Vasodilatation with captopril and prazosin in chronic heart failure: double blind study at rest and on exercise.

A double blind cross over study was performed to compare the long term hormonal, haemodynamic, and clinical responses to specific inhibition of the renin-angiotensin-aldosterone system (captopril) and of the alpha 1 adrenoceptors of the sympathetic system (prazosin) both at rest and during upright exercise in patients with chronic heart failure. Sixteen patients completed one month's treatment with each drug. During conventional diuretic treatment (control) plasma renin activity, aldosterone, and noradrenaline were increased at rest and on exercise. Control left ventricular filling pressures were raised, and correlated significantly with plasma renin activity both at rest and on exercise. Systemic vascular resistance was increased at rest, and its reduction during exercise correlated inversely with the increase in plasma renin activity and plasma noradrenaline. After one month's treatment with captopril there were reductions in plasma aldosterone, weight, left ventricular filling pressure, and systemic vascular resistance at rest and on exercise. Dyspnoea was relieved and exercise capacity increased. The greater fall in systemic vascular resistance on exercise no longer correlated with the increase in plasma renin activity. During treatment with prazosin there were increases in plasma noradrenaline and, transiently, in plasma aldosterone. Fluid retention occurred, and left ventricular filling pressure was unchanged. Compared with control values systemic vascular resistance was reduced at rest but not on exercise. Dyspnoea and exercise capacity did not improve. In chronic heart failure, vasodilatation by inhibition of the alpha adrenergic system with prazosin causes compensatory stimulation of the renin-angiotensin-aldosterone system and does not result in clinical benefit. Inhibition of the renin-angiotensin-aldosterone system with captopril causes secondary vasodilatation at rest and on exercise and results in improvement in symptoms and exercise capacity.     

Contribution of the renin-angiotensin-aldosterone system to development of tolerance and fluid retention in chronic congestive heart failure during prazosin treatment

To determine the effects of the renin-angiotensin-aldosterone system on development of tolerance and fluid retention in patients with chronic congestive heart failure during long-term prazosin treatment, plasma renin concentration, aldosterone, norepinephrine and maximal exercise tolerance were measured during chronic therapy with digitalis and diuretics, to which prazosin, captopril or a combination of both drugs was added. Plasma renin concentration and aldosterone level decreased slightly during prazosin therapy and norepinephrine level increased significantly. When captopril was given, plasma renin concentration increased as expected, aldosterone level normalized and norepinephrine level decreased significantly. When prazosin was added to captopril therapy, norepinephrine level increased and plasma renin concentration and aldosterone level did not change. Exercise capacity did not increase during prazosin treatment, but was increased with captopril treatment. Prazosin treatment was associated with an increase in body weight even though the dose of furosemide was increased. Inhibition of the renin-angiotensin system did not prevent fluid retention induced by prazosin during combination therapy. These findings suggest that the renin-angiotensin-aldosterone system is not substantially involved in development of tolerance and fluid retention during prazosin therapy; stimulation of plasma norepinephrine may be of decisive importance.     

The renal response to neuroendocrine inhibition in chronic heart failure: double-blind comparison of captopril and prazosin

Activation of the renin–angiotensin and sympathetic systemsin chronic heart failure causes important renal vasoconstriction.In a double-blind cross-over study, treatment with captoprilfor one month reduced systemic and renal vascular resistanceby 14% and 25%, increased renal blood flow by 12%, and increasedthe percentage of the cardiac output perfusion to the kidneyby 13%. Treatment with prazosin for one month also reduced systemicvascular resistance by 8%, renal vascular resistance increasedby 20%, and renal blood flow and the percentage of the cardiacoutput going to the kidney fell by 14% and 26%. During captopriltreatment, plasma aldosterone concentration was reduced to normal,but during prazosin treatment there was an initial increasein aldosterone of 45%, and a sustained increase in plasma noradrenalineconcentration of 26%. Body weight decreased by 1.7kg on captopril,but increased by 3.0 kg on prazosin, correlating inversely withthe changes in renal blood flow. Sympathetic inhibition withprazosin causes systemic vasodilatation which diverts bloodfrom the kidney and may result in fluid retention. Inhibitionof the renin system with captopril causes preferential renalvasodilatation and can improve renal perfusion in chronic heartfailure.     

Haemodynamic and neurohumoral response to exercise in patients with congestive heart failure treated with captopril

The contribution of the renin-angiotensin system to the cardiovascular response to exercise was studied in 12 patients with congestive heart failure. The haemodynamic effects of captopril were measured at rest and during supine bicycle exercise. After captopril administration, resting systemic vascular resistance fell by 26.6% and mean blood pressure by 16.7% and cardiac index increased by 19.7%. During exercise, captopril decreased systemic vascular resistance by 25.6% and mean blood pressure by 8.2% and increased cardiac index by 24.4%. Pulmonary wedge pressure fell by 25% at rest but was not altered by captopril during exercise. Pretreatment plasma renin activity increased from 13.4(16.0) ng/ml/hr (10.3(12.3) mmol/l/hr) at rest to 20.0(27.8) ng/ml/hr (15.4(21.4) mmol/l/hr) during exercise. Pretreatment plasma noradrenaline concentration increased from 659(433) pg/ml (39(25.6) nmol/l) at rest to 2622(1486) pg/ml during exercise (155(88) nmol/l). Captopril favourably alters systemic vascular resistance and cardiac index during exercise in patients with congestive heart failure. This may reflect inhibition of the increased activity of the renin-angiotensin system during exercise in these patients and a subsequent reduction in systemic vasoconstriction.     

Haemodynamic and neurohumoral response to exercise in patients with congestive heart failure treated with captopril.

The contribution of the renin-angiotensin system to the cardiovascular response to exercise was studied in 12 patients with congestive heart failure. The haemodynamic effects of captopril were measured at rest and during supine bicycle exercise. After captopril administration, resting systemic vascular resistance fell by 26.6% and mean blood pressure by 16.7% and cardiac index increased by 19.7%. During exercise, captopril decreased systemic vascular resistance by 25.6% and mean blood pressure by 8.2% and increased cardiac index by 24.4%. Pulmonary wedge pressure fell by 25% at rest but was not altered by captopril during exercise. Pretreatment plasma renin activity increased from 13.4(16.0) ng/ml/hr (10.3(12.3) mmol/l/hr) at rest to 20.0(27.8) ng/ml/hr (15.4(21.4) mmol/l/hr) during exercise. Pretreatment plasma noradrenaline concentration increased from 659(433) pg/ml (39(25.6) nmol/l) at rest to 2622(1486) pg/ml during exercise (155(88) nmol/l). Captopril favourably alters systemic vascular resistance and cardiac index during exercise in patients with congestive heart failure. This may reflect inhibition of the increased activity of the renin-angiotensin system during exercise in these patients and a subsequent reduction in systemic vasoconstriction.     

The contributions of sympathetic tone and the renin-angiotensin system to severe chronic congestive heart failure: Response to specific inhibitors (prazosin and captopril)

The contribution of sympathetic tone and the renin-angiotensin system to the pathogenesis of chronic heart failure was evaluated. In 20 paired studies of the same 10 patients, the baseline hemodynamic and humoral correlates of congestive heart failure, and the response to alpha adrenergic blockade (prazosin) and angiotensin converting enzyme inhibition (captopril) were assessed. Despite the extent of failure, baseline plasma renin activity ranged from normal to very high. In contrast, baseline plasma catecholamlne levels were always elevated. Baseline plasma norepinephrine reflected the severity of heart failure, correlating inversely with baseline cardiac index before administration of both drugs. Comparable improvement in left ventricular function was noted after acute therapy. Baseline renin and norepinephrine did not predict the response to prazosin, but baseline renin did predict the response to captopril: pulmonary wedge pressure (r = ?0.776, p < 0.01), stroke index (r = 0.752, p < 0.02), systemic vascular resistance (r = ?0.673, p < 0.05).In summary, elevated levels of plasma norepinephrine were inversely correlated with baseline cardiac function, but norepinephrine levels did not change despite improved hemodynamics with specific prazosin therapy. The renin-angiotensin system exhibited a wide spectrum of activity and hemodynamic improvement with captopril was related to this activity. Absence of a correlation between plasma norepinephrine and plasma renin activity suggested that their contributions to vasoconstriction were not interdependent. Increased sympathetic tone was consistent in severe heart failure, whereas renin-angiotensin activity differed widely. The response to captopril can be used to identify a subset of patients with severe heart failure and adverse angiotensin-mediated vasoconstriction.     

Prazosin and Captopril in Chronic Heart Failure: Comparison of Acute Haemodynamic and Hormonal Effects

Abstract: Prazosin and captopril in chronic heart failure: comparison of acute haemodynamic and hormonal effects. D. N. Sharpe and R. Coxon, Aust. N.Z. J. Med., 1982, 12, pp. 483–488.
Ten patients with severe chronic heart failure were given prazosin 5 mg and captopril 25 mg in random order on consecutive days. Small increases in cardiac index and reductions in heart rate were effected by both drugs, but these alterations and the accompanying increases in stroke volume index were significant only following captopril. Both drugs significantly reduced mean pulmonary capillary wedge pressure and mean right atrial pressure and also systemic vascular resistance and blood pressure, the effect of captopril being greater than that of prazosin. Following captopril, plasma aldosterone levels were significantly reduced and plasma renin activity increased from control values, whereas prazosin did not alter these hormone indices.     

Comparative hemodynamic and neurohormonal effects of intravenous captopril and digoxin and their combinations in patients with severe heart failure

The effects of intravenous captopril and intravenous digoxin given separately and in combination on rest and exercise hemodynamics were studied in 16 patients with severe heart failure and sinus rhythm. When given separately, both captopril and digoxin decreased the pulmonary capillary wedge pressure by, respectively, 24% (p = 0.003) and 34% (p = 0.004) and systemic vascular resistance by 23% (p = 0.09) and 20% (p = 0.03). Only digoxin increased cardiac index by 23% (p = 0.03) and stroke work index by 52% (p = 0.01). During maximal exercise, captopril alone decreased systemic vascular resistance by 28% (p = 0.0002) and increased cardiac index by 33% (p = 0.02). Digoxin alone decreased pulmonary capillary wedge pressure by 11% (p = 0.04) and increased stroke work index by 44% (p = 0.01). The combination of captopril and digoxin resulted in a decrease in pulmonary capillary wedge pressure and systemic vascular resistance and an increase in cardiac index and stroke work index both at rest and during exercise that was greater than values observed with either drug given alone. Cardiac index response to the combination of captopril and digoxin correlated with baseline serum aldosterone concentration (r = 0.81, p less than 0.001) and plasma renin activity (r = 0.74, p less than 0.0002). A significant decrease in norepinephrine concentration was noted after digoxin was administered alone or added to captopril. These findings demonstrate that in patients with severe heart failure, the acute administration of captopril and digoxin has an independent salutary hemodynamic effect. The combination of these agents, however, has an adjunctive effect on cardiac function at rest and during exercise.     

Untreated heart failure: clinical and neuroendocrine effects of introducing diuretics

The clinical and neuroendocrine response to diuretic treatment was assessed at rest and on exercise in 12 patients with heart failure. Before treatment all patients were limited by breathlessness on exercise; one was oedematous. Plasma renin activity and aldosterone were normal but plasma noradrenaline was raised both at rest and on exercise. After one month's treatment with frusemide (40 mg) and amiloride (5 mg) weight was significantly reduced by a mean of 3.5 kg and exercise capacity had doubled. Plasma noradrenaline fell to normal at rest but remained abnormally raised on exercise. Plasma renin activity and aldosterone increased significantly both at rest and on exercise. Diuretics bring about a considerable clinical improvement in patients with chronic heart failure but they stimulate the renin-angiotensin system. Activation of the renin-angiotensin system in moderate heart failure occurs as a response to diuretic treatment rather than as a result of the disease process itself.     

Untreated heart failure: clinical and neuroendocrine effects of introducing diuretics.

The clinical and neuroendocrine response to diuretic treatment was assessed at rest and on exercise in 12 patients with heart failure. Before treatment all patients were limited by breathlessness on exercise; one was oedematous. Plasma renin activity and aldosterone were normal but plasma noradrenaline was raised both at rest and on exercise. After one month's treatment with frusemide (40 mg) and amiloride (5 mg) weight was significantly reduced by a mean of 3.5 kg and exercise capacity had doubled. Plasma noradrenaline fell to normal at rest but remained abnormally raised on exercise. Plasma renin activity and aldosterone increased significantly both at rest and on exercise. Diuretics bring about a considerable clinical improvement in patients with chronic heart failure but they stimulate the renin-angiotensin system. Activation of the renin-angiotensin system in moderate heart failure occurs as a response to diuretic treatment rather than as a result of the disease process itself.     

Effects of prostaglandin synthesis inhibition on blood pressure and humoral factors in exercising, sodium-deplete normal man

A double-blind placebo-controlled study was carried out in 10 sodium-deplete normal men to determine whether prostaglandin synthesis inhibition (PG-inhibition) by indomethacin (150 mg daily for three days plus an additional 50 mg on the morning of the active experiments) affected blood pressure and humoral factors at exercise. Urinary sodium excretion during placebo averaged 39 mEq/24 h. Independent of the level of physical activity, PG-inhibition increased (P less than 0.001) intraarterial systolic pressure by 12 mmHg and mean and diastolic pressure by 5 and 3 mmHg, respectively. Heart rate, body weight and exercise capacity were not significantly changed. Following PG-inhibition plasma 13,14-dihydro-15-keto-prostaglandin F alpha, plasma renin, angiotensin II and aldosterone were reduced (P less than 0.001) to a similar degree at rest and exercise. However, PG-inhibition did not abolish the exercise related stimulation of the plasma renin-angiotensin-aldosterone system. PG-inhibition had no significant effect on the plasma catecholamines nor on the urinary excretion of aldosterone and kallikrein. Twenty-four-h urinary sodium (-15 mEq; P less than 0.01) decreased. In sodium-deplete subjects prostaglandins seem to exert a depressor action on the systemic circulation, and to have a tonic influence on the renin system. Both these effects are similar at rest and exercise. Prostaglandins are probably not involved in the exercise-induced stimulation of the plasma renin-angiotensin-aldosterone system.     

Hemodynamic Effects at Rest and during Exercise in Long-term Treatment with Prazosin in Chronic Congestive Heart Failure

ABSTRACT. The long-term effects of prazosin in chronic congestive heart failure were studied in 10 patients (New York Heart Association class III-IV) in a double-blind cross-over study. Patients with systolic blood pressure > 120 mmHg and left ventricular filling pressure > 15 mmHg were included. Prazosin lowered the arteriovenous oxygen difference both at rest and during exercise (p < 0.05), increased cardiac index (p < 0.01) and reduced right atrial pressure and systemic vascular resistance (p < 0.05) during exercise. Left ventricular filling pressure was also reduced, but not significantly, during exercise. Our data show that prazosin has beneficial long-term effects during exercise in patients with chronic congestive heart failure.     

Effect of captopril in left ventricular failure during the acute stage of myocardial infarction

The oral inhibitor of the converting enzyme of angiotensin has previously been used successfully in the treatment of chronic cardiac failure. Its action as an arterial and venous vasodilator and in significantly reducing the heart rate which we have previously reported, led us to assess its effects in left ventricular failure during acute myocardial infarction. The effects of captopril were compared with those of isosorbide dinitrate in 10 patients with left ventricular failure during acute myocardial infarction. An arterial and venous vasodilatation was obtained with both drugs. Captopril induced a greater fall in left ventricular filling pressures and significantly reduced the heart rate, leading to a slight increase in left ventricular systolic work index. Pulmonary arterial resistances decreased more significantly with captopril whilst systemic arterial resistances fell equally. The left ventricular function curve was shifted to the left by both captopril and isosorbide dinitrate, but only captopril induced an upward shift and only captopril caused very significant reductions in the rate-pressure product. The plasma renin activity of these patients was high but the correlation with the vasodilator effect was poor. There was little change in medium-term survival (50% mortality). These results indicate that captopril may be a valuable drug in the treatment of left ventricular failure in acute myocardial infarction. However, its oral presentation makes it difficult to determine the optimal dose.     

Efficacy of felodipine in chronic congestive heart failure: a placebo controlled haemodynamic study at rest and during exercise and orthostatic stress.

A vascular selective calcium antagonist, felodipine, was evaluated in a randomised, double blind, crossover trial in 18 patients with chronic congestive heart failure of ischaemic cause. Felodipine (10 mg twice daily) or a corresponding placebo was added to conventional treatment. After three weeks haemodynamic function was assessed at rest, during a standard supine leg exercise, and during 45 degrees passive upright tilt. In patients in the supine resting position, felodipine reduced the mean arterial pressure (9%) and systemic vascular resistance (24%) and increased the stroke volume (25%) and cardiac index (23%). The heart rate and right and left ventricular filling pressures were unchanged. During felodipine treatment the standard exercise was accomplished at a similar cardiac index but at a substantially lower heart rate (7%), arterial pressure (10%), systemic vascular resistance (17%), and left ventricular filling pressure (19%), and a higher stroke volume (13%). During both placebo and felodipine administration there were substantial reductions in cardiac filling pressure during upright tilting. Upright tilting during the placebo phase did not increase the heart rate. It also caused a greater fall in systemic vascular resistance while the arterial pulse pressure but not the mean pressure was maintained and the cardiac index and stroke volume increased. The reduced cardiac filling pressures during the felodipine upright tilt were accompanied by reductions in arterial pulse pressure and stroke volume and the patients were able to maintain the mean arterial pressure by an increase in both the heart rate and systemic vascular resistance. Thus three weeks treatment with felodipine improved haemodynamic function at rest and during standard exercise and normalised the baroreflex mediated haemodynamic response in patients with congestive heart failure. The haemodynamic efficacy of the drug in such patients may be associated with a baroreceptor mediated effect as well as direct vasodilatation.     

Circulatory adaptation to pregnancy--serial studies of haemodynamics, blood volume, renin and aldosterone in the baboon (Papio hamadryas)

To test the hypothesis that haemodynamic changes in pregnancy precede any significant increase in circulating blood volume, serial haemodynamic studies were performed in eight baboon pregnancies using Swan-Ganz catheterization and arterial cannulation. Simultaneous measurements were made of red cell and plasma volumes, and of plasma renin activity and aldosterone concentration. Haemodynamic changes identified by 4 weeks gestation included significant (P less than 0.01) reductions in right atrial pressure, systemic and pulmonary arterial pressures, and systemic and pulmonary vascular resistance. Stroke volume increased in early pregnancy (P less than 0.01), with a consequent increase in cardiac output. Plasma renin activity and aldosterone concentration were elevated by 4 weeks (P less than 0.01), but plasma volume did not expand until 12 weeks. At no stage in middle or late pregnancy was cardiac filling pressure increased. These results provide the first haemodynamic evidence that pregnancy is a state of reduced effective blood volume associated with vasodilatation from the early weeks.     

Effects of Captopril on Cardiorenal Hemodynamics in Patients with Severe Chronic Congestive Heart Failure

The effects of captopril on cardiorenal function were studied in patients with chronic congestive heart failure. A single oral dose of captopril in 16 patients significantly increased cardiac indices and decreased total systemic vascular resistance. These changes were greater in subjects with higher baseline plasma renin activity (PRA). The increase in PRA and decrease in plasma aldosterone were also greater in this group. During 7 days of captopril therapy, renal plasma flow distinctly increased in 10 patients in whom renal function was followed. The increase in renal blood flow was greater in subjects with higher PRA. Simultaneous infusion of aprotinin in eight of these subjects did not affect the captopril-induced increase in renal plasma flow: these responses were the same in both PRA subgroups. The results suggest that captopril reduces total systemic vascular resistance in patients with chronic congestive heart failure through the inhibition of the renin-angiotensin system and the preferential renal vasodilating effect of captopril seems exclusively to be the sole result of this inhibition, with the kallikrein-kinin system or kinin-mediated prostaglandins not playing a major role.     

Acute effects of captopril on cardiopulmonary hemodynamics and renin-angiotensin-aldosterone and bradykinin profile in hypertension

Hemodynamic variables were measured and plasma renin activity (PRA), angiotensin II (AII), aldosterone, and bradykinin assays performed in 21 hypertensive men on regular diet and thiazide diuretics before and 60 to 90 minutes after 25 mg oral captopril. Heart rate, right and left ventricular filling pressures, mean cardiac index (CI), and pulmonary vascular resistance (PVR) remained unchanged. The mean intra-arterial pressure (MAP) fell from 140 +/- 5 to 116 +/- 6 mm Hg (p less than 0.001) correlating with reduction of systemic vascular resistance (SVR) (r = 0.87, p less than 0.001), control PRA (r = 0.59, p less than 0.01), and All levels (r = 0.72, p less than 0.005) but not with control bradykinin or its postcaptopril rise (p less than 0.01). The fall in SVR correlated with reduction in plasma All (r = 0.80, p less than 0.001) and aldosterone concentrations (r = 0.53, p less than 0.05). Of four patients (19%) with precipitous fall in MAP after captopril, three needed volume expansion for circulatory support. We conclude: (1) All reduction by captpril and not bradykinin potentiation explains most of the agent's hemodynamic response in hypertensive circulation, (2) endogenous All may have a supportive role for SVR and possibly for CI but not for PVR, and (3) extra precaution is warranted while captopril is being started in patients taking diuretics.     

Neurohumoral and hemodynamic changes in congestive heart failure: lack of correlation and evidence of compensatory mechanisms

The objective of this study was to assess the hemodynamic and neurohumoral (plasma renin activity, aldosterone, epinephrine, norepinephrine, vasopressin, and atrial natriuretic peptide) determinants of systemic vascular resistance in 35 patients with stable congestive heart failure. In the supine position, although activation of the various neurohumoral systems tended to occur in the same patients, there was little correlation between activation of any of the neurohumoral systems, as reflected by circulating levels, and systemic vascular resistance. There was also little correlation between changes in circulating neurohormones and changes in either mean arterial pressure or systemic vascular resistance in the standing position. Acutely reducing the activity of the renin-angiotensin system with the use of captopril did not improve the correlation between other neurohumoral and hemodynamic variables. In fact there was no correlation between the effects of acute captopril therapy and baseline renin values. These results support the concept that activation of one or another vasoconstrictor neurohumoral system varies from patient to patient and that the effects of their activation are tempered by activation of parallel vasodilator systems and by attenuation of neurohormone release and effector organ response.     

Effects of a single administration of captopril on hemodynamics and serum angiotensin converting enzyme activity, plasma renin activity and plasma aldosterone concentration in hypertensive patients

Hemodynamic responses and behaviors of the renin-angiotensin-aldosterone system to a single administration of captopril (50 mg) were studied in 16 hypertensive patients (essential hypertension, n = 10; renovascular hypertension, n = 3; primary aldosteronism, n = 2; Cushing's syndrome, n = 1). In 10 essential hypertensive patients, the immediate blood pressure reduction caused by decreased total peripheral resistance after the administration of captopril was observed without changes of cardiac output and heart rate. Serum angiotensin converting enzyme activity and plasma aldosterone concentration significantly decreased, whereas plasma renin activity significantly elevated 2 hours after the administration of captopril. The close relationship between the pretreatment value of plasma renin activity and the maximum decrease in mean blood pressure in 16 hypertensive patients suggests that the depressor response to a single administration of captopril could evaluate the degree of angiotensin II dependency in the maintenance of high blood pressure in various types of hypertension.     

The role of renal hemodynamics in the antihypertensive effect of captopril

To evaluate the role of regional hemodynamics in mediating the long-term depressor effect of the converting enzyme inhibitor, captopril, at a low dose (37.5 mg/day), for 2 weeks, its systemic, renal, and forearm circulatory actions were determined in 12 patients with mild to moderate essential hypertension. After administration of captopril, there was a significant decline in mean blood pressure (average -12.1 +/- 1.9%) accompanied by a decrease in systemic vascular resistance (-9.1 +/- 3.3%), but cardiac output did not change. Although forearm vascular resistance was not altered, renal vascular resistance decreased considerably (-17.1 +/- 5.0%). Moreover, there was a highly significant (r = 0.891) correlation between the changes in mean blood pressure and renal vascular resistance. Plasma renin activity increased after therapy as plasma aldosterone decreased, while plasma norepinephrine slightly increased. The change in renal vascular resistance significantly (r = -0.617) correlated with the pretreatment level of plasma renin activity. These findings suggest that suppression of the renin-angiotensin system in essential hypertension induces selective vasodilation in the renal vasculature, which may play an important role in the long-term antihypertensive effect of the converting enzyme inhibitor. This renal vasodilator action appears to be the feature that distinguishes the converting enzyme inhibitor from conventional vasodilator drugs.