Baroreflex function in lifetime-captopril-treated spontaneously hypertensive rats

The effects of lifetime oral captopril treatment on baroreflex control of heart rate and lumbar sympathetic nerve activity were measured in 19-21-week-old spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). The sensitivity of baroreflex control of heart rate and lumbar sympathetic nerve activity were determined by the slopes of the relation between the change in mean arterial pressure (MAP) (mm Hg) versus the change in pulse interval (msec/beat) and the change in MAP versus the percent change in nerve activity, respectively. Untreated SHR had significantly higher MAP than WKY (157 +/- 3 vs. 115 +/- 3 mm Hg, p less than 0.001) and exhibited a decreased baroreflex control of heart rate. Lifetime treatment with captopril prevented the development of hypertension in SHR (MAP = 110 +/- 5 mm Hg) and increased the sensitivity of baroreflex function. The gains of the baroreflex control of heart rate for captopril-treated SHR and control SHR when MAP was raised or lowered by phenylephrine or nitroprusside were 2.38 +/- 0.49 vs. 1.10 +/- 0.33 msec/mm Hg (p less than 0.05) and 0.74 +/- 0.20 vs. 0.54 +/- 0.09 (NS) msec/mm Hg, respectively. The sensitivity of the baroreflex control of lumbar sympathetic nerve activity was greater in captopril-treated SHR than in control SHR when MAP was increased or decreased (-1.03 +/- 0.26 vs. -0.38 +/- 0.11, p less than 0.05; -0.84 +/- 0.2 vs. -0.04 +/- 0.58 (NS) mm Hg-1, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)     

Baroreceptor-heart rate reflex function before and after surgical reversal of two-kidney, one-clip hypertension in the rat

Baroreflex function was studied in conscious early phase (less than 6 weeks) two-kidney, one-clip hypertensive rats before and 24 hours after surgical reversal of hypertension by removal of the constricting renal artery clip or after pharmacological reduction of blood pressure by an infusion of hydralazine or captopril. A normotensive sham-clipped group was included. Another group of two-kidney, one-clip rats was studied 3 weeks after unclipping. Baroreflex sensitivity, as assessed by the steady-state method using a graded phenylephrine infusion, mean arterial pressure, and heart rate were measured preoperatively and at 24 hours postoperatively. Two-kidney, one-clip rats were significantly hypertensive preoperatively compared with control (mean arterial pressure, 183 +/- 4 vs. 106 +/- 2 mm Hg, p less than 0.001), heart rate was similar (420 +/- 9 vs. 401 +/- 9 beats/min, p greater than 0.05), and baroreflex sensitivity was significantly reduced (0.76 +/- 0.07 vs. 1.50 +/- 0.20 msec/mm Hg; p less than 0.001). There was a minimal change in heart rate despite the fall in mean arterial pressure in all hypertensive groups, indicating resetting of the baroreflexes. At 24 hours after the operation, baroreflex sensitivity was unchanged in all groups compared with the preoperative value. By 3 weeks, baroreflex sensitivity was significantly greater than in the hypertensive two-kidney, one-clip rats before the operation and 24 hours after they were unclipped, but not compared with normotensive sham-clipped rats. Thus, although resetting occurs within 24 hours, whatever the method of blood pressure reduction, baroreflex sensitivity remains impaired at this time.(ABSTRACT TRUNCATED AT 250 WORDS)     

Nadolol: evidence for sympathetic nerve inhibition by a beta blocker in essential hypertension

Although beta blockers' antihypertensive mechanisms have not been clearly delineated, their long-term effects may involve chronic reduction in systemic vascular resistance, which may be the result of sympathetic outflow inhibition. Although a central site of action has been advocated, we sought to identify a peripheral non-cardiac sympatholytic mechanism by studying autonomic function in a small group of nine hypertensive males during treatment with placebo and chronic oral nadolol, a noncardioselective hydrophilic beta blocker with little predicted brain penetration. Nadolol reduced blood pressure and heart rate (both P less than 0.005) while suppressing the blood pressure response to cold stimulus only after parasympathetic inhibition (P less than 0.05); the blunted response to cold stimulus did not correlate with the drug's overall blood pressure lowering effect. Baroreceptor sensitivities to phenylephrine and amyl nitrate stimuli were not enhanced. Several biochemical measures of sympathetic nervous system activity were not influenced by nadolol. Thus, nadolol, while not enhancing baroreflex sensitivity, does seem to have a peripheral non-cardiac sympatholytic effect, but this effect does not account entirely for the long term reduction in blood pressure observed in patients on the drug.     

Propranolol effects on autonomic function in hypertensive men

Summary: Beta blocker antihypertensive effects are incompletely understood, and may involve alterations in the autonomic nervous system. We studied autonomic function in 12 essential hypertensive men during treatment with placebo and chronic oral propranolol. Propranolol reduced blood pressure and heart rate (both p<0.01) with an associated increase in baroreflex sensitivity during phenylephrine testing (p<0.02), though amyl nitrite-tested baroreflex sensitivity was unchanged; blood pressure decrement did not correlate with baroreflex enhancement. Response to the cold pressor test and the blood pressure decrement to phentolamine alpha blockade were unaltered by propranolol, suggesting unchanged efferent sympathetic function; nor were several biochemical indices of sympathetic nervous activity influenced by propranolol. Propranolol does perturb autonomic function in man, but the perturbations do not correlate with blood pressure decrement; nor are physiologic or biochemical indices of efferent sympathetic activity reduced by propranolol.     

Differential effects of captopril and nicardipine on baroreflex control of sympathetic nerve activity and heart rate in renal hypertension.

OBJECTIVE: To test the hypothesis that an angiotensin I converting enzyme inhibitor and a calcium channel blocker have different effects on the arterial baroreflex in renal hypertension. DESIGN AND METHODS: We examined the baroreflex control of renal sympathetic nerve activity and heart rate before and after blood pressure was reduced by a similar magnitude (11 +/- 1 mmHg) with intravenous captopril or nicardipine in two-kidney, one clip hypertensive (mean arterial pressure 92 +/- 2 mmHg, n = 12) and normotensive rabbits (mean arterial pressure 75 +/- 1 mmHg, n = 9) in the conscious state. Data obtained during activation and deactivation of baroreceptors were analysed with logistic function curves, and the maximum slope of the curve was taken as the sensitivity of the baroreflex. RESULTS: The maximum slopes of the curves relating mean arterial pressure to renal sympathetic nerve activity and to the heart rate in hypertensive rabbits were significantly smaller than the maximum slopes in normotensive rabbits. In renal hypertensive rabbits, the maximum slope of the mean arterial pressure-renal sympathetic nerve activity curve was increased with captopril compared with that with vehicle. In contrast, the maximum slope of the mean arterial pressure-heart rate curve was increased with nicardipine compared with that with vehicle. CONCLUSIONS: Our data indicating that the baroreflex control of renal sympathetic nerve activity was improved by captopril and that baroreflex control of the heart rate was potentiated by nicardipine suggest that these classes of antihypertensive agents had differential effects in conscious hypertensive rabbits.     

Lack of reflex increase in myocardial sympathetic tone after captopril: potential antianginal effect

Many vasodilators have been tried as antianginal agents, but the reflex increase in sympathetic tone produced by these drugs necessitate their use with caution in patients with angina. In the first part of this study, captopril was given to 14 patients with angina and systolic arterial pressures of greater than 120 mm Hg. Over the short term, captopril decreased arterial blood pressure (from 110 +/- 18 to 98 +/- 18 mm Hg, p less than .01) without increasing heart rate (75 +/- 15 vs 74 +/- 15 beats/min), arterial concentrations of epinephrine (0.38 +/- 0.28 vs 0.34 +/- 0.25 nM) or norepinephrine (2.7 +/- 2.1 vs 2.8 +/- 2.1 nM), or transmyocardial norepinephrine balance (216 +/- 254 vs 146 +/- 170 p mol/min). Captopril decreased average myocardial oxygen consumption (9.7 +/- 4.1 to 8.2 +/- 2.7 ml/min, p less than .01). Given over the long term (mean 5.5 months), captopril decreased the severity of angina from NYHA classification 3.0 +/- 0.8 to 1.6 +/- 0.8. In the second part of this study, captopril was given in a prospective, randomized, double-blind, placebo-controlled study to 21 patients with stable exercise-induced angina and systolic arterial pressures greater than 120 mm Hg. Captopril increased exercise time (309 +/- 137 vs 374 +/- 142 sec, p less than .05) without changing anginal threshold (rate-pressure product 17.0 +/- 6.0 vs 17.1 +/- 5.6 X 10(-3)). We conclude that captopril decreases mean arterial pressure without causing a reflex increase in myocardial sympathetic tone.(ABSTRACT TRUNCATED AT 250 WORDS)     

Potentiation of the baroreceptor-heart rate reflex by sympathectomy in conscious rats

In both animals and humans, stimuli leading to sympathetic activation are accompanied by an impairment of the baroreceptor-heart rate reflex. To determine whether sympathetic activity normally interferes with this reflex function we examined in conscious Wistar-Kyoto (WKY) rats the effect of chemical sympathectomy by 6-hydroxydopamine on the bradycardic response to baroreceptor stimulation induced by raising blood pressure via intravenous phenylephrine boluses; control rats received vehicle. Spontaneously hypertensive rats were also studied because in these animals there is both a baroreceptor reflex impairment and a sympathetic overactivity. Baroreceptor reflex sensitivity, calculated as the ratio of the peak increase in pulse interval to the peak increase in mean arterial pressure, was 75% greater in sympathectomized WKY rats than in control WKY rats (1.28 +/- 0.15 versus 0.73 +/- 0.10 msec/mm Hg, mean +/- SEM; p less than 0.01). The sympathectomy-induced increase in sensitivity was even larger in spontaneously hypertensive rats (SHR) (1.26 +/- 0.12 versus 0.44 +/- 0.06 msec/mm Hg in sympathectomized SHR versus control SHR, +186%; p less than 0.01) so that the impaired baroreceptor reflex sensitivity observed in control SHR as compared with control WKY rats (-40%, p less than 0.01) was no longer detectable in the sympathectomized groups. To establish whether the sympathectomy-induced potentiation of the reflex was due to an increase in cardiac responsiveness to vagal stimuli, we subjected separate groups of anesthetized, vagotomized SHR and WKY rats to graded electrical stimulation of the right efferent vagus. The bradycardic effects of vagal stimulation, however, were similar in sympathectomized and control animals.(ABSTRACT TRUNCATED AT 250 WORDS)     

Modification of arterial baroreflexes by captopril in essential hypertension

Captopril lowers blood pressure without increasing heart rate and plasma norepinephrine, which suggests that this drug may potentiate arterial baroreflexes. In eight subjects with untreated essential hypertension, blood pressure was monitored intraarterially and the effects of baroreceptor stimulation or deactivation were assessed by measuring (1) the slopes of the relations between increase or reduction in systolic pressure (intravenous phenylephrine or nitroglycerin) and the resulting lengthening or shortening in R-R interval, and (2) the increase or decrease in mean arterial pressure induced by increasing and decreasing carotid transmural pressure (neck chamber). The measurements were made before and after a hypotensive oral dose of captopril (50 mg). Before captopril, the slopes of the R-R interval changes with increase and reduction in systolic pressure were 8 and 4 ms/mm Hg, respectively. The slopes of the mean arterial pressure changes with increase and reduction in carotid transmural pressure were 0.51 and 0.40 mm Hg, respectively. After captopril, the responses to baroreceptor stimulation were unaltered but those to baroreceptor deactivation were augmented. The presser and heart rate responses to hand-grip and cold exposure were unchanged by captopril.Administration of captopril is accompanied by a baroreflex potentiation which involves the lower portion of the stimulus-response curve of the reflex. This phenomenon (which may originate at the afferent baroreceptor fibers or centrally) may avoid a reduction in the tonic baroreflex influence during captopril-induced hypotension, thus contributing to the hemodynamic effects of the drug.     

Effects of heart failure on baroreflex control of sympathetic neural activity.

Baroreflex control of heart rate, vascular resistance and norepinephrine is impaired in patients with heart failure, but recent animal studies demonstrate preserved baroreflex control of sympathetic nerve activity in this disorder. Studies were therefore performed to compare baroreflex control of efferent sympathetic nerve activity to muscle in 10 normal subjects (age mean +/- SEM 21 +/- 1 years) and in 11 patients with moderate to severe heart failure (age 48 +/- 5 years, New York Heart Association class II to IV, left ventricular ejection fraction 19 +/- 2%, pulmonary capillary wedge pressure 27 +/- 2 mm Hg, cardiac index 2.04 +/- 0.22 liters/min/m2). Baroreflex activation was produced by intravenous infusion of phenylephrine (0.5 to 2.0 micrograms/kg/min) and deactivation by infusion of nitroprusside (0.4 to 2.5 micrograms/kg/min). During phenylephrine infusion, comparable increases in mean arterial pressure were produced in normal subjects (89 +/- 2 to 99 +/- 3 mm Hg, p less than 0.01) and in patients with heart failure (90 +/- 2 to 99 +/- 3 mm Hg, p less than 0.01). The patients with heart failure exhibited significantly attenuated (p less than 0.01 for normal vs heart failure) decreases in heart rate (93 +/- 5 to 90 +/- 6 beats/min, p = not significant [NS]) compared with normal subjects (67 +/- 3 to 58 +/- 4 beats/min, p less than 0.01) and tended to demonstrate attenuated sympathoinhibitory responses to this pressor stimulus. More strikingly, patients with heart failure demonstrated significant impairment of baroreflex responses during nitroprusside-induced baroreceptor deactivation. In normal subjects, nitroprusside produced a decrease in mean arterial (90 +/- 2 to 80 +/- 3 mm Hg, p less than 0.001) and right atrial (4 +/- 1 to 2 +/- 1 mm Hg, p less than 0.01) pressures with a resultant reflex increase in heart rate (68 +/- 3 to 81 +/- 4 beats/min, p less than 0.001) and muscle sympathetic nerve activity (326 +/- 74 to 746 +/- 147 U/min, p less than 0.01). In patients with heart failure (n = 10), nitroprusside produced comparable (p = NS for normal vs heart failure) decreases in mean arterial (89 +/- 2 to 77 +/- 2 mm Hg, p less than 0.001) and right atrial (6 +/- 1 to 1 +/- 1 mm Hg, p less than 0.001) pressures, but did not significantly alter heart rate (91 +/- 6 to 97 +/- 4 beats/min, p = NS) or sympathetic nerve activity (936 +/- 155 to 1179 +/- 275 U/min, p = NS).(ABSTRACT TRUNCATED AT 400 WORDS)     

Reduced baroreflex changes in muscle sympathetic nerve activity during blood pressure elevation in essential hypertension.

To determine whether the baroreflex control of sympathetic nerve activity is altered in patients with essential hypertension, muscle sympathetic nerve activity (MSNA) was recorded microneurographically from the tibial nerves of 23 normotensive subjects and 23 patients with essential hypertension. When phenylephrine (2 micrograms/kg) was injected intravenously, although the pressor response of mean arterial blood pressure (MAP) was significantly enhanced in the hypertensives as compared with the normotensives, the reflex decrease in MSNA was significantly smaller in the hypertensives. Furthermore, the baroreflex slope for MSNA, used as an index of baroreflex sensitivity and calculated by relating the change in MSNA to the change in MAP, was significantly less in the hypertensives. Following the injection of nitroglycerin (2 micrograms/kg), there were no significant differences between the normotensives and hypertensives in the depressor response, the reflex increase in MSNA or the baroreflex slope for MSNA. These observations suggest that the baroreflex change in sympathetic nerve activity is reduced during phenylephrine-induced blood pressure elevation but not during nitroglycerin-induced hypotension in the hypertensives, and that the blunted response of sympathetic nerve activity occurring during hypertension in these hypertensive patients may underlie the maintenance of high blood pressure in essential hypertension.     

Differential pressor and renal vascular reactivity to angiotensin II in spontaneously hypertensive and Wistar-Kyoto rats

The suggestion has been made that the Okamoto strain of spontaneously hypertensive rats (SHR) shares some features with a subgroup of patients with essential hypertension, called nonmodulators. One feature of nonmodulators is a renal blood flow response to angiotensin II (ANG II) that is blunted on a high salt diet; the blunted renal vascular response is corrected by converting enzyme inhibition. Renal blood flow (electromagnetic flowmeter) and pressor responses to graded ANG II doses (5-300 ng) were assessed in 24 SHR and 24 Wistar-Kyoto rats (WKY) ingesting 1.6% Na. In comparison to WKY, blood pressure was higher in SHR (155 +/- 4 vs 106 +/- 2 mm Hg; p less than 0.001), renal blood flow was lower (6.9 +/- 0.5 vs 8.2 +/- 0.4 ml/min/g; p less than 0.05), and the pressor response to ANG II was enhanced, (p less than 0.0005) but the renal vascular response was blunted (p less than 0.005). Captopril (1-30 mg/kg) reduced blood pressure more in SHR than in WKY but increased renal blood flow similarly in both strains. The blunted renal vascular response to ANG II in SHR was reversed by captopril, but inhibition of converting enzyme in the kidney did not parallel systemic inhibition. Maximum blockade of converting enzyme in the kidney appears to require a larger captopril dose than is required for systemic inhibition. These results suggest that the renal blood supply in SHR also shares some of the characteristics of nonmodulators and that the action of captopril on the renal blood flow probably reflects reversal of inappropriate intrarenal ANG II formation.     

Baroreflex control of renal sympathetic nerve activity is potentiated at early phase of two-kidney, one-clip Goldblatt hypertension in conscious rabbits

Conscious normotensive and two-kidney, one-clip Goldblatt hypertensive rabbits were studied to determine the sensitivity of the arterial baroreflex control of renal sympathetic nerve activity (RSNA) and heart rate. The relations of the mean arterial pressure-RSNA and mean arterial pressure-heart rate were examined over a wide range of blood pressures produced by infusions of phenylephrine and nitroglycerin. The maximum slope obtained by logistic function analysis was considered to represent the baroreflex sensitivity. In the early hypertensive group (n = 8; mean arterial pressure +/- SEM, 88 +/- 2 mm Hg) on day 5 after renal clip application, the maximum slope of the mean arterial pressure-RSNA relation was -11.3 +/- 1.2, which was significantly greater than that of the sham normotensive group (-6.9 +/- 0.3, p less than 0.05). The maximum slope (-4.3 +/- 0.2) of the mean arterial pressure-RSNA relation in the late hypertensive group (n = 8; mean arterial pressure, 96 +/- 3 mm Hg) on day 21 after renal clipping was significantly smaller than that of another sham group (-7.2 +/- 0.2, p less than 0.05). In contrast to these changes in the baroreflex control of RSNA, the control of heart rate was attenuated according to the magnitude of mean arterial pressure. To elucidate the mechanisms underlying the potentiated baroreflex, the effects of endogenous neuropeptides were investigated. First, plasma concentrations of angiotensin II and arginine vasopressin that are known to affect the baroreflex were determined. Plasma concentrations of vasopressin (3.1 +/- 0.6 pg/ml) as well as of angiotensin II (34 +/- 7 pg/ml) were increased in the early hypertensive group, and the plasma vasopressin returned to a similar level to the sham group in the late hypertensive group (1.3 +/- 0.4 pg/ml). Second, to study endogenous effects of these neuropeptides on the baroreflex, the maximum slopes of the baroreflex curves during infusions of antagonists for the peptides were determined in the early hypertensive group. The maximum slope of mean arterial pressure-RSNA during intravertebral arterial [Sar1, Ala8]-angiotensin II (-16.4 +/- 1.5) was significantly greater (p less than 0.05), whereas the maximum slope during intravertebral arterial infusion of d(CH2)5Tyr(Me)arginine vasopressin (-4.7 +/- 0.5) was significantly smaller (p less than 0.05) than that during vehicle infusion (-11.3 +/- 1.2).(ABSTRACT TRUNCATED AT 400 WORDS)     

Preserved cardiac beta-adrenergic sensitivity in early renovascular hypertension

To determine the mechanism of blunted sympathetic reflex responses in early renovascular hypertension, we measured inotropic and chronotropic responses of the heart to beta-adrenergic stimulation in vivo and myocardial beta-adrenergic receptor number and adenylate cyclase activity in 10 dogs during an early stage of one-kidney renal hypertension. Mean aortic pressure was higher in the hypertensive dogs (152 +/- 4 mm Hg) than in eight sham-operated dogs (122 +/- 1 mm Hg; p less than 0.001), but heart rate, cardiac output, and left atrial pressure did not differ between the two groups. Blood pressure reduction with a direct-acting vasodilator, pinacidil, resulted in marked increases in heart rate (+97 +/- 12 beats/min) and rate of change of left ventricular pressure (dP/dt; +1447 +/- 367 mm Hg/sec) in normotensive dogs but only blunted heart rate (+54 +/- 12 beats/min) and minimal left ventricular dP/dt (+376 +/- 264 mm Hg/sec) responses in hypertensive dogs. In contrast, intravenously administered isoproterenol produced similar increases in heart rate and left ventricular dP/dt in the two groups. These two groups also did not differ in either left ventricular beta-adrenergic receptor number and affinity or basal, isoproterenol-stimulated, and fluoride-stimulated adenylate cyclase activity. Thus, despite blunted reflex responses to blood pressure reduction, hypertensive dogs showed neither reduction in chronotropic and inotropic responses to direct beta-adrenergic stimulation nor beta-adrenergic desensitization of the myocardium, as assessed by beta-adrenergic receptor number and adenylate cyclase activity. Blunted reflex responses in this model of early hypertension must be due to factors operating at some locus other than the beta-adrenergic receptor-adenylate cyclase complex.     

Plasma renin activity and norepinephrine as predictors for antihypertensive effects of nifedipine and captopril

To examine predictors for the efficacy of antihypertensive agents, we investigated the effects of nifedipine and captopril on blood pressure (BP) and humoral factors in patients with essential hypertension. Eleven essential hypertensive patients (mean age: 54) were treated with long acting nifedipine at 20 to 40 mg/day for 8 weeks and 25 essential hypertensives (mean age: 51) were treated with captopril at 37.5 to 75 mg/day. Blood pressure was measured every 2 weeks. Plasma renin activity (PRA), and plasma concentrations of aldosterone, epinephrine and norepinephrine were determined before and at the end of treatment. Both nifedipine and captopril decreased BP (nifedipine: mean BP 119 +/- 3 to 101 +/- 2 mm Hg, captopril: 124 +/- 2 to 100 +/- 2, P less than .01 for each), whereas neither of them affected heart rate. The 8-week treatment of nifedipine showed no significant effect on humoral factors. Captopril increased PRA by 63% (P less than .05) and decreased plasma epinephrine by 42% (P less than .01) and norepinephrine by 35% (P less than .01). The change in mean BP was positively correlated with pretreatment PRA (r = 0.68, P less than .01) in nifedipine-treated patients and inversely with pretreatment norepinephrine (r = -0.53, P less than .01) in captopril treatment. The results suggest that both nifedipine and captopril were effective antihypertensive agents and that the long term treatment of nifedipine is more effective in essential hypertensives with lower PRA, while captopril is more effective in those with higher plasma norepinephrine concentration.     

Evaluation of the chronotropic property of captopril in hypertensive patients

Captopril was administered (50 mg orally) to 88 untreated hypertensive patients (70 with essential hypertension, eight with renal arterial disease, 10 with renal parenchymal disease) and to 25 hypertensive patients treated with sympatholytic or beta-blocking agent (20 with essential hypertension, five with renal arterial disease). In the former group, captopril caused a decrease in heart rate (HR) in 18 patients and an increase in only two. As a whole, captopril caused significant decreases in blood pressure without increase in HR. Significant negative correlation was observed between change in HR and plasma renin activity obtained before captopril administration (n = 79, r = -0.425, p less than 0.0001). Hypotensive and chronotropic effects of captopril were almost identical in untreated and treated patients. Hypotensive effects caused by captopril and nifedipine (20 mg orally) were almost identical. Nifedipine caused reflex tachycardia, while captopril caused slight bradycardia. Absence of compensatory tachycardia appears to be related to reduction of endogenous angiotensin II by captopril.U     

Renin dependency of blood pressure in isolated systolic hypertension

The role of the renin system in the maintenance of the elevated systolic blood pressure in isolated systolic hypertension was investigated in 31 patients who received long-term treatment with propranolol (120 mg daily) and in another group of 22 patients with isolated systolic hypertension who received a test dose of captopril (25 or 50 mg). The greatest systolic blood pressure decrease (35 +/- 5 mm Hg) by propranolol occurred in the high-renin group (n = 9), and the smallest decrease (3 +/- 2 mm Hg) in the low-renin group (n = 9), whereas in the normal-renin group (n = 13), systolic blood pressure was decreased by propranolol by 22 +/- 5 mm Hg. For all the propranolol-treated patients, the decrement in the systolic blood pressure by propranolol was related to the control plasma renin activity (r = 0.63, p less than 0.01) and to the concurrent change in plasma renin activity (r = 0.70, p less than 0.001). Captopril decreased the systolic blood pressure by 55 +/- 10 mm Hg in the high-renin group (n = 11) and by 17 +/- 5 mm Hg in the normal-renin group (n = 6), whereas the smallest decrease (12 +/- 5 mm Hg) in systolic blood pressure occurred in the low-renin group (n = 5). In all the captopril-tested patients (n = 22), the decrease in systolic blood pressure by captopril was related to the control plasma renin activity (r = 0.75, p less than 0.001). These results indicate that the plasma renin activity value indicates the participation of the renin-angiotensin system in the maintenance of the elevated systolic blood pressure in patients with isolated systolic hypertension.     

Contribution of prostaglandins to the antihypertensive action of captopril in essential hypertension

To determine whether prostaglandins contribute to the depressor response to the converting enzyme inhibitor, captopril, we measured the plasma prostaglandin levels by radioimmunoassy before and after captopril administration, and then examined the effect of prostaglandin synthetase inhibition on captopril's antihypertensive effect. When a single oral captopril dose (25-100 mg) was given to 31 sodium-restricted patients with essential hypertension, the levels of the stable transformation product of prostacyclin remained unmeasurable and that of thromboxane A2 did not change, while the metabolite of PGE2 (PGE-M) increased by 53% (34 +/- 4pg/ml pre-captopril, 52 +/- 5 pg/ml after; p less than 0.001). As expected, blood pressure (BP) and angiotension II (AII levels fell, and kinin levels rose (all changes p less than 0.001). We then blocked prostaglandin synthesis in 18 of these subjects for 24 hours with either indomethacin (n = 10) or aspirin (n = 8) before repeating the captopril dose, to assess the importance of these PGE-M increments. The PGE-M responses to captopril were effectively blocked in nine of 10 subjects receiving indomethacin and four of eight receiving aspirin. In these 13 patients, the depressor response to captopril was significantly blunted (-20 +/- 3mm Hg pre-synthetase inhibition vs - 13 +/- 2 mm Hg post; p less than 0.05). When these agents did not block the PGE-M response to captopril, the BP response was also unchanged (-15 +/- 4mm Hg pre, -18 +/- 5mm Hg post). Neither indomethacin nor aspirin changed the AII or kinin responses to captopril. We conclude that the prostaglandins may be important mediators of captopril's antihypertensive effect in the sodium-restricted state.     

Abnormal baroreflex control of heart rate in decompensated congestive heart failure and reversal after compensation

Congestive heart failure (CHF) causes impairment of baroreflex control of heart rate (HR). To determine if this derangement is reversible, the cardiac chronotropic control was assessed in 10 patients with class IV chronic CHF of various etiologies before and after compensation achieved by bed rest, salt restriction, diuretics and vasodilators. Mean time between the 2 studies was 15 +/- 3 days. The management was modified 3 days before the second autonomic evaluation, so as to reestablish the same diet and pharmacologic conditions of the previous study. Compensation led to significant reduction in symptom-based class, body weight, and pulmonary and systemic congestion. Mean +/- standard error of the mean HR responses (beats/min) before and after compensation were, respectively: (1) to atropine (0.04 mg/kg): 10 +/- 2 and 27 +/- 2 (p less than 0.01); (2) to handgrip (30% maximum capacity, 1 minute): 9 +/- 2 and 19 +/- 3 (p less than 0.005); (3) to headup tilt (5 minutes): 4 +/- 3 and 20 +/- 4 (p less than 0.005). Mean +/- standard error of the mean baroreflex sensitivity (ms/mm Hg) of RR responses to phenylephrine and amyl nitrate-induced changes in systolic pressure was, respectively, in each condition: phenylephrine, 0.9 +/- 0.2 and 8 +/- 2.3 (p less than 0.05); amyl nitrate, 0.3 +/- 0.2 and 4.1 +/- 1.1 (p less than 0.05). A significant correlation between improvement in HR responses to atropine and tilt and changes in body weight was obtained. These findings show a reversible component of impaired baroreflex control of HR in severe CHF, possibly due to its congestive effects.     

Captopril improves hemodynamic response to static exercise in patients with congestive heart failure: a double-blind, placebo-controlled, randomized trial

Systemic and peripheral hemodynamic response to isometric exercise by handgrip test at 30% maximal voluntary contraction (MVC) for 3 minutes was assessed in 16 patients with congestive heart failure (CHF) after short-term treatment with either captopril or placebo given according to a double-blind, randomized, cross-over sequence. During placebo, isometric exercise increased blood pressure (BP) and total peripheral vascular resistance (TPVR) and decreased cardiac index (CI). Captopril reduced the pressor response to exercise (mean +/- SD) (% systolic: from 14.7 +/- 6 to 11.7 +/- 3; p less than .05/% diastolic: from 12.4 +/- 4 to 8 +/- 3; p less than .005) and increased CI (from 2.3 +/- .6 to 2.6 +/- .9 liters/min/m2; p less than .01) whereas TPVR remained virtually unchanged (from 1479 +/- 597 to 1594 +/- 692 U; NS). The changes in mean BP after exercise were inversely related to the early increase in forearm blood flow (FBF) in exercising forearm during both placebo (r = .67) and captopril (r = .71). The extent of reduction in mean BP response after captopril was inversely related to the extra increase in exercising FBF determined by the drug when compared to placebo (r = .73). We conclude that captopril is able to improve the hemodynamic response to static exercise in patients with CHF, probably by increasing the blood supply to exercising muscles during contraction, thus blunting the extent of reflex pressor response.     

Persistent sympathetic activation during chronic antihypertensive therapy: a potential mechanism for long term morbidity?

Previous studies have demonstrated that antihypertensive treatment resets baroreflex control of heart rate (HR) and increases cardiac vagal baroreflex sensitivity. However, it is uncertain whether baroreflex control of muscle sympathetic nerve activity (MSNA) also resets after treatment. We tested the hypothesis that chronic antihypertensive therapy alters baroreflex regulation of MSNA in patients with untreated moderate hypertension. Seven newly diagnosed patients with systolic blood pressure (BP) of 159+/-5 mm Hg (mean+/-SE) and diastolic BP of 103+/-4 mm Hg were studied before and after 1 to 2 weeks ' and 3 months (chronic) of antihypertensive treatment with losartan-hydrochlorothiazide (Hyzaar). MSNA and hemodynamics were measured supine, during a Valsalva maneuver (VM), and at 70 degrees head-up tilt (HUT) for 10 minutes. Data were compared with those obtained in 7 age-matched healthy controls. We found that Hyzaar lowered mean BP acutely and chronically by 20+/-4 and 23+/-3 mm Hg (both P<0.01) but did not change HR. Supine MSNA increased by 43+/-11% and 34+/-11% after acute and chronic treatment (both P<0.01). However, MSNA responses to VM and HUT did not differ after treatment compared with before treatment, indicating unchanged reflex control. These data indicate that sympathetic neural activity was augmented substantially by antihypertensive treatment with Hyzaar, consistent with an ongoing baroreflex unloading, and did not return to baseline or "reset" after 3 months of therapy. We speculate that persistent and marked sympathetic activation by the baroreflex may be a potential mechanism for hypertension that is refractory to antihypertensive therapy and may provide a target mechanism for persistent morbidity despite adequate BP control.