the possible importance of aldosterone as well as renin in the long-term antihypertensive action of...

CLINICAL STUDIES

The Possible Importance of Aldosterone as Well as Renin

in the Long-Term Antihypertensive Action of Propranolol

JAN I. M. DRAYER, M.D.

MICHAEL A. WEBER, M.D.

DAVID L. LONGWORTH, B.S.

JOHN l-t. LARAGH, M.D.

New York. New York

From the Cardiovascular Center, The New York Hospital-Cornell Medical Center, 525 East 68th Street, New York, New York. This investigation was supported in part by Public Health Service Grant HL-18823SCR. Requests for reprints should be addressed to Dr. Jan I. M. Drayer, The New York Hospital-Cornell Medical Center, 525 East 68th Street, New York, New York, 10021. Manu- script accepted June 28, 1977.

In 50 patients with essential hypertension, propranolol produced a significant decrease in blood pressure. The decrease in mean pressure was greatest in patients classified by a renin sodium nomogram as having high rentn hypertension. In turn, blood pressure decreased more in patients with normal renin than in those with low renin levels. Indeed, a net increase in diastolic pressure occurred in the low renin subgroup. These findings confirm the value of pretreatment plasma renin measurements for predicting blood pressure responses to propranolol.

Over-all, seven of the 50 patients exhlbited increases in mean blood pressure during propranolol treatment. Presumably, this occurred because the mlnimal suppression of renin-angiotensin- mediated vasoconstrtction tn these patients was insufficient to compensate for the unopposed alpha-sympathetic vasoconstriction unmasked by peripheral vascular beta-blockade. Wtthin this group of patients, there was a significant inverse correlation between control renln values and the amplitude of the pressor response.

The decrements in plasma renin were slightly greater in patients classified as responders (decrease in mean blood pressure 110 per cent) than in nonresponders. However, when the propranolol-induced decrements in aktosterone excretion were taken into account, responders to treatment exhibited far greater decreases than nonresponders. Thus, higher levels of aldosterone during treatment may operate to oppose the antihypertensive action of propranolol. Ulti- mately, this dependency of the blood pressure response upon aldosterone levels is at least partly coordinated with propranolol- induced inhibttion of renin release, since we found a significant correlation between changes in these hormones during treatment.

The beta-adrenoreceptor blocking agent, propranolol, is widely effective in the treatment of hypertension [l-3]. In conjunction with its blood pressure-lowering properties, propranolol exerts a powerful suppressive action on plasma renin activity [4-61. The likelihood that this inhibitory effect on renin secretion is important in the antihypertensive action of propranolol was established in studies which showed that this agent is most effective in patients with high pretreatment renin values [7,8] and that there is a correlation between propranolol-induced decreases in blood pressure and in olasma renin activity [WI.

February 1979 The American Journal of Medicine Volume 64 187

LONG-TERM ANTIHYPERTENSIVE ACTION OF PFiOF’RANOLOL-DRAYER ET AL.

In the present study, we have further evaluated the role of the renin-aldosterone system in mediating the blood pressure response to propranolol in 50 outpa- tients with essential hypertension. In particular, we quantified the differences in induced changes in plasma renin activity and aldosterone excretion between patients classified as responders or nonresponders to treatment with propranolol.

METHODS

Patients. This study was performed in 50 hypertensive patients, 38 male and 12 female, whose ages ranged from 21 to 67 years (mean: 47.5 years). Prior to study, all patients were diagnosed as having essential hypertension using conventional clinical, biochemical and roentgenologic cri- teria. Clinical and biochemical screening in each patient confirmed the absence of intercurrent illnesses, including diabetes mellitus and cardiac, renal and hepatic disease. At the time of entering the study, patients had either never been treated for hypertension or had been without treatment for at least three weeks. All participants in this study were evaluated and treated on an outpatient basis in the Hyper- tension Center of The New York Hospital-Cornell Medical Center. Following at least two visits, during which base line and diagnostic studies were performed, measurements of blood pressure, pulse rate and body weight were obtained immediately prior to the start of treatment and repeated after at least three weeks of treatment with 80 to 160 mg propranolol per day orally. Plasma renin activity and urinary excretion of sodium and potassium were also determined before and during treatment. Blood and urinary chemistries were monitored similarly. Technics. Blood pressure was measured by a standard mercury sphygomanometer with the patient seated. Both plasma renin activity [lo] and urinary aldosterone excretion [ 1 I] were measured by radioimmunoassay. As an aid to analysis, each patient was classified into a high-, normal- or low-renin subgroup according to a nomogram relating renin values to concurrent 24-hour rates of sodium excretion 1-1.

The Wilcoxon test for paired data was used for statistical analysis within groups of patients, and the Wilcoxon test for nonpaired data was used for comparisons between groups. Regression analysis was also employed. The data are given as mean f standard error of the mean.

RESULTS

The 50 patients with essential hypertension who par- ticipated in the study were divided into high- (12 patients), normal- (31 patients) and low- (seven patients) renin subgroups according to a renin sodium nomogram. The three subgroups differed with respect to the patients’ mean age: the patients in the high-renin subgroup being the youngest (41.8 f 3.2 years), those in the normal-renin subgroup being older (47.5 i 2.2 years), and those in the low-renin subgroup being the oldest (56.1 f 3.7 years). All 12 patients in the high-renin subgroup were men; in the normal-renin subgroup 24

Mean

arterlol pressure

immHg)

Or- -5

i -10 i-

-15 1

High Renin Normal Renln Low Renln

n=l2 n=31 n=7

PI PZ p3

Figure 1. Changes (mean f SEM) in mean arterial pressure, heart rate and body weight during treatment with propranolol in subgroups of patients with high-, normal- and low-renin essential hypertension. p? = p value between the high- and the normal-renin subgroup; p2 = p value between the normal- and the low-renin subgroup; p3 = p value between the low- and the high-renin subgroup. l * l ’ = p <O.OOl; l l l = p <0.005; l l = p <0.025; l = p <0.05.

. of the 31 patients were men, but in the low-renin subgroup only two were men.

For the 50 patients as a whole, treatment with propranolol decreased systolic blood pressure from 168 f 3 to 150 f 3 mm Hg (p (0.001). The diastolic blood pressure decreased from 103 f 2 to 97 f 1 mm Hg (p <O.OOl). Mean blood pressure (calculated as the diastolic pressure plus one third of the pulse pressure) also decreased significantly, from 125 f 2 to 115 f 2 mm fig (p <O.OOl). Within the high-, normal- and low-renin subgroups the decreases in systolic blood pressure of 28 f 4 (p <O.OOl), 14 f 2 (p <O.OOl) and 19 f 7 (p <O.OOl) mm Hg were also significant. The differences among the subgroups in their changes in systolic pressure were not significant.

Although the decreases in diastolic blood pressure in the high-renin subgroup (11 f 4 mm Hg, p X0.02) and in the normal-renin subgroup (7 f 1 mm Hg, p KO.001) were significant, the low-renin subgroup actually experienced a slight increase in diastolic blood pressure (5 f 7 mm Hg). The change in diastolic blood pressure in the high-renin subgroup was not significantly different from that in the normal-renin subgroup, but the change in both of these groups differed from that in the low- renin subgroup (p <0.05 and p <O.Ol, respectively). The changes in mean arterial pressure during treatment in the three renin subgroups are shown in Figure 1. The decrement of 16 f 3 mm Hg in mean blood pressure in the patients with high renin levels was greater (p <0.03) than that of 9 f 2 mm Hg in the patients with

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LONG-TERM ANTIHYPERTENSIVE ACTION OF PROPRANOLOL-DFXAYER ET AL.

Plasma renin

activity (ng/ml/hr)

High Renin Normal Renin Low Renin r

n=l2 I ,

n=31 7 I n=7 1

Before During Before During Before During

y f\

PI

4 ***

J

**

2-

01

20

Urinary I5 1 h_ Figure 2. Plasma renin activity and urinary aldosterone excretion (mean f SEM) before and during treatment with propranolol in subgroups of patients with high-, normal- and low-renin essential hyperfension. For legend see Fig 1.

I *

k *Y f 1

\** k

p2 p3

** **y

**

normal renin levels which, in turn, was greater (p <0.05) than the decrement of 3 f 5 mm Hg in the patients with low renin levels. Pulse Rate and Body Weight. For all 50 patients, heart rate decreased from 83 f 2 to 65 f 1 beats/min (p <O.OOl). There was no difference among the changes in pulse rate observed in the three renin subgroups (Figure 1). There was no significant change in body weight in the patients as a whole or in the three renin subgroups during treatment with propranolol (Figure

1). Renln and Aldosterone. For all patients together, propranolol decreased plasma renin activity from 3.4 f 0.4 to 1.5 f 0.2 ng/ml/hour (p <O.OOl). Highly significant decreases in plasma renin activity occurred in both the high- and normal-renin subgroup. Although the absolute decrease in plasma renin activity was of lesser amplitude in the low-renin subgroup, the change was still significant (Figure 2). In the patients as a whole, urinary aldosterone excretion decreased significantly (p <O.Ol) from 13.3 f 1.8 to 8.8 f 0.8 pg/24 hours.

This decrease was most pronounced in the high-renin subgroup but also occurred in the normal-renin subgroup. The decrease in the low-renin subgroup was not significant.

A significant correlation was found between the control plasma renin activity and the decrease in mean arterial pressure, r = -0.43, 50 patients, p <O.Ol, and between the control urinary aldosterone excretion and the decrease in mean arterial pressure r = -0.31, 50 patients, p <0.05. A significant correlation was found between the induced changes in renin and in aldosterone, r = 0.59, 50 patients, p <O.OOl. No correlations were found between the changes in renin and in diastolic pressure, or between the changes in aldosterone excretion and in diastolic pressure. Similarly, there were no correlations between the changes in renin or aldosterone and the changes in mean arterial pressure. Blood Chemistry. Values for blood chemistry studies in all 50 patients before and during treatment with propranolol are given in Table I. Serum sodium decreased (p <0.05) and serum potassium (p <O.Ol) in-

TABLE I Blood Chemistry Values (mean f SEM) in 50 Hypertensive Patients Before and During Treatment with Propranolol

Plasma Plasma Serum Total Sodium Potaeelum Crealinine Proteln

(meqlllter) (meqlliter) (mgldl) (g/W

Before Treatment 142.1 f 0.5 4.4 f 0.1 1.34 f 0.04 7.7 f 0.1

During Treatment 140.9’ f 0.4 4.6’. f 0.1 1.37 f 0.03 7.6 f 0.1

NOTE: In this article l = p <0.05, l l = p <O.Ol when compared with pretreatment values.

Urinary Urinary Sodium Potesfdum

Excretion Excretion (meqI24 hr) (megi hr)

123 f 10 73 f 4

135f 11 76 f 4

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LONGTERM ANTIHYPERTENSIVE ACTION OF PROPRANOLOL-DRAYER ET AL.

creased during treatment, but there were no changes in serum creatinine or total protein concentrations. Uric acid increased during treatment from 6.2 f 0.2 to 6.9 f 0.3 mg/dl, p <O.Ol. Urinary sodium and potassium excretions did not change significantly with treatment. Moreover, there were highly significant correlations between urinary sodium excretion before and during treatment, r = 0.80, 50 patients, p <O.OOl, and between urinary potassium excretion before and during treatment, r = 0.46, 50 patients, p KO.001. Therefore, changes in dietary sodium or potassium intake were unlikely to have played a role in the effects described in this study. Responders and Nonresponders. In a second analysis the 50 patients were divided into responders, in whom mean blood pressure decreased by 10 per cent or more, and nonresponders. Twenty-one patients were classified as responders and 29 as nonresponders. Among the nonresponders, seven actually exhibited an increase in mean arterial pressure ranging from 1 to 17.3 per cent. A significant correlation (p cO.05) was found between the control plasma renin activity and the increase in mean arterial pressure in these seven patients

(r = -0.79). There were no significant differences between the

mean ages of the responders and nonresponders, 46.1 and 48.6 years, respectively. Ninety per cent (19) of the responders were male as were 66 per cent (19) of the nonresponders.

Changes in mean blood pressure, pulse rate and body weight in the responders and nonresponders are compared in Figure 3. Although there was a significant difference (p <O.OOl) between the blood pressure changes in the two groups, the changes in heart rate and in body weight were similar.

Pretreatment plasma renin activity was slightly, but not significantly, lower in nonresponders than in responders (3.0 f 0.4 and 4.0 f 0.6 ng/ml/hour, respectively). Propranolol induced significant (p <O.OOl) and similar decreases in plasma renin activity in both groups (1.8 f 0.3 and 2.1 f 0.6 ng/ml/hour). The mean control aldosterone excretion rate was significantly higher (p <0.05) in the responders than in the nonresponders, 17.8 f 3.4 and 10.3 f 1.3, respectively. The decrease in aldosterone excretion during treatment with propranolol was significantly greater (p <0.025) in the responders than in the nonresponders, 8.8 f 3.5 and 1.6 f 0.8 pg/24 hours, respectively (Figure 4).

Changes in blood chemistry values in the responders and nonresponders are compared in Table II. There was no difference between the changes in the responders and in the nonresponders.

COMMENTS

In this study, propranolol significantly lowered systolic and diastolic blood pressures during the outpatient

0

Mean -5 arterial _,. pressure (mmHg) -I5

-20

Responders Nan- Responders n=21 n=29

Heart ’ rate -to -

(bpm) _20 _ q

Figure 3. Changes (mean f SEM) in mean arterial pressure, heart rate and body weight during treatment with pro- pranoiol in responders (2 70 per cent decrease in mean pressure) and nonresponders (< 10 per cent decrease in mean pressure). l *** = p <O.OOl.

treatment of 50 patients with uncomplicated essential hypertension. Consistent with earlier studies [5, 7-9, 131, propranolol decreased the blood pressure most in patients with high renin levels and least in patients with low renin levels. Moreover, there was a significant correlation between pretreatment plasma renin activity values and propranolol-induced decreases in mean blood pressure. In parallel with the changes in mean arterial blood pressure, plasma renin activity decreased’ to a significantly greater extent in patients with high- renin levels than in those with normal-renin levels and to the least extent in those with low-renin levels.

Of clinical relevance, the patients comprising the high-renin subgroup, in which the greatest decreases in blood pressure occurred, tended to be younger than the patients in the other renin subgroups and to contain a higher proportion of men. This suggests that when it is not possible to profile patients by the renin-sodium nomogram prior to treatment, propranolol is particularly appropriate in the initial treatment of hypertension in younger patients and especially in men.

The treatment of patients with low-renin hypertension with propranolol produced divergent responses in blood pressure. Thus, although there was a marked decrease in systolic pressure, there was, over-all, an increase in diastolic blood pressure in this group. It is not surprising that systolic blood pressure decreased to the same extent in low-renin patients as in high- and normal-renin patients, since heart rate, and presumably cardiac output, were decreased uniformly in the three hypertensive subgroups. The change in diastolic blood pressure during treatment may best be explained on the

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LONG-TERM ANTIHYPERTENSIVE ACTION OF Pl?OPRANOLOL-DRAYER ET AL.

figure 4. Plasma renin ac?ivity and urinary aldosterone excretion (mean f SEM) before and during treatment with propranolol in responders (2 10 per cent decrease in mean pressure) and nonresponders (< 10 per cent decrease in mean pressure). l l l = p < 0.00 1; l l = p < 0.025; l = p <0.05.

6

Plasma renin 4

activity (ng/ml/ hrl 2

OL

20

Urinary I5 aldosterone

excretion IO

(,q/24hr) 5

0

Responders Non- Responders r

n=21 1 r

n=29 I

Before During Before During

P

7

\ ***

\ f\ ***

\I

basis of two separate peripheral effects of propranolol on blood pressure mechanisms: first, by blockade of peripheral vascular beta-adrenergic receptors, thereby abolishing their vasodilatory actions; and second, by inhibition of renin secretion with a consequent reduction in the peripheral vasoconstrictor action of the renin- angiotensin system. Hence, in the low-renin subgroup, in which the reduction in renin-angiotensin-mediated vasoconstriction mechanisms was insufficient to offset the propranolol-induced predominance of peripheral alpha-receptor activity, there was a net increase in diastolic blood pressure.

Of the 50 patients studied, there were seven (including three with low renin levels) in whom mean arterial pressure actually increased, the increases ranging from 1 to 17.3 per cent. Within this small subset of patients there was an inverse correlation between control renin values and the induced increase in blood pressure, blood pressure increasing most in those pa-

tients whose renin levels were lowest. The finding is consistent with our earlier report [ 151 indicating that a proportion of patients actually experience an increase in blood pressure during treatment with propranolol alone.

Using a decrease in mean blood pressure of 10 per cent or more as the criterion of blood pressure responsiveness to propranolol, 21 of the 50 patients were found to be responders and 29 to be nonresponders. There were no differences between the two groups in their changes in heart rate, body weight or clinical chemistry values. Consistent with our finding that patients with high renin levels exhibited the largest decrements in blood pressure during treatment, we found that the responders tended to be younger than the nonresponders and to have higher pretreatment renin values. However, the actual decreases in plasma renin activity in the responders and nonresponders were not significantly different from each other. But, in contrast,

TABLE II Changes (mean f SEM) in Blood Chemistry Values in Patients Classified as Responders (2 10 per cent in meah blood pressure) or Nonresponders (<lo per cent In mean blood pressure) After Treatment with Propranolol

Plasma Plasma Sodium Patasalum

(maWar) (msqlliler)

-1.5 f 0.8 +0.3 f 0.2

-0.8 f 0.8 +0.3 f 0.1

Urlnary Serum Total Sodium

Creatinina Prolain Excretion Wdl) W) (~24 hr)

Responders (21 patients) +0.01 f 0.04 -0.03 f 0.08 +6f 13

Nonresponders (29 patlents) +0.07 f 0.07 -0.23 f 0.12 +18*6

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LONGTERM ANTIHYPERTENSIVE ACTION OF PROPRANOLOL-DRAYER ET AL.

both the pretreatment aldosterone values and the treatment-induced changes in aldosterone excretion were clearly different in the two groups. Thus, control aldosterone values were significantly higher in the responders than in the nonresponders, but during treatment the aldosterone excretion rate decreased far more in the responders than in the nonresponders.

This finding, that patients who failed to respond to treatment were characterized by a failure of aldosterone levels to fall, is in keeping with previous studies in which we reported inappropriately high aldosterone levels in nonresponding patients during treatment with a variety of antihypertensive agents [ 14-161. Although aldosterone is a potent sodium and water-retaining miner- alocorticoid, there was no evidence in this study that its volume-retaining activities were critical to its effects on blood pressure, since the responders and the non-

responders experienced closely similar weight changes. Moreover, there were no differences between the two groups in their sodium or potassium values during treatment. Thus, it is entirely possible that a pressor action of aldosterone, independent of its volume-retaining effects in the kidney, may have been involved in sustaining high levels of blood pressure in the nonresponders. In this context, it is possible therefore to postulate a direct pressor action of aldosterone in sustaining arterial blood pressure. In turn, this dependency of the blood ljressure response upon drug-induced changes in aldosterone excretion may well be complementary to and ultimately determined by inhibition of renin release since there was a significant correlation between changes in aldosterone excretion and in plasma renin activity during treatment with propranolol.

REFERENCES

1.

2.

3.

8.

Pritchard BNC, Gillam PMS: Treatment of hypertension with propranolol. Br Med J 1: 7, 1969.

Zacharias FJ, Cowen KJ, Prestt J, et al.: Propranolol in hypertension. A study of long-term therapy, 1964-70. Am Heart J 83: 755, 1972.

Stokes GS, Weber MA. thornell IR, et al.: Effects of acute and chronic administration of propranolol on blood pressure and plasma renin activity in hypertensive patients. Drugs and the kidney (Edwards, ed), F’rog Biochem Pharmacol 9: 29, 1974.

Stokes GS, Weber MA, Thornell IR: Beta-blockers and plasma renin activity in hypertension. Br Med J 1: 60, 1974.

Hollifield JW, Sherman K, Vander Zwagg R, et al.: Proposed mechanisms of propranolol’s antihypertensive effect in essential hypertension. N Engl J Med 295: 68, 1976.

Michelakis AM, McAllister RG: The effect of chronic adrenergic receptor blockade on plasma renin activity in man. J Clin Endocrinol Metab 34: 386, 1972.

Buhler FR, Laragh JH, Baer L, et al.: Propranolol inhibition of renin secretion: a specific approach to diagnosis and treatment of renindependent hypertensive diseases. N Engl J Med 287: 1209, 1972.

Hollander W: Antihypertensive drugs in the prevention and treatment of complications of essential hypertension, Cardiovascular Medicine 2: 83, 1977.

9.

10.

11.

12.

13.

14.

15.

18.

Buhler FR, Laragh JH, Vaughan ED Jr, et al.: Antihypertensive action of propranolol. Specific antirenin responses in high and normal renin forms of essential, renal, renovascular and malignant hypertension. Am J Cardio132: 511, 1973.

Sealey JE. Laragh JH: Radioimmunoassay of plasma renin activity. Semin Nucl Med 5: 189, 1975.

Sealey JE, BLihler FR, Laragh JH, et al.: Aldosterone excretion: physiologic variations in man measured by radioimmunoassay or double isotope dilution. Circ Res 31: 367, 1968.

Brunner HR, Laragh JH, Baer L, et al.: Essential hypertension: renin and aldosterone, heart attack and stroke. N Engl J Med 286: 441, 1972.

Karlberg BE, Tolagen K: Different antihypertensive effect of beta-blocking drugs in low- and normal-high renin hypertension. Am J Med 60: 891, 1966.

Keim l-U, Drayer JIM, Thurston H, et al.: Triamterene-induced changes in aldosterone and renin values in essential hypertension. Arch Intern Med 136: 845, 1976.

Drayer JIM. Keim HJ, Weber MA, et al.: Unexpected pressor responses to propranolol in essential hypertension. Am J Med 60: 897, 1976.

Weber MA, Lopez-Ovejero JA, Drayer JIM, et al.: Renin re- activity as a determinant of responsiveness to antihypertensive treatment. Arch Intern Med 137: 284, 1977.

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the possible importance of aldosterone as well as renin in the long-term antihypertensive action of...

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