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Role of sympathetic nervous system activity in the blood pressure response to long-term captopril therapy in severely hypertensive patients
Role of Sympathetic Nervous System Activity in the Blood Pressure Response to Long-Term Captopril Therapy In Severely Hypertensive Patients
MYRON
H. WEINBERGER,
Indianapolis,
MD
Indiana
Twenty severely hypertensive subjects who did not achieve blood pressure control with combination therapy with a vasodiiator, a beta-adrenergic blocking agent and a diuretic received the angiotensin-converting enzyme inhibitor captoprii. Marked decreases in blood pressure were observed immediately. Achievement of sustained reductions in blood pressure into the normal range for up to 3 years of follow-up required the addition of a diuretic in ail patients and of a beta-adrenergic blocking agent in half. As expected, significant increases in plasma renin activity and decreases in plasma aidosterone were seen initially and sustained throughout the study. Plasma and urinary norepinephrine levels, which were markedly increased before captoprii treatment, decreased significantly and remained low for the duration of study. These observations suggest a link between the renal pressor and sympathetic systems which may be involved in the pathophysioiogy of severe, treatment-resistant hypertension, and suggest that part of the antihypertensive action of captoprii may be related to a decrease in sympathetic activity secondary to its interference with the generation of angiotensin ii.
In patients with severe or accelerated hypertension, several vasoconstrictor substances are found in circulating blood. Angiotensin II, norepinephrine and vasopressin have all been shown to be involved in the pathophysiology of severe human or experimental hypertensi0n.l Further, interactions between components of these three pressor systems have also been uncovered, suggesting a synergistic or multiplicative action. Captopril, an orally effective converting enzyme inhibitor, is known to markedly reduce angiotensin II generation and its effects on blood pressure. 2-5 The present study was performed to examine the response of the sympathetic nervous system to captopril in severely hypertensive subjects receiving the drug for 6 months or longer. Methods Protocol:
From the Specialized Center of Research-Hypertension, lndiia University School of Medicine, Indianapolis, Indiana. This study was supported by Grant HL 14159 from the Specialized Center of Research (SCOR) Hypertension and Grant RR 00750 from the General Clinical Research Center, U.S. Public Health Service, Bethesda, Maryland. Address for reprints: Myron H. Weinberger, MD, Clinical Building 477, Indiana University Medical Center, 1100 West Michigan Street, Indianapolis, Indiana 46223.
1542
Twenty patients with severe hypertension consented to participate in the study of this experimental drug. The study was approved by the Indiana University Human Use Committee and the Clinical Research Center Committee. All subjects had a supine diastolic pressure of 110 mm Hg or greater before entry and all subjects received hydralazine, 200 mg/day; propranolol, 320 mglday; and hydrochlorothiazide, 100 mg/day, as standard triple therapy. After documentation of supine diastolic pressure of 101 mm Hg or greater on two occasions during standard triple therapy, subjects were admitted to the Clinical Research Center for captopril titration. Blood pressure and pulse were measured in the nondominant arm three times in the recumbent position and after 2 minutes of upright posture four times during the day. The last dose of the standard triple therapy combination was given on the evening of the first day of hospitalization. Eighteen hours later, at 7:45 the next morning, supine blood samples were obtained for determination of plasma renin activity, aldosterone and norepinephrine, and pressure and pulse were measured three times every 5 minutes. If the average value was 100 mm Hg or greater, the patient was then given captopril, 25 mg orally at 8 A.M. Additional doses of 50,100 and 150 mg were given at 4 hour intervals if supine diastolic pressure did not decrease below 91 mm Hg. On the next day the patient was discharged to be followed up twice weekly as an outpatient. If captopril, 150 mg three times daily, did not maintain a supine
April 21, 1992 The AmericanJournalof CARDIOLOGY Volume 49
SYMPATHETIC
diastolic pressure of 90 mm Hg or less, the dose was increased to a maximum of 200 mg three times daily and then hydrochlorothiazide, 50 to 100 mg/day, and propranolol, 40 to 240 mg/day, were added in sequential fashion. Laboratory measurements: Screening laboratory studies, creatinine clearance and 24 hour urinary excretion of norepinephrine as well as baseline measurements of plasma renin activity, aldosterone, norepinephrine and electrolytes were obtained both before captopril titration and 2 hours after the first dose as well as during the outpatient phase. These measurements were made by analytical and radioassay techniques previously established in our laboratories.6,7 Statistical analyses included repeat measures analysis of variance and paired t tests where appropriate.
Results
TABLE
NERVOUS SYSTEM ACTIVITY
WITH CAPTOPRIL-WEINBERGER
I
Observations
Before
and During Captopril
MABP (mm I-Is) STT control
l
Captopril 2 hours 1 month 6 months 12 months
PRA (ng/mll3 h)
Treatment
PA (ng/ 100 ml)
PNE (ng/ml)
137 f4
12.0 f2.8
29.5 f5.3
0.91 f0.25
111 f4 li2 f3 112 f4 103 f4
55.8 f18.9 57.9 f14.7 49.9 f10.8 68.5 f20.4
8.7 f1.3 10.8 61.0 11.2 f1.4 10.9 51.6
0.66 f0.17 0.22 f0.05 0.21 rto.05 0.32 60.06
Standard triple therapy (STT) discontinued 18 hours earlier. MABP = mean arterial blood pressure; PA = plasma aldosterone; PNE = plasma norepinephrine; PRA = plasma renin activity. l
Maximal mean arterial pressure before treatment was 177 f 4 mm Hg and decreased with standard triple therapy (Table I). Two hours after the first 25 mg dose of captopril and 1,6 and 12 months after initiation of captopril therapy, a sustained reduction in blood pressure was observed. At 1 month all subjects required hydrochlorothiazide, 100 mg/day, and propranolol was needed in 50 percent. At 6 and 12 months all subjects required hydrochlorothiazide, and 70 and 40 percent, respectively, required propranolol. At 12 months the mean propranolol dose was 96 mglday, compared with 167 mg/day at 1 month. Captopril administration was associated with a significant (p
Discussion These observations document the efficacy of captopril in patients with severe, treatment-resistant hypertension. All 20 subjects maintained biood pressure control for at least 1 year (and up to 3 years in some)
after the addition of a diuretic (hydrochlorothiazide) in all and a beta-blocking agent (propranolol) in roughly half. The regimen was well tolerated despite transient side effects (rash, loss of taste) in seven patients. As anticipated, captopril administration was associated with a marked and persistent increase in plasma renin activity due to interruption of feedback inhibition because of a lack of generation of angiotensin II. Secondary to the inhibition of angiotensin II formation, plasma aldosterone also decreased significantly. The marked reduction in plasma (and urinary) norepinephrine after captopril administration was a novel and unexpected finding. The high plasma norepinephrine values recorded before the initiation of captopril might have been partly due to the previous antihypertensive therapy. However, that is unlikely because these agents had been discontinued 18 hours before sampling. The high values probably reflected the severity of the hypertensive process in our patients; it was this severity of hypertension that precluded, on ethical grounds, a longer waiting period before the initiation of captopril. This decrease in sympathetic nervous system activity, despite blood pressure reduction and diuretic and beta-blocker administration, may have resulted from captopril-induced interruption of angiotensin II-mediated sympathetic stimulation. Further, this decrease in sympathetic nervous system activity may have contributed to the salutary antihypertensive effect of captopril.
References Guyton AC, Lohmeier TE, Young DB. Positive feedbacks in hypertension: malignant hypertension. In: Guyton AG, ed. Arterial Pressure and Hypertension. Philadelphia: WB Saunders, 1980: 470-82. Gavras H, Brunner HR. Turlni GA, et al. Antihypertensive effects of the oral angiotensin converting enzyme inhibitor SQ 14225 in man. N Engl J Med 1978;298:991-5. Bravo EL, Tarazi RC. Converting enzyme inhibition with an orally active compound in hypertensive man. Hypertension 1979;1:3946. Case DB, Atlas SA, Laragh JH, Sealey JE, Sullivan PA, McKinstry DN. Clinical experience with blockade of the renin-angiotensinaldosterone system by an oral converting enzyme inhibitor (SQ
14225, captopril) in hypertensive patients. Prog Cardiovasc Dis 1979;21:195-201. 5. Johns DW, Baker KM, Ayers CR, et al. Acute and chronic effects of captopril in hypertensive patients. Hypertension 1980;2:56775. 6. Weinberger MH, Kern DC, Gomez-Sanchez C, Kramer NJ, Martin BT, Nugent CA. The effect of dexamethasone on the control of plasma aldosterone in normal recumbent man. J Lab Clin Med 1975;85:957-67. 7. Henry DP, Dentin0 M, Gibbs PS, Welnberger MH. Vascular compartmentalization of plasma norepinephrine in normal man. J Lab Clin Med 1979;94:429-37.
April 21, 1982
The American Journal of CARDIOLOGY
Volume 49
1543
MYRON
H. WEINBERGER,
Indianapolis,
MD
Indiana
Twenty severely hypertensive subjects who did not achieve blood pressure control with combination therapy with a vasodiiator, a beta-adrenergic blocking agent and a diuretic received the angiotensin-converting enzyme inhibitor captoprii. Marked decreases in blood pressure were observed immediately. Achievement of sustained reductions in blood pressure into the normal range for up to 3 years of follow-up required the addition of a diuretic in ail patients and of a beta-adrenergic blocking agent in half. As expected, significant increases in plasma renin activity and decreases in plasma aidosterone were seen initially and sustained throughout the study. Plasma and urinary norepinephrine levels, which were markedly increased before captoprii treatment, decreased significantly and remained low for the duration of study. These observations suggest a link between the renal pressor and sympathetic systems which may be involved in the pathophysioiogy of severe, treatment-resistant hypertension, and suggest that part of the antihypertensive action of captoprii may be related to a decrease in sympathetic activity secondary to its interference with the generation of angiotensin ii.
In patients with severe or accelerated hypertension, several vasoconstrictor substances are found in circulating blood. Angiotensin II, norepinephrine and vasopressin have all been shown to be involved in the pathophysiology of severe human or experimental hypertensi0n.l Further, interactions between components of these three pressor systems have also been uncovered, suggesting a synergistic or multiplicative action. Captopril, an orally effective converting enzyme inhibitor, is known to markedly reduce angiotensin II generation and its effects on blood pressure. 2-5 The present study was performed to examine the response of the sympathetic nervous system to captopril in severely hypertensive subjects receiving the drug for 6 months or longer. Methods Protocol:
From the Specialized Center of Research-Hypertension, lndiia University School of Medicine, Indianapolis, Indiana. This study was supported by Grant HL 14159 from the Specialized Center of Research (SCOR) Hypertension and Grant RR 00750 from the General Clinical Research Center, U.S. Public Health Service, Bethesda, Maryland. Address for reprints: Myron H. Weinberger, MD, Clinical Building 477, Indiana University Medical Center, 1100 West Michigan Street, Indianapolis, Indiana 46223.
1542
Twenty patients with severe hypertension consented to participate in the study of this experimental drug. The study was approved by the Indiana University Human Use Committee and the Clinical Research Center Committee. All subjects had a supine diastolic pressure of 110 mm Hg or greater before entry and all subjects received hydralazine, 200 mg/day; propranolol, 320 mglday; and hydrochlorothiazide, 100 mg/day, as standard triple therapy. After documentation of supine diastolic pressure of 101 mm Hg or greater on two occasions during standard triple therapy, subjects were admitted to the Clinical Research Center for captopril titration. Blood pressure and pulse were measured in the nondominant arm three times in the recumbent position and after 2 minutes of upright posture four times during the day. The last dose of the standard triple therapy combination was given on the evening of the first day of hospitalization. Eighteen hours later, at 7:45 the next morning, supine blood samples were obtained for determination of plasma renin activity, aldosterone and norepinephrine, and pressure and pulse were measured three times every 5 minutes. If the average value was 100 mm Hg or greater, the patient was then given captopril, 25 mg orally at 8 A.M. Additional doses of 50,100 and 150 mg were given at 4 hour intervals if supine diastolic pressure did not decrease below 91 mm Hg. On the next day the patient was discharged to be followed up twice weekly as an outpatient. If captopril, 150 mg three times daily, did not maintain a supine
April 21, 1992 The AmericanJournalof CARDIOLOGY Volume 49
SYMPATHETIC
diastolic pressure of 90 mm Hg or less, the dose was increased to a maximum of 200 mg three times daily and then hydrochlorothiazide, 50 to 100 mg/day, and propranolol, 40 to 240 mg/day, were added in sequential fashion. Laboratory measurements: Screening laboratory studies, creatinine clearance and 24 hour urinary excretion of norepinephrine as well as baseline measurements of plasma renin activity, aldosterone, norepinephrine and electrolytes were obtained both before captopril titration and 2 hours after the first dose as well as during the outpatient phase. These measurements were made by analytical and radioassay techniques previously established in our laboratories.6,7 Statistical analyses included repeat measures analysis of variance and paired t tests where appropriate.
Results
TABLE
NERVOUS SYSTEM ACTIVITY
WITH CAPTOPRIL-WEINBERGER
I
Observations
Before
and During Captopril
MABP (mm I-Is) STT control
l
Captopril 2 hours 1 month 6 months 12 months
PRA (ng/mll3 h)
Treatment
PA (ng/ 100 ml)
PNE (ng/ml)
137 f4
12.0 f2.8
29.5 f5.3
0.91 f0.25
111 f4 li2 f3 112 f4 103 f4
55.8 f18.9 57.9 f14.7 49.9 f10.8 68.5 f20.4
8.7 f1.3 10.8 61.0 11.2 f1.4 10.9 51.6
0.66 f0.17 0.22 f0.05 0.21 rto.05 0.32 60.06
Standard triple therapy (STT) discontinued 18 hours earlier. MABP = mean arterial blood pressure; PA = plasma aldosterone; PNE = plasma norepinephrine; PRA = plasma renin activity. l
Maximal mean arterial pressure before treatment was 177 f 4 mm Hg and decreased with standard triple therapy (Table I). Two hours after the first 25 mg dose of captopril and 1,6 and 12 months after initiation of captopril therapy, a sustained reduction in blood pressure was observed. At 1 month all subjects required hydrochlorothiazide, 100 mg/day, and propranolol was needed in 50 percent. At 6 and 12 months all subjects required hydrochlorothiazide, and 70 and 40 percent, respectively, required propranolol. At 12 months the mean propranolol dose was 96 mglday, compared with 167 mg/day at 1 month. Captopril administration was associated with a significant (p
Discussion These observations document the efficacy of captopril in patients with severe, treatment-resistant hypertension. All 20 subjects maintained biood pressure control for at least 1 year (and up to 3 years in some)
after the addition of a diuretic (hydrochlorothiazide) in all and a beta-blocking agent (propranolol) in roughly half. The regimen was well tolerated despite transient side effects (rash, loss of taste) in seven patients. As anticipated, captopril administration was associated with a marked and persistent increase in plasma renin activity due to interruption of feedback inhibition because of a lack of generation of angiotensin II. Secondary to the inhibition of angiotensin II formation, plasma aldosterone also decreased significantly. The marked reduction in plasma (and urinary) norepinephrine after captopril administration was a novel and unexpected finding. The high plasma norepinephrine values recorded before the initiation of captopril might have been partly due to the previous antihypertensive therapy. However, that is unlikely because these agents had been discontinued 18 hours before sampling. The high values probably reflected the severity of the hypertensive process in our patients; it was this severity of hypertension that precluded, on ethical grounds, a longer waiting period before the initiation of captopril. This decrease in sympathetic nervous system activity, despite blood pressure reduction and diuretic and beta-blocker administration, may have resulted from captopril-induced interruption of angiotensin II-mediated sympathetic stimulation. Further, this decrease in sympathetic nervous system activity may have contributed to the salutary antihypertensive effect of captopril.
References Guyton AC, Lohmeier TE, Young DB. Positive feedbacks in hypertension: malignant hypertension. In: Guyton AG, ed. Arterial Pressure and Hypertension. Philadelphia: WB Saunders, 1980: 470-82. Gavras H, Brunner HR. Turlni GA, et al. Antihypertensive effects of the oral angiotensin converting enzyme inhibitor SQ 14225 in man. N Engl J Med 1978;298:991-5. Bravo EL, Tarazi RC. Converting enzyme inhibition with an orally active compound in hypertensive man. Hypertension 1979;1:3946. Case DB, Atlas SA, Laragh JH, Sealey JE, Sullivan PA, McKinstry DN. Clinical experience with blockade of the renin-angiotensinaldosterone system by an oral converting enzyme inhibitor (SQ
14225, captopril) in hypertensive patients. Prog Cardiovasc Dis 1979;21:195-201. 5. Johns DW, Baker KM, Ayers CR, et al. Acute and chronic effects of captopril in hypertensive patients. Hypertension 1980;2:56775. 6. Weinberger MH, Kern DC, Gomez-Sanchez C, Kramer NJ, Martin BT, Nugent CA. The effect of dexamethasone on the control of plasma aldosterone in normal recumbent man. J Lab Clin Med 1975;85:957-67. 7. Henry DP, Dentin0 M, Gibbs PS, Welnberger MH. Vascular compartmentalization of plasma norepinephrine in normal man. J Lab Clin Med 1979;94:429-37.
April 21, 1982
The American Journal of CARDIOLOGY
Volume 49
1543