T o e l u c i d a t e w h e t h e r b a r o r e f l e x r e g u l a t e n o r a d r e n e r g i c i n p u t t o p o s t e r i o r h y p o t h a l a m u s i n SHR, c a t e c h o l a m i n e s w e r e m e a s u r e d i n t h e p e r f u s a t e c o l l e c t e d by m i c r o - d i a l y s i s o f t h e p o s t e r i o r h y p o t h a l a m u s i n SHR a n d WKY w i t h o r w i t h o u t s i n o a o r t i c d e n e r v a t i o n s ( S A D ) . N o r e p i n e p h r i n e w a s s i g n i f i c a n t l y h i g h e r i n 9 w e e k o l d SHR t h a n i n a g e d m a t c h e d WKY b e f o r e SAD o p e r a t i o n s . 2 4 h o u r s a f t e r SAD o p e r a t i o n s , s y s t o l i c b l o o d p r e s s u r e s w e r e s i g n i f i c a n t l y h i g h e r i n SAD-WKY t h a n in s h a m -o p e r a t e d WKY. H e a r t r a t e w a s a l s o i n c r e a s e d i n SAD-WKY. H o w e v e r , SAD d i d n o t e l e v a t e d b l o o d p r e s s u r e , n o r h e a r t r a t e i n SHR. E x t r a c e l l u l a r n o r e p i n e p h r i n e in t h e p o s t e r i o r h y p o t h a l a m u s w a s s i g n i f i c a n t l y l a r g e r i n SAD-WKY t h a n i n s h a m -o p e r a t e d WKY. In SHR, SAD d i d n o t i n c r e a s e t h e e x t r a c e l l u l a r n o r e p i n e p h r i n e . T h e s e f i n d i n g s s u g g e s t t h a t n o r a d r e n e r g i c i n p u t i n t o t h e p o s t e r i o r h y p o t h a l a m u s i s i n h i b i t e d by b a r o r e f l e x i n n o r m o t e n s i v e r a t s , h o w e v e r , n o r a d r e n e r g i c i n p u t i s e n h a n c e d i n SHR a n d i n h i b i t i o n by b a r o r e f l e x i m -p a i r e d .

E x t r a c e l l u l a r N o r e p i n e p h r i n e in H y p o t h a l a m u s

η SHAM SAD t

WKY 6 9 4 . 9 + 1 9 . 1 2 6 8 . 0 ± 3 8 . 0 P < 0 . 0 1

SHR 6 2 0 6 . 0 ± 2 4 . 8 2 6 6 4 ± 2 3 . 5 NS

1424 THE CELLULAR ACTION OF BRADYKININ ON VASCULAR SMOOTH MJJSCLE. K . T a k e u c h i 1 , K. A b e 2 , M. Yasujima] , M. S a t o 1 , K. Qmata1, Y. Kasai, M. Kanazawa and K. Yoshinaga . Second Department of Internal Medicine and ^Department of Clinical B i o l o g y and Homornal R e g u l a t i o n , Tohoku University School of Medicine, Sendai, JAPAN.

The aim i s t o examine e f f e c t s of BK on i n t r c e l l u l a r messengers, calcium (Ca ) and cAMP, in cul tured VSM c e l l s . VSM c e l l s were prepared from ra t mesenteric artery by enzymatic dispersion. Superfused monolayers of cultured VSM c e l l s loaded with a f l u o r e s c e n c e Ca indicator, fura -2 , were set in a fluorometer, and a simultaneous change in c y t o s o l i c f r e e calcium ( [ C a 2 + ] i ) and 6-keto-PGF-,a (a metabolite of PGI^, 6KF) production in p e r f u s a t e s was d e t e r m i n e d in o r d e r t o show a t i m e - c o u r s e relationship between them. 6KF and int race l lu lar cAMP were measured by RIA. In superfused VSM c e l l s , we observed a simultaneous increase in

C a 2 + ] i and 6KF production induced by BK (10" M). In the presence of a c e t y l s a l i c y l i c ac id

(10"°M, ASA), BK s t i l l induced an i n c r e s e in [Ca ] i whereas 6KF production was not detected. BK also induced dose-dependent increases in 6KF production and [Ca ] i . Moreover, BK stimulated cAMP formation, which was inhibited by ASA (10" ^4) s ignif icantly . These resul ts indicate that a BK-induced i n c r e a s e in [Ca ] i i s c l o s e l y a s s o c i a t e d with PGI2 synthes is and t h a t BK-induced cAMP f o r m a t i o n i s dependent on PG synthesis. I t i s suggested that the action of BK on VSM mav be brought about by an interaction between Ca and PG^-mediated cAMP messengers.

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HORMOME-INDUCED INTRACELLULAR CALCIUM MOBILIZATIIQN IN VASCULAR SMOQJH MUSCLE. K.TakeuchiT , K.Abe2, M.Yasujima , M. S a t o 1 , M. Kanazawa1 and K. Yoshinaga 1. Second Department of Internal Medicine and Department of Clinical B i o l o g y and Hormonal R e g u l a t i o n , Tohoku University School of Medicine, Sendai, JAPAN.

To study the mechanism of hormone-induced increase in cytosolic free calcium ([Ca ] i ) we examined e f f e c t s of v a s o a c t i v e hormones, vasopress in (VP), angiotensin I I ( A l l ) and bradykinin (BK) on [Ca ] i and a messenger for in t race l lu lar Ca mobilization, i n o s i t o l ( 1 , 4 - f 5 ) trisphosphate ( l n s ( 1 , Λ » 5 ) Ρ ^ ) , in cultured VSM c e l l s . [Ca ] i was measured in monolayers of cultured VSM ce l l s loaded with a fluorescence indicator for Ca , f u r a -2 , in a fluorometer InsPs were separated from -^H-myo-inositol labeled c e l l s using HPLC and the radioact ivi ty was measured. VP, All and BK increased [Ca ] i t r a n s i e n t l y . In the absence of e x t r a c e l l u l a r Ca , VP s t i l l induced an increase in [Ca ] i suggesting an int racel lular Ca mobilization. T h r o u g h HPLC a n a l y s i s , InsP-| , I n s P 2 » I n s ( 1 , 3 , 4 - ) P 3 » I n s ( l , 4 . , 5 ) PQ and InsP^ were s e p a r a t e d and i n d e n t i f i e d . Moreover , the formation of InsPr and InsP^ was suggested. VP and BK i n d u c e i t r a n s i e n t i n c r e a s e s i n Ins(l ,4- ,5 )P3» I n s ( 1 , 3 , 4 - )P3 and InsP^ within 3 0 seconds. These results indicate that hormone-induced increase in [Ca ] i i s partly due to the r e l e a s e of Ca from the i n t r a c e l l u l a r Ca storage s i t e s , and suggest that a formation of not only Ins(l , 4 , 5 ^ 3 but also Ins ( 1 , 3 , Λ ) ? 3 a 5 d

InsP/ may be involved in the int race l lular Ca iiobilization.

|1427|

THE EFFECT OF ORAL Ca AND Mg AND THE ROLE OF 0PI0IDERGIC SYSTEM ON THE DEVELOPMENT OF DOCA-SALT HYPERTENSION K. Hattori , H. Sano*, Y. Kubota, J . Kawahara, T. Miki, H. Suzuki and H. Fukuzaki. Kobe University, Kobe, 650, JAPAN

The purpose of this study was to determine the effect of oral calcium (Ca) and/or magnesium (Mg) and the role of opioidergic system on the development of DOCA-salt hypertension. Forty one male Wistar rats were divided into four groups and fed each of the d i e t s : 7%NaCl (C), 7%NaCl+ l%Ca (Ca), 7%NaCl+0.25%Mg (Mg) or 7%NaCl+l%Ca+ 0.25%Mg (Ca+Mg) were added to standard die t . All rats were treated DOCA (30 mg/kg) and blood pressure (BP; mmHg) was measured every week. After 5 weeks, the animals were sacrificed and intraerythrocyte sodium, magnesium and potassium contents (R-Na, Mg, K: mEq/Ι·cells) and plasma 3-endorphin concentration (3-END: pg/ml) were measured. Results were given below.

BP R-Na R-Mg 3-END C 227132 9 .2±1.2 7 .8±0.6 45.1±13.4 Ca 166134***8.110.9* 6 .8+0 .3***70 .7+17 .4** Mg 180+25** 7 .9+0.6** 7.7+0.4 58.0+20.1 Ca+Mg 163121***7.6+0.4***7.3+0.6 83 .8+24 .8***

* p<0.05, ** p<0.005, *** p<0.001 vs C group BP correlated significantly with both R-Na (r=0 .416 , p<0.001) and 3-END ( r = - 0 . 4 4 5 , p<0.005) . Between R-Na and 3-END, negative correlation was indicated ( r= -0 .437 , p<0.005) . These results suggest that Ca and/or Mg supplementation attenuates the development of DOCA-salt hypertension through decreased intracel lular sodium, and that this hypotensive effect of Ca is accompanied by the increase of plasma 3-endorphin.

|1426|

BENEFICIAL EFFECT OF DIETARY LINOLEIC ACID ON BLOOD PRESSURE IN RATS J . Kawahara, H. Sano*, Y. Kubota, K. Hattori , T. Miki, H. Suzuki and H. Fukuzaki. Kobe University, Kobe, 650, JAPAN

To elucidate the effects of dietary l inoleic acid (C^g_2) and sa l t on blood pressure, 28 male Wistar ra ts were fed a high LA (15%sunflower oil+5%lard o i l , HLA), a low LA diet (20%lard o i l , DLA), with basal sa l t (0.15%NaCl, BS) or high s a l t (8%NaCl, HS). We measured systol ic blood pressure (SBP, mmHg) every week. After 6 weeks, we determined erythrocyte sodium (R-Na; mEq/l« c e l l s ) , ouabain sensitive 2 2 Na efflux rate constant (Kos, / h ) , plasma fa t ty acid composition (umol/1) and urinary prostaglandin E2 excretion (PGE2; ng/day). Results were as follows.

SBP R-Na Kos BS-LA 123.6+5.6 8.21+0.68 0.809+0.090 BS-DLA 137.116.4* 8 .32+0.62 0.818+0.144 HS-LA 125.7+5.4 8.24+0.28 0.718+0.103 HS-DLA 145.6111.7## 8.75+0.42// 0.60510.070#

PGE2 Plasma C BS-LA 4 .412 .5 4 .0+1 .3 *p<0.05, **p<0.005 BS-DLA 1.4+0 .3** 1 .5+0.4** vs BS-LA HS-LA 1.6+0.3 3 .2+0 .9 //p<0.05, #//p<0.005 HS-DLA 1.3+0.2 1.4+1.0//// vs HS-LA SBP correlated with PGE2 ( r = - 0 . 7 1 , p<0.02) in BS and Kos ( r = - 0 . 5 8 , p<0.05) in HS. Kos correlated with R-Na ( r = - 0 . 5 8 , p<0.05) and plasma C 1 8 _ 2

concentration ( r=0 .66 , p<0.01) in HS. In conclusion, dietary l inoleic acid resulted in lowered blood pressure under both dietary sodium levels . I t s effect might be due to increase in PGE2 under the BS diet and the elevation of Na-K pump a c t i v i t y , resulting in a decrease in intracel lular sodium under the HS die t .

1 4 2 8

DIETARY LINOLEIC ACID PREVENTS THE DEVELOPMENT OF DOCA-SALT HYPERTENSION J . Kawahara, H. Sano*, Y. Kubota, K. Hattori , T. Miki, H. Suzuki and H. Fukuzaki. Kobe University, Kobe, 650 JAPAN

To examine the effect of l inoleic acid (LA) on the development of DOCA-salt hypertension, 32 male Wistar rats were fed one of the following diets with 8%NaCl: a high (20%sunflower oil;HLA), a moderate (5%lard oil+15%sunflower oil;MLA), or a low LA diet (20%lard oil;DLA). After 4 weeks, we determined erythrocyte sodium, magnesium concentration (R-Na, Mg;mEq/l*cells), erythrocyte ouabain sensitive 2 2 Na efflux rate constant (Kos; / h ) , lymphocyte magnesium content (L-Mg;nEq/mg. protein) and cytoplasmic free calcium concentration of thymic lymphocyte (L-[Ca2+]i ; nM). Results were as follows.

BP R-Na R-Mg HLA (n=ll) 152+15 7.35+0.58 7.19+0.41 MLA (n=10) 175+19//// 7.95+0.70// 6.76+0.24//// DLA (n=ll) 183+19** 8 .1910.32* 6 .6710.35**

Kos L-[Ca2+]j L-Mg HLA 0.775+0.169 114.3+9.5 159.2+37.7 MLA 0.631+0.129// 141. 1 + 22 .0* 130.3+15.3// DLA 0.59910.196// 130.2112.9* 130.2119.7//

// p<0.05, //// p<0.01, * p<0.005, ** p<0.001 vs HLA Blood pressure (BP;mmHg) correlated with R-Mg ( r = - 0 . 6 6 1 , p<0.001) and L - [ C a 2 f ] i ( r=0 .514 , p<0.005) . Kos correlated with R-Mg ( r=0 .658 , p<0.001) and R-Na ( r = - 0 . 3 9 2 , p<0 .05) . Dietary l inoleic acid attenuated the development of DOCA-salt hypertension. I t s hypotensive effect might be due to decrease in intracel lular sodium and calcium concentration and the elevation of Na-K pump ac t iv i ty possibly through increase in intracel lular magnesium content.

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SUPPRESSIVE EFFECT OF SULFATE ON THE DEVELOPMENT OF HYPERTENSION IN DOCA-SALT HYPERTENSIVE RATS Y. Kubota, H. Sano*, J. Kawahara, K. Hattori , T. Miki, H. Suzuki and H. Fukuzaki. Kobe University, Kobe, 650 JAPAN

Recently many investigators proposed the importance of anion, especially chloride, in the development of salt-dependent hypertension. The purpose of this study was to examine the effect of sulfate on blood pressure in DOCA-salt hypertension. At 4 weeks of age, 39 male Wistar ra ts were divided into 4 groups, and received one of the following drinking solution: d is t i l led water (C), 1% sodium chloride (Na), 1% sodium chloride plus 12 mM magnesium sulfate (S0) , or 1% sodium chloride plus 12 mM magnesium chloride (S©). All groups were treated with DOCA (30 mg/kg) every week. Blood pressure (BP; mmHg) was measured every week. After 5 weeks of feeding, intraerythrocyte calcium concentration (R-Ca; pmol/Lcell) and cardiac norepinephrine content (NE; ng/lOOg) were determined. Results (meaniSD) at the end of the study were'shown as follows.

C(n=ll) Na(n=7) S0(n=ll) S0(n=ll) BP 145110 204±26** 213±26$S 168±17*Δ R-Ca 11.7±6.1 15.7±8.0 1 7 . 4 ± 6 . 5 + 11.5±3.0 NE 628±103 366±95** 443±87**f j-671±66A * p<0.05, ** p<0.005 vs C; 1- ρ <0 .05 , i f ρ <0.005 S- vs S+; Δ p<0.005 vs Na

BP significantly correlated with NE ( r = - 0 . 7 0 , p<0 .001) , and R-Ca ( r=0 .45 , p<0.005) . R-Ca correlated with NE ( r = - 0 . 3 6 , p<0 .05) . These results suggest that sulfate ion suppresses the development of hypertension in DOCA-salt treated rats at least in part by i t s inhibitory effect on sympathetic nervous ac t iv i ty through the decreased intracel lular calcium concentration.

1 4 3 1

EFFECTS OF CALCIUM CHANNEL BLOCKERS ON RENAL FUNCTION AND ATRIAL NATRIURETIC POLYPEPTIDE IN SPONTANEOUSLY HYPERTENSIVE RATS (SHR) WITH RENAL ABLATION. M. Kanazawa, K. Abe, M. Yasujima*, K. Yoshida, M. Sato , K. Takeuchi, K. Tsunoda, K. Kudo, Y. Kasai , K. Yoshinaga. 2 n d Dept. of I n t e r n a l Medicine, Tohoku Univ. Sch. Med., Sendai, Japan

To determine whether c o n t r o l of blood pressure by calcium channel blockers could a f f e c t the renal funct ion and l e v e l s of a t r i a l nat r iuret ic polypeptide (ANP) in SHR with renal a b l a t i o n , we studied e f f e c t s of benidipine (B) ( 3 m g / k g / d a y ) and n i l v a d i p i n e (N) ( 1 0 mg/kg/day), newly developed blockers of calcium channel for I 4 days on s y s t o l i c blood pressure (SBP), serum c r e a t i n i n e , blood urea ni t rogen (BUN), and plasma ANP c o n c e n t r a t i o n in SHR subjected to 5 / 6 nephrectomy a week before . Three weeks af ter the surgery, SBP (mmHg) in the untreated group was 2 5 3 ± 9 ( n = 1 0 ) , in the Β group 1 9 7 ± 9 ( n = 7 , ρ < 0 . 0 5 ) and in the Ν group I 4 6 ± 9 ( n = 7 , ρ < 0 . 0 5 ) . Both serum creatinine and BUN were lower in the Β group but not in the Ν group 3 weeks a f t e r 5 / 6 nephrectomy compared to the unt rea ted group. Plasma ANP c o n c e n t r a i t o n was s i g n i f i c a n t l y reduced by the treatment with Β but not with N. The present r e s u l t s suggest t h a t e l e v a t i o n of plasma ANP l e v e l s in SHR with remnant kidney model i s not r e l a t e d only to e levated blood p r e s s u r e , but may depend on the s e v e r i t y of impaired r e n a l function.However, i t remains to be determined whether the reduct ion of blood pressure by calcium channel blockers may be involved in the delayed progress ion of r e n a l fa i lure in this model.

1 4 3 0

24 HOUR AMBULATORY BLOOD PRESSURE MONITORING DURING ONCE DAILY ENALAPRIL THERAPY J . YASKY* - J . Godoy - J . Roca - B. Yasky Universidad J.A.Maza . Mendoza. Rep. Argentina

Enalapril Maleate (E) is a converting enzyme inhib i t o r . The duration of the anti-hypertensive e f f e c t of (E) i s disputed. Using 24 hrs . ambulatory blood presure monitoring (A.B.P.M.) wich permite to obtain over 200 blood pressure (BP) determinations during 24 hrs, we performed a study to asses the duration of the action of (E) administered once daily and i t s effects on the 24 hrs . rhythm of the (BP) 20 patients (P) were studied. The (P) had a wash-out period of 4 weeks. The basal BP was 176 , 7 / 1 0 5 , 5 , After completion of the i n i t i a l recording, therapy was begun with an oral dose of 10 mg. CE). The CP) were followed up at 4 weeks intervals In CP) whose diastol ic B.P. did not decrease below 90 inmHg the dose of (E) was incresed to 20,30 and 40 mg/day. After a new period of 4 weeks of t r e a t ment each CP) underwent a new 24 hr. A.B.P.M. Both Systolic and Diastolic B.P. values remained significantly reduced throughout day and night (P. 0,05) The abnormal values over 140 Sis to l i c were 54,7% and over 90 Diastolic were 49,9%, after trea. tment the values were 23,3% (P. 0,05) and 16,9% (P 0,05) and the basal B.P. values 139 ,7 /88 ,2 . This study shows that : 1*CE) i s and excelent drug for treatment of mild

to moderate hypertension. 2'One dose is enough to normalize values through

out the day and night. 3*(E) i s a good anti-hypertensive drug and not a

simple hypotensive agent. 4*The secondary effec ts were only 10%.

1 4 3 2

CHRONIC EFFECTS OF SYNTHETIC ENDOTHELIN ON BLOOD PRESSURE AND SODIUM EXCRETION IN RATS. M. Yasujima*, K. Abe, M. Kanazawa, K. Yoshida, M. Sato, K. Takeuchi, K. Tsunoda, K. Kudo, Y. Kasai , K. Yoshinaga. 2 n d Dept. of I n t e r n a l Medicine, Tohoku Univ. Sch. Med., Sendai, Japan.

To assess whether endothelin could act as a circulating hormone in the regulaiton of blood pressure and sodium excretion, we studied the e f f e c t of c h r o n i c i n f u s i o n of s y n t h e t i c e n d o t h e l i n on s y s t o l i c blood pressure and urinary sodium excretion in conscious r a t s , and a l s o evaluated the e f f e c t s of benidipine, a newly developed blocker of calcium channel in r a t s infused with endothelin. Continuous i n f u s i o n of e n d o t h e l i n a t a r a t e of 6 0 ug/kg/day for 6 days in the jugular vein v ia osmotic minipumps induced a sustained increase in s y s t o l i c blood p r e s s u r e , but not in ur inary sodium excretion, compared to those in vehicle-infused r a t s . When 6 mg/kg/day of benidipine was administered by gavage simultaneously with 6 0 u g /kg /day of endothelin, the systol ic blood pressure rose on Day 1 to only 1 3 7 . 0 ± 2 . 4 mmHg, compared to the r i s e to 1 6 3 . 8 ± 4 . 7 mmHg when endothelin alone was infused (p < 0 . 0 5 ) . The a n t i h y p e r t e n s i v e e f f e c t of benidipine was sustained for the entire experimental period and was not associated with any significant change in ur ianry sodium e x c r e t i o n . The p r e s e n t r e s u l t s suggest t h a t endothelin can a c t as a circulating hormone and might be involved in the regulation of blood pressure. In addition, they c l e a r l y demonstrate t h a t blockade of calcium channel with benidipine attenuated the elevation of blood pressure induced by endothelin.

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|1435l EFFECTS OF ENDOTHELIN ON VASCULAR SMOOTH MUSCLE CELL PHOSPHOLIPID METABOLISM. TJ Resink, Τ Scott-Burden, FR Buhler. Dept. Research, University Hospital, B a s e l , Switzerland

Cultured vascular smooth muscle cells (VSMC) from bovine, porcine and rat aor-tae, and from human saphenous vein and omental microarterioles have been studied w i t h respect to biochemical responses to endothelin ( E T ) . Regardless of VSMC type ET-induced rapid polyphosphoinositide hydrolysis, accumulation of inositol polyphosphates and generation of d i a c y l -glycerol. Using [ 3 H ] - a r a c h i d o n i c acid ( [ 3 H ] - A A ) prelabelled VSMC, ET was found to cause extracellular release of [ 3H]-AA label which derived from p h o s p h a t i d y l i n o sitol and phosphatidylcholine. This p r o cess was sensitive to the phospholipase A 2 inhibitor quinacrine but insensitive to neomycin, a phospholipase C inhibitor, suggesting independent parallel activation of these signal transduction p a t h ways by ET. Release of [ 3H]-AA was in h i -bitable by lipoxygenase but not cyclooxygenase inhibitors. VSMC from s p o n t a n e o u s ly hypertensive and normotensive rats exhibited differential responses to ET. Although V S M C responses to ET were o p t i mally observed in quiescent V S M C , ET per se did not alter the mitogenic state of quiescent VSMC in spite of its ability to activate phospholipase C, elevate intracellular pH and promote S 6 - k i n a s e activation.

1 4 3 4

DIFFERENCES IN NOREPINEPHRINE (NE) INDUCED CONTRACTIONS, 8 6 Rb EFFLUX AND INOSITOL LIPID METABOLISM IN ARTERIES FROM WKY AND SHR. Robert H. Cox* and Edward LaBelle. Bockus Res. Inst, The Graduate Hosp. & Dept. of Physiol., Univ. of PA, Phila., PA

The objective of these studies was to explore possible mechanisms responsible for the augmentation of NE responsiveness of arteries in the SHR. The thoracic aorta (A), tail artery (TA) and mesenteric artery (MA) branches were obtained from 20 week old, male WKY and SHR. Rings (2.5-3mm) were mounted isometrically in a bath for measurement of contractile responses. Other segments (2-4mg) were mounted on glass holders and incubated for 3 hours in 8 6 Rb for conventional efflux experiments. The remaining segments were incubated in 3H-inositol for six hours to label phospholipids (PL). The tissues were frozen in liquid nitrogen, homogenized and inositol phosphate classes separated. For contractile responses, a larger EC50 to norepineprhine was observed in thoracic aorta (15 fold) and mesenteric arteries (3 fold) but not in tail arteries. Maximum active stress, however, was only lower in the thoracic aorta of SHR. For 8 6Rb efflux, basal rate constants were higher in all arteries from the SHR in the following order: A>MA>TA. Rate constants remained higher at all doses of NE in the SHR but no differences in sensitivity to NE were found at any site. For PI hydrolysis,basal rates of production of all inositol phosphates (IP, IP2 and IP3) in the presence of 10 mM Li were higher in the SHR aorta than WKY but not the other two sites. NE increased labeling of all the IPs in both WKY and SHR aorta with larger increases observed in the latter with no differences in sensitivity. The results also suggested an increase in labeling of IP3 in TA and MA of SHR. The results of this study suggest an augmented production of IPs in SHR aorta under basal as well as with NE activation contributing to augmented 8 6 Rb efflux and increased sensitivity of contractions to NE .

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ENDOTHELIAL V A S O C O N S T R I C T O R V A S O D I L A T O R IMBALANCE IN HYPERTENSION. TF Liischer. Departments of Research and Me d i c i n e ( C a r d i o l o g y ) , U n i v e r s i t y H o s p i t a l , B a s e l , Switzerland

The endothelium is a source of v a s o d i lator and vasoconstrictor hormones in the circulation. Endothelium-derived relaxing factor ( E D R F ) , the endogenous nitrate, is an important v a s o d i l a t o r . The endothelium can also release prostacyclin and e n d o thelium-derived hyperpolarizing factor ( E D H F ) . Under some c o n d i t i o n s , the e n d o thelium produces vasoconstrictors such as endothelin, angiotensin II, h y p o x i a - i n d u -ced endothelium-derived contracting factor ( E D C F X ) and a cycl o o x y g e n a s e - d e r i v e d contracting factor ( E D C F 2 ) . In h y p e r t e n sion, m o r p h o l o g i c a l and functional changes of the endothelium occur. E n d o t h e -lium-dependent relaxations are impaired in the aorta, carotid artery and in the mesenteric and cerebral m i c r o c i r c u l a t i o n of hypertensive rats. The me c h a n i s m involves a reduced responsiveness to EDRF in larger arteries and, at least in the spontaneously hypertensive rat, the r elease of E D C F 2 . The reduced endothelium-dependent relaxations in hypertension can be normalized by antihypertensive therapy. In hypertensive mesenteric resistance arteries, endothelin overrides EDRF. An imbalance of endothelial vasodilator and constrictor systems m a y contribute to the pathophysiology of hypertension.

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1 4 3 7

REGIONAL VASCULAR RESPONSES TO E N D O T H E L I N : EV ID EN CE THAT V A S O D I L A T A T I O N P R E D O M I N A T E S . H . L . L i p p t o n , J . G o f f , G . C o h e n , A . H y m a n . D e p a r t m e n t o f P u l m o n a r y , LSU M e d i c a l C e n t e r , New O r l e a n s , LA 7 0 1 1 2 .

T h e e f f e c t s h u m a n e n d o t h e l i n ( H E D T ) w e r e s t u d i e d i n t h e c e l i a c , r e n a l , h i n d q u a r t e r s a n d m e s e n t e r i c v a s c u l a r b e d o f t h e c a t u n d e r c o n d i t i o n s o f c o n s t a n t b l o o d f l o w s o t h a t c h a n g e s i n r e g i o n a l p e r f u s i o n p r e s s u r e d i r e c t l y r e f l e c t c h a n g e s i n r e g i o n a l v a s c u l a r r e s i s t a n c e . R a p i d b o l u s i n j e c t i o n s o f H E D T , 1 0 - 3 0 n g i n t o t h e c e l i a c a n d r e n a l v a s c u l a r b e d s d e c r e a s e d p e r f u s i o n p r e s s u r e w h e r e a s 1 0 0 n g p r o d u c e d a b i p h a s i c r e s p o n s e a n d h i g h e r d o s e s , 3 0 0 - 1 0 0 0 n g , i n c r e a s e d p e r f u s i o n p r e s s u r e . R a p i d b o l u s i n j e c t i o n s o f H E D T , 3 - 3 0 0 n g , m a r k e d l y d e c r e a s e d h i n d q u a r t e r s p e r f u s i o n p r e s s u r e i n a d o s e -d e p e n d e n t f a s h i o n . I n c o n t r a s t , H E D T , 3 0 - 3 0 0 n g p r o d u c e d o n l y d o s e - r e l a t e d i n c r e a s e s i n m e s e n t e r i c p e r f u s i o n p r e s s u r e w h i c h w a s n o t a l t e r e d b y m e c l o f e n a m a t e ( 2 . 5 m g / k g i . v . ) a n d p h e n t o l a m i n e ( 2 m g / k g i . v . ) . T h e m e s e n t e r i c v a s o c o n s t r i c t o r r e s p o n s e t o HEDT a n d t o B a y Κ 8 6 4 4 , a c a l c i u m c h a n n e l a g o n i s t a t l - 3 u g , w a s i n h i b i t e d b y i n f u s i o n o f n i f e d i p i n e , 3 i » . g / m i n i n t o t h e s u p e r i o r m e s e n t e r i c a r t e r y , n h e p r e s e n t d a t a d e m o n s t r a t e t h a t t h e r e g i o n a l v a s c u l a r r e s p o n s e t o HEDT v a r i e s . M e s e n t e r i c v a s o c o n s t r i c t i o n i n r e s p o n s e t o HEDT a p p e a r s t o o c c u r b y a m e c h a n i s m i n d e p e n d e n t o f a l p h a a d r e n o c e p t o r s a n d c y c l o o x y g e n a s e p r o d u c t s b u t may d e p e n d o n e x t r a c e l l u l a r c a l c i u m . S i n c e t h e s y s t e m i c r e s p o n s e t o i n t r a v e n o u s a d m i n i s t r a t i o n o f HEDT i n t h e c a t i s v a s o d i l a t i o n , i t i s l i k e l y HEDT e x e r t s a l a r g e p o r t i o n o f i t s a c t i o n s b y d i l a t i n g b l o o d v e s s e l s s u p p l y i n g s k e l e t a l m u s c l e . T h e p r e s e n t d a t a s u g g e s t t h a t a t l o w e r c o n c e n t r a t i o n s , t h e p r e d o m i n a n t a n d p o s s i b l y t h e p h y s i o l o g i c a l r e s p o n s e t o HEDT i s v a s o d i l a t a t i o n .

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SALTSENSITIVITY IN PATIENTS WITH ESSENTIAL HYPERTENSION: ROLE OF RENIN, ALDOSTERONE AND ANP. G. Wambach, Μ. S t i m p e l , S. D&genhardt, G. B a n n e r , W. Kaufmann. D e p t . of Medic ine I I U n i v e r s i t y of Cologne We i n v e s t i g a t e d t h e impact of h igh and low N a + - i n t a k e on a r t e r i a l blood p r e s s u r e ( b p ) , on r e n i n - a l d o s t e r o n e , and on ANP in e s s e n t i a l , h y p e r t e n s i o n ( E H ) . 19 p a t i e n t s w i t h EH ( 1 3 m / 6 f ) a g e 4 5 . . 8 ± 2 . 6 y , were i n c l u d e d . A f t e r 4 days on low N a ^ - d i e t ( N a + 4 0 - 6 0 , K+BO meq/d) and s i x d a y s o f sodium.- l o a d i n g ( N a + 2 8 . 0 - 3 2 0 , K + 6 0 meq/d ) , we m e a s u r e d : s i t t i n g b p , 2 4 - h o u r bp ( F a . N a t i c ) , u r i n a r y e x c r e t i o n of Na+ ( U N a - ) , K+(UK+) and a l d o s t e r o n e XUA). P l a s m a - r e n i n ( P R C ) , ANP and a l d o s t e r o n e (SA) were measured a t 8 a.m.. and a g a i n a f t e r 4h p o s t u r e . In a l l p a t i e n t s UNa +

r o s e from 6 1 . 7 1 5 . 5 t o 3 0 8 1 1 6 ( m e q / d ) ; PRC d e c r e a s e d from 2 9 . 7 + 5 . 2 t o 6 . 1 ± 1 . 2 ( μ ϋ / m l ) ; UA dropped from 2 7 . 2 ± 2 . 4 t o 1 1 . 8 ± 1 . 5 ( u ^ / d ) . ANP i n c r e a s e d from 6 8 . 4 1 1 6 . 0 t o 1 1 2 . 5 1 2 0 . 1 ( p g / m l ) . 5 p a t i e n t s w i t h a d i f f e r e n c e in d i a s t o l i c bp of more than 5 mmHg between high and low s a l t , i n t a k e were c l a s s i f i e d a s s a l t s e n s i -t i v e ( S S ) ; t h e r e m a i n i n g p a t i e n t s were s a l t r e s i s t a n t ( S R ) . There was no d i f f e r ence in a g e , s e x and UNa+ between SS and SR. The s y s t o l i c and d i a s t o l i c bp in SS was h i g h e r on low and high N a + i n t a k e . SS had lower PRC and h i g h e r ANP v a l u e s d u r i n g low sodium i n t a k e than SR. High ANP and t h e b l u n t e d r e n i n r e s p o n s e might c o n t r i b u t e t o s a l t s e n s i t i v i t y in EH.

1 4 3 8

HUMAN AND RAT E N D O T H E L I N PRODUCE S Y S T E M I C V A S O D I L A T A T I O N I N R A T , C A T AND R A B B I T . H . L . L i p p t o n , * G . C o h e n a n d A . H y m a n . D e p a r t m e n t o f P u l m o n a r y M e d i c i n e , L S U M e d i c a l C e n t e r O r l e a n s , LA 7 0 1 1 2 .

T h e e f f e c t s o f h u m a n a n d r a t e n d o t h e l i n ( E D T ) w e r e c o m p a r e d i n t h e s y s t e m i c v a s c u l a r b e d o f t h e a n e s t h e t i z e d r a t , c a t a n d r a b b i t . R a p i d b o l u s i n j e c t i o n s o f h u m a n o r r a t E D T , 1 0 0 - 1 0 0 0 n a n o g r a m s , i n t o t h e f e m o r a l v e i n d e c r e a s e d s y s t e m i c a r t e r i a l p r e s s u r e i n a l l s p e c i e s i n a d o s e - d e p e n d e n t m a n n e r . Human a n d r a t EDT i n c r e a s e d c a r d i a c o u t p u t a n d s i g n i f i c a n t l y d e c r e a s e d s y s t e m i c v a s c u l a r r e s i s t a n c e . M i l d s y s t e m i c h y p e r t e n s i o n l a s t i n g 5 - 1 0 m i n f o l l o w e d t r i e i n i t i a l v a s o d i l a t a t i o n . I n j e c t i o n s o f h u m a n EDT i n t o t h e r i g h t a t r i u m a n d l e f t a t r i u m p r o d u c e d s i m i l a r r e d u c t i o n s i n s y s t e m i c v a s c u l a r r e s i s t a n c e . T h e s y s t e m i c h y p o t e n s i v e r e s p o n s e t o h u m a n EDT i n c a t a n d r a b b i t w a s n o t a l t e r e d b y p r o p r a n o l o l , a t r o p i n e , i n d o m e t h a c i n a n d BN 5 2 0 2 1 i . v . When t h e d i s u l f i d e b r i d g e s i n EDT a r e b r o k e n , t h e r e s i d u a l 2 1 a m i n o a c i d p o l y p e p t i d e d i d n o t a l t e r s y s t e m i c a r t e r i a l K r e s s u r e . When s y s t e m i c r e s p o n s e s a r e c o m p a r e d ,

uman EDT h a s s l i g h t l y g r e a t e r a c t i v i t y t h a n r a t E D T . A l t h o u g h h u m a n a n d r a t EDT h a v e a s i m i l a r s e q u e n c e f o r t h e s i x a m i n o a c i d s a t t h e c a r b o x y -t e r m i n a l " t a i l , " t h i s h e x a p e p t i d e h a s n o h e m o d y n a m i c a c t i v i t y i n v i v o . T h e p r e s e n t d a t a d e m o n s t r a t e t h a t EDT H a s p o t e n t v a s o d i l a t o r p r o p e r t i e s . T h e p r e s e n t d a t a s u g g e s t EDT i s n o t a l t e r e d b y " f i r s t p a s s " p u l m o n a r y m e t a b o l i s m a n d f u r t h e r s u g g e s t EDT d i l a t e s t h e s y s t e m i c v a s c u l a r b e d i n d e p e n d e n t o f a c t i v a t i o n o f b e t a a d r e n e r g i c , m u s c a r i n i c a n d p l a t e l e t - a c t i v a t i n g f a c t o r r e c e p t o r s a s w e l l a s f o r m a t i o n o f c y c l o o x y g e n a s e p r o d u c t s . T h e p r e s e n t d a t a s u g g e s t t h a t t h e i n t e g r i t y o f t h e t h i o l b n d g e ( s ) i n t h e EDT m o l e c u l e a r e n e c e s s a r y f o r a c t i v i t y a n d may b e i m p o r t a n t i n t e r m i n a t i n g t h e p e p t i d e ' s a c t i o n .

1 4 4 0

D E T E R M I N A T I O N OF FREQUENCY AND DURATION OF A M B U LATORY BLOOD PRESSURE M 0 N I T I 0 R I N G . K . R . B a i l e y , C M . W i l t g e n , S . G . S h e p s * a n d P . K . Z a c h a r i a h * , M a y o C l i n i c , R o c h e s t e r , M N .

A u t o m a t e d a m b u l a t o r y b l o o d p r e s s u r e r e c o r d i n g s ( A B P R ) h a v e b e e n u s e d f o r t h e e v a l u a t i o n o f h y p e r t e n s i o n . H o w e v e r , t h e d u r a t i o n a n d f r e q u e n c y o f ABPR h a v e n o t b e e n e s t a b l i s h e d . T o a s s e s s t h e d u r a t i o n ( n u m b e r ( # ) o f h o u r s , A ) a n d f r e q u e n c y ( m e a s u r e m e n t s / h o u r , B ) n e c e s s a r y t o a c c u r a t e l y p r e d i c t m e a n 2 4 - h o u r B P , d a t a o n 2 2 h y p e r t e n s i v e s w i t h ABPR o n 2 s e p a r a t e d r u g - f r e e o c c a s i o n s w e r e a n a l y z e d b y a n a n a l y s i s o f v a r i a n c e w i t h t e r m s f o r p a t i e n t , o c c a s i o n , i i o u r o f d a y a n d m e a s u r e m e n t w i t h i n h o u r . V a r i a n c e c o m p o n e n t s d u e t o m e a s u r e m e n t v a r i a b i l i t y w i t h i n h o u r , b e t w e e n n o u r s , b e t w e e n p a t i e n t s , p a t i e n t s - b y - d a y s , p a t i e n t s - b y -h o u r s a n d p a t i e n t s - b y - d a y s - b y - h o u r s w e r e e s t i m a t e d a n d u s e d t o c r e a t e a f u n c t i o n g i v i n g t h e v a r i a n c e i n p r e d i c t i n g a p a t i e n t ' s t r u e 2 4 - h o u r m e a n i n t e r m s o f A a n d B . T h e t a b l e b e l o w s h o w s t h e r e s u l t s i n s t a n d a r d d e v i a t i o n s ( S D ) f o r r e p r e s e n t a t i v e v a l u e s o f A a n d B . T h e i m p l i c a t i o n s f o r s e n s i t i v i t y ( S T ) i n c o r r e c t l y d i a g n o s i n g a p a t i e n t a s h y p e r t e n s i v e ( d i a s t o l i c ( D ) B P > 9 0 mmHg) w h o s e t r u e 2 4 - h r m e a n DBP i s 9 5 o r 1 0 0 a r e a l s o

VARIOUS EXTREMES OF A AND Β A = l ; B = l t A = 1 ; B = 2 A = 4 ; B = 1 A = 4 ; B = 2 A = 2 1 ; B = 8

SD 1 1 . 3 7 9 . 8 3 6 . 4 4 5 . 7 7 3 . 8 8 S T * 6 7 % 70% 78% 8 1 % 9 0 % S T * * 8 1 % 8 5 % 9 4 % 9 6 % 9 9 . 5 %

t D e m o n s t r a t e s 1 o f f i c e r e a d i n g * = 9 5 mmHg; * * = 1 0 0 mmHg I n c o n c l u s i o n , a 4 - h o u r ABP r e c o r d w i t h 2 m e a -

s u r e m e n t s / h o u r y i e l d s m o s t o f t h e i m p r o v e m e n t i n ST a v a i l a b l e f r o m 2 4 h r s o f c o n t i n u o u s m o n i t o r i n g .

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114411 IS INCREASED SYMPATHETIC TONE IN EARLY ESSENTIAL HYPERTENSION AN EMOTIONAL ARTEFACT CAUSED BY AWARENESS OF HYPERTENSION? Μ Rostrup, A Westheim, SE Kjeldsen, I Eide. Med.Dep.,U1leva1 University Hospita1, Oslo, Norway.

36 19-year-old men, a l l with identical mildly elevated blood pressure a t a routine medical examination, were randomized in two groups. Group 1 (n=18) was informed that the blood pressure was elevated, group 2 (n=18) was not. A second examination included blind BP and heart ra te (HR) r e c ordings in a l l 36 subjects, while 25 (13 infromed and 12 uninformed) were examined further by i n t r a a r t e r i a l BP recording and a r t e r i a l plasma catecholamines a f t e r 30 min supine r e s t , during cold pressor t e s t (CPT) and mental s t r e s s (MST). Results:

p<0.05 ** p<0 .005) . η Informed Uninformed ρ

SystBP 1.exam (mmHg) 36 152.1+2.3 153.8+2.4 DiaBP 1.exam.(mmHg) 36 90 .7+1 .1 88.9+1.9 HR 2.exar:i. (bpm) 36 74 .5+3 .4 64 .7+2 .7 * Noerepi Rest (pg/ml) 25 207+15 143+13 ** Epi Rest 25 87+12 50+8 Norepi CPT " 25 254+26 173+20 * Norepi MST 25 288+29 198+25 Change in Epi MST" 25 132+35 64±23 Information about hypertension increases resting levels of plasma catecholamines, resting HR and plasma epinephrine response to mental stress. In addition we found an exaggerated pressure and HR response to information about the CPT in the in formed group.Conclusion: Awareness of hypertension may by i t s e l f increase sympathetic tone and response to mental s t r e s s , and a word of caution should be appreciated in studies on early pathophysiology in essential hypertension in which the subjects are aware of their high blood pressure.

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POTENTIAL HYPERTENSION MISDIAGNOSIS IN STRESSFUL MEDICAL EXAMINATIONS. JM Neutel. DHG Smith, DP Myburgh. Inst i tute for Aviation Medicine, Pretoria , S. Africa; University of California, Irvine/VA Medical Center, Long Beach, CA.

The pressor effec t of a doctor 's presence on the blood pressure (BP) of subjects dependent on the outcome of their medical examination was evaluated. In the f i r s t study, 70 pi lots (mean age 4 1 . 7 y r ) , diagnosed as hypertensive on i n i t i a l screening were monitored by an automated BP monitoring system (ABPS) for 40 min. BP was recorded at 6 min intervals in the absence of a doctor. In addition at 0, 20, and 40 min, BP was measured simultaneously by the ABPS and a doctor using the standard auscultatory method. In the second study, 102 normotensive pupil pi lots (mean age 17.6yr) were studied. Casual BP (CBP) was compared to that obtained on the ABPS, recorded in the same manner as in Study 1 but for 20 min. Subjects whose BP's remained elevated were monitored at home for 24h. Of the 70 pi lots in Study 1, 59 normalized within 40 min in the absence of a doctor. Nine of the 12 who remained hypertensive became normotensive within 2h of having l e f t the c l i n i c and remained normal for 24h at home. On casual recording 27.5% of the subjects in Study 2 had a BP within the hypertensive range. One subject (0.9%) remained hypertensive but normalized lh af ter leaving the c l i n i c . The mean diastol ic difference between CBP and ABPS (in Study 2) was 17.6+11.3 mmHg and the mean systol ic difference 17.8+10.6 mmHg (P<0.001) . Thus, in groups dependent on a favorable examination, the value of CBP recording l ies in the exclusion rather than in the diagnosis of hypertension.

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ACUTE HEMODYNAMIC RESPONSES TO SYMPATHETIC ACTIVATION (SA) IN HYPERTENSION AND EFFECTS OF NACADIPINE (NCD). Η Kawamura*, Κ Komatsu, Η Toraori, Κ Suzuki^ £5 1 to, Μ Hatano. Dept. of Medicine, Nihon Univ., Tokyo, Japan.

Acute hemodynamic responses by SA and the effects of new calcium antagonist, NCD, are not fully understood in hypertension. We therefore studied the hemodynamic responses and plasma catecholamines (PCA) by SA. NCD was given to spontaneously hypertensive rats (SHR) and to normotensive control Wistar-Kyoto rats (WKY)(0.1 mg/100 gBW). Hemodynamic parameters were monitored in conscious rats with direct measurement of arterial pressure (AP) and Doppler flowmetry. PCA was also assayed with HPLC. For the SA, foot shock (FS) was delivered to each rat with electrical stimulus. Mean arterial pressure (MAP) was higher in SHR (n=8) than in WKY (n=10)(136 ± 7 vs. 102 ± 5 mmHg, Ρ < 0.01). With FS, the increased MAP was greater in SHR than in WKY (ΔΜΑΡ: 1 7 + 3 vs. 8 ± 1 mmHg, Ρ < 0.01) and this increased MAP was mainly derived from increased total peripheral resistance (TPR). The increased norepinephrine (NE) was also greater in SHR than in WKY (ΔΝΕ: 2411 ± 333 vs. 1153 ± 22 pg/dl, Ρ < 0.01). After NCD treatment, the MAP decreased in SHR (137 ± 7 to 101 ± 5 mmHg, Ρ < 0.01). However, NCD did not decrease the acute elevation of AP and PCA in SHR by FS. We conclude: 1)SA increases AP by mainly increasing TPR in SHR. 2)NCD decreases the chronic elevation of AP in SHR. However, it doesn't decrease the acute elevation of AP by SA.

|14441 ANTIHYPERTENSIVE EFFECT 0Γ CILAZAPRIL IN SEVERE HYPERTENSION. LONG-TERM ASSESSMENT OF LEFT VENTRICULAR AND RENAL FUNCTION. RA Sanchez? CA Tra-balli, EJ Marco, T. Cianciulli, CA Giannone, AJ Ramirez*. Div. of Hypertension, Instituto de Car-diologia, Buenos Aires, Argentina.

The effect of cilazapril (CLZ) monotherapy or in combination with hydrochlorothiazide (IICTZ)was evaluated in 30 severe hypertensive patients, sitting diastolic blood pressure (SDBP) > 115 mm Hg, 23 males and 7 females, range 38-63 years. Fifteen patients had left ventricular hypertrophy (LVH) documented by 2D Doppler echocardiography and in 15 renal function was also studied. Sitting systolic blood pressure (SSEP) was reduced (xfS.E.M.) from 175.3±2.0 to 143.3±3.0 mm Hg after 25 days of therapy (p <0.0001); SDBP decreased from 117.0±0.5 to 87.8±2.0 mm Hg (p <0.0001) whereas heart rate (HR) remained unchanged. In 19 patients followed during 48 weeks the therapeutic response remained stable. The mean dose was CLZ 10 mg plus HCTZ 12.5-25 mg in 90 % of the patients. Glomerular fil tration rate and renal blood flow in 10 patients were not affected by therapy while renal vascular resistance decreased from 0.16^0.0 to 0.10 +0.0 RU (p<0.01). Left ventricular mass (LVM) assessed in 9 patients was reduced from 357+17 to 314± 22 g/1.73 m 2 b.s. (p <0.005) and a significant correlation (r = 0.57 ρ <0.01) was found between LVM and SSBP before and during treatment. Deceleration half time of peak early diastolic inflow velocity decreased from 128Ϊ9 to 108+7 msec (p < 0.05). In conclusion, CLZ plus HCTZ was effective in severe hypertension. LVH regression influenced favorably LV diastolic function in some patients whereas in others this function was not improved supporting the idea of an irreversibility of LVH.

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CORRESPONDENCE BETWEEN THE ACTIVITY OF THE RENIN-ANGIOTENSIN SYSTEM AND THE ERYTHROCYTE Na + TRANSPORT ABNORMALITIES IN HYPERTENSION. A Arrazoia, J Diez. Dept. of Medicine, Univ. of Zaragoza, Zaragoza, Spain.

A kinetic study of the interaction of internal Na + with different erythrocyte Na + transport pathways facilitates the distinction of several subgroups of hypertensives. We present here a study to estimate of the degree of activation of the renin-angiotensin system in each subgroup. The study was performed in 50 non-treated essential hyperten sives and 25 controls. Three subgroups of patients were distinguished: 12 with increased Km of the Na+,K+,C1~ cotransport for internal Na + (Co - patients); 7 with increased Vmax of Li +:Na + counter-transport (Counter + patients) and 31 without any of the above abnormalities (Non Co -,Νοη Counter + patients). As compared to control values plasma renin activity (PRA) was decreased in Co - (0.83+_ 0.20 vs 1.86+0.08 ng/ml/h,M+SEM,P<0.001), increased in Counter + (2.84+0.53,?<0.05) and normal in Non Co -, Non Counter + (1.86+0.64). According to the relation between PRA and urinary Na + excretion patients were categorized in low (L), normal (N) or high renin (H) as follows : Co -: L 42%, Ν 29%, Η 29% ; Counter +: L 0%, Ν 25%, Κ 75%; Non Co -, Non Counter +: L 6%, Ν 61%, Η 33%.

These results indicate that there are correspon dences between the activity of the renin-angiotensin system and the different Na+ transport abnormalities present in erythrocytes of patients with essential hypertension. Further studies are required to draw conclusions on the pathophysiological meaning of these correspondences.

[14471 LEFT WNEBXEAR SIHJUlira: IN fifiraHCIRfiNES EMERIN3 TfE TREMMENT OF MUD HflFEKENSICN SJMK (TOMB): HMJMNAIV B3raroiD3BEH[C CBSERtfKTICNS. FR LiftBcn*, GA Grardits, SB Etiuariaiiba*. Section of Cardiology, Rjsh-St. l ife's Madical Center, Chicapp, IL.

M-Mcde ErhocardiogrenB were obtained art: baseline for 902 mild hyperterBives (Diastolic W 90-99 m*§) to <rrmi left vaitidmlar (IV) septal thickness (ST), posterior wall thickness (FWT), IV internal dinersim (IVID), UJ mass and EV mass index ( I M ) .

Results from 450 physician read edrnyrlicgrans shewed these ed i.n idtiiiograriiic measures were sioriif ioantly associated with systolic blood pressure (SEP), body nass index (ecept for ΓλΜ), and sex. Nfean IV Mass for men was 228 g (DM 111 g/rc2) and for wemen 174 g (DM 96 g/m2). A total of 14% of men and 25% of wemen would be classified as having left VBrfcriccilar hypertrophy ( I M > 134 g/m2 for nm, > 110 g/m2 for wemen). Mean IV mass for tertiles of body mass index was 210,231, and 243 g for men and 156, 177 and 188 g for wemen. The mean IV mass for tertiles of SEP for men was 211, 229 and 245 g (DM 103, 112, 118 g/m2); for wemen 167, 179 and 176 g ( I M 92, 99 and 98 g/m2). No siprrifleant associations were found for age or previous use of antihypertensive drugs for any of the structural cratactpristics. There was no association of IV mass or ΠΜΓ with race (black vs white) trrxrji blacks tended to have larger ST and FWT but smaller IVTD. These results f=ujeml that for this hypertensive population SS 3, obesity as measured by body mass index and male gender are factors in increases in IV mass, but that race/ previous use of antihypertensive therapy and ags do not appear to be sdoriifinant (determinants.

1 4 4 6

BLOOD PRESSURE CHANGE AFTER 12 MONTHS OF FOLLOW-UP FOR BLACK AND WHITE PARTICIPANTS IN THE TREATMENT OF MILD HYPERTENSION STUDY (TOMHS).

Schoenberqer. J. Schnaper, H, Neaton, J, Mascioli, S, Grimm, R, Stamler, J, McDonald, R. For the TOMHS Research Group. Department of Preventive Medicine, Rush Presbyterian-St. Luke's Medical Center, Chicago, Illinois.

In TOMHS, 902 men and women have been randomized to one of six groups: nutritional-hygienic treatment plus either: 1) alphal-antagonist (doxazosin, 2 mg/day), 2) angiotension converting enzyme inhibitor (enalapril, 5 mg/day), 3) beta blocker (acebutolol, 400 mg/day), 4) calcium channel blocker (amlodipine, 5 mg/day), 5) diuretic (chlorthalidone, 15 mg/day), or 6) placebo. The race-sex distribution of randomized participants in TOMHS is 487 white men, 67 black men, 237 white women and 110 black women. As a result of eligibility criteria, baseline systolic (SBP) and diastolic blood pressure (DBP) were similar for blacks and whites, averaging 141 and 91 mmHg, for whites and 139 mmHg and 91 mmHg for blacks. Blacks reported significantly less annual income and were less educated than whites. After 12 months of follow-up, for blacks taking one of the five antihypertensive drugs, DBP decreased by an average of 11 mmHg (range among five groups: 9 to 14 mmHg p=0.31), and SBP decreased by an average of 14 mmHg (range 8 mmHg to 20 mmHg, p=0.04). Among whites the average decrease in DBP was 14 mmHg (range: 12 to 15 mmHg, p=0.34) and was 20 mmHg for SBP (range: 12 to 22 mmHg, p=0.19). For those participants given placebo the average BP decreases were similar for blacks and whites. These preliminary 12 months results based on 564 participants indicate that these active drug treatments given at low doses are effective in lowering BP in blacks and in whites, but may vary in their effectiveness in blacks in lowering SBP. Treatment differences will be discussed.

|1448[

QUALITY OF LIFE (QL) ASSESSMENT IN THE TREATMENT OF 'MILD' HYPERTENSION STUDY (TOMHS).

Grimm. RH. Hughes, G, Launer, C, Schoenberger, J*, McDonald, R, Mascioli, S, Remijas, T, Schnaper, H, Prineas, R \ Cutler, J, and Stamler, J. For the TOMHS Research Group. Divisions of Epidemiology and Biometry, School of Public Health, University of Minnesota.

Phase I of TOMHS is a randomized placebo controlled study of 902 black and white, men and women ages 45-69 with mild diastolic hypertension. Assignment was to one of six groups: 1) placebo, n-232; 2) diuretic, chlorthalidone, n-136; 3) beta blocker, acebutolol, n-132; 4) alpha antagonist, doxazosin, n-134; 5) ACE inhibitor, enalapril, n-135; 6) calcium blocker, amlodipine, n-129. All participants were also advised on weight loss, sodium and alcohol reduction. A QL battery (modified round) was administered at entry, 3 mo. and 12 mo. QL components included 1) general health; 2) energy/fatigue; 3) mental health; 4) general functioning; 5) satisfaction with physical abilities; 6) social functioning. QL parameters improved in all groups from BL to 3 and 12 mo. Only general functioning #4 was improved with combined active treatment compared to placebo. Difference among drug groups will be reported. In any treatment group there is no evidence of lowered QL at 3 and 12 mo.

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114491 HYPER ACTIVATION OF A DIOA-SENSITIVE IK1", C1"]-C0TRANSP0RT SYSTEM IN ERYTHROCYTES AND THYMOCYTES FROM SPONTANEOUSLY HYPERTENSIVE RATS (SHR). R G a r a y * . C Nazaret , A Ar razo la , R Rota, A Soler Diaz, Ρ Hannaert , Y Beuzard, Ε Cragoe J r . INSERM U7. Hopital I Necker. Pa r i s , INSERM U 9 1 . Cre te i l . France & Lansdale. FN. US A.

DIOA (dihydroirujenyloxy acetic acid) is a new compound that potent ly • inhibit.- a [ K + , C f ] - c o t r a n s p o r t sys tem wi thout side effects on the bumetanide-sensit ive [ N a + , K + , C r ] - c o t r a n s p o r t system (Garay et a l . , Mol Pharmacol , 3 3 : 6 9 6 , 1983 ) . In e r y th rocy tes and t hymocy tes , the DIOA-sensi t ive [ K 4 , C f ] - c o t r a n s p o r t sys tem is the unique regulator of cel l swe l l i ng , and has the fo l lowing proper t ies : ( i ) i t is si lent under physiological conditions and ( i i ) i t ext rudes KC1 f r om swol len cel ls (and ind i rect ly w a t e r ) v ia a signal probably transduced by the cytoskeleton. j

SHR e ry th rocy tes have a 10-16"8 decrease in mean corpuscular volume due to a decreased cel l wa te r (and hemoglobin) content(s) per ce l l . There fo re , we invest igated e r y t h r o c y t e and thymocyte [ K + , C I ] -co t ranspor t in f r o m SHR and WKY male ra t s aged 2 0 - 4 0 weeks.

In isotonic media, DIOA-sensi t ive K* e f f lux was 3.67 ± 1.20 and 0 .14 ± 0.14 mmol (1 .cells χ h)~* in SHR and WKY e ry th rocy tes respect ive ly (mean ± SEM of 5 exper iments ; ρ < 0 .05 ) . In hypotonic media ( 1 8 0 ± 5 mOsrn), DIOA-sensit ive K* e f f lux was 11.1 ± 2.6 vs 4.51 ± 0.75 mmol (1.cells χ h ) " 1 in SHR and WKY e r y t h r o c y t e s respect ive ly (p < 0 . 0 5 ) .

SHR thymocytes had normal o r s l ight ly increased cel l volume. In both SHR and WKY t h y m o c y t e s , a hypotonic s t ress ( 2 0 0 ± 5 mOsm) induced a 3 6 - 3 8 increase in cel l vo lume, and the regulatory capacity was 2 2 - 2 6 μ 3 a f te r 3 0 - 6 0 min . However , SHR thymocytes exhibi ted fas te r regulatory volume decrease than WKY thymocytes (t^ / 9 was 1 and 3.5

min in SHR and WKY thymocy tes respec t i ve l y ) . In conclusion, SHR e ry th rocy tes have a decreased cel l volume

because thei r [ K + , C T j - co t ranspor t sys tem is abnormally operat ing under physiological condit ions (due perhaps to a lack of repress ion by the cytoskeleton) . The hyper act ivated [ K + , Cl~ ] -cot ranspor t sys tem of SHR thymocytes and the presence o f a DIOA-sensit ive [ K + , CI j - co t ranspor t sys tem in vascular smooth muscle cells (see Abst rac t of Sai t ta et al.) suggest that this membrane-cytoskeleton defect may af fect vascular funct ion in SHR.

1 4 5 1

THE RENAL HEMODYNAMIC RESPONSE TO CAPTOPRIL D I F F E R E N T I A T E S R E

NOVASCULAR FROM E S S E N T I A L H Y P E R T E N S I V E S . F A r z i l l i * . R G i o v a n -

n e t t i , Μ L e n z i , A S a l v e t t i * . C l i n i c a M e d i c a I , U n i v e r s i t y o f P i

s a , 5 6 1 0 0 P i s a , I t a l y .

To d e t e c t a n g i o t e n s i n - m e d i a t e d f o r m s o f : h y p e r t e n s i o n , C a p t o

p r i l was a d m i n i s t e r e d t o 18 r e n o v a s c u l a r h y p e r t e n s i v e s ( R V )

w i t h m o n o l a t e r a l r e n a l a r t e r y s t e n o s i s a n d t o 8 u n c o m p l i c a t e d

e s s e n t i a l h y p e r t e n s i v e s ( E H ) a s c o n t r o l g r o u p . T h e t w o g r o u p s ,

w i t h o u t a n y t r e a t m e n t f o r a t l e a s t 3 w e e k s , w e r e m a t c h e d f o r

a g e , s e x , BP v a l u e s , a n d b a s a l r e n a l f u n c t i o n . 12 o u t t h e 18

RV r e p e a t e d t h e t e s t 1 0 d a y s a f t e r s u c c e s s f u l r e n a l r e v a s c u l a r i _

z a t i o n . P - a m i n o h y p p u r i c a c i d ( P A H ) a n d i n u l i n c l e a r a n c e u s e d

t o a s s e s s r e n a l p l a s m a f l o w ( R P F ) a n d g l o m e r u l a r f i l t r a t i o n r a

t e ( G F R ) , m e a s u r e d u n d e r p l a c e b o a n d a f t e r C a p t o p r i l 50mg b i d

f o r 2 d a y s , w e r e a s f o l l o w s :

EH R V ( n = 1 8 ) R V ( n = 1 2 )

b e f o r e

s u r g e r y

5 9 3 . 6 + 4 5 . 2

5 8 1 . 4 + 4 0 . 6

1 2 0 . 1 + 1 0 . 3

1 1 9 . 4 + 9 . 6

5 7 5 . 8 + 5 8 . 2 1

6 5 6 . 0 + 5 4 . 9 1

1 0 0 . 5 + 9 . 0 1

8 5 . 0 + 9 . 2 l

6 0 2 . 0 + 7 0 . 2 1 6 6 3 . 6 + 7 0 . 9

1 1 7 . 4 + 3 . 5 * 1 2 0 . 6 + 2 . 9 1

1 1 1 . 6 + 3 . 4 1 0 1 . 3 + 2 . 4 ]

A05-8 9 .

* 1 2 0 .

9 9 .

a f t e r

s u r g e r y

5 8 0 . 8 + 6 1 . 5

* 5 8 4 . 5 + 6 0 . 3

A 1 0 1 . 2 + 7 . 4

1 0 1 . 8 + ' 8 . 6

* 9 6 . 8 + 3 . 6

9 4 . 3 + 4 . 1

RPF P l a c e b o

C a p t o p r i l

GFR P l a c e b o

C a p t o p r i l

MPB P l a c e b o

C a p t o p r i l

* = p < 0 . 0 5

MBP was s i g n i f i c a n t l y r e d u c e d b y C a p t o p r i l i n EH a n d i n RV b e

f o r e s u r g e r y , w h i l e i t d i d n o t s i g n i f i c a n t l y c h a n g e i n RV a f t e r

s u r g e r y . A f t e r C a p t o p r i l RPF a n d GFR w e r e n o t m o d i f i e d i n E H ,

w h i l e RPF was s i g n i f i c a n t l y e n h a n c e d a n d GFR s i g n i f i c a n t l y r e

d u c e d i n t h e RV g r o u p b e f o r e s u r g e r y . A f t e r s u r g e r y t h e RV

g r o u p s h o w e d RPF a n d GFR v a l u e s a f t e r C a p t o p r i l s u p e r i m p o s a b l e

t o t h o s e o b s e r v e d a f t e r p l a c e b o .

T h e s e d a t a , w h i l e c o n f i r m i n g t h e r o l e o f A n g i o t e n s i n I I i n c o n

t r o l l i n g GFR i n R V , c a n s u g g e s t a n o n i n v a s i v e t e s t t o d e t e c t

RV h y p e r t e n s i o n .

1 4 5 0

COMBINED A C T I O N OF CALCIUMANTAGONISM AND A C E -I N H I B I T I O N ON RENAL F U N C T I O N AND BLOOD PRESSURE.

LR K r u s e l l * , LT J e s p e r s e n * , I S i h m , Κ Thorn-s e n , O . L e d e r b a l l e * . Med D e p t A a r h u s A m t s s y g e -h u s , D K - 8 0 0 0 A a r h u s , D e n m a r k

C a l c i u m a n t a g o n i s m i n c o m b i n a t i o n w i t h A C E - i n h i b i -t i o n h a s p r o o v e d t o b e a p o t e n t a n t i h y p e r t e n s i v e r e g i m e n . I n o r d e r t o i n v e s t i g a t e r e n a l h a e m o d y n a m i c a n d e x c r e t i o n a l e f f e c t s o f i s r a d i p i n e i n h y p e r t e n s i v e s u n s a t i s f a c t o r i l y c o n t r o l l e d o n c a p t o p r i l , 7 p a t i e n t s ( 3 women a n d 4 men mean a g e Wl + 7 . 3 y e a r s ) w e r e g i v e n a l o w - d o s e i n f u s i o n o f i s r a d i p i n e ( 0 . 0 5 mg i . v . ) d e v o i d o f e f f e c t o n b l o o d p r e s s u r e . F o l l o w i n g t h i s , a h i g h e r i n f u s i o n r a t e w a s a p p l i e d ( 0 . 0 4 m g / k g / m i n i . v . i n 2 0 m i n u t e s ) . T h e r e n a l p a r a m e t e r s G F R , RPF ( c o n s t a n t i n f u s i o n w i t h I - i o t h a l a m a t e a n d I - h i p p u r a n ) , c l e a r a n c e s ( C ) o f s o d i u m , p o t a s s i u m , u r i c a c i d a n d l i t h i u m , w e r e f o l l o w e d e v e r y Ξ0 m i n u t e s i n t h e s u p i n e p o s i t i o n d u r i n g a w a t e r l o a d i n g p r o c e d u r e . RESULTS A t t h e l o w d o s e t h e r e w a s a s i g n i f i c a n t i n c r e a s e i n CNa ( p = 0 . 0 5 ) a n d h e a r t r a t e ( P < 0 . 0 5 ) , w h e r e a s n o o t h e r v a r i a b l e s c h a n g e d s i g n i f i c a n t l y . F o l l o w i n g h i g h d o s e i n f u s i o n s y s t o l i c a n d d i a s t o l i c b l o o d p r e s s u r e f e l l a n d RPF i n c r e a s e d s i g n i f i c a n t l y . C l e a r a n c e s o f s o d i u m a n d l i t h i u m a n d u r i n a r y f l o w r a t e i n c r e a s e d s i g n i f i c a n t l y , w h i l e G F R , c l e a r a n c e o f u r i c a c i d a n d p o t a s s i u m i n c r e a s e d n o n - s i g -n i f i c a n t l y . D a t a o n ANP w i l l a l s o b e p r e s e n t e d .

CONCLUSION: C a l c i u m a n t a g o n i s m w i t h i s r a d i p i n e s t i l l p o s s e s e s n a t r i u r e t i c p r o p e r t i e s i n h y p e r t e n s i v e p a t i e n t s o n A C E - i n h i b i t o r s .

1 4 5 2

THE EFFECT OF INDOMETHACIN ON THE SYSTEMIC AND RENAL HEMODYNA

M I C RESPONSE TO ACUTE I N F U S I O N OF KETANSERIN I N E S S E N T I A L H Y

P E R T E N S I O N . AR L u c a r i n i * , Ρ A r r i g h i , R G i o v a n n e t t i , S F a v i l l a ,

A S a l v e t t i * . C l i n i c a M e d i c a I , U n i v e r s i t y o f P i s a , 5 6 1 0 0 P i s a ,

I t a l y

T h e r a t i o n a l e o f t h i s s t u d y i s b a s e d o n t w o c o n s i d e r a t i o n s :

1 ) t h e h e m o d y n a m i c e f f e c t o f many a n t i h y p e r t e n s i v e d r u g s i s r e

d u c e d w h e n p r o s t a g l a n d i n ( P G s ) s y n t h e s i s i s i n h i b i t e d 2 ) some

e x p e r i m e n t a l d a t a s u g g e s t a n i n t e r r e l a t i o n s h i p b e t w e e n s t i m u l a

t i o n o f PG s y n t h e s i s a n d t h e r e n a l h e m o d y n a m i c e f f e c t s o f s e r o

t o n i n . To a s s e s s w h e t h e r i n h i b i t i o n o f PG s y n t h e s i s i n d u c e d b y

t h e a d m i n i s t r a t i o n o f i n d o m e t h a c i n ( I N D ) i n t e r a c t s w i t h t h e h e

m o d y n a m i c ( s y s t e m i c a n d r e n a l ) e f f e c t s o f i . v . k e t a n s e r i n ( K E T )

a d m i n i s t r a t i o n , 8 p a t i e n t s w i t h u n c o m p l i c a t e d e s s e n t i a l h y p e r

t e n s i o n w e r e t r e a t e d f o l l o w i n g a r a n d o m i z e d s e q u e n c e f o r 3 d a y s

w i t h I N D ( 5 0 m g b i d ) a n d f o r 3 d a y s w i t h p l a c e b o ( P L ) . A t t h e

e n d o f e a c h p e r i o d , PL ( l O m g o f s a l i n e ) a n d KET ( l O m g ) w e r e a d

m i n i s t e r e d i . v . . T h e e f f e c t s o f PL a n d o f KET w e r e a s s e s s e d f o r

o n e h o u r b y m e a s u r i n g t h e f o l l o w i n g p a r a m e t e r s : b l o o d p r e s s u r e

( B P , m m H g ) , h e a r t r a t e ( H R , b / m i n ) , r e n a l p l a s m a f l o w ( R P F , m l /

m i n ) , g l o m e r u l a r f i l t r a t e ( G F R , m l / m i n ) , r e n a l v a s c u l a r r e s i s t e n

c e ( R V R ) , PRA ( n g / m l / h - 1 ) , p l a s m a a l d o s t e r o n e ( A L D , n g % ) , p l a s m a

n o r a d r e n a l i n e ( N A , p g / d l ) , s e r u m t h r o m b o x a n e ( s T x B 2 , n g / m l ) , u r i -

a a r y t h r o m b o x a n e ( u T x B 2 , n g / m g . c r . ) , a n d u r i n a r y 6 k e t o P G F ^

( u 6 k e t o P G F - ^ , n g / m g . c r . ) u n d e r p l a c e b o a n d a s c o m p a r e d t o s a

l i n e . KET s i g n i f i c a n t l y r e d u c e d B P ( 9 6 + 6 . 2 v s 1 1 5 + 5 . 1 p < 0 . 0 5 ) , ALD

( 1 7 . 9 + 1 . 6 v s 2 0 . 9 + 1 . 2 p < 0 . 0 5 ) . a n d R V R ( 0 . 1 3 + 0 . O l v s O . 1 6 + 0 . 0 1 p < 0 . 0 5 )

a n d i n c r e a s e d H R ( 7 6 + 3 v s 6 7 + 2 p < 0 . 0 5 ) , G F R ( 1 1 5 . 6 + 5 . 2 v s 8 5 . 6 + 4 . 2 ρ

< 0 . 0 5 ) , P R A ( 3 . 5 + 0 . 7 v s 2 . 5 + 0 . 6 p < 0 . 0 5 ) , N A ( 3 6 8 + 3 6 v s 3 0 2 + 2 4 p < 0 . 0 5 )

s T x B 2 ( 3 7 4 + 3 3 v s 2 4 9 + 2 1 p < 0 . 0 5 ) , U T X B T ( 0 . 3 7 + 4 . 9 V S O . 2 8 + 5 . 2 p < 0 . 0 5 )

a n d u 6 k e t o P G F l e t ( 0 . 4 9 + 6 v s 0 . 4 ± 4 p < 0 . 0 5 ) w i t h o u t m o d i f y i n g R P F . P r e

t r e a t m e n t w i t h I N D w h i c h s i g n i f i c a n t l y r e d u c e d s T x B 2 ( 3 0 . 6 ±

v s 2 4 9 ± 2 1 p < 0 . 0 5 ) , u T x B 2 ( 0 . 1 ± 0 . O l v s O . 2 9 ± 0 . 0 1 p < 0 . 0 5 ) a n d u 6

k e t o P G F l d ( 0 . 1 3 . ± 0 . 0 5 v s O . 4 ±u .05 p < 0 . 0 5 ) , p r e v e n t e d t h e r e n i n -

s t i m u l a t i n g e f f e c t ( 1 . 9 + 0 . 6 v s l . 7 + 0 . 5 n . s . ) a n d t h e i n c r e a s e i n

G F R ( 9 0 + 5 v s 8 9 + 5 . 1 n . s . ) i n d u c e d b y K E T , w i t h o u t c h a n g i n g t h e

o t h e r a c t i o n s o f t h i s d r u g . T h e s e d a t a s u g g e s t t h a t K E T , w h e n a -

c u t e l y g i v e n , i n c r e a s e s GFR b y s t i m u l a t i n g PG s y n t h e s i s ( v a s o d i l a

t i o n o f t h e a f f e r e n t a r t e r i o l e ) a n d b y i n t r a r e n a l f o r m a t i o n o f

A n g i o t e n s i n I I ( v a s o c o n s t r i c t i o n o f t h e e f f e r e n t a r t e r i o l e ) .

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1453 ARE PROSTAGLANDINS INVOLVED I N THE SYSTEMIC AND RENAL HEMODYNA

M I C ACTIONS OF L I S I N O P R I L ? AR L u c a r i n i * . Β A b d e l - H a q , Ρ A r r i g h i ,

A M a g a g n a , S F a v i l l a , A S a l v e t t i * . C l i n i c a m e d i c a I , U n i v e r s i t y

o f P i s a , 5 6 1 0 0 P i s a , I t a l y .

I t h a s b e e n h y p o t h e s i z e d t h a t o n l y ~ t h e S H - c o n t a i n i n g A C E - i n

h i b i t o r s ( A C E - I ) s t i m u l a t e p r o s t a g l a n d i n ^ P G s ) s y n t h e s i s a n d t h a t

i n d o m e t h a c i n ( I N D ) , a n i n h i b i t o r o f PGs s y n t h e s i s , r e d u c e s t h e

h y p o t e n s i v e e f f e c t o f c a p t o p r i l , b u t n o t t h a t o f o t h e r A C E - I .

H o w e v e r we h a v e s h o w n ( C I i n . E x p . H y p e r . 1 9 8 7 ) , t h a t I N 1 ^ r e d u c e s t h e

h y p o t e n s i v e e f f e c t o f E n a l a p r i l , a p r o d r u g w h i c h i s m e t a b o l i z e d

t o E n a l a p r i l a t , t h e a c t i v e d i a c i d c o n t a i n e d i n L i s i n o p r i l ( L I S ) ,

a n o t h e r A C E - I . T o a s s e s s w h e t h e r I N D i n t e r a c t s w i t h h u m o r a l a n d

w i t h t h e s y s t e m i c a n d r e n a l h e m o d y n a m i c e f f e c t s o f L I S , 9 p a

t i e n t s w i t h u n c o m p l i c a t e d e s s e n t i a l h y p e r t e n s i o n , w h o s e b l o o d

p r e s s u r e ( B P ) h a d b e e n s t a b l y r e d u c e d b y p r o l o n g e d ( 2 - 3 m o n t h s )

t r e a t m e n t w i t h L I S ( 2 0 - 8 0 m g / d a i l y ) , r e c e i v e d , a c c o r d i n g t o a

d o u b l e - b l i n d r a n d o m i z e d s e q u e n c e , I N D ( 5 0 m g χ 2 / d a i l y ) o r p l a c e b o

( P L ) f o r 1 w e e k , a n d t h e r e v e r s e t r e a t m e n t a f t e r 2 w e e k s . T h e

f o l l o w i n g p a r a m e t e r s w e r e m e a s u r e d b e f o r e ( d u r i n g P L ) , a n d a f t e r

L I S + P L a n d L I S + I N D : B P , r e n a l p l a s m a f l o w ( R P F ) , g l o m e r u l a r f i l

t r a t i o n r a t e ( G F R ) , A C E ( n m o l / m i n / m l ) , s e r u m t h r o m b o x a n e ( s T x B 2 ,

( n g / m l ) , u r i n a r y P G s : u P G E 2 ( n g / m g . c r . ) a n d u 6 k e t o - P G F ^ ( n g / m g .

c r . ) ( m e a n + S E M )

MBP RPF GFR ACE s T x B 2 uPGE2 U 6 K E T 0 P G F 1

PL 1 2 3 . 2 5 5 2 . 7 1 1 6 . 3 7 3 2 2 6 . 7 0 . 2 2 0 . 3 6

+ 3 . 1 + 3 6 . 3 + 4 . 6 + 1 0 + 4 8 + 0 . 0 1 + 0 . 0 1

L I S + P L 9 9 . 4 * 6 2 1 . 2 * 1 3 9 . 4 * 1 0 . * 2 7 7 . 0 * 0 . 1 9 0 . 3 6

+ 1 . 6 + 4 4 . 0 + 7 . 0 + 2 . 0 + 3 9 + 0 . 0 1 + 0 . 0 1 L I S + I N D 1 0 5 . 3 * § 6 4 5 . 5 * 1 2 9 . 4 * 6 . * 2 7 . 2 * § 0 . 0 6 * § 0 . 1 8 * §

+ 1 . 7 + 4 3 . 1 + 1 1 . 2 ± i - 9 + 1 0 + 0 . 0 1 + 0 . 0 0 1 * = p < 0 . 0 5 v s PL § = p < 0 . 0 5 v s L I S + P L

As c o m p a r e d t o p l a c e b o , L I S s i g n i f i c a n t l y r e d u c e d B P , ACE a n d

i n c r e a s e d R P F , GFR a n d s T x B 2 , w i t h o u t m o d i f y i n g u r i n a r y PGE2 a n d 6KET0-PGF-L . I N D s i g n i f i c a n t l y r e d u c e d s T x B 2 , u P G E 2 a n d u 6

KETOPGFi-1 a n d s i g n i f i c a n t l y i n c r e a s e d B P , w i t h o u t m o d i f y i n g ACE

RPF a n d GFR, T h e s e f i n d i n g s s u g g e s t t h a t s y s t e m i c PGs c a n p l a y

a r o l e i n t h e h y p o t e n s i v e a c t i o n o f L i s i n o p r i l , w h o s e r e n a l e f

f e c t s a r e u n r e l a t e d t o r e n a l PGs s y n t h e s i s .

1454 CALCIUM ENTRY BLOCKADE AND AGONIST-MEDIATED VASOCONSTRICTIONVC) IN HUMANS: DIFFERENCES BETWEEN NICARDIPINE(Ν) AND VERAPAMIL(V). R.Pedrinelli , S.Taddei, G.Panarace, M.Spessot, A.Salvetti* . Hypertension Unit, I Clinica Medica.Univ. of Pisa. PISA. I ta ly . Ν is more effect ive than V in antagonizing either exogenous (Clin Pharmacol Ther,1988) or endogenous (JACC, 1988) -adrenoceptor stimulation. Whether the same holds for non ot-adrenoceptor mediated stimuli is unknown . We tested the relat ive effect of Ν and V on VC induced by Angiotensin II (A) , in 6 mild uncomplicated hypertensive pts. A was infused into the brachial artery at three cumulat ive , systemically ineffective doses ( .02 , .06, .2 ug/min χ 3 min each) in presence of saline (S) or either Ν or V at two cumulatively increasing rates (10 & 30 jig/min χ 15 min each), at at least 8 hours intervals . Forearm blood flow(FBF, venous plethysography), HR and ia MAP were recorded throughout. In spite of comparable vasodilation (N: 4 .1±1.2 to 8 .9±1.7 and 14 .5±1 .8 ; V: 4 .+1 .3 to 9 .1+3.1 and 13.1+3.6 respectively) N(S: - 2 5 . 7 ± 3 . 4 , - 5 2 . 8 ± 7 . 2 , - 7 2 . 1 ± 5 . 1 ; Ν 10 ug/min: - 0 . 3 ± 1 . 6 , 0 . 2 + 0 . 5 , - 3 . 4 + 8 . 3 : Ν 30/ig/min: - 0 . 1 ± 0 . 4 , 0 .8+1 .1 , -1.4J1.6%) antagonized FVC to A more than V(S: - 2 2 . U 3 . 3 , -52 .2 + 3 . 5 ; - 7 1 . 6 + 2 . 8 ; V 10 ug/min: - 1 6 . 6 + 8 . 3 , - 2 8 . 9 + 8 . 4 , - 49 .3+6 .7 ; V 30 /jg/min: -0 .4 ± 0 . 6 , - 9 . 9 + 1 1 . 9 , -25.7+10.7%; p<.001 vs N). This property was not due to presynaptic fac i l i ta t ion of NE-release by A because local^( - ( phentolamine, PH, 80 ug/min χ 15 min; FBF from 3.6+ 1.2 to 8.2+ 4.6)andfr-(propranolol,100 ug/minx 15 min)blockade did not modify the effect of A (S: - 20 .2+4 .9 , - 4 9 . H 5 . 9 , - 6 5 . 3 + 8 . 9 ; PH: - 2 5 . 2 + 6 . 4 , -49 .3+8 . 3, -70.+8.2%; n=5 additional p t s ) . Thus, when infused at equieffeetive dose, Ν is more effective than V in antagonizing VC, independent of receptor-type stimulation. Interference with the effect of a series of agonists may contribute to the action of Ν and possibly other dihydropiridines.

|14551 INDENOLOL, A BETA BLOCKER DRUG , VASODILATES FOREARM(F) VASCULAR DISTRICT THROUGH ITS SYMPATHOMIMETICS) ACTIVITY IN ESSENTIAL HYPERTENSIVE PATIENTS. S.Taddei, R.Pedrinelli , M.Spessot, G.Panarace, G.Grothold", A.Salvetti* . Hypertension Unit, I Clinica Medica, University of Pisa, PISA; "Poli Research Center, MILAN; I ta ly .

S properties may reduce side - effects by ^-adrenoceptor blocking drugs. Indenoloi(I) is a new non select ive ^-adrenoceptor blocking agent Whose intr insic S properties, shown in vi tro and animal studies, could partecipate to i t s effect in man. However no data are available to support this hypothesis. For this reason we infused I at three jcumulative infusion rates (50,150,500 pg/min χ 15 ;min each) into the brachial artery in n=9 hypertensive patients . F blood flow (FBF, venous (plethysmography), MAP and HR were continously monitored. Active drug infusion was preceded by saline infusion (S, 0.2ml/min χ 15 min) that did not change FBF (from 3,3+1.1 to 3 . 3 + 1 . 3 ) , MAP and HR. During I infusion at 50 ug/min, FBF did not change (from 3.3+1.1 to 3 .3±1.2 ) , but F vasodilation to^-adrenoceptor stimulation by isoproterenol (0 .2 ug/min χ 3 min; n=l preliminary case) was abolished, further confirming the β-blocking properties of the drug. At the greater infusion rates I increased FBF (150 pg/min: from 3.3+1.1 to 4 . 3 + 1 . 9 , p<.05 vs S; 500 jig/min: from 4.3+1.9 to 7 .7+2 .7 , p<.01 vsS). This vasodilating action was due to 0-adrenoceptor stimulation since i t was abolished oy pretreatment with propranolol (100 ug/min χ 15 min), a (V-blocker devoid of S a c t i v i t y (S: 3 .3±0 .5 , PRO: I 50: 2 . 8±0 .9 , 150: 2 .7±0 .9 , 500: 3 . 9+1 .2 ; n=5 additional p t s ) . Thus I direct ly vasodilates forearm a r t e r i o l e s , when infused into the brachial artery, and this effect is abolished by previous (^-blockade. These data demonstrate the intr insic S ac t iv i ty of I also in man which may possibly contribute to i t s therapeutic action in man.

|1456|

Do Adenosine receptors have any modulatory role for ANF release in man ?

AR Lucarini*, S Favilla, Ρ Arrighi, MP Urbam, F Lattanzi, L Corelli, Ε Picano, A Salvetti*. Clinica Medica I arid CUP. Institute of Clinical Physiology. Pisa, Italy.

Atrial natriuretic factor (ANF) release is modulated by several hemodynamic and neuro-humoral factors. Tc our knowledge, the effects of adenosine receptors stimulation on ANF secretion in man remain unknown. Dipyridamole - which is commonly used as a pharmacological stressor in pts with suspected coronary artery disease - acts through myocardial extracellular adenosine accumulation and stimulation of adenosine receptors.

Aim of this study was to assess whether dipyridamole infusion (0.84 mg/kg' over 10") may affect ANF release in man. Five pts (3 males, 2 females) were studied under no therapy; all had history of chest pain and none had evidence of ischemia - by symptomatic:. electrocardiographic or echocardiographic criteria -during dipyridamole infusion. Dipyridamole infusion was performed in all pts with two dimensional echocardiography and 12 lead EC& monitoring; blood pressure was recorded each minute by cuff sphygmomanometer. After dipyridamole, no significant changes were recorded in diastolic blood pressure (baseline: 84+3 vs peak dipyridamole: 81+4 mmHg, p=nsj, systolic blood pressure (140+11 vs 133+12 mmHg, p=ns), left ventricular end-diastolic diameter (42±3 vs 42+2 m, p=ns), left atrial dimension (31+2 vs 31 ±2 mm, p=ns) or ANF values (21+6 vs 27+5 pg/ml, p=ns).

We conclude that dipyridamole infusion does not increase ANF release in man, suggesting that adenosine plays no major direct modulatory role on ANF secretion

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"ISCHEMIC-LIKE"ST SEGMENT DEPRESSION DURING DIPYRIDAMOLE STRESS IN ESSENTIAL HYPERTENSIVES: ITS RELATION WITH HUMORAL AND HEMODYNAMIC VARIABLES. AR L u c a r i n i * , E P i c a n o , S F a v i l l a , F L a t t a n z i , V Di Legge, Ρ A r r i g h i , A D i s t a n t e , A L 'Abbate , A S a l v e t t i * C l i n i c a Medica I , and CNR- I n s t i t u t e " , 56100 P i s a , I t a l y '

I t has been p r e v i o u s l y r e p o r t e d t h a t asymptomatic e s s e n t i a l h y p e r t e n s i v e s can show i s c h e m i c - l i k e ( > 0 . 1 m V o l t from b a s e l i n e ) S T segment d e p r e s s i o n , without t r a n s i e n t r e g i o n a l dyssynergy ,during high dose Dipyridamole Echocardiography t e s t ( D E T : 1 2 l e a d ECG and 2-dimensional echo monitoring with dipyridamole i n f u s i o n up t o 0.84mg/Kg over 1 0 ' ) . The p a t h o p h y s i o l o g i c a l meaning of t h i s DET response remains t o be e l u c i d a t e d .To a s s e s s whether the p o s i t i v i t y (+·) of the DET could be l inked t o any hemodynamic and humoral v a r i a b l e s , we e v a l u a t e d l e f t v e n t r i c u l a r mass (LV m a s s , g / m2)the d u r a t i o n of h y p e r t e n s i o n ( D - H , y e a r s ) c a s u a l mean blood pres. s u r e (C-MBP, mmHg), p e r c e n t a g e MBP i n c r e a s e t o mental s t r e s s ( A %ms) and t o hand g r i p (&%HG), PRA(ng,ml ,h) , plasma a l d o s t e r o n e (ALD, ng%), plasma n o r a d r e n a l i n e (NA, p g / m l ) , and a d r e n a l i n e ( A , p g / m l ) , a t r i a l n a t r i u r e t i c pept ide (ANF,pg/ml) , in 16 e s s e n t i a l h y p e r t e n s i v e p a t i e n t s : 8 with DET ( + ) and 8 with DET ( - ) , ma' t ched f o r a g e , s e x , family h i s t o r y of hyper tension and smoking h a b i t s . P a t i e n t s with DET ( + ) did not d i f f e r from those with DET ( - ) a s f a r as C-MBP,A%HG,&%MS,PRA,ALD,NA,A.and ANF a r e concerned. LV-mass was s l i g h t l y but not s i g n i f i c a n t l y g r e a t e r in DET ( + ) p t s ( 1 4 9 . 3 + 1 7 . 6 vs 1 3 3 . 5 + 1 1 . 9 n s ) , who r e p o r t e d t h a t t h e i r dura t i o n of hyper tension was s i g n i f i c a n t l y longer than t h a t of DET(-* p t s ( 1 1 . 1 + 2 . 6 vs 4 . 6 + 1 . 4 p < 0 . 0 5 ) . Taken t o g e t h e r t h e s e d a t a i n d i c a t e t h a t n e i t h e r hemodynamic nor humoral f a c t o r s can account f o r DET ( + ) , while the longer d u r a t i o n of hyper tension i s import a n t in determining the " i s c h e m i c - l i k e " e l e c t r o c a r d i o g r a p h i c response t o dipyridamole i n f u s i o n in asymptomatic e s s e n t i a l h y p e r t e n s i v e s . .

114591

ABNORMAL KINETIC PROPERTIES OF THE ERYTHROCYTE CALCIUM PUMP IN A SUBSET OF ESSENTIAL HYPERTENSIVE PATIENTS. A Pe la S i e r r a * . JP G l l i v ie r , Ρ Hannaert, Ν Senn, A C o c a * , R G a r a y * . INSERM U7. Hta l . Necker. See de Cardiologie Hta l . Val-de Grace, Par i? .

We developped a new f lux technique, useful f o r the cl in ical invest igat ion o f Ca*- pump kinetics in intact e r y th rocy tes . The in i t ia l j r a te o f S r 2 * e f f l ux (mediated by the C a 2 + pump) was studied as a I funct ion o f steady state e r y th rocy te S r 2 + and C a 2 + contents in 22\ essential hypertensive patients and compared w i t h 20 normotensive cont ro l subjects. Kinetic analysis of the data by using a two -s i t es model al lowed the determinat ion o f the apparent dissociation constants f o r in ternal C a 2 * (ΚςΡ and f o r in ternal S r 2 + ( K c r ) and the max imal r a te o f S r x + e f f lux ( V m a x ) . Mean values o f these kinet ic parameters w e r e

sl ight ly increased in the hypertensive population. However , only the increase in KQ3 reached s ta t is t i ca l signif icance ( 7 3 ± 7 vs 55 ± 3

Urnol / l .cel ls, Mann-Whitney U t e s t : 1 3 2 ; ρ = 0 . 0 4 2 ) . Individual analysis of the data showed that 6 essential hyper tensives had a K^ a higher than the upper normal l im i t ( 9 5 % confidence l i m i t ) o f the normotensive group. In addi t ion, mean values o f V m a x and were also s igni f icant ly higher in these s i x essential hyper tensives.

In another abst ract o f th is Meet ing, Takaya, A v i v et a l . show s imi la r findings by measuring C a 2 + - A T P a s e kinet ics in plate lets. In addi t ion, these authors have found an inverse cor re la t ion between and plasma

renin ac t i v i t y (PRA). In 15 hypertensives whose PRA were measured, we also found an inverse corre la t ion although the s ta t i s t i ca l signif icance was only border l ine ( r = - 0 . 4 6 ; ρ = 0 .076 ) .

In conclusion, about 25 % of the hyper tensive patients had a decreased apparent a f f in i ty of the C a 2 + pump f o r in ternal C a 2 + , which appears to be compensated ( in the basal s ta te) by an increased maximal pump ra te . A s imi la r abnormali ty in vascular smooth muscle cells may induce increased con t rac t i l i t y by t rans i to ry ce l l C a 2 + re tent ion a f te r the opening o f C a ^ * channels. On the other hand, increased cytosol ic f ree C a i + contents in the juxtaglomerular apparatus may inhibit renin secret ion.

1 4 5 8

ENDOTHELIN STIMULATES Na +, K + PUMP, [Na*, K+, Crj-COTRANSPORT SYSTEM A N D Na +: H + E X C H A N G E IN CULTURED VASCULAR S M O O T H M U S C L E CELLS. C Rosati, C Nazaret, Ε Jeanclos, Ρ Hannaert, Μ Braquet, PE Chabrier, Ρ Braquet, R Garay*. INSERM U7. Hopital Necker. Paris. Clinical Research Unit, HopitaJ Percy, Clamart & IHB Research Lab. Le Plessis-Robinson. France. The effect of endothelin on vascular smooth muscle cell N a +

and K + regulation was studied in the A10 cell line. Na +, K +

pump activity was equated to the ouabain-sensitive R b + influx, fNa+, K +, CT]-cotransport system to the bumetanide -sensitive R b + influx and Na +; H + exchange to the amiloride-sensitive Li* influx. Endothelin concentrations higher than 10"^ Μ were able to

stimulate Na*: H + exchange in A10 cells and, in contrast with other vasoconstrictors, it were also able to stimulate the Na +, K + pump and the [Na+, K +, Cr]-cotransport system. In particular, endothelin concentrations of 10"^ Μ stimulated by about 200 % bumetanide-sensitive R b + influxs. These effects did not appeared to reflect a direct interaction with the transport proteins because endothelin was without effect on these transport systems in human red cells. Indomethacin, at concentrations of 10"*> Μ, was able to counteract the pump and cotransport stimulation by endothelin in Al 0 cells. In conclusion, endothelin stimulates Na +: H + exchange in

vascular smooth muscle, a phenomenon possibly related to the increases in cytosolic free calcium contents. In addition, the potent vasoconstrictive action of endothelin induces a negative feedback mechanism, via a cyclooxygenase product, which enhances the ability of the vascular smooth muscle pump and cotransport systems to regulate cellNa+ and K + contents.

1 4 6 0

DEMONSTRATION OF A DIOA-SENSITIVE (K +, CT] -COTRANSPORT SYSTEM IN T H E VASCULAR S M O O T H M U S C L E A10 CELL LINE. Μ Saitta. R Garay*, Ε Cragoe Jr, Ρ Hannaert. INSERM U7. Hopital Necker. Paris. France & Lansdale. PN. USA.

A [K+, CT]-cotransport system was previously demonstrated in human erythrocytes by its sensitivity to DIOA (dihydrcdndenyloxyacetic acid), a new compound without side effects on the bumetanide-sensitive [Na+, K +, Cr]-cotransport system (Garay et al., Mol Pharmacol, 33: 696, 1988). This DIOA-sensitive [K +, Cl"]-cotransport system is the uniqueregulator of erythrocyte (and thymocyte) swelling, and has the following properties : (i) it is silent under physiological conditions and (ii) it extrudes K G from swollen cells (and indirectly water) via a signal probably transduced bythecytoskeleton. The existence of a [K +, CTj-cotran sport system in vascular smooth

muscle cells was investigated by studying the effect of DIOA on ouabain and bumetamde-resistant K*, R b + and CT fluxes (OBR fluxes) in the Al 0 ceil line. Hypotonic media (150 mOsm) stimulated by about 40 % OBR R b + influx (and K + efflux) in cultured A10 cells. DIOA counteracted the R b + influx stimulation with an IC5Q of

about 2-3 10"^ M. DIOA-sensitive R b + influx was a sigmoidai function of the decrease in osmolality, with a threshold at about 250 mOsm (in isotonic media, DIOA was able to inhibit about 5 0 % of O B R R b + influx). DIOA was also able to inhibit OBR 3 6C1" influx. DIOA-sensitive '"CI" influx was much higher than tDIOA-sensitive R b + influx and was almost not changed by the decrease in osmolality. Thus the CT to R b + stedemometry was between 7 and 10 in isotonic media and between 2 and 3 in hypotonic media. In conclusion. vascular smooth muscle cells have a DIOA-sensitive

[K +, CT]-cotransport system. Dissipation of the outwardly directed CT gradient with a CI" to K + stoichiometry higher than 2 or 3 may provide the energy to ensure (net K + extrusion and) cell swelling regulation in these cells. j

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CAPTOPRIL-RESISTANT ESSENTIAL HYPERTENSIVES : ERYTHROCYTE ION TRANSPORT ABNORMALITIES AND SENSITIVITY TO CLONIDINE. Ν Sena, JP Oilivier, Ρ Frohly and R Garay*. INSERM U7. Htal Necker. See de Cardiologie. Htal Val-de-Grace. Paris. & Lab. Boehringer. Reims. France.

18 essential hypertensive patients (16 males, 2 females; aged 39 to 61 years) have been selected on the basis of absence of blood pressure normalization (diastolic blood pressure > 95 mmHg) after 1 month of Captopril treatment (the last 15 days with 100 mg/day of Captopril). After a washout of at least two days, the ion transport characteristics of these Captopril -resistant hypertensives were studied in the erythrocytes.

4 hypertensives had increased Na: Li counter-transport, 9 had increased Na leak, 5 had decreased affinity of the Na, Κ cotransport system for internal Na (Co (-) abnormality), 5 had increased Na, Κ cotransport fluxes and only 4 hypertensives had no ion transport abnormalities in erythrocytes.

At DO the patients received 150 μg/day of clonidine, alone or in addition to Captopril (in some cases the dose of clonidine was increased up to 450 μ g/d ay as a function of the therapeutical response). After 1 month of clomdine-treatment, 9 patients (50%) normalized blood pressure (3 in monotherapy and 6 in association with Captopril). Of these 9 clonidine-sensitive hypertensives, 4 had a Co (-) abnormality and 3 had no ion transport abnormalities. On the other hand, 7 hypertensives were moderate responders and only 2 were resistant to clonidine.

In conclusion, Captopril-resistant essential hypertensive patients have an abnormally high frequency of erythrocyte ion transport abnormalities. In addition, they exhibithigh sensitivity to clonidine, particularly those with Co (-) abnormalities (in whom an increased plasma norepinephrine was previously reported).

[14631

UPREGULATION OF AVP RECEPTORS IN THE SEPTUM OF THE RAT. Ch. Lebrun, M.G. Gruber, M. Meister and Th. Unger. German Institute for High Blood Pressure Research and Dept of Pharmacology, Univ of Heidelberg , Im Neuenheimer Feld 366, 6900 Heidelberg, FRG The pressor responses to intracerebroventricular (i.c.v) injections of arginine vasopressin (AVP) display a sensitization upon repeated challenge with AVP. In order to study the regulation of the sensitivity of the AVP receptors involved, we investigated the AVP induced hydrolysis of inositol p h o s pholipids in septal slices of rats p r e -treated with and without AVP. Rats were sacrified 24 hours after an icv injection of 100 ng AVP or isotonic saline. Septal slices w e r e incubated with ( H) m y o - i n o s i t o l . Inositol p h o s phates w e r e separated by application 4 t o Dowex c o l u m n s . Carbachol (10 M) increased ( Η) IPl by 174% (p<0.01) indicating a functional assay system. Slices from rats pretreated with saline did not respond with significant increases of ( Η) IPl 1*14% p>0.05) when incubated with AVP (10 M) . In contrast, slices from rats pretreated with AVP responded with a 45% increase (p<0.05) when incubated with AVP. Our results demonstrate an upregulation of brain AVP receptors by the endogenous agonist pointing to an unexpected autoregulatory mechanism of the AVP system in the brain.

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THYROID HORMONE MODULATES THE RELEASE OF ATRIAL NATRIURETIC PEPTIDES IN HYPOPHYS-ECTOMIZED RATS. Ν Zamir. Μ Slover. KP Ohmarf. Sackler School of Medicine, Tel Aviv 69978, Israel and Department of Internal Medicine, University Hospital, S-58185 Linkoping, Sweden.

Mechanisms that control the release of atrial natriuretic peptides (ANP) from cardiac atria are not fully clarified and a number of agents may modify the release of ANP either by direct action on the atrial myocytes or indirectly through changes in central hemodynamics. We have shown that the normal release of ANP following an acute blood volume expansion is markedly blunted in hypophysectomized (Hx) rats. Furthermore, abnormalities in cardiac function and renal electrolyte excretion are observed in thyroid hormone difficiency states. We therefore investigated the role of thyroid hormone for ANP release induced by acute blood volume expansion in Hx rats.

Hx rats were given daily s.c. injections of thyroxine 30 μg/kgbw for one week beginning 5 days after Hx (HxT4 group). Control Hx (HxCo) and shamoperated (Sh) rats were given injections of vehicle (0.9% NaCl, pH 9.0). The last injection was given 24 hours prior to the experiment. Mean arterial pressure (MAP) and heart rate (HR) were measured continuously during the acute experiment.

Thyroxine treated rats had higher MAP and HR than HxCo rats but HR was still lower than in Sh rats. The plasma level of free thyroxine in HxT4 rats was similar to Sh rats and not detectable in HxCo rats, while p-corticosterone levels were close to limit of detection in both Hx groups. A rapid significant increase in circulating ANP occured in both HxT4 and Sh rats following an acute blood volume expansion. The ANP release was blunted in HxCo rats and the volume stimulated plasma concentration of ANP was not significantly different from the basal level.

In conclusion we find that thyroid hormone may play an important role for a normal ANP-releasing function of atrial myocytes in response to acute blood volume expansion in hypophysectomized rats.

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HEMODYNAMIC CHARACTERIZATION OF E N D O THELIN IN CONSCIOUS RATS. P. R o h m e i s s , J. Photiadis, S. Rohmeiss and Th. Unger Dept of Pharmacology, Univ of H e i d e l berg, Im Neuenheimer Feld 366, 6900 Heidelberg, FRG Intravenous injection of endothelin (ET) (10, 30, 100, 300 ng) in c o n s c i o u s , chronically instrumented rats produced a dose-dependent biphasic blood pressure (BP) r e s p o n s e : an initial short lasting (15.2+1.4 sec) BP decrease (maximum -41.3+1.5 m m H g ) , followed by an increase (maximum +4 4.6+2.2 mmHg) of u p to one hour duration. The corresponding responses in cardiac output (CO, Doppler p r o b e ) , heart rate and efferent splanchnic nerve activity were reciprocal to the BP c h a n g e s . Mesenteric blood flow showed an immediate and sustained d e crease; renal blood flow (RBF) and hind limb blood flow (HLF) increased i n i t i ally in response to low doses (RBF) or all doses (HLF) but decreased s u b s e quently. Compared to sodium n i t r o p r u s side, ET produced a markedly different regional hemodynamic response pattern and induced greater increases in CO, that persisted upon autonomic cardiac blockade. Compared to m e t h o x a m i n e , ET produced greater v a s o c o n s t r i c t i o n in the kidney and skeletal m u s c l e . Our results demonstrate that E T has v a s o d i l a t o r and vasoconstrictor properties inducing a hemodynamic response pattern different from classical vasodilators and ©(-adrenoceptor v a s o c o n s t r i c t o r s .

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[14651 N-TERMINAL PRO ANP CIRCULATING IN HUMAN PLASMA MG Buckley, GA Sagnella, ND Markandu, GA MacGregor*. Blood Pressure Unit, Department of Medicine, Charing Cross & Westminster Medical School, London W6 8RF, UK. Immunoreactive-N-terminal Pro ANP(N-ANP) and C-terminal ANP(99-126;C-ANP) was measured after extraction on Sep-pak in 25 normal individuals (NT), 29 patients with essential hypertension(HT), 6 cardiac transplant recipients(CT), 7 patients with chronic renal failure(CRF) dialysis independent and in 11 patients with CRF dialysis dependent pre(PRD) and post(PSD) dialysis. Results expressed as means:

NT HT CT CRF PRD PSD (N-ANP) 235 364 1240 1637 10336 9605 pg/ml (C-ANP) 12.5 23.9 53-0 64.0 351.0 252.0 pg/ml Plasma N-ANP and C-ANP were significantly elevated in all patient groups when compared with the NT group (P<0.01). In CRF patients undergoing dialysis C-ANP but not N-ANP declined significantly after dialysis (P<0.001). No significant relationship was found between N-ANP and blood pressure in either NT or HT subjects. There was a good correlation between plasma N-ANP and C-ANP for all plasma measurements obtained (r=0.8; P<0.001; N=89). Gel filtration of extracted plasma from normal subjects and patients gave a single N-ANP peak corresponding with the elution volume identical to human cardiodilatin (1-67). No N-ANP activity was detected at the elution volume corresponding to the shorter N-terminal standard (1-30). These results suggest that cardiodilatin (1-67) is the major circulating form of N-ANP in human plasma.

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PLASMA ATRIAL NATRIURETIC PEPTIDE (ANP) AND THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM: EFFECTS OF GRADUAL ALTERATIONS IN DIETARY SODIUM INTAKE IN MAN. GA Sagnella, ND Markandu, MG Buckley, MA Miller, DRJ Singer and GA MacGregor*. Blood Pressure Unit, Department of Medicine, Charing Cross & Westminster Medical School, London W6 8RF, UK.

Large alterations in sodium intake are associated with changes in plasma ANP, aldosterone and renin activity, but the sensitivity to small and gradual changes in sodium intake is not known. We studied in 6 normotensive subjects the effect of small (50 mmol/day) increases in sodium intake starting from 10 mmol/day and reaching 350 mmol/ day within 7 days.

As expected there was a ^rogressive^increase in urinary sodium from 12.2-4.2 (mean -SEM) to 314.8^31.4 mmol/24 hr by the end of the study. Plasma ANP increased gradually from 9-9-1.1 to 23.1-2.2 pg/ml (P<0.001; ANOVA) and this progressive increase in plasma ANP was closely associated with the increases in cumulative sodium balance. Both plasma aldosterone and plasma renin activity decreased progressively with the increases in sodium intake. However, within the first day of the raised sodium intake (i.e. from 10 to 50 mmol/day) there was a significant fall in plasma aldosterone but not in PRA.

This study demonstrates a marked sensitivity in the responses of both the ANP and the renin-aldosterone system to changes in sodium intake within the physiological range and clearly points to the importance of these hormones in the renal adaptations to small alterations in dietary sodium intake.

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HOW IMPORTANT ARE ATRIAL NATRIURETIC PEPTIDES AND ALDOSTERONE IN THE RESPONSE TO AN ACUTE SODIUM LOAD? DRJ Singer*, ND Markandu*, MA Miller, MG Buckley, AL Sugden, GA Sagnella, DG Shirley, GA MacGregor*. Blood Pressure Unit, Department of Medicine, Charing Cross & Westminster Medical School, London W6 8RF, UK.

The relative importance of ANP and aldosterone in the renal response to saline infusion is not clear. In a double-blind study on 2 days one week apart in 8 healthy males on constant dietary sodium intake, 21 saline (0.9%) was infused during the second hour of a 6 hr aldosterone (3 pmol/kg/min) or placebo infusion. Immediately after saline there was a significant increase in urinary sodium excretion and plasma ANP with and without aldosterone. However, with aldosterone, from 60 to 300 min after saline, the increase in urinary sodium excretion was then significantly less than on the control day (ANOVA, P<0.05). Cumulative net sodium loss after saline with aldosterone was 16.2-15-7 mmol, after placebo 31-1-17-4 mmol. There was a similar decrease in plasma renin activity after saline infusion both with and without aldosterone. Average plasma aldosterone during aldosterone infusion was 439-44 pmol/1; after placebo 137-12 pmol/1. These findings would be consistent with a possible role for ANP in the immediate increase in sodium excretion with saline infusion. However, much of the later increase in urinary sodium excretion up to 5 hours after saline may be explained by suppression of aldosterone.

[14681

AMBULATORY BLOOD PRESSURE PATTERNS IN NORMOTENSIVE SUBJECTS: W. E. Miller*, D. K. Haupt, D. A. Maichle. Dept. of Medicine, Medical Center of Delaware, Wilmington, Delaware

Twenty-four hour ambulatory blood pressure monitoring (ABPM) has found increasing usefulness in defining clinical hypertension, in identifying "white coat syndrome", and in assessing the effectiveness of antihypertensive therapy. However, there is still too little published data of 24 hour ABPM in normotensive subjects. We examined the records of 50 normotensive volunteers (18 males and 32 females) ranging in age from 21 to 64. Twenty-four hour BP average for all subjects was 163/69 with no discernible difference between males and females. Blood pressure variations from "casual" to more "basal" settings were examined by comparing initial office readings to evening monitor readings. As a measure of lability, mean plus one and two standard deviation confidence limits were calculated for each subject's record and averaged for the group as well as by sex. Average duration of diurnal decline for diastolic blood pressure was calculated. We recognize that our sample size is small and not racially (46 Cauc.; 4 black) nor gender representative. However, if taken with similar reports of normotensive patients, it may serve as a truer "normal" reference point for evaluation of the hypertensive patient.

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114691 NON-INVASIVE BLOOD PRESSURE MONITORING AT THE FINGER FOR STUDYING SHORT-LASTING PRESSOR RESPONSES IN MAN Y C h r i s t e n . Β Waeber*, J Nussberger*, HR Brunner*. Hypertension Divis ion, University Hospital, Lausanne, Switzerland.

The establishment of dose-response curves to p r e s s o r agents in man r e q u i r e s a c c u r a t e measurement of short - last ing changes in blood pressure (BP). We investigated whether rapid increases in systol ic BP (SBP) can be measured accurately by monitoring continuously finger BP using a non-invasive device (Finapres). Six normal volunteers were investigated on 2' consecutive days. On the f i r s t day, increasing doses of angiotensin I (ANG I) were injected i . v . every 15 min with the aim to determine a test-dose which raised SBP by 25 to 40 mmHg. After oral administration of a placebo, this individual test-dose of ANG I was injected 15 times over the next 24 hours to each subject. The SBP increase induced by the test-dose was 3 3 . 1 ± 3 .5 mmHg (mean ± SD, η = 15) in the subject with the best and 31.1 ± 7.6 mmHg in the subject with the poorest reproducibility. The coeffic ients of variat ion were 10 and 24%, r e s p e c t i v e l y (mean 14.8%, η = 6 ) . On the second day, the subjects took 6.25 (n = 3) or 25 mg (n = 3) c a p t o p r i l p . o . and the same test-dose of ANG I was injected 10 times over the next 4 hours . Captopri l caused a dose-dependent inhibition of the pressor effec t of ANG I . These data indicate that non-invasive BP monitoring at the finger represents a useful tool to study short - last ing BP changes in man produced by pharmacologic agents.

114711 CHANGES IN PLASMA ANF DURING SEQUENTIAL FLUID REMOVAL AND BIOCHEMICAL CORRECTION IN END-STAGE CHRONIC RENAL FAILURE PATIENTS. G.Tonolo*Μ.McMillan,A.M.Richards,Ρ.Montors i,A.Soro Patologia Medica,Universita'di Sassari,Italy MRC Blood Pressure Unit,Western Infirmary,Glasgow Arterial plasma levels of ANF were measured in seven end-stage chronic renal failure patients(on constant haemodialysis),during random sequential fluid removal ( ultrafiltration , 1 l/lhr,UF)and biochemical correction without fluid removal(3hrs,BC),in this order (UF-BC)or the reverse(BC-UF),lweek apart.Blood pres sure (BP), heart rate(HR) ,^iHct, serum creatinine and '•• K+ and plasma renin concentration(PRC)were monitored throughout the studies.Arterial ANF at the end of fluid removal fell by 30+2%,p<0.01,during UF-BC and by 23+2%,p<0.01 at the end of biochemical correction during BC-UF.In either sequences a further slight reduction in plasma ANF was observed during the second phase(8+5%,n.s..biochemical correction ofUF-BC; and 13+2%,p<0.05,fluid removal of BC-UF).ANF was not removed by the machinery for UF or BC.BC did not modify the jjHct in either sequences,while it was significantly increased by UF(12+1% and 13+1%, ptO.01,respectively.Serum creatinine and K+ decreased significantly at the end of the BC while they were unmodified during UF.BP tended to be only slightly de creased at the end of UF.No significant changes in PRC were seen.Our results indicate that circulating levels of plasma ANF can be regulated by humoral factors in addition to the well known regulation by the plasma volume.

11470| CHRONIC ENALAPRIL IN HYPERTENSIVE WOMEN: EFFECTS ON PLASMA PRORENIN AND RENIN AND ON THE OVULATION. C.Troffa*,G.Tonolo*,A.Pazzola,A.Soro and N.Glorioso* Hypertension Center, University of Sassari, Italy. Six normally menstruating hypertensive women(WHO I) were studied before and during the 3rd month of ena lapril regimen(E, lOmg bid) since angiotensin II(AII) was reported to play a key role in the ovulation in the rat (Pellicer A. et al., Science 1988).Estradiol (E2) .progesterone(P4)", LH, FSH,prorenin(PRO) and renin (AR)were measured during the cycles (Ria, mean+SEM). Peak LH-FSH was used as day 0. BP was normalized by E.

-8 -1 0 +3 +6 +14 PRO 12+0.4 12+1.2 25+3.5 14+0.3 20+3 18+5 AR 22+8 39+17 52+19 34+16 41+11 25+9 Ε did not affect the hormonal pattern found during-the basal cycles and previously reported for normal subjects (PNAS 1985, JCEM 1987). The synchronization of the peak of PRO with the other hormones was unaf fected. AR was stable throughout the basal cycles except for a slight increment during the luteal pha se. Under chronic Ε it was clearly higher than befo re (22+8 vs 2.2+0.9 ng/ml/hr, ρ<0.01) and increased up to day -1(E2 508+87 pg/ml) . It peaked at day 0(FSH-LH surge) , still high at +6(P4 13+3) and back to baseline at +14. Our data show that plasma AI-AII conversion blockade does not affect the pituitary guidance and the ovarian hormonal response during menstrual cycles also in terms of PRO synthesis and secretion. The suppression of plasma All could unmask the renal and/or ovarian synthesis and secretion of AR synchrony zed with the hormones of the menstrual cycle.

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BRAIN KININS MEDIATE THE HYPERTENSIVE EFFECT OF INTRACEREBROVENTRICULAR CAPTOPRIL IN SPONTANEOUSLY HYPERTENSIVE RATS. P.Madeddu. N.Glorioso, Patologia Medica,Universita Sassari, Italy. The components of the kallikrein-kinin system are present in the brain. Intracerebroventricular (ICV) administration of exogenous bradykinin increases blood pressure (BP) in rats. To elucidate the role of endogenous brain kinins in the central regulation of BP, we studied the effect of the ICV infusion of

0 3 5,8 a competitive antagonist DArg ,Hyp ,Thi ,DPhe bradykinin (K.ant.) on mean BP in awake spontaneously hypertensive rats (SHR). 1) ICV K.ant (20 ug/kg) had no effect on mean BP (control: 165+2, experimental:166+:

3 mmHg,p>.05). 2) ICV captopril (1 mg), an inhibitor ; of kininase II (the enzyme responsible for angiotensin II formation and kinin degradation), induced a significant increase in mean BP, which peaked at 2 min (from 165+2 to 205+10 mmHg, p<.01) and lasted for 16 min. 3) The hyper tensive effect of captopril was initially prevented and then reversed into a vasodepressor effect by ICV K.ant. (control:167+4, 16 min ; after captopril: 145+3 mmHg, p<.05). In conclusion, accumulation of endogenous kinins in the brain can result in an increase of BP. Furthermore,the finding, that simultaneous blockade of brain kinin and renin-; angiotensin systems by k.ant. and captopril decreases BP suggests a role of these two systems in the regulation of BP in SHR.

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[1473I

EFFECTS OF FJNDOTrELIN ON BLOOD PRESSURE AND RENAL FUNCTION IN AWAKE NORMOTENSIVE RATS. P.Madeddu, N.Glorioso. Patologia Medica, Universita di Sassari, Italy. ;

Endothelin (E) is a potent vasoconstrictor peptide isolated from ; cultured porcine endothelial cells. In anesthetized rats, Ε indu^ ces initially hypotension and then marked long-lasting hyperten- \ sion. We investigated whether bilateral nephrotomy (Nx) or pre- ;

treatment with nifedipine (5 mg i.p.) prevent the changes in mean; blood pressure (MBP) and heart rate (HR) induced by E. We also investigated the effect of a subpressor dose of Ε on glomerular filtration rate (GFR) , renal blood flow (RBF), filtration fra- ; ction (FF), urinary volume (Uv), urinary sodium excretion (UvNa) < and PRA. 1) Ε (1.7 ug/kg) initially decreased MBP (13+3 mmHg) and increased HR (80+15 b/min) ,pC.01. These effects were followed; by an increase in MBP and decrease in HR, both peaking at 10 min-' (32+3 nmHg and 77+10 b/min,respectively,ρ<.01). Bilateral Nx enh-, anced the vasodepressor effect (43+3 mmHg, p<.05); however the reflex tachicardia, which accompanied the decrease in MBP, was ;

less pronouced (32+8 b/min). Nifedipine completely blocked the hypertensive effect induced by E.2) At a dose of .17 ug/kg, Ε caused no change in MBP,HR,GFR,Uv,UvNa and PRA, but decreased RBF (19%) and increased FF (35%), p<.05. In conclusion,1) The enhan^ cement of the initial MBP-decrease in Nx rats might be due to a-reduced Ε clearance, b- systemic vasodilation not balanced by re-; nal vasoconstriction. The long-lasting hypertensive effect of Ε may be mediated by enhanced Ca influx through the dihydropiridi-ne sensitive Ca channels. 2)The renal vascular bed is very sensitive to Ε-induced vasoconstriction, since a subpressor dose of Ε significantly reduced RBF.

[U75J ONSET OF SYSTEMIC HYPERTENSION (H) IN HEART TRANSPLANT (TP) RECIPIENTS UNDER CYCLOSPORINE (Cy) CLINICAL ANALYSIS AND RELATION TO RENAL FUNCTION D. FARGE, J . JULIEN, G. DREYFUS, C. AMREIN, R. GUILLEMAIN, C. VULSER, J . P . C0UETIL, A. CARPENTIER Broussais Hospital, Paris , FRANCE.

Incidence and risk factors associated with post TP Η were studied in 85 patients under Cy. Η was ' defined as BP > 140/90 mm Hg or normal BP under at least 2 antihypertensive drugs. PreTP risk factors (H, tobacco and hypercholesterolemia) as postTP serum creatinine (Cr)(ymol/ l ) , weight gain and i . v . bolus of methylprednisolone were recorded.PostTP Η incidence was 67% (follow up 12.48+8.75months(M)) with no difference in age, sex r a t i o , i n i t i a l cardiac disease, cold ischemia time in hypertensive (HT) vs normotensive (N) patients . Η was diagnosed 4 .5+4 .9 Μ postTP. Ν patients were followed 8.4+ 5.4 M. None of the preTP cardiovascular risk factors was significantly associated with postTP H. Weight gain and i . v . steroids were higher, although not significantly in Ν patients , and were therefore not associated with Η onset. From day 8 to 1 M, Cr increased in HT (101+33 to 125+51, p<0 .05) , but not in Ν patients (102+10 to 106+17). In both groups, Cr rose at 6M vs IM (H=149+56, Ν = 134+9, p<0.05) but not at 12 Μ vs 6M (H=163+58, N=143+37 NS) CONCLUSION : High incidence of Η af ter cardiac TP (67%) is not related to preTP cardiovascular risk f a c t o r s , nor to weight gain nor to i . v . bolus of s teroids . Renal function deteriorates faster in Η patients within the l s t M after TP, but i t s relat ion to onset of Η remains to be determined. No direct relationship could be established between r ise in Cr and H, although Cy is their common causal fac tor .

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SEASONAL VARIATIONS OF ARTERIAL BLOOD PRESSURE IN NORMOTENSIVE AND ESSENTIAL HYPERTENSIVES. B.K. SHARMA, S. Sagar, G.K. Sood, S.Varma and O.P. Kalra/ Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh-160012/ India.

Marked seasonal variations in environmental fluid losses and arterial blood pressure (BP) have been observed by us. Factors causing these changes in BP have been investigated. Effect of seasonal variation on BP was studied in 15 controls and 15 essential hypertensives. Mean temperature and relative humidity in well defined 5 local seasons was recorded. Monthly observations included the plasma levels and 24 hours urinary excretion of +

norepinephrine (NE), epinephrine (Ε), sodium (Na ) and potassium (K ) . Average systolic, diastolic and mean BP were higher in winter season in both the groups (P.^0.01). In hypertensives this variation was observed despite a significant increase in drug consumption during winter season (P <0.001). Both the groups revealed higher plasma levels and daily urinary excretion of NE and Ε during winter month| (P./0^05 - < 0.001). 24 hrs urinary volume, Na and Κ were significant -ly higher in winter season ( P < 0 . 0 5 - < 0.001). These parameters showed a negative correlation with mean ambient temperature. Increased sympathetic nervous activity as documented by increased NE and Ε in plasma and urine, and decreased environmental loss of fluids and sodium may be contributory to this rise inblood pressure during winter season.

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S T R E S S T E S T S IN H Y P E R T E N S I V E S A N D N O R M O T E N S I V E S ; C O N T R A S T I N G R E S U L T S O B T A I N E D W I T H DIFFERENT B A S E L I N E V A L U E S . S G i a c o m * . C . P a l o m b o * . D . V o l t e r r a n i . C . M a r a b o t t i * . A . G e n o v e s i - E b e r t * , Ρ P e t r u c c i a m . S . G h i o n e . C N P I n s t i t u t e o f C l i n i c a l P h y s i o l o g y , P I S A , I T A L I A . A p a t t e r n o f h y p e r r e a c t i v i t y t o s t r e s s t e s t i n g i n h y p e r t e n s i v e s i s a d m i t t e d o n l y b y s o m e A u t h o r s a n d o n l y f o r s o m e s p e c i f i c t e s t s . A i m of t h e p r e s e n t s t u d y w a s t o c o m p a r e t h e c a r d i o v a s c u l a r r e s p o n s e t o a s e r i e s of s t a n d a r d i z e d s t r e s s t e s t s i n 2 7 n o r m o t e n s i v e ( N T ) , 2 5 b o r d e r l i n e ( B H T ) a n d 2 4 m i l d h y p e r t e n s i v e s u b j e c t s ( E H T ) o f c o m p a r a b l e age a n d s e x T h e p a t i e n t s u n d e r w e n t h a n d g r i p , m e n t a l a r i t h m e t i c t e s t , m a x i m a l m u l t i s t a g e b i c y c l e e x e r c i s e a n d a 2 4 - h r a m b u l a t o r y n o n i n v a s i v e B P m o n i t o r i n g ( A B P M , S p a c e l a b s 5 2 0 0 ) . T h e r e s p o n s e s o f b l o o d p r e s s u r e a n d h e a r t r a t e t o h a n d g r i p a n d m e n t a l t e s t w e r e a s s e s s e d a s t h e a b s o l u t e d i f f e r e n c e b e t w e e n t h e p e a k a n d 1 ) t h e p r e - t e s t v a l u e s 2 ) t h e m e a n n i g h t - t i m e A B P M v a l u e s . F o r b i c y c l e e x e r c i s e t h e s l o p e s o f t h e r e g r e s s i o n l i n e s o f s y s t o l i c b l o o d p r e s s u r e a n d h e a r t r a t e on t i m e w e r e u s e d . S t a t i s t i c a l e v a l u a t i o n f o r c o m p a r i s o n b e t w e e n g r o u p s w a s m a d e w i t h K r u s k a l l - W a l l i s a n d W i l c o x o n t e s t s . H y p e r t e n s i v e s s h o w e d an e n h a n c e d r e s p o n s e o f s y s t o l i c b l o o d p r e s s u r e a n d h e a r t r a t e t o b i c y c l e e x e r c i s e c o m p a r e d t o N T ( S B P p < 0 5 , HR p< . 0 1 ) . F o r h a n d g r i p a n d m e n t a l t e s t o n l y w h e n t h e r e s p o n s e s w e r e e v a l u a t e d a s t h e d i f f e r e n c e s b e t w e e n p e a k a n d n i g h t - t i m e v a l u e s , h i g h e r s y s t o l i c b l o o d p r e s s u r e a n d h e a r t r a t e i n c r e m e n t s w e r e f o u n d f o r B H T a n d EHT ( h a n d g r i p : S B P p < . 0 5 , HR p < . 0 1 ; m e n t a l t e s t ; S B P p < 0 5 , HR p < 0 0 1 ) . In f a c t , t h e d i f f e r e n c e s b e t w e e n d a y - t i m e a n d n i g h t - t i m e S B P a n d HR m e a n v a l u e s w e r e g r e a t e r i n h y p e r t e n s i v e s t h a n i n n o r m o t e n s i v e s ( S B P a n d HR p < 0 5 ) . B y c o n t r a s t w h e n p r e - t e s t m e a s u r e m e n t s w e r e c o n s i d e r e d a s b a s e l i n e v a l u e s , no d i f f e r e n c e s b e t w e e n g r o u p s w e r e f o u n d . T h e s e r e s u l t s s e e m t o s u g g e s t t h a t t h e e x p e c t a n c y o f t h e t e s t s p e r s e m a y r e p r e s e n t a s t r e s s s i t u a t i o n f o r t h e h y p e r t e n s i v e p a t i e n t s w h i c h t e n d s t o o b s c u r e a n e n h a n c e d c a r d i o v a s c u l a r r e s p o n s e . T h e r e f o r e a d i f f e r e n t r e l a x i n g s t a t u s b e f o r e t e s t s c o u l d , a t l e a s t i n p a r t , e x p l a i n t h e d i f f e r e n t r e s u l t s o b t a i n e d b y t h e v a r i o u s A u t h o r s w h o h a v e s t u d i e d t h i s s u b j e c t .

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[14771 EFFECT OF BETA BLOCKERS ON LEFT VENTRICULAR FILLING: A PULSED WAVE DOPPLER STUDY A. G e n o v e s i - E b e r t * . C. M a r a b o t t i * . S. G i a c o n i * , C. P a l o m b o * . S.j G h i o n e * C.N R. i n s t i t u t e of C l i n i c a l P h y s i o l o g y , P iSA , ITALIA | INTRODUCTION, A b n o r m a l i t i e s in d i as to l i c f u n c t i o n have been desc r i bed b y seve ra l A u t h o r s i n h y p e r t e n s i v e hea r t d isease, i n p a r t i c u l a r , by Dopp le r techn iques , an inc rease of a t r i a l c o n t r i b u t i o n to le f t v e n t r i c u l a r f i l l i n g r e l a t e d to blood p r e s s u r e has been r e p o r t e d . A I M of the s tudy was to eva lua te the p o s s i b i l i t y of b e t a b l o c k e r s to r e v e r s e t h i s d i as to l i c d y s f u n c t i o n

^MATERIALS AND METHODS. In 14 m i l d to modera te h y p e r t e n s i v e p a t i e n t s (age 4 5 ± 8 δ y r s , BP 163± 1 4 / 1 0 5 ± 7 m m H g ) t r a n s m u r a l fow v e l o c i t i e s w e r e eva lua ted by Pu lsed W a v e t c h o - D o p p l e r

, technique basa l l y and a f te r 3 mon ths of h y p o t e n s i v e t e r a p y w i t h a teno lo l ( 8 p t s ) o r mep indo lo l ( 6 p a t i e n t s ) . B lood p r e s s u r e was measured by an au toma t i c o s c i l l o m e t r i c techn ique at 3 . 0 0 P.M. bo th basal l y and a f t e r t r e a t m e n t . Lef t v e n t r i c u l a r t h i c kness and d i a m e t e r s w e r e eva lua ted acco rd ing to A S E . conven t i on E a r l y ( E ) and la te ( A ) t r a n s m u r a l peak f l o w v e l o c i t y , A / E r a t i o and e a r l y f i l l i n g f r a c t i o n ( E P F ) w e r e ob ta ined as indexes o f LV d i as to l i c f u n c t i o n . RESULTS No s i g n i f i c a n t d i f f e rences w e r e found between the ef fect o f the two d r u g s on e i t h e r BP o r d i as to l i c indexes, i n the o v e r a l l g r o u p s i g n i f i c a n t r e d u c t i o n o f BP ( s y s t o l i c and d i a s t o l i c ) and hea r t r a t e a f t e r t r e a t m e n t (ρ<ΟΟΠ w e r e observed . End d i as to l i c d i a m e t e r inc reased s i g n i f i c a n t l y ( p < . 0 1 ) . No d i f f e rences i n LV t h i c k n e s s w e r e observed . A peak decreased ( p < . 0 1 ) and EFF increased ( p < . 0 5 ) s i g n i f i c a n t l y CONCLUSIONS. Beta b l o c k e r s appear to tend to r e v e r s e the

j a b n o r m a l i t i e s of the le f t v e n t r i c u l a r d i a s t o l i c p a t t e r n i n h y p e r t e n s i v e pa t iens as ind ica ted by the r e d u c t i o n o f the r e l a t i v e

[ a t r i a l c o n t r i b u t i o n to le f t v e n t r i c u l a r f i l l i n g . To wha t ex ten t t h i s can ;be e x p l a i n e d b y changes i n hea r t r a t e o r b y r e d u c t i o n of b lood p r e s s u r e r e m a i n s to be c l a r i f i e d

11479| CURATIVE EFFICACY OF CICLETANINE IN SALT-DEPENDENT GENETIC HYPERTENSION M.T. Droy-Lefaix, M.M. Ruchoux, G. Narcisse, J . Guillemain, F. Bakri, D. Bosquet. IHB/IPSEN Research Laboratories, 17 avenue Descartes 92350 Le Plessis Robinson, iFrance. j Genetically hypertensive rats rapidly developed typical lesions of malignant hypertension. This Jpresent study was to determine the curative effect of an antihypertensive drug, the cicletanine (synthetic furopyridine) pathophysiological characteristics of hypertension.

55 male SHR-SP/A3N rats at 11 weeks of age from Iffa-Credo were randomly divided into 4 groups, one control group and 3 groups treated with cicletanine (10, 30 and 90 mg/kg/po/d). All animals received 1 aL NaCl ad libitum in their drinking water. Systolic arterial blood pressure, lethality, body weight evolution were regularly observed. After 38 days, all rats were sacrificed. Specimens of heart and kidney were taken out for histology. Heart weights were noted.

In control group hypertension development induced drop in body weight evolution and an important lethality (20 dead/21). Morphological analysis confirmed marked alterations in heart and kidney. Curative treatment with cicletanine according to a dose-response effect protected body weight evolution, reduced the lethality (10 mg/kg 4 dead/12, 30 mg/kg 3 dead/11, 90 mg/kg 0 dead/11) and the heart weights. Only minimal lesions were observed.

These observations demonstrated that curative treatment with cicletanine protected against the deleterious effects of genetic hypertension by enhancing the ratio of prostacyclin.

1478 R E L A T I O N S H I P S BETWEEN BLOOD PRESSURE A N D LEFT VENTRICULAR. F ILL ING INDEXES IN E S S E N T I A L H Y P E R T E N S I O N . C M a r a b o t t i * . a G e n o v e s i - E b e r t * , S . G i a c o n i * , C. P a l o m b o * , S . Gh ione C.N.R. I n s t i t u t e o f C l i n i c a l P h y s i o l o g y , P I S A , I T A L I A .

The p r e s e n c e o f a b n o r m a l i t i e s i n l e f t v e n t r i c u l a r ( L V ) f i l l i n g h a s b e e n w i d e l y r e p o r t e d in h u m a n h y p e r t e n s i o n , b u t r e l a t i v e l y f e w d a t a a r e a v a i l a b l e on t h e r e l a t i o n s h i p s b e t w e e n b l o o d p r e s s u r e ( B P ) a n d L V f i l l i n g i t s e l f , in p a r t i c u l a r , w h e t e r o r n o t a m b u l a t o r y a n d s t r e s s B P v a l u e s a r e b e t t e r c o r r e l a t e d w i t h L V f i l l i n g t h a n " c a s u a l " o n e s r e m a i n s t o be e s t a b l i s h e d To i n v e s t i g a t e t h e s e r e l a t i o n s h i p s , 2 2 b o r d e r l i n e t o m i l d e s s e n t i a l h y p e r t e n s i v e p a t i e n t s u n d e r w e n t an e c h o - D o p p l e r s t u d y in o r d e r t o o b t a i n , f r o m t r a n s m u r a l b l o o d f l o w , t h e l a t e - t o - e a r l y peak v e l o c i t y r a t i o ( A / E ) a n d t h e e a r l y f i l l i n g f r a c t i o n (EFF. r a t i o b e t w e e n t h e v e l o c i t y - t i m e i n t e g r a l o f e a r l y peak and t h e w h o l e d i a s t o l i c v e l o c i t y - t i m e i n t e g r a l ) . In t h e s a m e d a y a s e t o f c a s u a l b l o o d p r e s s u r e m e a s u r e m e n t s , a 2 4 - h r a m b u l a t o r y n o n i n v a s i v e B P m o n i t o r i n g ( A B P M , S p a c e l a b s 5 2 0 0 ) a n d a m e n t a l a r i t h m e t i c t e s t ( H T ) w e r e a l s o p e r f o r m e d in o r d e r t o r e d u c e t h e i n f l u e n c e o f a p r e - t e s t B P i n c r e a s e , due t o t h e e x p e c t a n c y o f t h e t e s t i t s e l f , t h e r e s p o n s e o f b l o o d p r e s s u r e t o m e n t a l t e s t w a s a s s e s s e d as t h e a b s o l u t e d i f f e r e n c e b e t w e e n t h e peak a n d t h e m e a n n i g h t - t i m e A B P M v a l u e s . The p r e s e n c e o f l i n e a r r e l a t i o n s h i p s b e t w e e n b l o o d p r e s s u r e a n d t h e f i l l i n g p a r a m e t e r s w a s a s s e s s e d b y l i n e a r r e g r e s s i o n a n a l y s i s . No s i g n i f i c a n t r e l a t i o n s h i p s w e r e o b s e r v e d b e t w e e n L V f i l l i n g i n d e x e s a n d c a s u a l s y s t o l i c a n d d i a s t o l i c b i o o d p r e s s u r e . On t h e c o n t r a r y , s i g n i f i c a n t r e l a t i o n s h i p s w e r e f o u n d b e t w e e n m e a n d i a s t o l i c d a y - t i m e B P a n d A / E ( r - 0 . 4 6 8 , p< 0 2 5 ) a n d b e t w e e n s y s t o l i c B P r e s p o n s e t o M T a n d b o t h A / E a n d EFF f r - 0 5 0 . p< 0 2 5 , r — 0 4 8 , p < , 0 2 5 r e s p e c t i v e l y ) . In c o n c l u s i o n , o u r d a t a s e e m t o c o n f i r m t h e l i n k b e t w e e n b l o o d p r e s s u r e l e v e l s a n d t h e r e d u c e d e a r l y f i l l i n g a n d t h e i n c r e a s e d l a t e d i a s t o l i c b l o o d v e l o c i t y p r e v i o u s l y d e s c r i b e d as t y p i c a l f e a t u r e s o f h y p e r t e n s i o n . In p a r t i c u l a r , i n e a r l y s t a g e s o f h y p e r t e n s i o n , B P r e s p o n s e t o s t r e s s a n d a m b u l a t o r y B P a p p e a r t o be b e t t e r d e t e r m i n a n t s o f L V f i l l i n g t h a n c a s u a l b l o o d p r e s s u r e ,

114801 THE N A T R I U R E T I C AND D I U R E T I C E F F I C A C Y OF AN ORALLY ACTIVE ATRIOPEPTIDASE I N H I B I T O R ( A P I ) , U K - 7 9 , 3 0 0 IN M I C E , GMR S a m u e l s , P L B a r c l a y * , Ρ E l l i s , NB S h e p p e r s o n , P f i z e r C e n t r a l R e s e a r c h , S a n d w i c h , K e n t C T 1 3 9 N J , U . K .

A d m i n i s t r a t i o n o f s a l i n e ( 2 . 4 % o f b o d y w t . i . v . ) t o c o n s c i o u s m i c e e v o k e s a t r a n s i e n t r i s e i n p l a s m a ANF ( p A N F , m e a s u r e d b y R I A ) f r o m 7 8 + 2 1 t o 1 6 0 + 2 5 p g / m l (max e f f e c t 5 m i n p o s t d o s e n = 6 ) . T h i s i s a c c o m p a n i e d b y a d i u r e s i s ( D , 1 5 3 + _ 2 2 μ ΐ / m o u s e ) a n d n a t r i u r e s i s ( N , 2 6 + _ 2 μ E q / m o u s e ) d u r i n g t h e f i r s t h o u r p o s t d o s e ( n = 1 5 ) . ANF a n t i b o d i e s r e d u c e d t h e s e e f f e c t s b y 5 0 % a n d 5 6 % r e s p e c t i v e l y ( n = 6 ) , d e m o n s t r a t i n g t h e r o l e o f ANF i n t h i s r e s p o n s e . A d m i n i s t r a t i o n o f t h e A P I U K -6 9 , 5 7 8 ( 0 . 3 t o 1 0 m g / k g i . v . ) w i t h t h e v o l u m e l o a d (VL) p r o d u c e s a d o s e r e l a t e d p o t e n t i a t i o n o f Ν ( + 1 7 % a t 0 . 3 m g / k g , + 1 0 0 % a t 1 0 m g / k g ) a n d D ( + 4 2 % a n d + 8 4 % ) . T h e e f f e c t o f U K - 6 9 , 5 7 8 o n ρANF

w a s i n v e s t i g a t e d i n a n a e s t h e t i s e d m i c e . F o l l o w i n g VL ρANF r o s e b y 1 2 0 % w i t h i n 5 m i n , a n d r e t u r n e d t o c o n t r o l l e v e l s b y 1 0 m i n p o s t - l o a d . A d m i n i s t r a t i o n o f U K - 6 9 , 5 7 8 ( 3 m g / k g , n = 3 ) w i t h t h e V L , e l e v a t e d ρANF f r o m c o n t r o l l e v e l s b y 1 5 4 % f o r t h e d u r a t i o n o f t h e e x p e r i m e n t ( 3 0 m i n ) . U K -6 9 , 5 7 8 i s m a r k e d l y l e s s p o t e n t f o l l o w i n g o r a l a d m i n i s t r a t i o n t o c o n s c i o u s m i c e ( 2 2 % i n c r e a s e i n Ν a t 3 0 m g / k g , n = 8 ) . H o w e v e r , o r a l a d m i n i s t r a t i o n o f t h e i n d a n y l - e s t e r o f i t s a c t i v e e n a n t i o m e r , U K - 7 9 , 3 0 0 , e v o k e s a d o s e r e l a t e d ( 1 . 0 - 3 0 m g / k g ) e n h a n c e m e n t o f t h e Ν ( + 2 3 % a t 1

m g / k g , + 5 1 % a t 3 0 m g / k g ) a n d D ( + 3 7 % a t 1 m g / k g , + 7 5 % a t 3 0 m g / k g ) r e s p o n s e s t o V L . T h e s e r e s u l t s d e m o n s t r a t e t h a t U K - 7 9 , 3 0 0 , a n o r a l l y a c t i v e A P I e n h a n c e s t h e ANF d e p e n d e n t D a n d Ν r e s p o n s e s t o a n a c u t e p l a s m a v o l u m e e x p a n s i o n i n m i c e .

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1 4 8 1

THE ACUTE INTERACTIVE EFFECTS OF SODIUM AND CALCIUM ON BLOOD PRESSURE. JP Nicholson*, J Cigarroa, Ν Ward, D Marion, ED Vaughan J r . , LM Resnick*,JH Laragh*. Hypertension Center, Cornell Univ. Med. College, New York, NY.

Exogenous factors such as sodium (Na) have been postulated to affect levels of intracel lular c a l cium (Ca) and thus influence calcium mediated c o n t r a c t i l i t y and blood pressure (BP). To further assess the interactions of Na and Ca, we measured mean BP (MAP), heart rate (HR), plasma renin ac t iv i ty (PRA) and serum ionized calcium (Ca ion) in ten conscious normotensive female dogs who underwent three isosmolar infusions:1)NaCl alone (500ml NS), 2)CaCl alone (4.5mg/kg), and 3)NaCl (500ml NS) plus CaCl2 (4.5mg/kg), each for one hour.

NaCl Alone CaC12 Alone CaC12 plus NaCl t=0 t=60 t=0 t=60 t=0 t=60

MAP 95±7 96±6 94±5 96±5 106±2 113±3** (mmHg) Ca ion 1.30 1.31 1.32 1.48 1.38 1.48** (mM) ±0.01 ±0.01 ±0.03 ±0.01 ±0.01 ±0.01 PRA 4.4±1 1 .5± .3* 3±.5 3 .5+1.1 3 .6± .4 1 .5± .3** (ng/ml/hr) *p<0.02, **p<0.005 vs t=0

Although Ca ion was increased by both Ca and Ca plus Na, and PRA was decreased by both Na and Ca plus Na, MAP was significantly increased only by Ca plus Na. These results demonstrate that the abi l i ty of saline-volume expansion and/or calcium to elevate BP in the normotensive awake dog are mutually interdependent. We speculate these acute intravenous effec ts might re f lec t similar underlying mechanisms regulating the longer-term BP effec ts of dietary sa l t and calcium intake.

114831 PLASMA CONCENTRATION VS EFFECT RELATIONSHIPS FOR FELODIPINE. Blychert E, Edgar B, Elmfeldt D, Shapiro D, Astra Cardiovasular, Sweden & Merck Sharp and Dohme Research Laboratories, USA

T h e r e is a l inear r e l a t i o n b e t w e e n t h e d o s e of f e l o d i p i n e (F) g i v e n a n d t h e p l a s m a c o n c e n t r a t i o n o b t a i n e d in t h e r a n g e f r o m 1 0 - 4 0 m g . Af ter i n t a k e of F t h e b l o o d p r e s s u r e (BP) v s t i m e c u r v e m i r r o r s t h e p l a s m a c o n c e n t r a t i o n (CpF) v s t i m e c u r v e . It is t h u s o b v i o u s t h a t t h e r e is a r e l a t i o n s h i p b e t w e e n BP-reduction a n d CpF bu t h o w s h o u l d it b e d e s c r i b e d ?

T h e d e s c r i p t i o n of q u a n t i t a t i v e r e l a t i o n s h i p s b e t w e e n d r u g p l a s m a c o n c e n t r a t i o n s ( C ) a n d r e s p o n s e (E) is o f t e n b a s e d o n a m o d e l w h i c h a s s u m e s t h a t t h e e f f e c t is h y p e r b o l i c a l l y r e l a t e d to t h e l o g a r i t h m i c p l a s m a c o n c e n t r a t i o n . T h i s c a n b e d e s c r i b e d b y a m o d i f i e d E m a x -m o d e l w h e r e t h e t h e o r e t i c a l l y m a x i m a l r e s p o n s e ( E m a x ) a n d t h e C a t 5 0 % of E m a x ( E C 5 0 ) a s w e l l a s t h e C a t w h i c h n o e f f e c t c a n b e d e t e c t e d ( C m i n ) a r e i n c l u d e d in t h e f u n c t i o n : E m a x ( C - C m i n )

E=(EC 5 0 -2Cmin+C) W h e n th is m o d e l is u s e d t o d e s c r i b e F d a t a a n a l m o s t l i nea r r e l a t i o n b e t w e e n BP-reduction a n d C p F is s e e n in t h e r a n g e f r o m a p p r o x i m a t e l y 2 to 2 0 n m o l / l . It a l s o s h o w s t h a t re la t i ve ly little e x t r a e f f e c t for a n i n c r e a s e in C p F c a n b e e x p e c t e d a b o v e 2 0 n m o l / l .

T h e c o n v e n t i o n a l l i n e a r c o r r e l a t i o n a n a l y s i s is of l i m i t e d v a l u e w h e n s t u d y i n g p l a i n F t a b l e t s s i n c e t h e C p F is o f t e n n o t in t h e l i n e a r r a n g e of t h e h y p e r b o l i c c u r v e a t t h e t i m e of p e a k , a n d if l o w e r d o s e s a r e g i v e n , a l s o a t t r o u g h . F o r t h e o n c e - d a i l y e x t e n d e d r e l e a s e ( E R ) t a b l e t of F, w h e r e t h e t r o u g h C p F a r e h i g h e r a n d t h e p e a k l e v e l s l o w e r t h a n for t h e s a m e d a i l y d o s e s of t h e p l a i n t a b l e t , t h e C p F is w i t h i n t h e l inear p a r t of t h e BP-reduction v s l o g C p F c u r v e d u r i n g t h e m a j o r p a r t of t h e d a y . T h e l i n e a r c o r r e l a t i o n s h o u l d t h u s b e a c c u r a t e to u s e for t h e E R t a b l e t .

C o n c l u s i o n ο T h e r e i s a l i n e a r r e l a t i o n b e t w e e n d o s e g i v e n a n d t h e p l a s m a

c o n c e n t r a t i o n o b t a i n e d f o r f e l o d i p i n e . ο T h e r e i s a g o o d r e l a t i o n s h i p b e t w e e n t h e C p F a n d t h e D B P -

r e d u c t i o n . ο T h e r e l a t i o n s h i p b e t w e e n B P - r e d u c t i o n a n d l o g C p F i s a l m o s t

l i n e a r b e t w e e n 2 a n d 2 0 n m o l / l .

1 4 8 2

CELLULAR CALCIUM UPTAKE MEDIATES THE PRESSOR EFFECTS OF CALCIUM-SODIUM-VOLUME EXPANSION JP Nicholson*, J Cigarroa, Ν Ward, D Marion, ED Vaughan, J r * , LM Resnick*, JH Laragh*. Hypertension Center, Cornell University Medical College, New York, NY.

We have previously shown that acute I.V. NaCl loading in the presence of concurrent I.V. calcium raises blood pressure, but not when either ion is administered alone. To investigate possible underlying mechanisms we measured mean blood pressure (MAP) and serum ionized calcium (Ca ion) in conscious normotensive female dogs that underwent three infusions: 1) NaCl (500 mg NS) + CaCl2 10 mg/kg for 60 minutes, 2) nicardipine (Ν) 1 yg/kg/min) and 3) NaCl + CaCl2 for 60 minutes with prior ongoing N.

2 + NaCl Nicardipine N+CaCl+NaCl (n=8) (n=ll) (n=5)

pre post pre post MAP 106±2 113±3* 108±3 101±3 99±3 (mmHg) Ca ion 1.38 1 .48* 1.3 1.28 1.43* (mM) ±0.01 ±0.01 ±0.01 ±0.01 ±0.04

*p<0.005 vs . T=0 Ν prevented the pressor response to NaCl +

CaCl 2 , (ΔΜΑΡ= -2±3 vs + 7±2 mmHg, p<0.001) and enhanced the CaCl? induced r ise in extracel lular Ca ion (Δ=0.15±0.02 vs. 0.10±0.01 mM, p<0.05) These results support the hypothesis that the abi l i ty of acute sodium-volume expansion to elevate pressure is 1) a calcium-mediated process , and 2) i s c r i t i c a l l y dependent on calcium uptake from the extracel lular space.

1 4 8 4 24-HOUR ANTIHYPERTENSIVE EFFECT OF FELODIPINE ONCE DAILY GIVEN AS MONOTHERAPY TO 102 ELDERLY PATIENTS. A DOUBLE-BLIND STUDY VS PLACEBO. J Hosie and A W Mulder for the Binational MC Study Group (UK and NL), The Surgery, Glasgow, Scotland and Catharina Ziekenhujs, Eindhoven, Holland. Felodipine (PlendiP) 's an antihypertensive calcium antagonist which selectively reduces the contractile activity of the resistance vessels. A total of 102 elderly (ages 64-82 years) hypertensive patients with a diastolic blood pressure (DBP) >100 mm Hg were randomised to felodipine (F) extended release (ER) 5 mg once daily (n=49) or placebo (P, n=52). If, after 2 weeks, the DBP was >95 mm Hg, the dose was doubled and the treatment continued for another 2 weeks. Blood pressure (BP), heart rate (HR) and body weight were measured 24 hours after dose intake. Adverse events (ADE) were reported spontaneously and by open questioning. Routine laboratory investigations were performed before and at the end of the study. After 2 weeks' treatment F 5 mg daily resulted in a BP fall of 12/12 mm Hg (baseline 177/105 mm Hg) compared with 4/8 mm Hg on Ρ (baseline 180/106). The difference in change was statistically significant for SBP (p=0.01). The dose was then increased in 41 % of the F group and in 50 % of the Ρ group. At the end of the study, BP was reduced by 14/13 mm Hg on F and by 4/8 mm Hg on P. The fall was significantly greater on F than on Ρ both for SBP (p=0.005) and DBP (6=0.007). The proportion of responders (DBP <95 mm Hg or tall in DBP >10 mm Hg) was 75 % on F and 42~% on Ρ (p=0.0008). HR and body weight remained unchanged. No clinically significant changes occurred in any of the laboratory variables. Reported ADE were few and of similar magnitude in both groups, headache and ankle swelling being the most frequent. Six patients were withdrawn from the study, 4 because of ADE (3 on F). In this large group of 102 elderly patients, felodipine ER tablets 5 to 10 mg once daily, given as monotherapy, was effective and well tolerated in the treatment of hypertension.

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11485| PROSTAGLANDIN-RENIN INTERACTIONS AND BLOOD PRESSURE REGULATION DURING ACUTE WITHDRAWAL IN HUMAN ALCOHOLISM. A Malanowska-Kantoch, S Flaschner, D Campanella, JB Lee*, Dept. of Medicine, SUNY at Buffalo, Buffalo, N.Y.

A prospective study was undertaken to establish patterns and possible etiological factors in blood pressure (BP, mmHg) during 4 days (D1-D4) of acute withdrawal in 123 chronic alcoholics. On DI, 46% of the patients were hypertensive (163 ± 2/103 ± 2) as compared to 11% on D4 (156 ± 5/103 ± 2 ) . Based on these observations, three patterns were identified. Normotensive (N): BP, 124 ± 3/78 ± 3 during the entire period D1-D4; initially hypertensive (IH): BP, 157 ± 3/105 ± 4 on DI with a significant (p<0.001) fall to normotensive levels on D4 (137 ± 3/87 ± 2 ) ; hypertensive (H): BP, 165 ± 6/108 ± 3 during the entire period D1-D4. Plasma renin activity (PRA, ng/ml/hr) and urinary Prostaglandin E2 (UpGE2^' n§/24 hr) were measured daily by specific radioimmunoassay in 31 patients. PRA averaged 3.57 ± 1.2 which did not significantly change during D1-D4 in all 3 groups. In H, there was a marked significant (p<0.01) rise in UpQ ^ 2 v

(+3236 ± 1032) coinciding with the fall in blood pressure in contrast to Ν and Η where there was a consistent but insignificant rise in UpQ^V (+850 ± 612 and 881 ± 461 respectively). The results suggest 1) although hypertension is common in alcoholism, it is persistent in only 25% of the hypertensive patients after withdrawal, 2) in patients where initial hypertension decreases to normotensive levels, the associated rise in UpQjpV may reflect an antihypertensive role for renal PGE2 and 3) reversible hypertension in chronic alcoholism may be mediated, at least in part, by alcohol induced suppression of renal PCE2 synthesis.

1 4 8 7

AMBULATORY BLOOD PRESSURE MONITORING: COMPARATIVE EVALUATION OF 4 SYSTEMS ( D e v i c e s , I n s t r u m e n t s ) ( A v i o n i c s PIV, N0VAC0R DIASYS 2 0 0 , SPACELABS 9 0 2 0 2 , TAKEDA TM2420) . R De Gaudemaris ,A D e l o r a i n e , P C o u r t u r i e r , S PARAT, Μ J a l b e r t , Ν Cugnardey, JP S i c h e , JM Mall i o n . C o n s u l t a t i o n d 1 ΗΤΑ, CHRG, BP217X, 3 8 0 4 3 GRENOBLE FRANCE O b j e c t i v e : t o perform a c o m p a r a t i v e a n a l y s i s of a systems of ambulatory blood p r e s s u r e (BP) measurement ( p r e c i s i o n and r e l i a b i l i t y of m e a s u r e m e n t s ) . Methodology : BP was measured s i m u l t a n e o u s l y by a p h y s i c i a n and by t h e a u t o m a t i c d e v i c e ( t h e d i s p l a y was hidden) ; measurements were taken a t t h e same arm with a mercury column p l a c e d in d e r i v a t i o n | For each s y s t e m , 30 p a i r s o f measurements were c a r r i e d o u t a t r e s t in 10 normal or h y p e r t e n s i v e s u b j e c t s . Analysi s : Data d i s t r i b u t i o n n o r m a l i t y , s t u d e n t Τ t e s t , r e g r e s s i o n , and study of r e s i d u a l s . R e s u l t s : t h e f o l l o w i n g t a b l e shows t h e p r e c i s i o n of t h e d i f f e r e n t s y s t e m s .

AVIONICS N0VAC0R SPACELABS TAKEDA SBP DBP SBP DBP SBP DBP SBP DBP

Mean D i f . 0 . 3 2 . 3 1 . 6 4 . 2 2 . 1 1 . 2 4 . 5 0 . 2 SD 6 . 9 12 2 . 4 2 . 7 4 . 3 5 . 2 6 . 3 3 . 9 C o r r . . 9 5 . 7 7 . 9 9 . 9 8 . 9 8 . 8 8 . 9 4 . 9 3 Conclusion : in comparison with sys tems p r e v i o u s l y t e s t e d : t h e s y s t o l i c c o r r e l a t i o n s appear s a t i s f a c t o r y f o r a l l of t h e s y s t e m s . The r a t h e r e x c e p t i o n a l d i a s t o l i c c o r r e l a t i o n l e v e l s f o r N0VAC0R and TAKEDA a r e p a r t l y due t o t h e method : t h e l a c k o f microphone s e n s i t i v i t y adjus tment l e a d s t o t h e d i s p l a y , in some s u b j e c t s , o f DBP wich a r e t o o h i g h . S i n c e t h e s e d e v i c e s can not be d e f l a t e d manually a f a l s e DBP i s f o l l o w e d by an immediate a u t o m a t i c d e f l a t i o n which does not alow t h e p h y s i c i a n enough t ime t o o b t a i n a manual r e a d i n g . These measurements can not be i n c l u d e d in t h e a n a l y s i s t h e r e b y a r t i f i c i a l l y e l e v a t i n g t h e c o r r e l a t i o n s .

|1486l

CAPTOPRIL (C) ADMINISTRATION IN THE DIAGNOSIS OF RENAL ARTERY STENOSIS (RAS) BY RENAL SCINTOGRAPHY (RS). SJ Mann*, TG Pickering*, S Sarkar, Τ Sos, JH Laragh*. Hypertension Center, Dept. of Radiology & Nuclear Medicine, New York Hospital-Cornell Medical Center, New York, NY.

Fifty-one patients (36 with RVH: 21 unilateral (U) renal artery stenosis (RAS), and 15 b i l a t e r a l (B)RAS, and 15 with essential hypertension (EHT), were scanned before and after administration of 25 mg C, using TcDTPA as an index of glomerular f i l t r a t i o n rate (GFR). Presence of asymmetry of: 1) tracer uptake (Up) at 1^-2^ minutes (unil a t e r a l uptake <40% of t o t a l ) , and 2) time to peak (difference >5 minutes), or % of peak uptake retained at 15 minutes (difference >20%), were determined.

Asymmetry of RVH EHT SENS SPEC l.Up pre-C 20/35 0/15 55% 100%

post-C 28/35 0/15 80% 100% 2. Ret or pre-C 22/36 1/15 61% 93%

time to peak post-C 29/36 1/15 61% 93% 1 or 2 pre-C 29/36 1/15 81% 93%

post-C 35/36 1/15 97% 93% In conclusion: 1) a single post captopril scan

can detect RVH with good sens and spec, 2) when RAS is severe, administration of C does not alter Up or Ret and cannot distinguish (U)RAS from (U)parenchymal disease, 3) (B)RAS can be detected and distinguished from (B)parenchymal disease due to asymmetry of renal ischemia. B(RAS) and (U)RAS may be indistinguishable on scan, 4) truly symmetric (B)RAS may be missed unless more reproducible estimates of GFR can be obtained to enable comparison of pre- and post-C GFR.

1 4 8 8

COMPARISON OF THE EFFECTIVENESS OF LISINOPRIL VERSUS CAPTOPRIL IN A SINGLE DAILY DOSE BY AMBULATORY BLOOD PRESSURE MEASUREMENT. JP S i c h e , Ρ MANS0UR, R De Gaudemaris, JM Mai l i o n Medecine I n t e r n e e t C a r d i o l o g i e , CHRG, BP 217X - 38043 GRENOBLE Cedex, FRANCE O b j e c t i v e s : To compare during a c t i v i t y , t h e evening and a t n i g h t t h e e f f e c t i v e n e s s of L i s i n o p r i l v e r s u s C a p t r o p i l given in a s i n g l e d a i l y d o s e . Methodology : double b l ind s tudy in 14 m o d e r a t e l y h y p e r t e n s i v e p a t i e n t s , 7 r e c e i v i n g L i s i n o p r i l and 7 r e c e i v i n g C a p t o p r i l . Ambulatory blood p r e s s u r e measurement ( S p a c e l a b s ) e v e r y 15 minutes during t h e day , and every 3o minutes a t n i g h t a t t h e end of t h e placebo p e r i o d , and a t 4 th and 8th weeks of t r e a t m e n t . The r e c o r d i n g a t the 4 th week i s used f o r adjustment of the posology on both m e d i c a t i o n s ( 2 0 or 40 mg of L i s i n o p r i l 50 or 100 mg of C a p t o p r i l ) a c c o r d i n g t o r e f e r e n c e c r i t e r i a . Analysi s : Study of i n d i v i d u a l hourly means and (Wi Icoxon t e s t ) a n a l y s i s of v a r i a n c e with r e p e a t e d measures f o r t h e t r e a t m e n t e f f e c t , indivudual e f f e c t and hourly per iod ( s c h e d u l e ) e f f e c t , and t h e i r i n t e r a c t i o n s . R e s u l t s : t h e h i s t o g r a m shows t h e r e s p e c t i v e e f f e c t i v e n e s s on t h e 2 Products ( 8 t h w e e k - p l a c e b o ) a t d i f f e r e n t p e r i o d s of t h e day.

Conclusion : t h e s y s t o l i c e f f e c t i v e n e s s o f L i s i n o p r i l i s c o n s t a n t l y g r e a t e r than t h a t of C a p t o p r i l while t h e d i a s t o l i c e f f e c t i v e n e s s of L i s i n o p r i l i s g r e a t e r only a t n i g h t .

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114891 THE EFFECTS OF LABETALOL ON BLOOD PRESSURE AND ARTERIAL COMPLIANCE EVALUATED DURING STRESS-TESTING. JP Siche, Ρ Mansour, R De Gaudemaris, JM M a l l i o n . Medecine In te rne et C a r d i o l o i g e , CHRG, BP 217X, 38043 GRENOBLE Cedex - France. Ob jec t i ve : Tes t ing the e f f e c t s of l a b e t a l o l on blood pressure (BP), hear t r a t e (HR) and a r t e r i a l compliance (AC) at r e s t and du r i ng exerc ise i n b o r d e r l i n e to moderately hyper tens ive p a t i e n t s se lec ted by r e s t c r i t e r i a . M e t h o d o l o g y : 2 eva lua t ions a f t e r .15 days of placebo ( E l ) and 1 month of Labe ta lo l t reatment (E2 ) . CA i s eva luated by measurement of pulsewave conduct ion v e l o c i t y (PWCV) on the r i g h t forearm by pulsed dopp le r , in the s u b - c l a v i a n / r a d i a l a r t e r i a l segment. At El and E2 measurements are r e a l i z e d at r es t and dur ing s t ress t e s t (4 th min) on ergometr ic b i c y c l e . Resul ts : BP decrases s i g n i f i c a n t l y under l a b e t a l o l at r e s t and dur ing e x e r c i s e . The HR unchanged at r e s t , i s s i g n i f i c a n t l y decreased at 50-75W increment .

fo^t ^ ™ ! ^ « " » R « t

A f t e r 1 month o f t reatment (E2) the PWCV i s not s i g n i f i c a n t l y mod i f ied at r e s t . During e x e r c i s e , under l a b e t a l o l , the PWCV immediately decreases s i g n i f i c a n t l y to an average l e v e l which remains s t a b l e , w i t h a reduc t i on i n the standard d e v i a t i o n . This r e f l e c t s an improvement i n AC du r i ng exerc ise s i g n i f i c a n t at 75 and 100W. Conclusion : The v a r i a t i o n of PWCV under l a b e t a l o l does not seem to be c o r r e l a t e d w i t h t h a t o f BP and of HR since f o r a same s i g n i f i c a n t decrease i n BP at r e s t and dur ing e x e r c i s e , the v a r i a t i o n i n PWCV i s s i g n i f i c a n t on ly du r i ng e x e r c i s e . These r e s u l t s suggest t h a t improvement i n AC by l a b e t a l o l depends a lso on i t s i n f l u e n c e on vasomotor tonus and the r e g u l a t i o n of t h i s system dur ing e x e r c i s e .

[14911 I M P R O V I N G H Y P E R T E N S I O N T H E R A P Y G . R .

G R E E N W E L I ? L . I . F . E . C L I N I C B r a n d o n , F l o r i d a A n a v e r a g e o f 1 8 d a y s t h e r a p y ( R x ) o n e

h o u r d a i l y , d i r e c t e d t o w a r d i m p r o v i n g o x y g e n ( 0 2 ) p e r f u s i o n p r o c e s s e s , g r e a t l y i m p r o v e d 9 2 % o f 8 3 h y p e r t e n s i v e p a t i e n t s ( p t s ) . f i f t y o n e h a d b e e n m e d i c a l l y t r e a t e d ( M ) p r i o r t o R x w i t h t r a d i t i o n a l m e d i c a t i o n s . B e t a - b l o c k e r s (Β ) w e r e d i s c o n t i n u e d p r i o r t o R x . n o n e r e q u i r e d r e s u m i n g Β a f t e r R x . A v e r a g e p r e s s u r e ( B P ) c h a n g e s a r e s h o w n b e l o w .

B e f o r e R x A f t e r R x A l l p t s 1 5 7 / 9 3 1 3 5 / 81 N o p r i o r Μ 1 6 1 / 1 0 0 1 4 0 / 82 Μ p r i o r t o R x 1 5 6 / 8 9 1 3 4 / 7 9 S y s t o l i c > 1 5 9 1 7 5 / 9 9 1 4 9 / 8 4 R x c o n s i s t e d o f d a i l y : D i p y r i d a m o l e 5 0 m g m e a c h 8 h r s . ; n a s a l 0 2 a t 4 1 i t e r s / m i n . d u r i n g h y p e r t h e r m i a ( 2 0 m i n . ) & r e s t ( 5 m i n . ) , t h e n 5 m i n . r e s t , t h e n 5 m i n . e x e r s i z e w a r m u p , t h e n e x e r c i s e a t m a x i m u m s t e a d y s a f e , s t e a d y - s t a t e p u l s e r a t e 2 0 m i n . , a n d 1 0 m i n r e s t . C o n c l u s i o n : I m p r o v i n g 0 2 p e r f u s i o n p r o c e s s e s c a n i m p r o v e h y p e r t e n s i o n . M o r e s t u d i e s s h o u l d b e d o n e t o d e t e r m i n e h o w i m p r o v e m e n t i s p r o d u c e d i n s u c h p t s .

1 4 9 0

STUDY OF ARTERIAL COMPLIANCE DURING EXERCISE IN HYPERTENSIVE AND CONTROL SUBJECTS OF THE SAME AGE JP S i c h e , Ρ Mansour, Μ TERREL, A D e l o r a i n e , R De Gaudemaris, JM M a l l i o n . C o n s u l t a t i o n d 1 ΗΤΑ, CHRU de Grenob le , 38043 Grenoble Cedex - France O b j e c t i v e : Study o f t he e v o l u t i o n o f a r t e r i a l compl iance (AC) a t r e s t and d u r i n g e x e r c i s e i n normotens ive (NT) t o moderate h y p e r t e n s i v e s u b j e c t s (HT) . Study M a t e r i a l : 59 NT and 31 HT (mean age 48+6 yea rs ; range 20 t o 55 y e a r s ) . Methodology : AC Ts eva lua ted by measurement o f t he pu lse wave conduc t i on v e l o c i t y (PWCV) on the s u b - c l a v i a n / r a d i a l a r t e r i a l segment us ing a pu lsed dopp le r r e c o r d i n g coup led bo t he EKG. AC i s measured at r e s t and a t the end o f each w o r k - l o a d i nc remen t , 50,75 and 100W. R e s u l t s : 1° - Normal s u b j e c t s , e v o l u t i o n by age group :

no («/» *" , η η " = 30 = 1J)

Hyper tens ive s u b j e c t s (age 31-50 y r s )

AC i s a l t e r e d more i n h y p e r t e n s i v e s u b j e c t s i n comparison w i t h c o n t r o l s o f t he same age. The d i f f e r e n c e i s however not s i g n i f i c a n t . 3° - Study o f c o r r e l a t i o n between PWCV and BP-HR at e x e r c i s e : Few l i n k a t r e s t . They are more appareent d u r i n g e x e r c i s e o n l y f o r the HR (ad rene rg i c r e g u l a t i o n ) .

BP-PWCV I REST | 50W | 75W | 100W | 4 REST

j 0 . 2 2 * * I .13 I I I I 0 . 4 3 * :

I 0 .05

»| 0 . 2 4 * * | 0 . 2 7 * * I 0 . 2 9 * * * | 0.23*>

j 0 .17 j 0 . 3 7 * * * | 0 . 3 3 * * * | 0 .16

Conc lus ion :The impo r tan t v a r i a b i l i t y per increment i s e x p l a i n e d by the h e t e r o g e n e i t y i n t h e degree o f v a s c u l a r d i sease and i n hemodynamic r e g u l a t i o n d u r i n g e x e r c i s e . The v a r i a t i o n o f t he AC on e x e r c i s e t e s t i s dependent on the degree o f ad rene rg i c l e v e l . These c o n s t a t a t i o n may have t h e r a p e u t i c i m p l i c a t i o n s , t o judge o f t he t r ea tmen t e f f i c i e n c y .

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ADRENAL MASSES WITH HYPERTENSION AND UNKCWDN ALDOSTERONE DERIVATIVES -VARIANTS OF CONN'S SYNDROME? Abdelhamid.S., Vecsei,P.*, Lewicka,S.*, Bige,K.*, Kirk,D.N.**, Bonhof,J.-A., Muller-Lobeck,H. Deutsche Klinik fur Diagnostik, Hypertension Unit, 6 2 0 0 Wiesbaden, *Pharrnakologisches Institut der Universitat Heidelberg, FRG, **Dept. Chemistry, Queen Mary College, University of London, U.K. Cases with elevated blood pressure, normal "traditional" aldosterone values and adrenal adenomas were detectedt by computerized tomography. Considering some aldosterone metabolic anomalies we determined 21-deoxy-aldosterone (aldosterone percusor) as well as its possible metabolite 11-beta: 18 (S), 1 8 : 2 0 alpha-dioxy-5-bete-pregnan-3-alpha-01 (first described by Kelly. W.G. et al: biochemistry 1 ( 1 9 6 2 ) 1 7 2 ) and further 18-hydroxy-corticosterone (18-OH-B). The steroids were determined by radioimmunoassay after paper chromatography und repeated HPLC. In 5 of 8 patients with adrenal adenomas and hypertension - on normal, high dietary salt and salt depreviation - elevated and unchanged excretions of the Kelly-steroid and 21-deoxy-ald were found. In all aldosterone18-glucoronide, tetrahydro-aldo-sterone and 18-OH-B were normal, reninactivity was low. After adrenalectomy blood pressure normalized in 4 and improved in the fifth. In the further 3 cases with adrenal adenoma 18-OH-B was the only elevated steroid - under the mentioned conditions and potassium-suplementation -(in 1 case urinary 17-OH-corti-costeroids were normale to slightly elevated, free Cortisol was elevanted, however, the specificity of the assay is still under examination). Blood pressure was normalized after adrenalectomy in 2 of the 3 cases. On the basis of the results of surgery we believe that there is a correlation between the found abnormalities and the blood pressure elevation. Conclusions: In hypertensive patients especialy those wich discovered adrenal adenoma and normal tradionall aldosterone values the determination of the above mentioned steroids ist recommended. Further it ist possible that they may participate in the pathogenesis of hypertension. The described cases indicate the wide spectrum of Conn's Syndrome.

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114931 A NOVEL NEUROPEPTIDE IN BOVINE CHROMAFFIN CELLS: ALDOSTERONE SECRETION INHIBITORY FACTOR. T.T. Nguyen, C. Lazure, K. Babinski, H. Ong, and A. De Lean. Clinical Research Institute of Montreal, Montreal, CANADA.

We have previously characterized an Aldosterone Secretion Inhibitotry Factor (ASIF) in bovine adrenal medulla. This factor purified from chromaffin granules was identified as atrial natriuretic factor (ANF). We have shown that both ANF-(99-126) and its prohormone are synthesized and secreted by cultured chromaffin cells, indicating that ANF behaves as an endogenous neuropeptide in the adrenal medulla. We now report the identification and the primary structure of another ASIF, a novel neuroendocrine peptide which is detected only by ANF radioreceptor assay but not by radioimmunoassay. The peptide was isolated from 1 .5 χ 1 0 1 0

cultured bovine chromaffin cells by reversed-phase and ion exchange high pressure liquid chromatography. It is chromatographically and structuraly distinct from ANF. This new ASIF is predominant in cultured chromaffin cells and cross-reacts with ANF receptor sites involved in the inhibition of aldosterone production in zona glomerulosa cells. The sequence of this 35-amino acid peptide includes the shorter fragment isolated from porcine brain confirming its neuropeptide character. The presence of both ASIF and ANF together with norepinephrine and epinephrine in the adrenal medulla suggests that ASIF might be acting more as a local neuromodulator in the paracrine regulation of aldosterone production, while ANF might be rather acting as a circulating hormone.

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1,25 (OH)2 VITAMIN D3 INCREASES THE SENSITIVITY OF ISOLATED RESISTANCE ARTERIES OF THE SPONTANEOUSLY HYPERTENSIVE RAT (SHR) TO NOREPINEPHRINE AND SEROTONIN. D. Kremer. DA McCarron*, RD Bukoski*, Div. Neph., Ore. Hlth. Sci . Univ., Portland, OR.

We have shown that acute treatment of r e s i s tance a r te r ies of SHR with 1,25 (OH)2 vitamin D 3 (VitD) increases their sens i t iv i ty to norepinephrine (NE) and enhances NE-induced C a 2 + mobilization. The current study tested the hypothesis that VitD acts spec i f i ca l ly on the α-adrenergic receptor. Resistance a r t e r i e s (188+23 μτα. i . d . , n=8) were isolated from 11 week old male SHR and placed in a wire myograph for measurement of isometric force development, axial length and wall thickness. The vessel was set to a diameter equivalent to 90% of that which i t would have with a transmural pressure of 100 mmHg. After i n i t i a l challenges with KC1 and NE, the vessels were treated with VitD (1 ng/ml) or vehicle (EtOH) for 10 min, then NE was cumulatively added to determine the dose-response relationship. After washing, VitD or EtOH was re-added and the response to serotonin (5HT) was determined.

ED50 (μη) PQ (mN/mm2) VitD EtOH VitD EtOH

NE 0.60±0.15 1.07±0.27 106±27 124±14 5HT 0.09±0.02 0 .21+0.06 101±20 121+32

Each value is mean+sem, n=4. The apparent increase in sensi t iv i ty to both NE and 5HT af ter VitD indicates that the ef fec t of the hormone is not specific for the a-adrenergic system and suggests that i t exerts a more general action on the resistance artery smooth muscle c e l l . Supported by HL41816 and the National Dairy Research Board.

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THE RELATIONSHIP BETWEEN THE SYMPATHETIC NERVOUS SYSTEM (SNS) AND THE RENIN-ANGIOTENSIN SYSTEM IN RENOVASCULAR HYPERTENSION. CX Zamboulis, AJ Karagiannis, SN Douma, KV Vogiatzis, MN Doumas, AT Vyzantiadis, PA Me-taxas, SC Efremidis. ET Prop.Dept. of Int.Medicine, Aristotelian University of Thessaloniki/Radiology Dept. Ippokration Hosp., Thessaloniki, Greece.

The SNS involvement in the pathogenesis of human renovascular hypertension was studied in 10 hypertensive patients with unilateral renal artery stenosis, who underwent percutaneous transluminal angioplasty (PTA). Bebore PTA, systolic/diastolic BP readings (m±SEM) were 185,3±7,8/123,2*5,1 mmHg, peripheral PRA values were 8,63±2,27ngAI/ml/h, the ratio RVRR was 2,15+0,27, the ratio V1-IVC/IVC was 1,00+0,23 (V1=PRA from the renal vein of the stenotic side, IVC=PRA from the inferior vena cava) and the ratio V2-IVC/IVC was 0,04+0,02 (V2=PRA from the renal vein of the non-stenotic side);30 min after successful PTA the respective values of the above measured parameters were: 144,2+6,7/98,2*3,1 mmHg (p<0,01), 8,13+2,21ngAI/ml/h (p<0,005), 1,79+ 0,19(p<0,01), 0,68+0,18 (p<0,001) and 0,06+0,02 (p< 0,005). Peripheral plasma noradrenaline levels (pINA) were 0,694+ 0,058ng/ml, pINA levels from the renal vein of the stenotic side were 0,962+0,108ng/mI and pINA levels from the renal vein of the non-stenotic side were 0,759+0,092ng/ml;30 min after successful PTA the respective values were 0,518+0,055 ng/ml (p<0,01), 0,681+0,078ng/ml (p<0,005) and 0,510+0,063ng/ml (p< 0,005). It is suggested that the reversal of chronic renal ischaemia by PTA induced statistically significant changes in the SNS activity, parallel to the changes of renin secretion.

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24 Η BP LEVELS IN NORMOTENSIVE SUBJECTS. A COLLABORATIVE ITALIAN MULTICENTRIC STUDY. S.Lattuada, M.Antivalle *, M.Rindi *, M.Paravicini, F.Leali, A.Libretti. Clinica Medica Universita degli Studi, Milano - Italy

A multicentric collaborative trial involving 5 Italian Universities cohordinated by Rome's prof. Corsi uas performed in order to define nonal values of ambulatory BP. The population consisted of 246 untreated subjects (131 Μ and 115 F), divided into three age groups: < 40 yrs, 40-60 yrs, and > 60 yrs. Noriotension Mas defined as CBP levels < 140/90 mmHg on three separate occasions under the age of 60 and < 160/90 mmHg over that age.In all patients a complete 24 h non invasive ambulatory •onitoring of BP was perfoned during the usual daily activities. 91+/-23 valid readings were obtained on average during the 24 h. The ICR 5200, the Pressurometer Ρ III and Ρ IV were adopted. In the whole population, lean 24 h BP levels were 118.8+/-10.9 mmHg for SBP, and 74.1*7-7.0 for DBP. In age and sex subgroups, mean values Mere as follows: SBP ALL < 40 40-60 > 60 MALES 121.3+MO 120.3+/- 8 119.7+/-12 124.5+/-10 FEMALES Π6.0+/-11 109.3+/- 8 119.3+/-10 124.3+/-10

DBP MALES 74.5+/- 7 72.4+/- 7 76.4+/- 7 76.5+/- 7 FEMALES 73.6+/- 7 70.0+/- 6 77.2+/- 5 75.6+/- 8

The analysis of variance showed that SBP was significantly higher in tales under the age of 60, while DBP was not significantly different between the two sexes. Under the age of 60, SBP increased steadily in females. No effect of age on BP was observed in sales. BP variability was not different between sexes, while a significant reduction of DBP variability was observed with advancing age. Mean values in our normotensive population were closely comparable to the data of the literature. However, the differences observed between age and sex-corrected mean values of patients from different centers were statistically significant (p<0.0001). While data on 24 h BP in normotensive subjects from different sources are very similar, single institutions should build up their own normality intervals.

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11498| V A L I D A T I O N O F T H E B A R O - G R A F N O N I N V A S I V E A M B U L A T O R Y B L O O D P R E S S U R E H O N I T O R , K . A n t i v a l l e * , S . L a t t u a d a , M . R i n d i * ,

H . P a r a v i c m i , F . L e a l i , A . L i b r e t t i . C l i n i c a H e r i i c a U n i v e r s i t a d e g l i S t u d i - M i l a n e I t a l y

T h e I r i s t r o s e d i u B a r o - G r a f <BG 2 H ) i s a r e c e n t l y d e v e l o p e d a m b u l a t o r y BP r e c o r d e r . T h e d e v i c e i s s n a i l ( 8 . 6 x 1 3 . 6 x 3 . 7 cm)

a n d l i g h t w e i g h ( 3 3 0 g w i t h b a t t e r i e s ) . BP m e a s u r e m e n t a r e t a k e n a u t o m a t i c a l l y a t p r o g r a m m a b l e i n t e r v a l s u s i n g t h e

a u s c u l t a t o r y mehod t o d e t e c t K o r o t k o f f s o u n d s . T h e B a r o - G r a f w a s t e s t e d i n 2H p a t i e n t ( 1 5 s a l e s a n d 9 f e m a l e s * mean a g e

5 1 . 8 + / - 1 6 . 3 y r s ) . I n e a c h s u b j e c t , 1 0 BP r e a d i n g s w e r e p e r f o r m e d s i m u l t a n e o u s l y b y t w o t r a i n e d b l i n d e d o b s e r v e r s a n d

b y t h e m o n i t o r . T h e B a r o - G r a f w a s c o n n e c t e d t o a H a w k s l e y R a n d o m - Z e r o s p h y g m o m a n o m e t e r w h i c h w a s r e s e t b e t w e e n e a c h

m e a s u r e m e n t . T h e t r a n s d u c e r w a s p o s i t i o n e d o v e r t h e b r a c h i a l a r t e r y 3 - 5 cm a b o v e t h e e l b o w . T h e o b s e r v e r s m e a s u r e m e n t s

w e r e p e r f o r m e d u s i n g a d o u b l e s t h e t o s c o p e w i t h a s i n g l e d i a p h r a g m p o s i t i o n e d o v e r t h e a n t e c u b i t e l f o s s a . F a s e 1 a n d f a s e 5 K o r o t k o f f s o u n d d e f i n e d S B P a n d D B F ' . BP m e a n s a n d r a n g e s , a s d e t e r m i n e d b y t h e mean o f t h e o b s e r v e r s r e a d i n g s ,

w e r e H I . 3 ( 9 3 - 1 9 2 ) mmHg f o r S B P a n d 8 3 . 7 ( 6 1 - 1 2 1 ) f o r D B P . T h e m e a n d i f f e r e n c e b e t w e e n t h e 2 o b s e r v e r s w a s . 0 3 + / -

mmHg « r = . 9 ? 5 > f o r S B P a n d . 8 3 + / - 2 . 6 mmHg ( r = . 9 8 2 ) f o r D B P . T h e a v e r a g e d i f f e r e n c e b e t w e e n t h e o b s e r v e r s a n d t h e B a r o -

G r a f was 2 . 3 6 + / - < t . 6 mmHg ( r = . 9 S M f o r S B P , a n d 2 . 9 8 + M . 0 8 mmHg ! r = . 9 5 6 ) f o r D B P . S B P a n d D B P d i f f e r e n c e s w e r e

c o m p a r a b l e i n a l l BP r a n g e s , w i t h a t e n d e n c y t o l o w e r r e a d i n g s b y t h e BG a t v e r y l o w BP v a l u e s . T h e s e r e s u l t s a r e

w i t h i n t h e p r o p o s e d A A M I s t a n d a r d s . I n a l l s u b j e c t s , a c o m p l e t e 2<+ h a m b u l a t o r y m o n i t o r i n g w a s p e r f o r m e d d u r i n g

u s u a l d a i l y a c t i v i t i e s . O n a v e r a g e , 8 7 X o f < a l i d r e a d i n g s w a s o b t a i n e d d u r i n g 2 4 h m o m t o r i r i g s , i t i s c o n c l u d e d t h a t t h e BG 2H i s c o m p a r a b l e i n t e r m s o f a c c u r a c y a n d d u r a b i l i t y t o t h e o t h e - d e v i c e s p r e s e n t l y a v a i l a b l e .

115001 R E T I N O P A T H Y OR M Y O C A R D I A L HYPERTROPHY AS A M O R E SENSITIVE M A R K E R OF ORGAN DAMAGE INHYPERTENSION ? V , d e L e o n a r d i s * , Μ. De S c a l z i , A. B e c u c c i , C. ' Lusini, P. C i n e l l i , Istituto di Clinica Medica IV, U n i v e r s i t a di Firenze, ITALY.

Since m o s t patients with mild to m o d e r a t e hypertension have no symptoms directly referable to the disease, the m a i n objective is to ascertain the extent of organ damage that has already resulted from the high blood pressure; this is achieved by retinal and cardiac examinations and by tests of renal function. 55 hypertensives with no other cardiovascular disease (33 m a l e s , 2 2 f e m a l e s , m e a n age 5 2 ± 1 3 ) , divided into 8 groups according to the cardiac and retinal involvement, were studied to determine w h e t h e r retinal examination is more sensitive than echocardiographic evaluation to assess the extent of organ damage. Among the 18 patients w i t h cardiac involvement, 10 had septal (SH) and 8 had concentric hypertrophy ( L V H ) . Among the 4 5 patients w i t h retinal involvement,19 had grade I retinopathy ( R P ) , 19 grade II and 7 grade I I I ) . Only I of the 10 patients with no RP showed SH. Among the 3 7 w i t h normal hearts 9 had no sign of R P , 12 had grade I, 13 grade II and 3 grade III. No significant difference was found in blood pressure among the groups. We conclude that. RP is far m o r e m a n i f e s t than LVH or SH and that cardiac and retinal involvement, do not depend on blood pressure levels.

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NIFEDIPINE AS FIRST AND SECOND-LINE ANTIHYPERTENSIVE THERAPY IN PREGNANCY AND PUERPERIUM M. Dulitzky, T Rosenthal, I. Frenkel, G. Ben-Baruch, A. Manf, S. Mashiach, Obstetrics and Gynecology Department, and Hypertension Unit, Tel Hashomer, Israel Nifedipine, a calcium channel blocking agent, was given to 18 women in acute hypertensive condition, in pregnancy and the puerperium. Fifteen of them were refractory to conventional treatment, or developed impeding side effects while on previous treatment, and 3 patients (pts) received the drug as first-line therapy. Thirteen pts, including 5 chronic hypertensives, 5 with SLE, and 3 with pregnancy induced hypertension, received the drug as tablets (PO) divided into 2 doses (40-60 mg/d) during pregnancy and the puerperium, and 5 pts with pregnancy induced hypertension were given the drug as sublingual capsules (10 mg) during delivery. Nifedipine reduced blood pressure (BP) significantly (MAP from 131.5+7 to 115+3). Despite BP decrease neither renal function deterioration nor fetal distress were observed. Maternal side effects were mild, including ankle oedema (12), headache (8), tachycardia (3), flushed (3), and nausea (2). Although nifedipine is an arterial vasodilator that acts by relaxation of smooth muscles, none of the treated group had excess uterine bleeding in the immediate postpartum period. Except for 2 cases of mild fetal heart tachycardia (165+170 BPM) no difference was found in the scores before and after treatment. We found nifedipine efficacious and safe in the treatment of pregnant women, and as a drug of choice as first-line therapy in SLE.

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CARDIAC ANATOMY AND FUNCTION IN PATIENTS WITH PHEOCHROMOCYTOMA. E. Agabiti-Rosei *, M.L. Muiesan *, G. Romanelli, Μ. Castellano *, M. Beschi *, D. Rizzoni *. G. Muiesan *. Clinica Medica, University of Brescia, Brescia, Italy.

It has been suggested that an increased adrenergic activity in hypertension may affect not only cardiac function, but also the degree of left ventricular hypertrophy. The effects: of increased adrenergic activity on cardiac anatomy and function can be most properly evaluated in patients (pts) with pheochromocytoma (PH). Therefore, we assessed left ventricular (LV) anatomic characteristics as well as systolic (Syst) and diastolic (Diast) function by echocardiography (TM, 2D guided) in 8 pts (2F, 6M, age range 28-62 yrs) with PH, confirmed by surgical removal and pathological examination. In all pts LV mass (LVM) was^ within normal limits (LVM index = 82 +18, range 66-117 g/m ). No correlation was observed between LVM and a) plasma or urinary catecholamine concentrations, b) systolic and diastolic arterial pressure values (mean of severaI,repeated casual and /or monitored values), c) known duration of arterial hypertension. LV Syst function was evaluated by the relationship between fractional shortening (SF = 43 +9 ,range 33j62 %) and end-systolic stress (ESS = 5 9 +18,range 34-81 10 dynes/cm ); a significant negative correlation was found between SF and ESS, and, considering each point of the correlation between SF and ESS, in respect to 9 5 % prediction limits previously obtained in normal subjects, LV Syst function was at the upper limit in 4 pts, and clearly increased in 2 pts. No significant alteration of Diast function was observed in respect to normal subjects or to hypertensives without LV hypertrophy. Inotropic (% SF) and chronotropic (CD25= dose that increases heart rate by 25 b/min) responses to B-adrenergic receptors stimulation with Isoproterenol were significantly reduced (CD25 range 6.2-10.6 ug/m2). After surgical removal of PH, no anatomical change was observed, while B-adrenergic receptors sensitivity was within normal limites. In conclusion, LV Syst function resulted within normal limits or "supernormal", while no evidence of impaired LV Diast function was observed in pts with PH. Furthermore, LVM was normal, thus indicating that the role of adrenergic nervous system in inducing LV hypertrophy in man is not determinant and/or that down-regulation of B-adrenergic receptors can limit the effects of catecholamines on the heart, at least in pts with PH.

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A S S E S S M E N T O F I N I T I A L C A R D I O V A S C U L A R S T R U C T U R A L C H A N G E S I N H Y P E R T E N S I O N A S R E L A T E D T O 2 4 H O U R S B L O O D P R E S S U R E M O N I T O R I N G M . L . M u i e s a n * , D . R i z z o n i * , A . G e n " , P . R o s s i n i , R . Z u l l i , E . A g a b i t i - R o s e i * , G . M u i e s a n * . C l i n i c a M e d i c a , U n i v e r s i t y o f B r e s c i a , B r e s c i a , I t a l y S e v e r a l o b s e r v a t i o n s i n d i c a t e t h a t i n h y p e r t e n s i v e p a t i e n t s t h e d e g r e e o f t a r g e t o r g a n d a m a g e c o r r e l a t e s m o r e c l o s e l y w i t h a v e r a g e b l o o d p r e s s u r e r e c o r d e d b y a m b u l a t o r y m o n i t o r i n g t h r o u g h o u t 2 4 h r s ( 2 4 h A P ) t h a n w i t h c a s u a l b l o o d p r e s s u r e ( C B P ) . F e w s t u d i e s a l s o s u g g e s t t h a t a m b u l a t o r y b l o o d p r e s s u r e m o n i t o r i n g ( A B P M ) m a y b e s u p e r i o r t o C B P i n p r e d i c t i n g c a r d i a c h y p e r t r o p h y a s e v a l u a t e d b y e c h o c a r d i o g r a p h y ( E C H O ) . W e h a v e e x a m i n e d a g r o u p o f 6 4 c l i n i c a l l y h e a l t h y s u b j e c t s ( 4 1 Μ a n d 2 3 F , a g e r a n g e 1 9 - 5 6 y e a r s , 4 4 h y p e r t e n s i v e s a n d 2 0 n o r m o t e n s i v e s a c c o r d i n g t o C B P ) . I n t h e s e s u b j e c t s t h e p o s s i b i l i t y o f i n i t i a l c a r d i o v a s c u l a r s t r u c t u r a l c h a n g e s w a s i n v e s t i g a t e d b y E C H O a n d v e n o u s · o c c I u s i o n p l e t h y s m o g r a p h y ; i n f a c t , a s a n i n d e x o f v a s c u l a r s t r u c t u r a l c h a n g e s ( V S C ) , f o r e a r m m i n i m a l v a s c u l a r r e s i s t a n c e ( M V R ) w a s c a l c u l a t e d , f r o m m e a n a r t e r i a l p r e s s u r e a n d m a x i m a l p o s t i s -c h e m i c b l o o d f l o w a s s e s s e d b y p l e t h y s m o g r a p h y . T h e r e s u l t s w e r e c o r r e l a t e d t o C B P o r 2 4 h A P ( m e a s u r e d b y n o n - i n v a s i v e A B P M I C R 5 3 0 0 , S p a c e l a b s I n c . ) . L e f t v e n t r i c u l a r m a s s ( L V M ) w a s c o r r e l a t e d m o r e c l o s e l y w i t h a v e r a g e B P r e c o r d e d d u r i n g 2 4 h r s , o r i n t h e 6 a m - 6 p m p e r i o d ( 1 2 h d A P ) o r i n t h e 6 p m - 6 a m p e r i o d ( 1 2 h n A P ) ( r = 0 . 3 9 , 0 . 3 5 , 0 . 4 3 r e s p e c t i v e l y , f o r s y s t o l i c , j n d r = 0 . 5 3 , 0 . 5 0 , 0 . 5 3 f o r d i a s t o l i c ) t h a n w i t h C P B ( r = 0 . 2 5 f o r s y s t o l i c a n d r = 0 . 3 5 f o r d i a s t o l i c ) . MVR w a s a l s o s i g n i f i c a n t l y c o r r e l a t e d t o 2 4 h A P , 1 2 h d A P a n d 1 2 h n A P ( r = 0 . 3 8 , 0 . 3 3 , 0 . 4 2 r e s p e c t i v l y f o r s y s t o l i c ) , b u t t h e c o r r e l a t i o n w a s s i m i l a r t o t h a t o b s e r v e d w i t h C B P ( r = 0 . 3 4 f o r s y s t o l i c ) . M V R w a s s i g n i f i c a n t l y c o r r e l a t e d t o B P v a r i a b i l i t y , a s e v a l u a t e d b y t h e s t a n d a r d d e v i a t i o n o f t h e m e a n ( r = 0 . 3 6 f o r s y s t o l i c a n d r = 0 . 3 8 f o r d i a s t o l i c ) . L V M w a s n o t c o r r e l a t e d t o B P v a r i a b i l i t y . M V R r e s u l t e d a l s o s i g n i f i c a n t l y h i g h e r ( p < 0 . 0 5 ) i n a s u b g r o u p o f p a t i e n t s i n w h o m B P w a s n o t s i g n i f i c a n t l y r e d u c e d d u r i n g t h e n i g h t . 2 4 h A P , L V M a n d M V R w e r e n o t s i g n i f i c a n t l y c o r r e l a t e d t o p l a s m a c a t e c h o l a m i n e s o r P R A . T h e r e s u l t s o f t h i s s t u d y c o n f i r m t h a t e l e v a t e d a v e r a g e d a y - t i m e B P i s a s s o c i a t e d t o h i g h e r L V M ; i n a d d i t i o n t h e y s u g g e s t t h a t i n c r e a s e d B P v a r i a b i l i t y s e e m s t o b e a s s o c i a t e d t o e v i d e n t V S C , a s e v a l u a t e d b y M V R . W h e t h e r c a r d i a c h y p e r t r o p h y a n d / o r V S C a r e c a u s e o r c o n s e q u e n c e o f i n c r e a s e d B P v a l u e s a n d v a r i a b i l i t y r e m a i n t o b e c l a r i f i e d . A B P M , f r o m t h i s s p e c i f i c v i e w p o i n t , i s m o r e u s e f u l t h a n C B P f o r t h e c l i n i c a l a s s e s s m e n t o f h y p e r t e n s i v e p a t i e n t s , b e i n g m o r e c l o s e l y r e l a t e d t o i n i t i a l c a r d i o v a s c u l a r s t r u c t u r a l c h a n g e s .

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HEMODYNAMIC AND ECHOCARDIOGRAPHIC CORRELATES OF PLASMA ATRIAL NATRIURETIC PEPTIDE IN CARDIAC IMPAIRMENT. LJalatino*,G.Greco,* B. Stancanelli*, G. Polizzi, C. Leonardi, G. Russo, C. Tamburino, G. Greco, G. Giuffrida, G. Tamburino. Institute of Clinical Medicine, University of Catania, Catania, Italy.

To study the secretion of alpha-human Atrial Natriuretic Peptide (ANP) and its relationships with cardiac pressures and sizes, regional plasma ANP concentrations were measured in an unselected series of 32 pts (14M,18F, 26-72 yr-old;II-IU NYHA grades) undergoing cardiac catheterisation for ischemic heart disease,congestive heart failure and symptomatic valvular lesions.Twenty seven were in normal sinus rhythm and 5 had chronic atrial fibrillation.Blood samples were taken from Aorta (Ao),5uperior Uena Cava (SOC),Brachial Vein (BU),Right Atrium (RA) and Pulmonary Artery (PA). Echocardiographic tracings were obtained according to the criteria of the American Society of Echocardiography. Results are expressed as mean + SEM. Plasma ANP concentration in PA (247.6+45 pg/ml) was significantly (p<0.001) higher than that seen in 5UC (134.5+40.5 pg/ml) and B v (101.9+23.7 pg/ml),while a negligible difference (Δ=-132) was shown in Ao. Plasma ANP concentration in PA correlated closely (p<0.001) with mean right atrial pressure (MRAP) (r=0.96),wedge pressure (rrO.85),pulmonary artery pressure (PAP) (r-0.76),while weaker relations were found with right(r=0.51) and left (r-0.50) atrial sizes and cardiac index(r=-0.49).Plasma ANP concentration in BU, although much lower than that in PA, was significantly related with MRAP (r-rO.68;p<0.001) and wedge pressure ( r r 0 . 55 ; p<0.01). When blood sampling was made in RA, the correlation between ANP and MRAP ( r r 0 .79) was not as close as the one found with the blood drawn from PA (r=0.96). Our results are consistent with the hypothesis that ANP release would be more sensitive to "chronic" elevations in atrial pressures than to "chronic" increases in atrial sizes or impaired ventricular function on its own. PA is the best site for blood sampling.However,the significant relations found with BU blood sampling may encourage the use of this site in the follow-up of patients with chronic heart failure.

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R E S P O N S E O F A D H T O L O A D I N G A N D U N L O A D I N G O F C A R D I O P U L M O N A R Y B A R O R E C E P T O R S D . R i z z o n i * , P . R o s s i n i , M . C a s t e l l a n o * , M . B e s c h i * , G .

R o d e l l a , A . P i z z o c c o l o , E . A g a b i t i - R o s e i M o n t a n i , M u i e s a n * . C l i n i c a M e d i c a , U n i v e r s i t y o f B r e s c i a , B r e s c i a , I t a l y T h e i n v o l v e m e n t o f c a r d i o p u l m o n a r y a n d a r t e r i a l s i n o a o r t i c r e c e p t o r s i n t h e c o n t r o l o f a n t i d i u r e t i c h o r m o n e ( A D H ) r e l e a s e i s s t i l l c o n t r o v e r s i a l i n h u m a n s . W e s t u d i e d 1 5 m a l e s u b j e c t s , a g e 1 8 - 5 8 ( 6 n o r m o t e n s i v e s a n d 9 m i l d h y p e r t e n s j v e s , WHO I - I I ) a f t e r 3 d a y s o f n o r m a l , c o n s t a n t N a a n d Κ i n t a k e . E v e r y s u b j e c t u n d e r w e n t s e l e c t i v e l o a d i n g a n d u n l o a d i n g o f c a r d i o p u l m o n a r y r e c e p t o r s ( C R ) , i n a r a n d o m i z e d s e q u e n c e , b y a p p l i c a t i o n o f a p o s i t i v e ( L B P P ) o r n e g a t i v e ( L B N P ) p r e s s u r e t o t h e l o w e r b o d y ( s t e p s : + 1 0 , + 2 0 , + 4 0 , - 1 0 , - 4 0 mm H g , e a c h f o r 3 0 ' ) , t h r o u g h a p l e x y -g l a s s - c o n s t r u c t e d t u b u l a r a p p a r a t u s w i t h a r u b b e r a d h e s i o n r o u n d t h e p a t i e n t s ' w a i s t . B l o o d s a m p l e s w e r e t a k e n a t t h e e n d o f e v e r y s t e p f o r m e a s u r e m e n t o f A D H , A N P , P R A a n d a l d o s t e r o n e ( A L D O ) b y R I A , n o r a d r e n a l i n e ( N A ) a n d a d r e n a l i n e ( A ) b y H P L C . C u f f a r t e r i a l p r e s s u r e w a s m e a s u r e d e v e r y 5 m i n , w h i l e h e a r t r a t e ( H R ) w a s e v a l u a t e d b y c o n t i n u o u s E K G r e c o r d i n g . H y p e r t e n s i v e s u b j e c t s u n d e r w e n t r i g h t a t r i a l p r e s s u r e ( R A P ) m e a s u r e m e n t b y a n i . v . c a t h e t e r a n d a n e v a l u a t i o n o f f o r e a r m b l o o d f l o w ( F B F ) a t r e s t a n d d u r i n g t h e d i f f e r e n t s t e p s ( v e n o u s o c c l u s i o n p l e t h y s m o g r a p h J a n s s e n P e r i f l o w ) . D u r i n g L B N P , A D H p l a s m a l e v e l s i n c r e a s e d p r o g r e s s i v e l y ( B : 8 . 5 + 6 . 7 , ^ 1 0 : 9 . 3 + 6 . 3 , ^ 4 0 : 2 0 . 9 + 1 2 . 4 p g / m l ( p < 0 . 0 1 ) w h i l e d u r i n g L B P P n o s i g n i f i c a n t c h a n g e w a s d e t e c t e d . A N P i n c r e a s e d s i g n i f i c a n t l y d u r i n g L B P P o n l y a t + 2 0 p < 0 . 0 5 ) . D u r i n g L B N P , A N P c h a n g e s w e r e n o t s i g n i f i c a n t . NA a n d A i n c r e a s e d p r o g r e s s i v e l y d u r i n g t h e L B N P ( N A - 1 0 : p < 0 . 0 1 , - 4 0 : p < 0 . 0 0 1 ) w h i l e d u r i n g L B P P n o s i g n i f i c a n t c h a n g e w a s o b s e r v e d . D u r i n g L B N P , P R A a n d A L D O i n c r e a s e d s i g n i f i c a n t l y o n l y a t t h e e n d o f t h e ΑΡ_ s t e p ( P R A p < 0 . 0 5 A L D O p < 0 . 0 1 ) . D u r i n g L B P P o n l y A L D O s h o w e d a s i g n i f i c a n t r e d u c t i o n ( + 1 0 : p < 0 . 0 1 , + 2 0 p < 0 . 0 0 1 ) . S y s t o l i c a r t e r i a l p r e s s u r e w a s s i g n i f i c a n t l y r e d u c e d o n l y a t - 4 0 w h i l e d i a s t o l i c p r e s s u r e s h o w e d a s i g n i f i c a n t i n c r e a s e d u r i n g L B P P . HR d i d n o t c h a n g e s i g n i f i c a n t l y . R A P w a s s i g n i f i c a n t l y r e d u c e d d u r i n g L B N P a n d i n c r e a s e d d u r i n g ' L B P P . F o r e a r m B F d e c r e a s e d d u r i n g L B N P ( - 1 0 : p < 0 . 0 1 , - 4 0 : p < 0 . 0 1 ) w h i l e i n c r e a s e d , b u t n o t s i g n i f i c a n t l y d u r i n g L B P P . I n c o n c l u s i o n , t h i s s t u d y c o n f i r m s p r e v i o u s r e p o r t s o f a n i n c r e a s e d s y m p a t h e t i c a c t i v i t y a n d d e c r e a s e d f o r e a r m B F d u r i n g s e l e c t i v e u n l o a d i n g o f C R ; t h e i n c r e a s e o f A D H w a s s i g n i f i c a n t o n l y a t a s t e p o f L B N P i n w h i c h a n i n v o l v e m e n t o f t h e s i n o a o r t i c r e c e p t o r s c a n n o t b e e x c l u d e d . T h e s e l e c t i v e l o a d i n g o f CR m a y p l a y a r o l e i n t h e m o d u l a t i o n o f A N P a n d A L D O r e l e a s e .

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ACUTE RENIN INHIBITION BY C G P - 3 8 5 6 0 A IN HYPERTENSIVE PATIENTS X J e u n e m a i t r e * , J M e n a r d 0 , TT G u y e n e * * , J N u s s b e r g e r 0 0 , Η B r u n n e r 0 0 , PF P l o u i n * , Ρ C o r v o l * . S e r v i c e d ' H y p e r t e n s i o n A r t e r i e l l e * e t d e M e d e c i n e N u c l e a i r e * * , H o p i t a l B r o u s s a i s , P a r i s . L a b o r a t o i r e C i b a - G e i g y 0 B a s e l , CHUV L a u s a n n e 0 0 , S w i t z e r l a n d .

Human r e n i n i n h i b i t o r s h a v e b e e n s t u d i e d i n n o r m a l v o l o n t e e r s , b u t t h e i r b l o o d p r e s s u r e e f f e c t s a r e n o t known i n h y p e r t e n s i v e p a t i e n t s . CGP 3 8 5 6 0 A i s a p a t e n t , l o w m o l e c u l a r w e i g h t , human r e n i n i n h i b i t o r . I t w a s a d m i n i s t r e d b y a 3 0 min i n t r a - v e n o u s i n f u s i o n t o 1 2 h y p e r t e n s i v e p a t i e n t s who h a d f a v o r a b l y r e s p o n d e d t o 5 0 mg c a p t o p r i l . S i x p a t i e n t s ( 3 9 + 1 6 y e a r s ) r e c e i v e d a c u m u l a t i v e d o s e o f 0 . 1 2 5 mgAg a n d t h e o t h e r s i x ( 3 8 + 6 y e a r s ) 0 . 2 5 0 m g / k g - MABP w a s m o n i t o r e d e v e r y 2 m i n u t e s ( o s c i l l o m e t r i c m e t h o d , S e n t r o m ) . P l a s m a r e n i n a c t i v i t y ( P R A ) , a c t i v e r e n i n ( A R ) , a n g i o t e n s i n I (ANG I ) a n d a n g i o t e n s i n I I w e r e m e a s u r e d . T h e r e s u l t s o b t a i n e d w i t h b o t h d o s e s a r e i n d i c a t e d b e l o w .

T O T 1 0 T 2 0 T 3 0 T 4 5 T 6 0 T 9 0 T 1 2 0

MABP (mmHg) 1 1 3 1 1 0 1 0 7 ° 1 0 7 ° 1 0 8 ° 1 1 0 1 1 3 1 1 5 PRA ( n g / m l / h ) 2 . 5 0 ° 0 ° 0 ° 0 ° 0 ° 0 . 4 ° 0 . 5 ° ANGI ( p g / m l ) 2 2 . 2 5 . 3 ° 5 . 4 ° 4 . 0 ° 1 9 . 1 2 5 . 7 3 3 . 0 2 3 . 2 A N G I I ( p g / m l ) * 9 . 5 1 . 7 ° 1 . 4 ° 1 . 8 ° 2 . 8 ° 5 . 6 7 . 5 6 . 8 AR ( p g / m l ) 5 2 9 3 ° 1 8 8 ° 2 2 9 ° 3 2 7 ° 2 9 8 ° 1 8 6 ° 1 4 9 °

0 p < 0 . 0 5 , c o m p a r e d t o t h e i n i t i a l v a l u e , * n = 1 0 T h e r e w a s a r a p i d f a l l i n MABP, s i m i l a r w i t h t h e 2 d o s e s . T h e m a x i m u m d e c r e a s e o c u r r e d b e t w e e n t h e 2 0 t h a n d t h e 3 0 t h m i n ( - 5 + 3 % , p < 0 . 0 1 ) . PRA f e l l b e l o w t h e d e t e c t i o n l i m i t i n a l l p a t i e n t s f r o m t h e 1 0 t h t o t h e 4 5 t h m i n a f t e r s t a r t i n g t h e i n f u s i o n a n d r e m a i n e d u n d e t e c t a b l e w i t h t h e 0 . 2 5 0 mgAg d o s e u p t o t h e 1 2 0 t h m i n . T h e r e w e r e m a r k e d p a r a l l e l f a l l s i n p l a s m a ANGI a n d ANGII , b u t b o t h r e t u r n e d t o t h e i r i n i t i a l l e v e l s a t t h e 6 0 t h m i n . C o n s e q u e n t l y , AR r o s e o n a v e r a g e b y 3 2 2 % , m a x i m u m a t t h e 4 5 t h m i n , w i t h a s i g n i f i c a n t c o r r e l a t i o n t o i t s i n i t i a l l e v e l ( r = 0 . 7 1 , p < 0 . 0 1 ) .

O u r c o n c l u s i o n s a r e : 1 ) CGP 3 8 5 6 0 A l o w e r e d <BP i n t h e s e h y p e r t e n s i v e p a t i e n t s b y p r e v e n t i o n o f A N G g e n e r a t i o n . 2 ) s i n c e t h e f a l l i n P R A i s a r t e f a c t u a l , p l a s m a A N G c o n c e n t r a t i o n s s h o u l d b e u s e d t o e v a l u a t e t h e e f f i c a c y o f a r e n i n i n h i b i t o r .

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