arterial baroreceptor control of peripheral vascular resistance in experimental heart failure

I I IIIII

Arterial baroreceptor control of peripheral vascular resistance in experimental heart failure

Heart failure is known to impair arterial baroreceptor control of heart rate. To determine if baroreceptor control of peripheral vascular resistance is also impaired, heart rate and hind l imb vascular responses to phenylephrine and nitroglycerin administration were compared in control dogs and in dogs with heart failure produced by chronic rapid ventricular pacing. Baroreflex control of the heart rate was depressed in the dogs with heart failure, as ev idenced by a reduced slope of the blood pressure-to-heart rate relationship (controls: - 2 . 5 _+ 0.3 bea ts /mm Hg versus heart failure: - 1 . 5 • 0.2 bea t s /mm Hg [(p < 0.04)]). Arterial blood pressure in the dogs with heart failure was also reduced (controls: 90 • 3 mm Hg versus heart failure: 75 • 3 mm Hg [(p < 0.O1]). Nevertheless, dogs with heart failure exhibited normal slopes of the blood pressure versus hind l imb vascular resistance relationship (controls: - 2 . 4 • 0.4 un i ts / ram Hg versus heart failure: - 2 . 9 • 0.5 un i t s /mm Hg [(p = NS]), consistent with preserved baroreflex control of the peripheral vasculature. These data suggest that heart failure impairs arter ia l baroref lex control of heart rate and lowers the baroreflex pressure operating range but does not alter baroreflex cont ro l of per ipheral resistance. (AM HEART J 1990; 119:1122.)

John R. Wilson, MD, Vita Lanoce, M~, Martin J. Frey, MD, and Nancy Ferraro, RIN Philadelphia, Pa.

Baroreceptor control of the peripheral circulation plays a key role in stabilizing the arterial blood pressure. Normally, arterial baroreceptors inhibit sympathetic efferent outflow from the medulla. An increase in arterial pressure produces further sympathetic inhibition, resulting in bradycardia and peripheral vasodilation and a return of arterial pressure toward the normal level. A decrease in arterial pressure reduces medullary inhibition, producing an increase in heart rate and sympathetic vasoconstriction and an increase in arterial pressure toward the normal level. Prior observations indicate that heart failure impairs arterial baroreceptor control of the heart rate. Patients with heart failure exhibit attenuated heart rate responses to phenylephrine-induced hypertension and nitrate-induced hypotension, 1'2 reflex changes that are largely mediated by arterial baroreflexes. Similar abnormalities have been noted in experimental models of heart failure. 3, 4

From the Cardiovascular Section of the Hospital of the University of Penn- sylvania.

Supported by grant RO-1 HL34834 and by Research Career Development Award No. HL01766 to Dr. Wilson, both from the National Institutes of Health, Bethesda, Md.

Received for publication May 25, 1989; accepted Jan. 2, 1990.

Reprint requests: John R. Wilson, MD, Cardiovascular Section, 3rd Floor, White Bldg., Hospital of the University of Pennsylvania, 3400 Spruce St., Philadelphia, PA 19104.

4 /1 /19074

1122

The effect of heart failure on baroreceptor control of the peripheral vasculature is less certain. In patients with heart failure, attenuated forearm vasoconstrictor responses to orthostatic tilt and lower body negative pressure have been observed. 5-8 It has been suggested that these abnormalities indicate abnormal arterial baroreceptor control of the peripheral vasculature. However, both orthostatic tilt and lower body negative pressure produce their reflex effects largely by activating cardiopulmonary receptors.9,10 A blunted increase in arterial blood pressure, mesenteric vascular resistance, and renal resistance with manipulation of carotid arterial pressure has been described in dogs with right-sided heart failure, suggesting altered arterial baroreceptor control of peripheral resistance, a, 4 However, in dogs with heart failure due to aorto-vena caval fistulas, normal arterial baroreceptor control of renal sympathetic nerve activity has been notedJ 1 This model also exhibits normal carotid sinus pressure-discharge curves when carotid sinus pressure is increased using a ramp rate similar to that found in the presence of pulsatile flowJ 2

The present study was therefore undertaken to further investigate the effect of heart failure on arterial baroreceptor control of vascular resistance. Studies were performed in an experimental canine model of heart failure produced with chronic rapid

Volume 119 Number 5 Baroreceptors in CHF 1123

ventricular pacing. Baroreflex function was assessed by measuring reflex changes in heart rate and hind limb vascular resistance in response to pharmacolog- ically-induced changes in arterial blood pressure.

METHODS

Twenty-one adult male mongrel conditioned dogs (weight: 19.3 _+ 0.2 kg) were studied: Nine dogs were included in a heart failure group and 12 were included in a control group. The heart failure group was anesthetized with pentobarbital sodium (30 mg/kg), following which a ventricular pacing lead (Medtronic sutureless type, Medtronic Inc., Pacing Systems Group Division, Minne- apolis, Minn.) was attached to the left ventricular apex through a small left thoracotomy. The lead was tunneled to the back where a multiprogrammable pulse generator (Medtronic Inc.) was implanted. After the dogs' recovery from anesthesia, pacemakers were programmed to pace at 260 beats/min. Dogs were then returned to a chronic care facility where they received a standard diet and free access to water.

Over the following 6 weeks, dogs were monitored closely for the development of signs of heart failure. Dogs who de~ veloped massive ascites and/or tachypnea at rest underwent terminal studies early (n -- 3; at 4, 4.5, and 5 weeks). The remaining dogs were monitored for the full 6 weeks. Control dogs underwent terminal studies with no prior preparation. At the terminal study, pacemakers in the pacing dogs were reprogrammed to a pacing rate of 30 beats/min, permitting resumption of normal sinus rhythm. Dogs were then anesthetized with morphine sulfate (4 to 6 mg/kg) and chloralose (75 mg/kg); prior experience indicated that dogs may develop circulatory collapse if they are anesthetized while they are still being paced at 260 beats/ min. Dogs were intubated, and a continuous infusion of chloralose was initiated at 10 mg/kg/hr. Ventilatory pa- rameters were adjusted to maintain arterial blood gases within a normal range (Po2 > 90 mm Hg; Pco2 = 35 to 45 mm Hg; pH = 7.35 to 7.45). If necessary, supplemental 02 was administered.

The right femoral vessels were isolated. A Swan-Ganz catheter (Baxter Healthcare Corp., Edwards Division, Santa Ana, Calif.) was inserted into the femoral vein and was advanced to the pulmonary artery. A small polyethyl- ene catheter was inserted into the left brachial artery to monitor arterial blood pressure. Rapid ventricular pacing was reinitiated and, 5 minutes later, pulmonary wedge, pulmonary artery, right ventricular, right atrial, and arterial blood pressures were measured. Thermodilution cardiac output determinations were obtained in triplicate. Pacing was then discontinued. An incision was made over the pacemaker and the pacemaker was removed. Hemody- namic measurements were also made in control dogs, but without ventricular pacing.

Hind limb preparation. To assess baroreceptor function, a preparation described by Guo et al. z3,14 was utilized (Fig. 1). This preparation involves isolating a hind limb and perfusing it via an extracorporeal delay circuit. This delay circuit prevents arrival of systemically-administered drugs

PRESSURE

Fig. 1. Hind limb preparation.

for at least I minute. Reflex hind limb vascular response to drug-induced arterial blood pressure manipulation can thereby be observed before systemically-administered drugs directly affect the hind limb vasculature.

In brief, a midline abdominal incision was made and all ascites was removed. The left common iliac artery and vein were isolated. Heparin, 10,000 units, was administered, following which the left iliac vessels were cannulated for subsequent perfusion of the hind limb. The Swan-Ganz catheter was removed and the right femoral vessels were also cannulated. Blood from the right femoral artery was then delivered to the left iliac artery. The extracorporeal delay circuit consisted of a coil of Tygon tubing (Norton Plastics, Akron, Ohio) that could hold 150 ml of blood and that was immersed in a water bath maintained at 37 ~ C. This circuit was primed with the dog's own blood. Blood flow through the tubing was fixed with a roller pump at a level that maintained the left iliac artery perfusion pressure at 100 mm Hg, as monitored by a Statham pressure transducer (Spectramed Inc., Critical Care Division, Ox- nard, Calif.) connected to the perfusion line close to where it entered the iliac artery. A Biotronex extracorporeal flow probe (Biotronex Laboratory, Inc., Kensington, Md.) was positioned in the perfusion line to monitor flow. Blood from the left iliac vein was delivered to the right femoral vein. Venous pressure was monitored with a Statham pressure transducer connected to the tubing at a point close to the iliac vein cannula. The left deep circumflex iliac, median sacral, and caudal mesenteric arteries were ligated to produce left hind limb vascular isolation. To assure isolation, flow to the limb was temporarily reduced to zero. Demon- stration that the perfusion pressure decreased to < 20 mm Hg was invariably present and was considered evidence of vascular isolation.

May 1990 1 1 2 4 Wilson et al. American Heart Journal

50

0

- 5 0

- 1 0 0 . . . . - 4 0 - 2 0

PRE BLOCKADE (= --) POST BLOCKADE (o- o)

tgJ

I 1 I I

0 20 40 CHANGE ZN BP [mmHg]

Fig. 2. Comparison of percentage changes in hind limb vascular resistance before and after high spinal blockade in eight of the control dogs. To graphically display responses~ data points were grouped into 10 mm Hg ranges based on the change in blood pressure (1 to 10, 11 to 20, 21 to 30, 31 to 40 mm Hg, etc.). Data within each range were then averaged and displayed on the graph. The number of data points contributing to each mean value is noted in paren- theses.

P r o t o c o l . After completion of surgery, the hind limb perfusion pressure was monitored for 30 minutes to assure a stable baseline. Phasic and mean blood pressure, heart rate, and hind limb perfusion pressure and venous pressure were recorded continuously. Following demonstration of a stable baseline period, intravenous boluses of phenylephrine (2, 4, 12, 24, and 48 ~g/kg) and nitroglycerin (1, 2, 4, 8, and 16 ttg/kg) were administered. The order of administration of different doses was randomized from animal to animal. Injections were separated by at least 5 minutes. Following administration of all doses, bilateral cervical vagotomy was performed. Fifteen minutes after vagotomy, reflex responses to all drug doses were remeasured. Fol- lowing completion of all measurements, dogs were killed by the administration of potassium chloride. The heart was then removed and weighed.

E v a l u a t i o n o f h ind l imb preparation. Use of the hind limb preparation to evaluate baroreceptor function as- sumes that systemically-administered drugs do not affect the hind limb until after reflex changes occur. To assure that this was the case, eight control dogs underwent high spinal blockade after completion of the above protocol. A spinal needle was inserted between C-1 and the base of the skull and was used to introduce a small catheter into the subdural space. Four milliliters of 10% procaine were administered into the subdural space to block sympathetic outflow to the hind limb. Repeat doses of phenylephrine and nitroglycerin were then administered systemically.

Minimal or no changes in hind limb vascular resistance were observed over the time period during which reflex vascular changes had previously been observed (Fig. 2).

Creation of the hind limb preparation involves surgical manipulation of areas near the sympathetic nerves that in- nervate the hind limb. To assure that this surgical manipulation does not interfere with sympathetic control of the hind limb, three dogs were studied. The right femoral artery was cannulated and perfused at a constant pressure of 100 mm Hg using a roller pump. A bipolar silver stimulat- ing electrode was then placed around the right lumbar sympathetic chain at the L4-L5 level. The chain was stim- ulated at frequencies of 1, 3, and 5 Hz using a voltage of 15 V and a stimulus duration of 10 msec. Femoral arterial and venous pressures and femoral flow were monitored continuously, permitting measurement of the increase in femoral bed resistance produced by lumbar chain stimulation. Fol- lowing stimulation at 1, 3, and 5 Hz, the right iliac artery and vein were isolated and prepared for cannulation; can- nulas were not inserted. Following this surgical manipulation of the iliac vessels, lumbar sympathetic chain stimulation was repeated. Percentage increases in femoral bed resistance were comparable before and after surgical manipulation of the iliac vessels (before--1 Hz: 49 _+ 21%, 3 Hz: 89 -+ 36%, 5 Hz: 105 __ 22%; after: 1 Hz: 60 _+ 21%, 3 Hz: 96 __ 21%, 5 Hz: 139 + 27%), suggesting that this manipulation does not impair sympathetic innervation of the hind limb.

The hind limb preparation also involves maintaining the hind limb perfusion pressure at 100 mm Hg in all dogs, re- gardless of the dog's intrinsic blood pressure. Therefore the hind limb perfusion pressure is often different from the preinstrumentation pressure. To assure that the perfusion pressure does not influence the hind limb response to baroreceptor activation, the hind limb preparation was created in four normal dogs. The percentage change in hind limb vascular resistance in response to phenylephrine (4, 12, and 24 ttg/kg) and nitroglycerin (8 ttg/kg) was then compared at hind limb perfusion pressures of 80 and 100 mm Hg. Similar percentage changes in hind limb vascular resistance were noted at perfusion pressures of 100 mm Hg (phenylephrine: 24 #g/kg: -56 _+ 13 %, 12 #g/kg: -54 + 10%, 4 ttg/kg: -22 _+ 3%; nitroglycerin: 8 ttg/kg: 25 + 4%) and 80 mm Hg (phenylephrine: 24 ttg/kg: -57 + 12%, 12 ttg/kg: -57 _+ 15%, 4 #g/kg: -13 _+ 1%; nitroglycerin: 8 ttg/kg: 29 + 2 %).

To maximize data acquisition from dogs enrolled in this study, six of the dogs in the heart failure group and six of the control dogs underwent open skeletal muscle biopsies from the right hind limb immediately after induction of anesthesia. Following hind limb vascular isolation, hind limb vascular responses to intra-arterial injection of isoproterenol in boluses ranging from 0.001 to 1 tLg/kg were evaluated. Results of these measurements were used to assess skeletal muscle/~-adrenergic receptors and will be re- ported separately. Baroreceptor studies were begun at least 30 minutes after completion of the isoproterenol protocol.

To assure that administration of isoproterenol did not alter hind limb vascular responses to baroreceptor activa-

Volume 119 Number 5 Baroreceptors in CHF 1 1 2 5

tion, three of the four dogs in whom the effect of different hind limb perfusion pressures was evaluated also had hind limb vascular responses reassessed after administration of 0.1 and I ttg/kg of isoproterenol. Percentage change in hind limb vascular resistance was comparable before (phenylephrine: 4 ttg/kg: -19 _+ 0%, 12 ttg/kg: -47 + 10%, 24 t~g/ kg: -45 _ 9% ; nitroglycerin: 8 ttg/kg: 25 + 4% ) and after isoproterenol (phenylephrine: 4 ttg/kg: -20 + 0%, 12 ttg/ kg : -29 _+ 19%, 24 #g/kg:-39 + 9%; nitroglycerin: 8 ttg/ kg: 30 _+ 7 %).

Calculated variables. Systemic vascular resistance was calculated as {mean arterial blood pressure - right atrial pressure)/cardiac output. Hind limb vascular resistance was calculated as (arterial perfusion pressure - hind limb venous pressure)/hind limb blood flow.

Statistical analysis . Results are expressed as mean + SEM. To graphically display baroreceptor responses, data points were grouped into 10 mm Hg ranges based on the change in blood pressure (i.e., 1 to 10, 11 to 20, 21 to 30, and 31 to 40 mm Hg). Data within each range were then averaged and displayed on the graph. To compare responses between groups, the heart rate and vascular response to arterial blood pressure administration were correlated with changes in mean arterial blood pressure using least squares linear regression analysis. This correla- tion was performed separately in each dog. The slopes of these relationships were then compared in control dogs versus dogs in the heart failure group using nonpaired t testing. Only correlations with coefficients > 0.8 were included in this comparison. A p value < 0.05 was considered statistically significant.

RESULTS

T h e initial weights of the dogs in the hear t failure group (19.0 _+ 1.4 kg) and of the control dogs (19.5 _+ 0.2 kg) were comparable. Over the s tudy period, the dogs in the hear t failure group increased thei r weights to 23.4 _+ 1.0 kg (p < 0.01 versus initial weight) and developed an average 3.9 _+ 1.3 L of ascites. Dogs in the hear t failure group exhibi ted elevated r ight atrial and pu lmonary wedge pressures and reduced cardiac ou tpu t values (Table I), consis- t en t with the deve lopment of biventr icular hear t failure. H e a r t weight was also greater in the dogs in the hear t failure group (160 _+ 6 gm) than in the con- t rol dogs (144 _+ 5 gm) (p < 0.05).

Blood pressure responses. Blood pressure responses to the adminis t ra t ion of phenylephr ine and nitroglycerin are i l lustrated in Fig. 3. Compared with control dogs, the dogs with hear t failure exhibi ted b lun ted pressor responses to phenylephr ine at doses of 12, 24, and 48 #g/kg, and b lun ted depressor responses to ni troglycerin at doses of 2 and 4/~g/kg.

Baroreflex responses before vagotomy. Prior to drug adminis t ra t ion, comparable hea r t rates were observed in control dogs (149 _+ 14 beats /min) and dogs

Table I. Comparison of hemodynamic measurements in control dogs and dogs with heart failure

Controls Heart failure

Hear t ra te (bea t s /min) 149 _+ 14 260 _+ 0* Righ t atr ial p ressure ( m m Hg) 4 _+ 0.1 11 + 1" P u l m o n a r y wedge pressure ( m m Hg) 7 _+ 0.1 23 _+ 2* Cardiac o u t p u t (ml /min/kg) 111 + 10 71 +__ 5* Mean ar ter ia l p ressure ( m m Hg) 90 _+ 3 75 +_ 3* Sys temic vascular res is tance (uni ts) 43 _+ 5 40 _+ 4 H i n d l imb blood flow (ml /min) 84 +_ 14 85 _+ 13

1.5 _+ 0.2 H ind l imb vascular res is tance (units) 1.8 _+ 0.2

*p <~ 0.01 versus control group.

with hear t failure (137 + 7 beats /min) )p = NS). The hear t ra te response to changes in blood pressure is il- lus t ra ted in Fig. 4. Th e slope of the blood pressure to hear t ra te response was significantly lower in dogs with hea r t failure ( -1 .5 _+ 0.2 bea t s /mm Hg) than in the control dogs ( -2 .5 + 0.3 bea t s /mm Hg) (p < 0.04).

To assure tha t this difference was not due to dif- ferences in the blood pressure range over which reflex slopes were determined, slopes were also de termined from da ta obta ined with blood pressure changes between only - 2 0 and +20 m m Hg. Using this more narrow pressure range, the difference between slopes noted in the dogs with hear t failure ( -1 .6 + 0.7 beats / ram Hg) and control dogs ( -4 .1 _+ 1.9 beats / mm Hg) was even more significant (p < 0.002) than when a wider pressure range was utilized.

Pr ior to drug administrat ion, h ind l imb vascular resistance was comparable in control dogs (1.8 _+ 0.2 units) and dogs with hea r t failure (1.5 + 0.2 units) (p = NS). Th e effect of changing arterial blood pressure on hind limb vascular resistance is i l lustrated in Fig. 5. Slopes of the blood pressure- to-hind limb vascular resistance response were comparable in bo th groups when calculated over the ent i re pressure range s tudied (controls: -2 .4 _+ 0.4 uni ts /min H g . un i t s /mm Hg, versus hear t failure group: -2 .9 _+ 0.5 un i t s /mm Hg �9 un i t s /mm Hg) or when calculated over a pressure range of only - 2 0 to +20 mm Hg (controls: -3 .1 _+ 0.5 un i t s /mm Hg �9 uni t s / m m Hg, versus hear t failure group: -3 .5 _+ 0.6 uni t s / mm Hg �9 un i t s /mm Hg) (both p = NS). There was also no significant difference in the h ind limb vascular response when it was expressed as percentage change in h ind limb vascular resistance from the resting level; slopes of the relat ionship were comparable in the two groups when calculated over the ent i re pressure range s tudied (controls: -1 .4 + 0 .1 %/m m Hg versus hear t failure group: -1 .9 _+ 0 .4 %/m m Hg) or when calculated over a

May 1990

1126 W i l s o n e t al. American Heart Journal

50

30

CONTROL [= :] HF {o- -o)

*~p<. 01 . r ~

J / I J . _ j "

i I i i

2 4 12 24 48

PHENYLEPHRINE (ug/t<g)

30

0

-iO

CONTROL (= --2 HF [o- ~)

L - - - L T

~p<. 01

- 2 0 , ~ , i , 1 2 4 8 1 5

N I TROGL Y C E R I N [ u g / / c g }

Fig. 3. Effect of phenylephrine and nitroglycerin on arterial blood pressure in control dogs (n = 12) and in dogs with heart failure (n = 9).

pressure range of only -20 to +20 mm Hg (controls: -1.9 • 0.2%/mm Hg versus heart failure group: -2.2 _+ 0.4%/mm Hg) (both p = NS).

Baroreceptor reflexes after vagotomy. Immediately prior to vagotomy, blood pressures in both groups were lower than at the beginning of the study, aver- aging 67 • 3 mm Hg in the control dogs and 53 • 1 mm Hg in the dogs with heart failure. This was prob- ably due to loss of blood from the abdominal surgical site during the study.

Vagotomy had no significant effect on blood pressure in the control dogs (63 + 5 mm Hg) but resulted in a significant decrease in blood pressure in the nine dogs with heart failure, to 42 • 6 mm Hg. Four of these nine dogs developed marked hypotension so that the study had to be terminated. The remaining five dogs had a blood pressure of 56 + 9 mm Hg, similar to the blood pressure in the control dogs, Heart rates averaged 176 • 21 beats/rain in the control dogs and 138 +_ 5 beats/rain in the dogs with heart failure (p = NS). Compared with the control dogs, these five dogs with heart failure exhibited comparable slopes of the relationship of change in blood pressure to change in hind limb resistance (control: -2.6 • 0.8 units/ram Hg versus heart failure group: -1.9 + 0.8 units/mm Hg) and to percentage change in hind limb resistance (control: -1.2 _+ 0.2%/ram Hg versus heart failure group: -1.2 • 0.1%/ram Hg) (both p = NS) (Fig. 5). Both groups had minimal or no change in heart rate following vagotomy (Fig. 4).

DISCUSSION

The present study was undertaken to investigate the effect of experimental heart failure on arterial baroreceptor control of the peripheral vasculature. A canine model of heart failure induced by chronic rapid ventricular pacing was chosen for study be- cause this model is characterized by biventricular heart failure and left ventricular contractile dysfunction, 151s changes commonly seen in patients with heart failure. Neurohumoral changes are also similar to those seen in man. 1~-1s

Baroreceptor function was assessed by monitoring heart rate and hind limb vascular responses to phar-

�9 macologically-induced changes in arterial blood pressure, an approach previously described by Guo et al.13,14 This methodology was utilized rather than selective mechanical carotid pressure manipulation since it is more physiologic than is mechanical pressure manipulation. Baroreflex function was also assessed before and after vagotomy to investigate whether cardiopulmonary receptor input influenced baroreceptor responses.

At the end of 6 weeks of pacing, dogs exhibited hemodynamic changes similar to those described previously from this and other laboratories, l~-n Right atrial and pulmonary wedge pressures were elevated, while arterial blood pressure and cardiac output were reduced. Hemodynamic measurements were made

�9 while pacing the dogs with heart failure, since this represents the hemodynamic condition of the dogs during the study better than do measurements made without pacing. However, we have previously shown

Volume 119

Number 5 Baroreceptors in C H F 1 1 2 7

that discontinuation of pacing does not alter central hemodynamic measurements over the short term. 19

Systemic vascular resistance and hind limb vascular resistance were not elevated, a pattern we have noted in awake dogs with pacing-induced heart failurel5,19 Prior studies 1719 have demonstrated that this model is associated with elevated norepineph- rine levels and plasma renin activity, presumably re- flecting heightened medullary center sympathetic efferent outflow and circulating angiotensin II levels. The fact that these neurohumoral vasoconstrictor influences do not increase systemic and hind limb vascular resistance suggests the presence of counter- balancing vasodilatory influences, such as atrial natriuretic peptide 2~ and/or vascular hyporesponsive- ness to vasoconstrictor influences. 21

Administration of phenylephrine and nitroglycerin produced changes in arterial blood pressure in both control dogs and dogs with heart failure. How- ever, the arterial blood pressure responses to the three highest doses of phenylephrine and to two of the five doses of nitroglycerin were depressed in the dogs with heart failure. The attentuated blood pressure response to nitrates most likely reflects higher initial venous blood volume and venous distension in the dogs with heart failure than in the control dogs; in this situation, nitroglycerin would be expected to produce less venous blood pooling than in control dogs. The attenuated blood pressure response to phenylephrine may reflect reduced responsiveness of the peripheral vasculature to a-adrenergic agonists.

Over the range of blood pressure changes tested, the heart rate response to manipulation of arterial blood pressure was blunted in the dogs with heart failure, consistent with altered baroreflex control of the heart rate. Altered baroreflex control of heart rate has been described previously in patients with heart failure 1, 2 and in dogs with heart failure induced with tricuspid avulsion and pulmonary stenosis, 3, 4 or an arteriovenous fistula. 22' 23 In the dogs with heart failure due to tricuspid avulsion and pulmonic stenosis, defective sinus node responsiveness to postganglionic sympathetic nerve stimulation and to vagal nerve stimulation has been described, 3, 24 suggesting a defect in the efferent limb of the baroreflex arc.

In contrast to the observed abnormality of heart rate control, baroreceptor control of hind limb vascular resistance appeared to be normal in the dogs with heart failure. This was the case whether the hind limb vascular response was expressed as a change in absolute hind limb vascular resistance or as a percentage change in resistance from the baseline level. Following vagotomy and removal of cardiopulmonary receptor input, baroreflex control of hind limb

~o

100

50

0

- 5 0

- 1 0 0

- 1 5 0

PRE- VA GO TOM Y

CONTROL (% : ) /'IF (o-- -o)

p<.

i i i i i i i

- 2 0 0 20 40 CHANGE IN BP (mmHg)

i

- 4 0

100

~ 50

a~ 0

~ - 5 0

-JO0

POST-VAGOTOMY

s lZf) (~

CONTROL h :) HE [ c~- -o ]

-150 ~ ' ' , . , ,

-40 "20 0 20 40

CHANGE IN .BP (mmHg)

Fig. 4. Effect of changes in arterial pressure on heart rate in control dogs and in dogs with heart failure pre- and post-vagotomy. Graphs were constructed as described in Fig. 1. To compare the two groups, the slope of the blood pressure-to-heart rate response was calculated in each in- dividual dog. Slopes in the control dogs were significantly steeper than those in dogs with heart failure (p < 0.04).

resistance remained comparable in control dogs and in dogs with heart failure.

Our findings of normal arterial baroreflex control of hind limb resistance is consistent with prior observations in dogs with heart failure due to aorto- vena caval fistulas. In this model, Zucker et al. 11 noted normal arterial baroreceptor control of renal

May 1990

1128 W i l s o n e t al . American Heart Journal

PRE-VAGOTOHY

-7O

70 70

.kJ W CONTROL A :)

HF ( ~ ~ )

~J - \ hl

p = N S

. t~3 i L i J i , J

- 2 0 0 20 40 CHANGE I N BP (mmHg)

-70

POS T-VAGO TOHY

p - N S

C O N T R O L ,~ :; HE ( ~ --o)

i i i i

0 20 CHANGE I N BP (mmHg)

- 1 4 0 I - I 4 0 ' ' ' ' - 4 0 - 4 0 - 2 0 40

4O 4O

~1~, ,~ j CONTROL ~- =Y ~ - . . ~ CONTROL [: -9

- 2 o - 2 o

I I L I I I --~0 I I I I I I I -60

- 4 0 - 2 0 0 20 40 - 4 0 - 2 0 0 20 40 CHANGE I N BP [mmHg) CHANGE I N 8P [mmHg)

Fig. 5. Effect of changes in arterial pressure on hind limb vascular resistance in control dogs and in dogs with heart failure pre- and post-vagotomy. Graphs were constructed as described in Fig. 1.

sympathetic nerve activity and normal carotid sinus pressure-discharge curves when pressure was increased at a ramp rate similar to that found in the presence of pulsatile flow. 12 Our findings are also consistent with those of a preliminary report by Dib- ner-Dunlap and Thames 25 that the relation between aortic baroreceptor input and renal sympathetic nerve output is preserved in dogs with pacing- induced heart failure. In dogs with heart failure due to tricuspid avulsion and pulmonic stenosis, Higgins et al. 4 noted that bilateral carotid artery occlusion produced less vasoconstriction of the mesenteric and renal vascular beds than in control dogs, suggesting that heart failure impairs arterial baroreceptor control of the peripheral vasculature. However, in this study, only one change in carotid sinus pressure was performed. To what extent this approach provides a valid assessment of arterial baroreflex function is uncertain.

The presence of normal baroreflex control of hind limb vascular resistance, normal resting hind limb resistance, and a reduced arterial blood pressure suggests that the arterial baroreceptor pressure-discharge curve is shifted leftward in pacing-induced heart failure, Such resetting has been observed previously when the arterial blood pressure is either chronically increased by hypertension or chronically decreased.26, 27 In chronic hypotension, this resetting appears to be due to local mechanical factors rather than to the pathologic and histologic changes in ves- sel walls or nerve fiber architecture. 26

Resetting of the arterial baroreceptor pressure operating range in heart failure could be a desirable effect. Such resetting would minimize baroreceptor. mediated sympathetic vasoconstriction and cardiac afterload. However, it is also possible that such resetting has major adverse consequences. This resetting could reduce sympathetic stimulation of the

Volume 119

Number 5 Baroreceptors in CHF 1 1 2 9

heart and thereby exacerbate cardiac pump dysfunction. A decrease in the arterial blood pressure operating range could also compromise blood flow to tis- sues. During exercise, for example, blood flow to working skeletal muscle is dependent in part on the arterial blood pressure. If the arterial blood pressure is reduced below normal, this could produce skeletal muscle underperfusion and exertional fa- tigue.

Results of this study also suggest that an abnormality of arterial baroreflex control of heart rate in heart failure does not necessarily indicate altered baroreceptor control of the peripheral vasculature. Prior investigators have also observed dissociations between baroreflex control of heart rate and peripheral resistance, both in animals and in man. 13,14, 2s, 29 For example, Guo et al. 14 recently observed that baroreflex control of hind limb vascular resistance and lumbar sympathetic nerve activity is preserved in hypertensive resistance and lumbar sympathetic nerve activity is preserved in hypertensive rabbits despite impaired baroreflex control of heart rate. Such dissociation may be related to redundant control of sympathetic but not vagal activity by aortic and carotid baroreceptors; denervation of either aortic or carotid sinus baroreceptors has minimal effect on reflex control of vascular resistance but significantly impairs reflex control of heart rate. lu

To what extent the conclusions of this study can be generalized remains to be determined. In this regard, several limitations of the present study should be noted. Studies were performed in anesthetized animals. All available forms of general anesthesia de- press baroreceptor-mediated peripheral responses. 3~ It is possible that anesthesia alters baroreceptor- mediated responses differently in control dogs than in dogs with heart failure. Therefore our findings cannot necessarily be extrapolated to awake animals.

A second potential limitation of this study is that control dogs did not undergo sham operations. It is conceivable that the altered baroreceptor control of heart rate noted in dogs with heart failure was due to adverse effects of pericardial inflammation on cardiopulmonary baroreflexes. This seems unlikely, since preliminary observations by Angus e t al. ~1 in awake dogs serially monitored during the induction of pacing-induced heart failure have also demonstrated altered arterial baroreflex control of heart rate.

Finally, several limitations of the post-vagotomy measurements should be emphasized. The low arterial blood pressures noted at the time of vagotomy indicated deterioration of the preparation. Bilateral

cervical vagotomy may produce sectioning of the aortic depressor nerve and thereby altered baroreflex responses. Exclusion of the four paced dogs who developed unacceptable hypotension following vagotomy may have biased the results. Therefore the post-vagotomy data should be interpreted with cau- tion: In conclusion, results of the present study suggest that pacing-induced heart failure in the dog alters arterial baroreflex control of the heart rate but not of hind limb vascular resistance.

REFERENCES

1. Eckberg DL, Drabinsky M, Braunwald E. Defective cardiac parasympathetic control in patients with heart disease. N Engl J Med 1971;285:877-83.

2. Goldstein RE, Beiser GD, Stampfer M, Epstein SE. Impair- ment of autonomically mediated heart rate control in patients with cardiac dysfunction. Circ Res 1975;36:571-8.

3. White CW. Abnormalities in baroreflex control of heart rate in canine heart failure. Am J Physiol 1981;240:H793-9.

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Effects of nifedipine on transmitral Doppler blood flow velocity profile in patients with concentric left ventricular hypertrophy

To examine the effects of calcium channel blockade on left ventricular diastolic function, transmitral blood flow was evaluated by Doppler echocardiography following administration of sublingual nitroglycerin and nifedipine in 10 younger normal subjects and in 10 subjects with concentric left ventricular hypertrophy (LVH) and abnormal Doppler transmitral flow patterns. Nitroglycerin decreased peak early filling velocity (E velocity) in both normal (p < 0.01) and LVH subjects (p < 0.05) but did not significantly alter peak late filling velocity (A velocity), early filling velocity time integral (VTI E), or late velocity time integral (VTI A). In normal subjects, nifedipine decreased E velocity (p < 0.01) but did not significantly change A velocity, VTI E, or VTI A. In LVH subjects nifedipine increased E velocity (p < 0.05) as well as VTI E (p < 0,05) and the ratio of VTI E /VTI A (p < 0.05). Thus nifedipine, unlike nitroglycerin, improves the transmitral Doppler flow profile in patients with concentric LVH. (AM HEART J 1990 ;119 :1130 . )

R i c h a r d T. Lee , M D , C h r i s t o p h e r P. L o r d , BS, T e d P l a p p e r t , C V T , a n d

M a r t i n St , J o h n S u t t o n , M R C P . Boston, Mass.

D i a s t o l i c f i l l ing o f t h e l e f t v e n t r i c l e is i m p a i r e d in m a n y p a t i e n t s w i t h h e a r t d i sease , even w h e n sys to l i c

From the Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School. Dr. Lee is the recipient of a National Institutes of Health Physician Scien- tist Award (No, HL-01835).

Received for publication June 5, 1989; accepted Dec. 3, 1989.

Reprint requests: Richard T. Lee, MD, Cardiovascular Division, Brigham and Women's Hospital, 75 Francis St., Boston, MA 02115.

4/1/19089

f u n c t i o n is p r e s e r v e d . 1,~ I n p a t i e n t s w i th s y s t e m i c h y p e r t e n s i o n , t h e s e v e r i t y o f d i a s t o l i c d y s f u n c t i o n c o r r e l a t e s w i t h t h e deg ree 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 a n d , f u r t h e r m o r e , r e d u c t i o n of l e f t v e n t r i c u - l a r m a s s b y a n t i h y p e r t e n s i v e t h e r a p y l e a d s to im-

p r o v e d d i a s t o l i c func t ion . 3 W h e n c o n c e n t r i c 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 is severe , p a t i e n t s m a y deve lop c l in i ca l conges t i ve h e a r t f a i l u re t h a t r e s p o n d s p o o r l y to i n o t r o p i c agen t s . 4 D i a s t o l i c d y s f u n c t i o n of h y p e r t r o p h i e d m y o c a r d i u m is b e l i e v e d to b e due to

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arterial baroreceptor control of peripheral vascular resistance in experimental heart failure

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