Acta med. scand. Vol. 197, pp. 457461, 1975

PLASMA RENIN ACTIVITY, BLOOD PRESSURE AND SODIUM EXCRETION DURING TREATMENT WITH CLONIDINE

F. Fyhrquist, K. Kurppa and M. Huuskonen

From The Minerva Institute for Medical Research and The Lauttasaari Research Center, Helsinki, Finland

Abstracr. Clonidine, 225 pg a day, has been given orally for 3 months to 15 patients with essential hypertension. Mean BP was reduced from 159/107 to 143/87 mmHg. The antihypertensive effect of the drug was dissociated from changes in plasma renin activity (PRA) during clonidine treatment. PRA levels decreased initially in 6 patients with the highest PRA values before treatment, but then in- creased again. In 6 patients with lower pretreatment PRA levels, PRA rose continuously. Opposite patterns of 24- hour urinary sodium excretion were observed in these arbitrary subgroups. The antihypertensive effect of clonidine in essential hypertension appears to be indepen- dent of changes in PRA.

Recent observations that clonidine, an antihyper- tensive drug, decreases plasma renin activity (PRA) when administered i.v. (4, 9) or orally to normo- and hypertensive people (2, 7 , 9) have prompted suggestions that suppression of renin secretion may contribute to the antihypertensive effect of clonidine (2, 9). The mechanisms by which cloni- dine exerts its antihypertensive and renin suppres- sive effects (9) are incompletely understood. There is evidence for a suppressive effect on central sympathetic vasomotor mechanisms and peripheral effects as well (4, 8).

Previom work on PRA during clonidine therapy has been largely concerned with acute and short- time studies (2, 4, 9). Chronic treatment with clonidine reportedly causes suppression of PRA levels in hypertensive patients (7). I n patients with essential hypertension, clonidine is reported to cause retention of sodium (2, 9) and suppression of urinary aldosterone excretion (2).

We investigated the effect of a low oral dose of clonidine on PRA levels, BP, and urinary excretion of sodium and potassium in patients with mild, es- sential hypertension. The results indicate that

suppression of PRA is not a consistent feature dur- ing prolonged antihypertensive therapy with cloni- dine.

PATIENTS AND METHODS Fifteen patients, 3 of them female, mean age 38.7 years (range 21-55), were included in the study. Excluded were patients with any of the following: signs of secondary hypertension, heart failure, renal or hepatic disease, metabolic or endocrine diseases, psychiatric disorders, known duration of hypertension above 10 years. All had a diastolic BP consistently PI00 mmHg, measured in the supine, sitting and upright postures on several occasions during at least 3 months. Individual clinical data are given in Table I. Only WHO stage 1-11 hypertension was in- cluded. The examination included X-ray of the chest, i.v. pyelography, ECG, estimation of Na, K, chlorides, and creatinine concentrations in serum, and urinary excretion of Na and K (flame photometry).

Study prorocol. A detailed information sheet was given to each patient. Eleven patients had no previous antihypertensive treatment. The other 4 were without drugs for at least 2 weeks before starting the study. Clonidine, 75 pg 3 times a day, (Catapresanm, Boehringer Ingelheim) was given orally for 3 months on a non-blind, outpatient basis. No dietary restriction was introduced, and ordinary outpatient antihypertensive treatment was mimicked as closely as possible. Each patient was seen immediately before treatment, after I month and after 3 months. Each visit to the clinic included clinical examina- tion, BP measurements, and collection of samples for the estimation of PRA, serum concentration of Na and K, and urinary excretion of Na and K.

During the course of the study, the physicians examin- ing patients were not aware of PRA data, and the labora- tory personnel did not know about the clinical data.

Renin assay. Venous blood for PRA assay was col- lected into ice-chilled tubes containing disodium-EDTA (15 mM final conc.) after 12 hours of fasting and 2 hours of upright posture (walking) at 1&11 a.m. Plasma, separated by centrifugation at + 4 T , was stored at -20°C until assayed. PRA was estimated with a radioimmunoassay for

Acra med. srand. 197

458 F. Fyhrquist et al.

Table I . Clinical data of the patients studied LVH =left ventricular hypertrophy

Duration Supine BP, of hyper- 1st visit, Serum Possible

Pat. Age tension without drugs creatinine complications no. (Y.) (Y.) (mmHg) (pmole/l) of hypertension

1

2 3 4 5 6 7 8" 9"

10 11" 12 13 14 15 Mean

fS.E.M.

34

25 41 33 44 40 55 43 55 40 41 21 48 33 28 38.7 f2.6

3.5

6 0.5 1 0.5 0.5 0.5 0.5 3.5 0.5 0.5 0.5 I 0.5 2 1.4 - +0.43

160/100

160/100 165/105 160/100 l55/ 100 145/100 l50/l00 170/110 l80/ 120 170/110 160/110 190/110 170/115 l80/ 120 160/100 165f3.1 107f1.9

91

88 101 86 91 82 85 76 97 82

113 84 96

100 85

90k2.5

Subarachnoidal

None None None None None Slight signs of LVH None Slight signs of LVH None None None Slight signs of LVH None None

haemorrhage in 1972

a Female.

angiotensin I by a method modified according to the method of Stockigt et al. (10). Reference values for 232 normotensive, healthy subjects under identical conditions were 1.06f0.13 (S.E.) ng/ml/h. Interassay variation was I 1 % (S.D.) and intraassay variation 8.2%. Significant correlations were found between data obtained from identical plasma samples with the present radioim- munoassay and PRA bioassay according to Boucher et al. (3) (n = 16, r =0.77).

RESULTS

Plasma renin activity. After 1 month of clonidine treatment, mean PRA decreased from 0.81 to 0.61 ng/ml/h (not significant), and then increased to 1 .OO ng/ml/h @<0.05) after 2 further months (Table 11). Two patterns of change in PRA could be distin-

guished, namely a decrease of the highest levels, followed by an increase after 3 months (Fig. I ) , and an increase of PRA in those with pretreatment val- ues below the mean, followed by either a further increase or decreases with 2 further months of clonidine therapy.

A study of the 6 patients with the highest pre- treatment PRA levels and the 6 with low pretreat- ment and continuously increasing PRA values (Fig. 1) revealed a contrary pattern for sodium excretion.

Blood pressure. BP decreased significantly after one month of clonidine therapy (systolic, supine and upright p<O.OOl, diastolicp<0.001) but did not decrease significantly with 2 further months of drug treatment (Table 11). Two of 15 patients had end-

Table 11. Blood pressure, plasma renin activity, and urinary 24-hour excretion of sodium and potassium (mean +S.E.)

BP (mmHg) Urinary 24-hour

Supine Upright excretion (mEq) PRA

Systolic Diastolic Systolic Diastolic (ng/ml/h) Na K

159f3.8 107f2.6 0.81 f0 .22 209k I8 78f6.3 Pretreatment 158f3.6 106f2.3 After 1 month 143+3.4** 92+2.2** 143+2.5** 93f2.5** 0.61f0.11 185k13 75f6.0

1.00f0.15* 204k20 75f5.7 After 3 months 145f3.3 89f2.0 143f3.2 87k1.9

* p<0.05, ** p<O.OOl.

Acta med. scand. 197

Antihypertensive effect of clonidine 459

Init ially decreasing

I I 1 I l l

SUPPRESSED PRA

treatment diastolic BP > l o 0 mmHg, and were con- sidered clinical failures. The antihypertensive effect of clonidine was considered good and the side- effects observed were few (Table 111). Although the best responses of diastolic BP were observed in patients with low pretreatment PRA levels (Fig. 2), no significant correlation was found between diastolic BP decrease and either pretreatment ( N = I 5 , r=0.37) or end-treatment PRA values ( N = 1 5 , r=O.14).

Excretion of sodium and potassium. The mean pretreatment 24-hour sodium excretion decreased

I I I I l l

LOW PRA Continuously increasing

Fig. I. PRA and 24-hour uri- nary excretion of sodium be- fore treatment ( I ) , after 1 month (ZI), and after 3 months (111) of clonidine therapy. Mean values are in- dicated by horizontal lines.

after 1 month of clonidine therapy (not significant, Table 11) and returned to pretreatment levels after 3 months of drug treatment. In 5 of the 6 patients with the highest pretreatment PRA levels (Fig. l ) , an increase in sodium excretion after 1 month (not significant) was followed by decreased 24-hour sodium excretion. In the 6 patients with low PRA levels before treatment and continuously increasing PRA during clonidine therapy, a significant de- crease (p<0.05) in sodium excretion was followed by an increase (p<O.OS) back to pretreatment levels.

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460 F. Fyhrquist et al.

Table 111. Antihypertensive effect of clonidine

Duration of Re- treatment No. of Normo- spon- Side-effects (mo.1 pats. tensiveO siveb (no. of pats.)

1 15 6 5 Drowsiness 5 Dry mouth 3 Swollen legs 2

3 I5 8 5 Drowsiness 1

B P ~ 1 4 0 / 9 0 mmHg (upright). * B P ~ 1 5 0 / 9 5 mmHg (upright) or BP reduced 20/20 mmHg or more.

Urinary 24-hour excretion of potassium and serum concentrations of sodium and potassium, did not change significantly during the study (Table 11).

DISCUSSION

The present study, in contrast to previous reports (2, 7, 9), revealed increased PRA levels during clonidine therapy in a considerable proportion of patients with mild, essential hypertension. De- creased PRA values were observed in patients with the highest pretreatment PRA levels but even in these patients PRA levels were not significantly suppressed after 2 further months of clonidine therapy. Much of the differences between these results and previous reports may depend on the low dose of clonidine (225 pg a day) used by us. Moreover, previous investigations on the effect of clonidine on PRA levels have been largely con-

0 n=15 r =0.37

0 0

0

0 e

0 0

0 0

n

c 1 . 1 , -50 -40 -30 -20 -10 0 +I0

A DIASTOLIC BLOOD PRESSURE

Fig. 2. PRA before treatment compared to change of diastolic BP in upright posture. Linear regression analysis not significant.

Acra med. scand. 197

cerned with acute (4, 9) or short-time (2,9) effects, while we studied the effect of clonidine during 3 months. Previous reports (4, 7, 9) on PRA during clonidine administration have been based upon the bioassay method of Boucher et al. (3), or radioim- munoassay of angiotensin I (2). Data obtained by our immunoassay method (10) correlated signifi- cantly with results using bioassay according to Boucher et al. Therefore, it appears unlikely that differences in results could be explained by differ- ent renin assay techniques.

Baer et al. (2) reported suppression of PRA in 22 hypertensive patients on a constant metabolic regi- men and treated with 300 pg clonidine a day for 5 days. They also observed sodium retention and suppression of urinary aldosterone excretion. They suggested that clonidine may be useful for patients with hyperreninemia and aldosteronism. Our data do not favour such a conclusion. Hokfelt et al. (7) reported suppression of PRA levels in various types of hypertension with clonidine doses ranging from 300 to 900 pg daily for 6-30 days. However, clonidine did not inhibit an increase in PRA in re- sponse to sodium restriction in one of their patients.

Clonidine reportedly causes a decrease in renal vascular resistance in patients with essential hy- pertension during orthostatic stimulation with 45" tilting (9). We measured PRA after stimulation in upright posture. The increased levels of PRA during treatment with clonidine reported here, may be due to decreased renal vascular resistance. Other sympathetic inhibitors (reserpine, trimetaphan) re- ported to increase PRA in dogs with experimental hypertension (l), may cause release of renin by a similar mechanism.

During dietary sodium restriction (30 mEq Na daily), a powerful stimulus for renin release, clonidine 100 pg 4 times a day administered orally for 5 days to patients with essential hypertension caused suppression of PRA in both the supine and in the 45" tilted posture (9). This may be explained in part by initial retention of sodium and fluid caused by clonidine (2,9) in addition to inhibition of sympathetic nervous mechanisms (8). In agreement with such an explanation, we observed the most impressive reductions of PRA in the patients with ankle edema and weight gain. During sodium reple- tion, however, when PRA levels are generally low- er, the inhibitory effect of clonidine on renal reflex vasoconstriction in response to orthostatic stimula- tion (9) may override the inhibitory sympathetic

Antihypertensive effect of clonidine 461

nervous mechanisms (8). The net effect would be an increase in PRA during upright posture as observed by us in “low renin” hypertensive patients.

The antihypertensive effect of the low dose of clonidine (225 p g daily) used in this study appeared better than that reported by Onesti et al. (9), using 400-900 pg a day. The lower dose of clonidine,may explain the lower frequency of side-effects ob- served by us. Antihypertensive responses similar to those reported here were observed by Baer et al. (2) in patients receiving 300 pg clonidine daily for 5 days.

The antihypertensive effect of clonidine was not significantly correlated to pretreatment PRA levels, and was dissociated from changes in PRA levels during therapy. This was not altered when our pa- tients were divided into subgroups according to 24-hour urinary excretion of sodium, as described by Brunner et al. ( 5 ) . It would appear that clonidine may be used as an antihypertensive agent even in mild, essential hypertension, regardless of the PRA levels.

The possibility remains, that in clinical states with inappropriate hypersecretion of renin, e.g. re- novascular hypertension, suppression of renin re- lease may be beneficial. However, this may require higher doses, a s used by Hokfelt et al. (7). Moreover, the hypertensive and vasoconstricting effect of exogenous angiotensin and catecholamines i n rats is blunted by clonidine (6). Thus, clonidine may in fact stimulate renin release while simultane- ously counteracting the pressor activity of an- giotensin generated by renin.

The opposite patterns of sodium excretion observed in patients with “high” and “low”, con- tinuously increasing PRA levels (Fig. 1 ) seem to indicate that clonidine causes different changes in sodium excretion, and perhaps ingestion, in these two arbitrary subgroups of essential hypertension. The tendency towards stabilization of sodium ex- cretion after 3 months of clonidine therapy suggests that the effect on sodium balance is transient, fol-

lowed by adaptive adjustments which d o not abolish the antihypertensive effect of the drug.

,ACKNOWLEDGEMENTS This study was supported by grants from the Sigrid Juselius Foundation and the Finnish Medical Society.

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REFERENCES Ayers, C. R., Harris, R. H., Jr & Lefer, L. G.: Con- trol of renin release in experimental hypertension. Circulat. Res., Suppl. 1: 103, 1969. Baer, L., Brunner, H. R., Bard, R. & Laragh, J.: Suppression of renin and aldosterone by clonidine. Ann. intern. Med. 74: 830, 1971. Boucher, R., Veyrat, R., De Champlain, J. & Genest, J.: New procedures for measurement of human plasma angiotensin and renin activity levels. Canad. med. Ass. J. 90: 194, 1964. Brod, J., Horbach, L., Just, H., Rosenthal, J . & Nicolescu, R.: Acute effects of clonidine on central and peripheral haemodynamics and plasma renin activity. Europ. J. clin. Pharmacol. 4: 107, 1972. Brunner, H. R., Laragh, J. H., Baer, L., Newton, M. A., Goodwin, F. T., Krakoff, L. R., Bard, R. H. & Biihler, F. R.: Essential hypertension: Renin and aldosterone, heart attack and stroke. New Engl. J. Med. 286:441, 1972. Formanek, K., Lindner, A. & Selzer, H.: Die Testung von Antihypertensiva mit protrahierter Wirkung. Wien. klin. Wschr. 80: 185, 1968. Hokfelt, B., Hedeland, H. & Dymling, J . F.: Studies on catecholamines, renin and aldosterone following Catapresan@ (2-(2.6-dichlor -phenylamine)-2-imida- zoline hydrochloride) in hypertensive patients. Europ. J. Pharmacol. 10:389, 1970. Kobinger, W.: Pharmacological basis of the car- diovascular actions of clonidine. In: Hypertension: Mechanisms and management (ed. G. Onesti, K. E. Kim & J . H. Moyer), p. 369. Grune & Stratton, New York and London 1973. Onesti, G., Schwartz, A. B., Kim, K. E., Paz- Martinez, V. & Swartz, C.: Antihypertensive effect of clonidine. Circulat. Res., Suppl. 2: 53, 1971. Stockigt, J . R., Collins, R. D. & Biglieri, E. G.: De- termination of plasma renin concentration by an- giotensin I immunoassay. Circulat. Res., Suppl. 2: 175, 1971.

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