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Renin and aldosterone suppression in the antihypertensive action of clonidine
Renin and Aldosterone Suppression in the Antihype~~nsive Action of Clonidine
MICHAEL A. WEBER, MD DAVID B. CASE, MD LESLIE BAER, MD JEAN E. SEALEY, DSc JAN I. M. DRAYER, MD JORGE A. LDPEZ-DVEJERO, JOHN H. LARAGH, MD
MO
Mew York, New York
From the Cardiovascular Center, The New York Hospital-Cornell Medical Center, New York, N. Y. This study was supported in part by U. S. Public Health Service Grant HL 16323 SCR. Address for reprints: Michael A. Weber, MD, Cardiovascular Center, The New York HospitalCornell Medical Center, 525 East 68th St., New York, N. Y. 10021.
In 18 hypertensive patients receiving a constant (100 mEq/day) sodium diet, treatment with cfonidine (0.3 mg/day for 5 days) decreased blood pressure in 11 patients with high and normal renin levels and 7 with low renin levels. fhe high and normal renin group had early and rapid reductions in Mood pressure and plasma renfn activity. in contrast, the low renfn group had a more gradual hy~t~ve response and onfy a small absolute decrease in plasma renin. For all patients, pretreatment renin levels were related to the initial decrease in blood pressure but not to the reductions measured after 5 days. Thus, two mechanisms of action of clonidine are possible, one related to acute fnhibftfon of the.renin-angiotensin system in patients with high and normal renin levels and another that is independent of renin mechanisms and occurs in ail hypertensive patients. in six additional patients with high renfn levels Induced by prior sodium depletion (10 mEq/day sodium diet), clonidine did not reduce blood pressure or renfn, thus indicati~ that the suppressive actfon of this agent on renin pressor mechanisms occurs onfy in patients whose elevated renfn levels are intrinsic to hypertension and unrelated to sodium depletion. Of the 18 patients receiving a normal sodium diet, 13 were classfffed as responding to treatment (decrease in both systolic and diastolic pressures of at least 10 percent). The five nonresponders had a greater weight gain and higher values for aldosterone excretion. For all patients, there was a signfticant correlation between decrements in blood pressure and in aldosterone, suggesting that the countervailing effects of fluid accumulation on blood pressure in nonresponding patients resulted from a failure of aldosterone to be suppressed. Changes in aidosterone, in turn, correlated signiffcantfy with changes In renin. Thus, the antfrenfn effect of cionfdfne enhances its antihype~ensive action not only by acutely ablating renin-angiotensin pressor mechanisms, but also by inhfbiting afdosterone production and thereby minimizing longer-term reactive volume retention during treatment,
Treatment with clonidine effectively reduces blood pressure in a majority of hypertensive patients3 The agent acts principally within the central nervous system, where it exhibits a stimulatory effect on alpha adrenergic receptors.” This, in turn, leads to reduced activity of the sympathetic nervous system and a decrease in blood pressure.5 Clonidine also decreases renal secretion of renin.s7 The inhibition of renin release by certain other antihypertensive agents, including beta adrenergic blocking drugssg and methyldopa,‘O has been held to contribute to the reduction of blood pressure. Thus, it is possible that the antihypertensive effectiveness of clonidine is dependent to some degree upon its suppressive action on renin. To evaluate the importance of hormonal factors in the action of clonidine in man, we studied the effects of clonidine on plasma renin activity and aldosterone excretion in hospitalized hypertensive patients. The study was carried out in a metabolic ward while the patients were re-
November 23, 1976
The American Journal of CARDIOLOGY
Volume 38
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CLONIDINE IN HYPERTENSION-WEBER
ET AL
ceiving a constant intake of sodium and potassium so as to avoid diet-induced alterations in renin and aldosterone mechanisms. In the sodium-depleted rat treated with diuretic agents, blood pressure is maintained to a significant degree by a compensatory rise in activity of the reninangiotensin system; 11~2 in these animals, clonidine induces a hypotensive response that is mediated by its renin-reducing action. l3 To determine whether a comparable mechanism exists in hypertensive man subjected to sodium depletion, a further group of patients were treated with clonidine during a period of controlled dietary salt deprivation.
the study, plasma renin activity, measured at noontime in the ambulatory state, and urinary aldosterone excretion were
measured during the day before the start of treatment with clonidine (control day), and similarly during the final day of treatment. In nine of these patients, these values were also measured during the 1st day of clonidine treatment. In the six patients subjected to sodium depletion, renin and aldosterone were measured on the last day of the 100 mEq/day sodium diet, on the last day of treatment with the low sodium diet alone, and on the final day of combined treatment with sodium depletion and clonidine. Techniques: Plasma renin activityI and urinary aldosterone excretion15 were measured by radioimmunoassay. Metabolic balance procedures and routine electrolyte determinations were performed as described previously.16 To facilitate analysis, each patient was classified into a high, normal or low renin category according to a nomogram relating renin values to concurrent. daily sodium excretion.17 Because only three patients were in the high renin category, their data were included with those of the normal renin group. The Wilcoxon test, for paired differences was used for statistical analysis within groups of patients, and the Wilcoxon test for nonpaired data for comparisons between groups. Regression analysis was performed by the Spearman method. Data are given as mean f standard error of the mean.
Methods Patients: Studies were performed in 24 hypertensive subjects, 13 men and ll’women aged 28 to62 years (mean 44 years), admitted to a metabolic ward. All patients gave informed consent for the study and either had never been treated for hypertension or had discontinued all antihypertensive medication at least 4 weeks before admission. Diagnostic evaluation before the study established that 20 patients had essential hypertension, 3 had renovascular hypertension and 1 had hypertension related to chronic gIomerulonep~tis. In all cases, medical history, physical examination and laboratory screening had excluded intercurrent. heart or liver disease or diabetes mellitus. With the exception of the one patient with chronic glomerulonephritis, whose blood urea nitrogen was slightly increased (25 mg/dl), all patients had normal renal function. Study protocol: After admission to the metabolic ward, each patient was given a diet containing 100 mEq sodium/day and a constant amount of potassium. After 6 days on this diet, 18 patients were given a 5 day course of clonidine (Catapres”, Boehringer Ingelheim), 0.3 mg/day given in three oral doses of 0.1 mg, while they continued the 100 mEq sodium diet. In the other six patients, sodium intake was reduced from 100 to 10 mEq/day after 6 days. After 6 more days of this low sodium diet, cionidine was administered in the previous manner for 5 days while the low sodium diet was continued. In each patient, daily values for blood pressure and pulse rate were determined as the average of four readings taken in the seated position at 4 hour intervals during the day. Patients were weighed at a constant time each morning. In the 18 patients who received a 100 mEq/day sodium diet throughout
TABLE
Results Patients Receiving a Constant Sodium Diet Of the 18 patients who received a constant 100 mEq/day sodium diet throughout the study, 11 were classified in the high and normal renin group (average age 40 years) and 7 in the low renin group (average age 46 years). Blood pressure: The effects of clonidine, 0.3 me/day, in the two renin groups are summarized in Table I. By the end of the 5 day treatment period, systolic and diastolic blood pressures were significantly reduced in each group. However, although the ultimate effectiveness of clonidine in reducing blood pressure did not differ significantly in the two groups, the rate of reduction did differ (Fig. 1). Thus, during the 1st day of treatment, the decrease in diastolic pressure of 14 f 2 mm Hg (P
I
Values Immediately error of the mean)
Before
and During
Treatment
With
___-- Blood Pressure (mm Hg)
High and Normal Before After
183” 139i
II lo*
(0.3 mg daily for 5 days) (mean + standard
Pulse Rate (per mini
Diastolic
Systolic
Clonidine
Body Weight (kg)
Renin Group
Low Renin Group
169 i-c11
Before After
146+-
*P ~0.05,
826
+P 10.025,
111 +6 93 * 6+
95 SP (0.01
November 23,1976
when compared
76% 3 6% t 3” with control
Urinary Aldosterone b&24 hours)
7.9 + 2.3 3.0 i o.&
21.3 t 2.9 13.0 t 2.1+
0.8 + 0.2 0.5 * 0.1
16.7 f 3.5 10.6 i 2.7”
1f )
(no. = 7) 74.0 i 6.3 74.5 2 6.2
value.
The American Journal of CARDIOLOGY
=
69.9 f 4.1 70.3 * 4.1
782 4 68 -t 3+
117% 7 91 i 4$
(no.
Plasma Renin Activity (ng/ml per hour)
Volume 36
CLONIDINE IN HYPERTENSION-WEBER ET AL.
in the low renin group (3 f 2 mm Hg). Similarly, the initial decrease in systolic pressure was greater (P <0.05) in the high and normal renin group (25 f 15 mm Hg) than in the low renin group (7 f 3 mm Hg). In the succeeding days of treatment there was no significant difference between the additional reductions in blood pressure in the two groups. During the treatment period, pulse rate was significantly reduced in both groups, decreasing by 10 beats/ min (P CO.025) in the high and normal renin group and by 8 beats/min (P <0.05) in the low renin group. Sodium and potassium: There were no significant changes in either group in mean body weight or plasma concentration of sodium or potassium. There was also no difference between the two renin subgroups in the cumulative retention (sum of the differences between daily dietary intake and urinary output) of sodium and potassium during the treatment period (average values 125 and 97 mEq in the high and normal renin group and 125 and 107 mEq in the low renin group). Plasma renin activity: There was a 61 percent decrease in plasma renin activity in the high and normal renin group during the study (P
in two representative patients, one with a high renin level and one with a low level are shown in Figure 2. In contrast to the renin findings, the control urinary aldosterone values in the two groups were not significantly different from each other (P >O.l), and decreased to a similar extent during treatment with clonidine. Thus, mean urinary aldosterone excretion decreased from 21 f 3 to 13 f 2 fig/day (P
l
Day
*r I”
z
-lO-
0
I
/
/
of
treatment 3 t
2 ,
4 1
5 ,
o High and normal patients l
Low renin
renin
patients
; -20 ; 2 Q) -30 & n 8 -4o=
a.
C .1
o High
7
renrn patient
0 Low renin patient
Q
.c
::
a
Ii t
* 0 I
,
i
L
1
1
0
I
2
3
4
5
Day of treatment FIGURE 1. Changes in blood pressure in 11 patients with a high or normal renin level and in 7 patients with a low renin level during 5 days of treatment with clonidine, 0.3 mg/day.
FIGURE 2. Changes in blood pressure and plasma renin activity in a patient with high renin hypertension (open circles) and a patient with low renin hypertension (closed circles) during 5 days of treatment with clonidine, 0.3 mglday.
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diastolic blood pressure (r = 0.48, P <0.05) during treatment. Regression analysis further indicated that the changes in aldosterone excretion were associated with changes in plasma renin activity (r = 0.51, P
TABLE Effects -
increased to a greater extent (P <0.05) in the nonresponders than in the responders. Net sodium retention was also somewhat greater in the nonresponders than in the responders during treatment (P
II of Clonidine
in Hypertensive
Responders
Change in Blood Pressure (mm fig) Systolic
and Nonresponders
Change in Pulse Rate (per min)
Diastolic
I 6
-9
-30*4
_ .__
t 2
(mean 2 standard
Change in Plasma Renin Activity f%)
Change in Body Weight (kg) Responders
-40
to Clonidine
error of the mean)*
--__-...-
Cumulative Sodium Retention (mEq)
Change in Aldosterone Excretion f%)
(no. = 13)
+0.3 + 0.4
-54
+ 75
--44i8
102 i 20 -
Nonresponders
--_._,? I 7:: __^.. _-
_
5 f 2f
-
-7
f 2
(no. = 5) --~
---
+1 .o * 0.3”
-12
+7 -c 20
*Responders had reductions of IO percent or more in both diastolic and systolic blood pressure: nonresponders 10 percent in systolic or diastolic pressure, or both, after 5 days of treatment with clonidine (0.3 mg/day). +P cO.05; $P
TABLE
i 14+ ~.__
122 + 15
had reductions
of less than
III
Data in Six Hypertensive
Patients
with
Sodium
Depletion
and Treatment
With Clonidine
(mean + standard
error of the mean)”
Blood Pressure (mm Hg)_. Systolic I. Control II. Sodium
1562 144*
depletion II I. Sodium
-.-
depletion clonidine
7 6
123 ?; 6%
Diastolic --. loot 3 96 * 2 82 + 5%
Pu ise Kate (per min)
Body Weight (kg)
Plasma Renin Activity (ngiml per hour)
Urinary Aldosterone (pg/24 hours)
76 t 5 78+ 4
65.9 t 4.4f 64.7 i 4.4
2.3 i 0.6if 6.5 t 2.2
32.8 i 16.3t 52.4 + 14.4
135.7 134.5
t 0.8 i: 2.0
3.9 * 0.1 3.9 f 0.1
71 ?- 3+
64.7
5.7 i’ 1.9
46.7
131.8
$: 1.8
3.9 + 0.1
i 12.6
Plasma Potassium lmEq/li~r)
plus
*I = control period of 100 mEq/day sodium diet; II = after sodium depletion plus treatment with clonidine (0.3 mglday). +P (0.05, SF <0.025, when compared with value obtained
828
+ 4.5
Plasma Sodium (mEq/liter)
November 23, 1978
10 days of sodium depletion during period
The American Journal of CARDIOL~Y
(IO mEq/day
II (sodium depletion
Volume 38
alone).
sodium diet); Ill = after 5 more days of
CLONIDINE IN HYPERTENSION-WEBER
(systolic -8 mm Hg, diastolic -3 mm Hg). However, pulse rate in the patients with sodium depletion decreased by an average of 7 beatslmin (P CO.05). Plasma renin activity, which increased threefold during sodium depletion alone (P <0.025), decreased by a mean of only 8.3 percent when clonidine was given. This change was significantly less (P <0.025) than that observed in the 18 patients who received the 100 mEq/ day sodium diet throughout the treatment period. Thus, patients in the high and normal renin group with prior sodium depletion resembled patients in the low renin group both in failure to show decreases in plasma renin activity and in pattern of blood pressure response. Urinary aldosterone excretion, which increased during the period of sodium depletion alone (P <0.05), also did not change signi~c~tly when clonidine treatment was added. Plasma concentrations of sodium and potassium did not vary significantly. Discussion These studies show that clonidine as a single agent provides effective antihypertensive treatment in the hospitalized patient. Thus, 17 of 24 patients (71 percent) receiving either a normal or a reduced sodium diet responded to clonidine (0.3 mg/day) with reductions of at least 10 percent in both systolic and diastolic blood pressures. Renin-suppressive action of clonidine: Although clonidine significantly reduced blood pressure in patients with high and normal renin levels as well as a low level of renin, the rate of reduction in the two groups was not the same. Whereas blood pressure decreased evenly during the treatment period in the low renin group, the reduction was significantly more rapid in the high and normal renin group, half of the total decrease occurring within the 1st day of treatment. This rapid reduction was probably related to a reduction in vasoconstrictor mechanisms rather than to an effect on volume factors because the changes in body weight and electrolyte balance that occurred in the high and normal renin group were closely similar to those in the low renin group. It is likely that this rapid inhibition of vasopressor mech~isms, which characterized the difference in blood pressure response between the two groups, was dependent upon the suppressive effect of donidine on renin release. Thus, although plasma renin decreased to less than 50 percent of its control value within the 1st day of treatment in the high and normal renin group, it did not change appreciably in the low renin group. Moreover, for the patients as a whole there was a significant correlation between pretreatment renin values and blood pressure decrements on the 1st day of treatment, although there was no relation between these renin values and the reductions in blood pressure measured at the end of the study. Hence, the acute antirenin effect of clonidine constitutes an important component of its antihypertensive action. Renin-suppressive mechanisms also have previously been shown to play a part in the actions of other antihypertensive compounds, including beta adrenergic blocking agentsay and methyldopa.‘O
ET AL.
mechanism of clonidine’s antihypertensive action: The temporal difference between the two renin groups in their patterns of blood pressure response, together with the difference in their renin responses, appears to confirm a dual mode of action of clonidine: a rapid reduction of blood pressure in patients with high and normal renin levels, related to an acute inhibition of renin-angiotensin pressor mechanisms, and a more gradual antihypertensive effect that occurs in all hypertensive patients regardless of renin status. This latter mechanism may be associated with the reduction in sympathetic activity known to be produced by clonidine,5 because heart rate decreased uniformly in all hypertensive subjects studied. In patients whose blood pressure failed to respond to clonidine (nonresponders) weight gain was si~i~cantly greater than in responders. There was no difference between these two groups in the degree of bradycardia induced by clonidine, thus further suggesting that the absence of a reduction in blood pressure in nonresponders was due primarily to volume retention rather than to a failure of clonidine to exhibit its antisympathetic effect. In turn, this volume retention appears to have been related to the lack of a decrease in aldosterone production in these patients, for the reduction in aldosterone excretion in the nonresponders was significantly less than that in the responders. The further observation in this study that there was a positive correlation between falls in aldosterone excretion and falls in blood pressure underlines the importance of aldosterone inhibition in the antihypertensive action of clonidine. Clonidine and aldosterone secretion: There is no known mechanism by which clonidine directly suppresses aldosterone secretion. However, the reninangiotensin system is known to play a major role in the control of aldosterone,l* and it is likely that the reductions in aldosterone excretion that occurred in this study resulted from clonidine-induced inhibition of renin release. Thus, in parallel with aldosterone, plasma renin activity decreased significantly in patients classified as blood pressure responders, but failed to change in nonresponders. Moreover; in the patients as a whole, there was a significant correlation between the changes in aldosterone excretion and plasma renin during the study period. The other major factors that can influence aldosterone secretion, alterations in sodium1e~20 and potassiums1*22 balance, were not found to do so in this study. From these findings a second mechanism by which suppression of renin contributes to the antihypertensive action of clonidine can be postulated: namely, that inhibition of the renin-angiotensin system by clonidine leads to a reduction in aldosterone secretion, thereby preventing the fluid retention that would otherwise reduce or abolish the decrease in blood pressure. The importance of renin suppression in this context was supported in this study by the additional finding of a significant correlation between the induced decrements in plasma renin activity and blood pressure during treatment. This critical antirenin action of clonidine
November 23,1976
The Amerkan
Journal of CARDIOLOGY
Volume 36
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CLONIDINE IN HYPERTENSION-WEBER
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occurred in all patients studied, including those with low renin levels. Thus, although the decrements in plasma renin caused by clonidine in the low renin group were small, the relative (percent) changes were sufficiently large to produce substantial reductions in aldosterone and thereby to diminish the participation of volume factors in the maintenance of the high blood pressure state. Effects of sodium depletion on antirenin action of clonidine: In the patients subjected to sodium de-
pletion before and during treatment, clonidine decreased blood pressure but produced only slight reductions in plasma renin activity and aldosterone excretion. Although pretreatment renin levels in these patients did not differ from levels in the high and normal renin group receiving a normal sodium diet, plasma renin activity decreased to a much greater degree in the latter group (60 percent) than in the former (8 percent). Thus, clonidine was far more effective in inhibiting renin release in hypertensive subjects whose renin levels were inherently high than in those whose renin levels were high as a result of sodium depletion. Clonidine inhibits renin secretion through its action in the central nervous system,“” abolishing the component of renin secretion dependent upon neural governance. Clonidine may also affect renin by directly stimulating alpha adrenergic receptors within the kidney.24 However, neither the sympathetic nervous system nor intrarenal alpha receptors appear to be substantially
involved in the renin response to sodium depletion. Despite administration of clonidine in sufficiently large doses to produce significant reductions in heart rate and blood pressure, we found no change in plasma renin activity in the patients who were subjected to salt deprivation. These results are in apparent conflict with data from recent studies in the sodium-depleted rat in which the hypertensive action of clonidine was found to be dependent upon its renin-lowering properties.13 However, in the rat studies sodium depletion was achieved with the use of furosemide, and it is thus likely that renin levels were being sustained, at least in part, by mechanisms other than those involved in the renin response to sodium depletion induced by dietary salt deprivation.“s During the 5 day treatment period, clonidine produced significant reductions in both systolic and diastolic blood pressures in our sodium-depleted patients. Consistent with the absence of a decrease in plasma renin activity in these subjects was the absence of the rapid phase of the hypotensive response found in patients in the high and normal renin group receiving a normal sodium diet. Although aldosterone excretion did not decrease in these patients, the continued rigorous salt deprivation prevented reduction in the antihypertensive response that might otherwise have been caused by fluid retention as in the group eating more sodium.
References 1. Raffos J, Bauer GE, Lewis RG, et al: Clonidine in the treatment of severe hypertension. Med J Aust 1:786-793, 1973 2. Onesti G, Schwartz AB, Kim KE, et al: Antihypertensive effect of cionidine. Circ Res 28: Suppl 1153-69, 1971 3. Parsons WB, Moriedge JH: Antihypertensive effect of a new imidazoiine compound (clonidine) and chiorthalidone, individuallyand in combination. Am J Cardiol 26:258-261, 1970 4. Finch L: The central hypotensive action of cionidine and BAY 1470 in cats and rats. Ciin Sci Moi Med 48:273s-276s 1975 5. Kobinger W: Pharmacologic basis of the cardiovascular actions of cionidine. in, Hypertension: Mechanisms and Management (Onesti G, Kim KE, Mayer JH. ed). New York, Grune & Stratton, 1973, p 369 6. Hokfeit B, Hedeiund H, Dymiing JF: Studies on catecholamines, renin and aldosterone following Catapresan (2-[2, 6-dichlorphenyiaminel-2-imidazoline hydrochloride) in hypertensive patients Eur J Pharmacol 10:389-397, 1970 7. Onesti G, Paz-Martinez V, Kim KE, et al: Effect of cionidine on renin release. in Ref 5, p 405 8. Buhier FR, Laragh, JH, Vaughan ED Jr, et al: Antihypertensive action of propranoiol. Am J Cardiol 32:51 l-522, 1973 9. Castenfors J, Johnsson H, Oro L: Effect of alprenolol on blood pressure and plasma renin activity in hypertensive patients. Acta Med Stand 193:189-193, 1973 IO. Weidmann P, Hirsch D, Maxwell MH, et al: Plasma renin and blood pressure during treatment with methyidopa. Am J Cardioi 34: 671-676, 1974 11. Gavras H, Brunner HR, Vaughan ED Jr, et al: Angiotensin-sodium interaction in blood pressure maintenance of renal hypertensive and normotensive rats. Science 180:1369-1372. 1973 12. Spieiman WS, Davis JO: Renin-angiotensin system and aidosterone secretion during sodium depletion in the rat. Circ Res 35:615-624, 1974 13. Pals DT: Hypotensive effect of clonidine during sodium depletion in the rat. Circ Res 37:795-801, 1975
830
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14. Seaiey JE, Laragh JH: Radioimmunoassay of plasma renin activity. Seminars Nuci Med 5: 189-202, 1975 15. Seaiey JE, Buhier FR, Laragh JH, et al: Aidosterone excretion. Physiological variations in man measured by radioimmunoassay or double-isotope dilution. Circ Res 31:367-378, 1972 16. Heinemann HO, Demariini FE, Laragh JH: The effect of chiorothiazide on renal excretion of electrolytes and free water. Am J Med 26:853-861, 1959 17 Brunner HR, Laragh JH, Baer L, et al: Essential hypertension: renin and aldosterone, heart attack and stroke. N Engi J Med 286: 441-449.1972 18 Laragh JH, Angers M, Kelly WG, et al: Hypotensive agents and pressor substances. The effect of epinephrine, norepinephrine, angiotensin Ii and others on the secretory rate of aidosterone in man. JAMA 1741234-240, 1960 19. Blair-West JR, Coghian JP, Denton DA, et al: Effect of variations of plasma sodium concentration on the adrenal response to angiotensin ii. Circ Res 17:386-393, 1965 20. McCaa RE, Read VH, Bower JD, et al: Adrenal cortical response to hemodiaiysis, ACTH and angiotensin ii in anephric man (abstr). Circulation 44: Suppi il:ii-67, 1971 21. Davis JO, Urquharf J, Higgins JT Jr: Effects of alteration of plasma sodium and potassium concentration on aldosterone excretion. J Ciin Invest 42:597-609, 1963 22. Bayard F, Cooke CR, Tiller DJ, et al: Regulation of aidosterone secretion in anephric man. J Clin invest 50:1585-1595, 1971 23. Reid IA, MacDonald DM, Pachnis B, et al: Studies concerning the mechanism of suppression of renin secretion by cionidine. J Pharmacoi Exp Ther 192:713-721, 1975 24. Pettinger WA, Keeton TK, Cambeii WB, et al: Evidence for a renal alpha-adrenergic receptor inhibiting renin release. Circ Res 38: 338-346, 1976 25. Vander AJ, Carison J: Mechanism of the effects of furosemide on renin secretion in anesthetized dogs. Circ Res 25:145-152, 1969
Volume 38
MICHAEL A. WEBER, MD DAVID B. CASE, MD LESLIE BAER, MD JEAN E. SEALEY, DSc JAN I. M. DRAYER, MD JORGE A. LDPEZ-DVEJERO, JOHN H. LARAGH, MD
MO
Mew York, New York
From the Cardiovascular Center, The New York Hospital-Cornell Medical Center, New York, N. Y. This study was supported in part by U. S. Public Health Service Grant HL 16323 SCR. Address for reprints: Michael A. Weber, MD, Cardiovascular Center, The New York HospitalCornell Medical Center, 525 East 68th St., New York, N. Y. 10021.
In 18 hypertensive patients receiving a constant (100 mEq/day) sodium diet, treatment with cfonidine (0.3 mg/day for 5 days) decreased blood pressure in 11 patients with high and normal renin levels and 7 with low renin levels. fhe high and normal renin group had early and rapid reductions in Mood pressure and plasma renfn activity. in contrast, the low renfn group had a more gradual hy~t~ve response and onfy a small absolute decrease in plasma renin. For all patients, pretreatment renin levels were related to the initial decrease in blood pressure but not to the reductions measured after 5 days. Thus, two mechanisms of action of clonidine are possible, one related to acute fnhibftfon of the.renin-angiotensin system in patients with high and normal renin levels and another that is independent of renin mechanisms and occurs in ail hypertensive patients. in six additional patients with high renfn levels Induced by prior sodium depletion (10 mEq/day sodium diet), clonidine did not reduce blood pressure or renfn, thus indicati~ that the suppressive actfon of this agent on renin pressor mechanisms occurs onfy in patients whose elevated renfn levels are intrinsic to hypertension and unrelated to sodium depletion. Of the 18 patients receiving a normal sodium diet, 13 were classfffed as responding to treatment (decrease in both systolic and diastolic pressures of at least 10 percent). The five nonresponders had a greater weight gain and higher values for aldosterone excretion. For all patients, there was a signfticant correlation between decrements in blood pressure and in aldosterone, suggesting that the countervailing effects of fluid accumulation on blood pressure in nonresponding patients resulted from a failure of aldosterone to be suppressed. Changes in aidosterone, in turn, correlated signiffcantfy with changes In renin. Thus, the antfrenfn effect of cionfdfne enhances its antihype~ensive action not only by acutely ablating renin-angiotensin pressor mechanisms, but also by inhfbiting afdosterone production and thereby minimizing longer-term reactive volume retention during treatment,
Treatment with clonidine effectively reduces blood pressure in a majority of hypertensive patients3 The agent acts principally within the central nervous system, where it exhibits a stimulatory effect on alpha adrenergic receptors.” This, in turn, leads to reduced activity of the sympathetic nervous system and a decrease in blood pressure.5 Clonidine also decreases renal secretion of renin.s7 The inhibition of renin release by certain other antihypertensive agents, including beta adrenergic blocking drugssg and methyldopa,‘O has been held to contribute to the reduction of blood pressure. Thus, it is possible that the antihypertensive effectiveness of clonidine is dependent to some degree upon its suppressive action on renin. To evaluate the importance of hormonal factors in the action of clonidine in man, we studied the effects of clonidine on plasma renin activity and aldosterone excretion in hospitalized hypertensive patients. The study was carried out in a metabolic ward while the patients were re-
November 23, 1976
The American Journal of CARDIOLOGY
Volume 38
825
CLONIDINE IN HYPERTENSION-WEBER
ET AL
ceiving a constant intake of sodium and potassium so as to avoid diet-induced alterations in renin and aldosterone mechanisms. In the sodium-depleted rat treated with diuretic agents, blood pressure is maintained to a significant degree by a compensatory rise in activity of the reninangiotensin system; 11~2 in these animals, clonidine induces a hypotensive response that is mediated by its renin-reducing action. l3 To determine whether a comparable mechanism exists in hypertensive man subjected to sodium depletion, a further group of patients were treated with clonidine during a period of controlled dietary salt deprivation.
the study, plasma renin activity, measured at noontime in the ambulatory state, and urinary aldosterone excretion were
measured during the day before the start of treatment with clonidine (control day), and similarly during the final day of treatment. In nine of these patients, these values were also measured during the 1st day of clonidine treatment. In the six patients subjected to sodium depletion, renin and aldosterone were measured on the last day of the 100 mEq/day sodium diet, on the last day of treatment with the low sodium diet alone, and on the final day of combined treatment with sodium depletion and clonidine. Techniques: Plasma renin activityI and urinary aldosterone excretion15 were measured by radioimmunoassay. Metabolic balance procedures and routine electrolyte determinations were performed as described previously.16 To facilitate analysis, each patient was classified into a high, normal or low renin category according to a nomogram relating renin values to concurrent. daily sodium excretion.17 Because only three patients were in the high renin category, their data were included with those of the normal renin group. The Wilcoxon test, for paired differences was used for statistical analysis within groups of patients, and the Wilcoxon test for nonpaired data for comparisons between groups. Regression analysis was performed by the Spearman method. Data are given as mean f standard error of the mean.
Methods Patients: Studies were performed in 24 hypertensive subjects, 13 men and ll’women aged 28 to62 years (mean 44 years), admitted to a metabolic ward. All patients gave informed consent for the study and either had never been treated for hypertension or had discontinued all antihypertensive medication at least 4 weeks before admission. Diagnostic evaluation before the study established that 20 patients had essential hypertension, 3 had renovascular hypertension and 1 had hypertension related to chronic gIomerulonep~tis. In all cases, medical history, physical examination and laboratory screening had excluded intercurrent. heart or liver disease or diabetes mellitus. With the exception of the one patient with chronic glomerulonephritis, whose blood urea nitrogen was slightly increased (25 mg/dl), all patients had normal renal function. Study protocol: After admission to the metabolic ward, each patient was given a diet containing 100 mEq sodium/day and a constant amount of potassium. After 6 days on this diet, 18 patients were given a 5 day course of clonidine (Catapres”, Boehringer Ingelheim), 0.3 mg/day given in three oral doses of 0.1 mg, while they continued the 100 mEq sodium diet. In the other six patients, sodium intake was reduced from 100 to 10 mEq/day after 6 days. After 6 more days of this low sodium diet, cionidine was administered in the previous manner for 5 days while the low sodium diet was continued. In each patient, daily values for blood pressure and pulse rate were determined as the average of four readings taken in the seated position at 4 hour intervals during the day. Patients were weighed at a constant time each morning. In the 18 patients who received a 100 mEq/day sodium diet throughout
TABLE
Results Patients Receiving a Constant Sodium Diet Of the 18 patients who received a constant 100 mEq/day sodium diet throughout the study, 11 were classified in the high and normal renin group (average age 40 years) and 7 in the low renin group (average age 46 years). Blood pressure: The effects of clonidine, 0.3 me/day, in the two renin groups are summarized in Table I. By the end of the 5 day treatment period, systolic and diastolic blood pressures were significantly reduced in each group. However, although the ultimate effectiveness of clonidine in reducing blood pressure did not differ significantly in the two groups, the rate of reduction did differ (Fig. 1). Thus, during the 1st day of treatment, the decrease in diastolic pressure of 14 f 2 mm Hg (P
I
Values Immediately error of the mean)
Before
and During
Treatment
With
___-- Blood Pressure (mm Hg)
High and Normal Before After
183” 139i
II lo*
(0.3 mg daily for 5 days) (mean + standard
Pulse Rate (per mini
Diastolic
Systolic
Clonidine
Body Weight (kg)
Renin Group
Low Renin Group
169 i-c11
Before After
146+-
*P ~0.05,
826
+P 10.025,
111 +6 93 * 6+
95 SP (0.01
November 23,1976
when compared
76% 3 6% t 3” with control
Urinary Aldosterone b&24 hours)
7.9 + 2.3 3.0 i o.&
21.3 t 2.9 13.0 t 2.1+
0.8 + 0.2 0.5 * 0.1
16.7 f 3.5 10.6 i 2.7”
1f )
(no. = 7) 74.0 i 6.3 74.5 2 6.2
value.
The American Journal of CARDIOLOGY
=
69.9 f 4.1 70.3 * 4.1
782 4 68 -t 3+
117% 7 91 i 4$
(no.
Plasma Renin Activity (ng/ml per hour)
Volume 36
CLONIDINE IN HYPERTENSION-WEBER ET AL.
in the low renin group (3 f 2 mm Hg). Similarly, the initial decrease in systolic pressure was greater (P <0.05) in the high and normal renin group (25 f 15 mm Hg) than in the low renin group (7 f 3 mm Hg). In the succeeding days of treatment there was no significant difference between the additional reductions in blood pressure in the two groups. During the treatment period, pulse rate was significantly reduced in both groups, decreasing by 10 beats/ min (P CO.025) in the high and normal renin group and by 8 beats/min (P <0.05) in the low renin group. Sodium and potassium: There were no significant changes in either group in mean body weight or plasma concentration of sodium or potassium. There was also no difference between the two renin subgroups in the cumulative retention (sum of the differences between daily dietary intake and urinary output) of sodium and potassium during the treatment period (average values 125 and 97 mEq in the high and normal renin group and 125 and 107 mEq in the low renin group). Plasma renin activity: There was a 61 percent decrease in plasma renin activity in the high and normal renin group during the study (P
in two representative patients, one with a high renin level and one with a low level are shown in Figure 2. In contrast to the renin findings, the control urinary aldosterone values in the two groups were not significantly different from each other (P >O.l), and decreased to a similar extent during treatment with clonidine. Thus, mean urinary aldosterone excretion decreased from 21 f 3 to 13 f 2 fig/day (P
l
Day
*r I”
z
-lO-
0
I
/
/
of
treatment 3 t
2 ,
4 1
5 ,
o High and normal patients l
Low renin
renin
patients
; -20 ; 2 Q) -30 & n 8 -4o=
a.
C .1
o High
7
renrn patient
0 Low renin patient
Q
.c
::
a
Ii t
* 0 I
,
i
L
1
1
0
I
2
3
4
5
Day of treatment FIGURE 1. Changes in blood pressure in 11 patients with a high or normal renin level and in 7 patients with a low renin level during 5 days of treatment with clonidine, 0.3 mg/day.
FIGURE 2. Changes in blood pressure and plasma renin activity in a patient with high renin hypertension (open circles) and a patient with low renin hypertension (closed circles) during 5 days of treatment with clonidine, 0.3 mglday.
November 23,1976
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CLONIDINE IN HYPERTENSION-WEBER
ET AL.
diastolic blood pressure (r = 0.48, P <0.05) during treatment. Regression analysis further indicated that the changes in aldosterone excretion were associated with changes in plasma renin activity (r = 0.51, P
TABLE Effects -
increased to a greater extent (P <0.05) in the nonresponders than in the responders. Net sodium retention was also somewhat greater in the nonresponders than in the responders during treatment (P
II of Clonidine
in Hypertensive
Responders
Change in Blood Pressure (mm fig) Systolic
and Nonresponders
Change in Pulse Rate (per min)
Diastolic
I 6
-9
-30*4
_ .__
t 2
(mean 2 standard
Change in Plasma Renin Activity f%)
Change in Body Weight (kg) Responders
-40
to Clonidine
error of the mean)*
--__-...-
Cumulative Sodium Retention (mEq)
Change in Aldosterone Excretion f%)
(no. = 13)
+0.3 + 0.4
-54
+ 75
--44i8
102 i 20 -
Nonresponders
--_._,? I 7:: __^.. _-
_
5 f 2f
-
-7
f 2
(no. = 5) --~
---
+1 .o * 0.3”
-12
+7 -c 20
*Responders had reductions of IO percent or more in both diastolic and systolic blood pressure: nonresponders 10 percent in systolic or diastolic pressure, or both, after 5 days of treatment with clonidine (0.3 mg/day). +P cO.05; $P
TABLE
i 14+ ~.__
122 + 15
had reductions
of less than
III
Data in Six Hypertensive
Patients
with
Sodium
Depletion
and Treatment
With Clonidine
(mean + standard
error of the mean)”
Blood Pressure (mm Hg)_. Systolic I. Control II. Sodium
1562 144*
depletion II I. Sodium
-.-
depletion clonidine
7 6
123 ?; 6%
Diastolic --. loot 3 96 * 2 82 + 5%
Pu ise Kate (per min)
Body Weight (kg)
Plasma Renin Activity (ngiml per hour)
Urinary Aldosterone (pg/24 hours)
76 t 5 78+ 4
65.9 t 4.4f 64.7 i 4.4
2.3 i 0.6if 6.5 t 2.2
32.8 i 16.3t 52.4 + 14.4
135.7 134.5
t 0.8 i: 2.0
3.9 * 0.1 3.9 f 0.1
71 ?- 3+
64.7
5.7 i’ 1.9
46.7
131.8
$: 1.8
3.9 + 0.1
i 12.6
Plasma Potassium lmEq/li~r)
plus
*I = control period of 100 mEq/day sodium diet; II = after sodium depletion plus treatment with clonidine (0.3 mglday). +P (0.05, SF <0.025, when compared with value obtained
828
+ 4.5
Plasma Sodium (mEq/liter)
November 23, 1978
10 days of sodium depletion during period
The American Journal of CARDIOL~Y
(IO mEq/day
II (sodium depletion
Volume 38
alone).
sodium diet); Ill = after 5 more days of
CLONIDINE IN HYPERTENSION-WEBER
(systolic -8 mm Hg, diastolic -3 mm Hg). However, pulse rate in the patients with sodium depletion decreased by an average of 7 beatslmin (P CO.05). Plasma renin activity, which increased threefold during sodium depletion alone (P <0.025), decreased by a mean of only 8.3 percent when clonidine was given. This change was significantly less (P <0.025) than that observed in the 18 patients who received the 100 mEq/ day sodium diet throughout the treatment period. Thus, patients in the high and normal renin group with prior sodium depletion resembled patients in the low renin group both in failure to show decreases in plasma renin activity and in pattern of blood pressure response. Urinary aldosterone excretion, which increased during the period of sodium depletion alone (P <0.05), also did not change signi~c~tly when clonidine treatment was added. Plasma concentrations of sodium and potassium did not vary significantly. Discussion These studies show that clonidine as a single agent provides effective antihypertensive treatment in the hospitalized patient. Thus, 17 of 24 patients (71 percent) receiving either a normal or a reduced sodium diet responded to clonidine (0.3 mg/day) with reductions of at least 10 percent in both systolic and diastolic blood pressures. Renin-suppressive action of clonidine: Although clonidine significantly reduced blood pressure in patients with high and normal renin levels as well as a low level of renin, the rate of reduction in the two groups was not the same. Whereas blood pressure decreased evenly during the treatment period in the low renin group, the reduction was significantly more rapid in the high and normal renin group, half of the total decrease occurring within the 1st day of treatment. This rapid reduction was probably related to a reduction in vasoconstrictor mechanisms rather than to an effect on volume factors because the changes in body weight and electrolyte balance that occurred in the high and normal renin group were closely similar to those in the low renin group. It is likely that this rapid inhibition of vasopressor mech~isms, which characterized the difference in blood pressure response between the two groups, was dependent upon the suppressive effect of donidine on renin release. Thus, although plasma renin decreased to less than 50 percent of its control value within the 1st day of treatment in the high and normal renin group, it did not change appreciably in the low renin group. Moreover, for the patients as a whole there was a significant correlation between pretreatment renin values and blood pressure decrements on the 1st day of treatment, although there was no relation between these renin values and the reductions in blood pressure measured at the end of the study. Hence, the acute antirenin effect of clonidine constitutes an important component of its antihypertensive action. Renin-suppressive mechanisms also have previously been shown to play a part in the actions of other antihypertensive compounds, including beta adrenergic blocking agentsay and methyldopa.‘O
ET AL.
mechanism of clonidine’s antihypertensive action: The temporal difference between the two renin groups in their patterns of blood pressure response, together with the difference in their renin responses, appears to confirm a dual mode of action of clonidine: a rapid reduction of blood pressure in patients with high and normal renin levels, related to an acute inhibition of renin-angiotensin pressor mechanisms, and a more gradual antihypertensive effect that occurs in all hypertensive patients regardless of renin status. This latter mechanism may be associated with the reduction in sympathetic activity known to be produced by clonidine,5 because heart rate decreased uniformly in all hypertensive subjects studied. In patients whose blood pressure failed to respond to clonidine (nonresponders) weight gain was si~i~cantly greater than in responders. There was no difference between these two groups in the degree of bradycardia induced by clonidine, thus further suggesting that the absence of a reduction in blood pressure in nonresponders was due primarily to volume retention rather than to a failure of clonidine to exhibit its antisympathetic effect. In turn, this volume retention appears to have been related to the lack of a decrease in aldosterone production in these patients, for the reduction in aldosterone excretion in the nonresponders was significantly less than that in the responders. The further observation in this study that there was a positive correlation between falls in aldosterone excretion and falls in blood pressure underlines the importance of aldosterone inhibition in the antihypertensive action of clonidine. Clonidine and aldosterone secretion: There is no known mechanism by which clonidine directly suppresses aldosterone secretion. However, the reninangiotensin system is known to play a major role in the control of aldosterone,l* and it is likely that the reductions in aldosterone excretion that occurred in this study resulted from clonidine-induced inhibition of renin release. Thus, in parallel with aldosterone, plasma renin activity decreased significantly in patients classified as blood pressure responders, but failed to change in nonresponders. Moreover; in the patients as a whole, there was a significant correlation between the changes in aldosterone excretion and plasma renin during the study period. The other major factors that can influence aldosterone secretion, alterations in sodium1e~20 and potassiums1*22 balance, were not found to do so in this study. From these findings a second mechanism by which suppression of renin contributes to the antihypertensive action of clonidine can be postulated: namely, that inhibition of the renin-angiotensin system by clonidine leads to a reduction in aldosterone secretion, thereby preventing the fluid retention that would otherwise reduce or abolish the decrease in blood pressure. The importance of renin suppression in this context was supported in this study by the additional finding of a significant correlation between the induced decrements in plasma renin activity and blood pressure during treatment. This critical antirenin action of clonidine
November 23,1976
The Amerkan
Journal of CARDIOLOGY
Volume 36
829
CLONIDINE IN HYPERTENSION-WEBER
ET AL
occurred in all patients studied, including those with low renin levels. Thus, although the decrements in plasma renin caused by clonidine in the low renin group were small, the relative (percent) changes were sufficiently large to produce substantial reductions in aldosterone and thereby to diminish the participation of volume factors in the maintenance of the high blood pressure state. Effects of sodium depletion on antirenin action of clonidine: In the patients subjected to sodium de-
pletion before and during treatment, clonidine decreased blood pressure but produced only slight reductions in plasma renin activity and aldosterone excretion. Although pretreatment renin levels in these patients did not differ from levels in the high and normal renin group receiving a normal sodium diet, plasma renin activity decreased to a much greater degree in the latter group (60 percent) than in the former (8 percent). Thus, clonidine was far more effective in inhibiting renin release in hypertensive subjects whose renin levels were inherently high than in those whose renin levels were high as a result of sodium depletion. Clonidine inhibits renin secretion through its action in the central nervous system,“” abolishing the component of renin secretion dependent upon neural governance. Clonidine may also affect renin by directly stimulating alpha adrenergic receptors within the kidney.24 However, neither the sympathetic nervous system nor intrarenal alpha receptors appear to be substantially
involved in the renin response to sodium depletion. Despite administration of clonidine in sufficiently large doses to produce significant reductions in heart rate and blood pressure, we found no change in plasma renin activity in the patients who were subjected to salt deprivation. These results are in apparent conflict with data from recent studies in the sodium-depleted rat in which the hypertensive action of clonidine was found to be dependent upon its renin-lowering properties.13 However, in the rat studies sodium depletion was achieved with the use of furosemide, and it is thus likely that renin levels were being sustained, at least in part, by mechanisms other than those involved in the renin response to sodium depletion induced by dietary salt deprivation.“s During the 5 day treatment period, clonidine produced significant reductions in both systolic and diastolic blood pressures in our sodium-depleted patients. Consistent with the absence of a decrease in plasma renin activity in these subjects was the absence of the rapid phase of the hypotensive response found in patients in the high and normal renin group receiving a normal sodium diet. Although aldosterone excretion did not decrease in these patients, the continued rigorous salt deprivation prevented reduction in the antihypertensive response that might otherwise have been caused by fluid retention as in the group eating more sodium.
References 1. Raffos J, Bauer GE, Lewis RG, et al: Clonidine in the treatment of severe hypertension. Med J Aust 1:786-793, 1973 2. Onesti G, Schwartz AB, Kim KE, et al: Antihypertensive effect of cionidine. Circ Res 28: Suppl 1153-69, 1971 3. Parsons WB, Moriedge JH: Antihypertensive effect of a new imidazoiine compound (clonidine) and chiorthalidone, individuallyand in combination. Am J Cardiol 26:258-261, 1970 4. Finch L: The central hypotensive action of cionidine and BAY 1470 in cats and rats. Ciin Sci Moi Med 48:273s-276s 1975 5. Kobinger W: Pharmacologic basis of the cardiovascular actions of cionidine. in, Hypertension: Mechanisms and Management (Onesti G, Kim KE, Mayer JH. ed). New York, Grune & Stratton, 1973, p 369 6. Hokfeit B, Hedeiund H, Dymiing JF: Studies on catecholamines, renin and aldosterone following Catapresan (2-[2, 6-dichlorphenyiaminel-2-imidazoline hydrochloride) in hypertensive patients Eur J Pharmacol 10:389-397, 1970 7. Onesti G, Paz-Martinez V, Kim KE, et al: Effect of cionidine on renin release. in Ref 5, p 405 8. Buhier FR, Laragh, JH, Vaughan ED Jr, et al: Antihypertensive action of propranoiol. Am J Cardiol 32:51 l-522, 1973 9. Castenfors J, Johnsson H, Oro L: Effect of alprenolol on blood pressure and plasma renin activity in hypertensive patients. Acta Med Stand 193:189-193, 1973 IO. Weidmann P, Hirsch D, Maxwell MH, et al: Plasma renin and blood pressure during treatment with methyidopa. Am J Cardioi 34: 671-676, 1974 11. Gavras H, Brunner HR, Vaughan ED Jr, et al: Angiotensin-sodium interaction in blood pressure maintenance of renal hypertensive and normotensive rats. Science 180:1369-1372. 1973 12. Spieiman WS, Davis JO: Renin-angiotensin system and aidosterone secretion during sodium depletion in the rat. Circ Res 35:615-624, 1974 13. Pals DT: Hypotensive effect of clonidine during sodium depletion in the rat. Circ Res 37:795-801, 1975
830
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The American Journal of CARDIOLOGY
14. Seaiey JE, Laragh JH: Radioimmunoassay of plasma renin activity. Seminars Nuci Med 5: 189-202, 1975 15. Seaiey JE, Buhier FR, Laragh JH, et al: Aidosterone excretion. Physiological variations in man measured by radioimmunoassay or double-isotope dilution. Circ Res 31:367-378, 1972 16. Heinemann HO, Demariini FE, Laragh JH: The effect of chiorothiazide on renal excretion of electrolytes and free water. Am J Med 26:853-861, 1959 17 Brunner HR, Laragh JH, Baer L, et al: Essential hypertension: renin and aldosterone, heart attack and stroke. N Engi J Med 286: 441-449.1972 18 Laragh JH, Angers M, Kelly WG, et al: Hypotensive agents and pressor substances. The effect of epinephrine, norepinephrine, angiotensin Ii and others on the secretory rate of aidosterone in man. JAMA 1741234-240, 1960 19. Blair-West JR, Coghian JP, Denton DA, et al: Effect of variations of plasma sodium concentration on the adrenal response to angiotensin ii. Circ Res 17:386-393, 1965 20. McCaa RE, Read VH, Bower JD, et al: Adrenal cortical response to hemodiaiysis, ACTH and angiotensin ii in anephric man (abstr). Circulation 44: Suppi il:ii-67, 1971 21. Davis JO, Urquharf J, Higgins JT Jr: Effects of alteration of plasma sodium and potassium concentration on aldosterone excretion. J Ciin Invest 42:597-609, 1963 22. Bayard F, Cooke CR, Tiller DJ, et al: Regulation of aidosterone secretion in anephric man. J Clin invest 50:1585-1595, 1971 23. Reid IA, MacDonald DM, Pachnis B, et al: Studies concerning the mechanism of suppression of renin secretion by cionidine. J Pharmacoi Exp Ther 192:713-721, 1975 24. Pettinger WA, Keeton TK, Cambeii WB, et al: Evidence for a renal alpha-adrenergic receptor inhibiting renin release. Circ Res 38: 338-346, 1976 25. Vander AJ, Carison J: Mechanism of the effects of furosemide on renin secretion in anesthetized dogs. Circ Res 25:145-152, 1969
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