enalaprilat-anhydrous and Cardiac-Output--Low

The contribution of nonangiotensinergic effects of converting enzyme inhibitors to their hemodynamic effects in patients with chronic heart failure is not clear. A comparison of the effects of renin and converting enzyme inhibition should help to clarify this issue.. Thirty-six patients with chronic heart failure (New York Heart Association class II or III) were randomly assigned to receive double-blind either intravenous placebo, the renin inhibitor remikiren, or the converting enzyme inhibitor enalaprilat followed by coinfusion of a second placebo infusion, the addition of remikiren to enalaprilat, or the addition of enalaprilat to remikiren, respectively. Systemic hemodynamics (Swan-Ganz and radial artery catheters) were measured before (rest and submaximal recumbent bicycle ergometry), during (rest), and at the end (rest and exercise) of each 45-minute single- or combination-infusion period. Placebo did not change hemodynamics or renin activity. Effective inhibition of the renin-angiotensin system by remikiren and enalaprilat was indicated by increases of plasma immunoreactive renin together with rapid and complete inhibition of renin activity after remikiren and an increase after enalaprilat (all P < or = .05). Remikiren and enalaprilat rapidly and to a similar extent reduced resting blood pressure through a reduction of systemic vascular resistance, and these changes were significantly correlated to baseline plasma renin activity. Both compounds also decreased pulmonary artery, pulmonary capillary wedge, and right atrial pressures to a similar extent (P < .05). During exercise, pulmonary capillary wedge and right atrial pressures were equally reduced and stroke volume index was increased with remikiren and enalaprilat (P < .05) for both). The combination of converting enzyme with renin inhibition or vice versa did not cause additional hemodynamic changes.. Specific renin inhibition in patients with chronic heart failure produces short-term hemodynamic effects that are almost indistinguishable from those of converting enzyme inhibition. This finding and the lack of additional effects of converting enzyme inhibition added to renin inhibition suggest that nonangiotensinergic effects of converting enzyme inhibitors do not play a significant role in their short-term hemodynamic effects in patients with chronic heart failure.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Cardiac Output, Low; Chronic Disease; Double-Blind Method; Drug Therapy, Combination; Enalaprilat; Female; Hemodynamics; Humans; Imidazoles; Male; Middle Aged; Renin

To determine the role of the renin-angiotensin system and the bradykinin pathway in the mechanism of action of angiotensin-converting enzyme inhibitors in heart failure, the acute effects of enalaprilat (1 mg/kg) were compared with those of a renin inhibitor (ciprokiren, 1 mg/kg i.v.) in 10 chronically instrumented conscious dogs with heart failure induced by right ventricular pacing (3 wk, 240 beats/min). The effects of enalaprilat and ciprokiren on bradykinin infusion (3, 10, and 30 micrograms/min) and the effects of enalaprilat in the presence of the bradykinin B2 receptor antagonist Hoe-140 (10 micrograms/kg i.v.) were also examined. Both inhibitors significantly decreased mean aortic pressure and increased cardiac output. However, enalaprilat induced significantly greater hemodynamic effects than ciprokiren (mean aortic pressure, -13 +/- 3 vs. -6 +/- 1 mmHg; cardiac output, 0.4 +/- 0.1 vs. 0.15 +/- 0.1 l/min). Bradykinin infusion led to dose-dependent decreases in mean aortic pressure and increases in cardiac output that were not modified by pretreatment with ciprokiren but were potentiated 10-fold by enalaprilat. Hoe-140 significantly reduced the hemodynamic effects of enalaprilat. Thus endogenous bradykinin is involved in the acute hemodynamic effects of enalaprilat in experimental heart failure.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Bradykinin Receptor Antagonists; Cardiac Output, Low; Dogs; Enalaprilat; Female; Hemodynamics; Hormones; Imidazoles; Male; Renin; Time Factors

This study investigates the effect of angiotensin-converting-enzyme inhibition by intravenous enalaprilat (100 micrograms/kg) on splanchnic vascular capacitance during acute left ventricular failure induced by coronary microembolization in alpha-chloralose/urethan anesthetized dogs. Changes in hepatic and splenic vascular volumes were determined from organ diameters (sonomicrometry) at 15, 30, and 45 min after enalaprilat injection. Changes in vascular capacitance were assessed from organ pressure-diameter curves obtained during transient hepatic outflow occlusion. Thirty minutes after enalaprilat, hepatic volume was increased by 52 +/- 14 ml (P < 0.01), and portal and hepatic vein pressures were decreased from 10.2 +/- 0.9 to 8.7 +/- 0.8 mmHg (P < 0.01) and from 3.9 +/- 1.6 to 3.1 +/- 0.7 mmHg (P < 0.05), respectively. Splenic volume did not change. Enalaprilat shifted the hepatic pressure-diameter curve upward, resulting in a larger hepatic volume at any given pressure. Curve intercept was increased, suggesting an increase in unstressed vascular volume. Curve slope was unchanged. In conclusion, enalaprilat increased hepatic vascular volume during acute left ventricular failure in dogs. The pressure-diameter curve shift suggests a reduction in the smooth muscle tone of hepatic capacitance vessels.

Topics: Acute Disease; Animals; Cardiac Output, Low; Coronary Thrombosis; Dogs; Enalaprilat; Female; Hemodynamics; Male; Myocardial Ischemia; Splanchnic Circulation; Vascular Resistance

Haemodynamic comparison of three vasodilation regimens [intravenous (i.v.) hydralazine and isosorbide dinitrate (ISDN) combined, i.v. doxazosin, and i.v. enalaprilat] was undertaken in 36 patients with acute left ventricular (LV) failure due to recent myocardial infarction. Each regimen achieved similar reductions in pulmonary artery occluded pressure (PAOP, preload) and systemic arterial pressures (afterload), with increased cardiac and stroke volume (SV) indexes (p less than 0.01). Only the hydralazine and isosorbide combination induced resting tachycardia. Balanced vasodilatation after selective alpha-adrenoceptor blockade (doxazosin) and angiotensin-converting enzyme (ACE) inhibition (enalaprilat) without increase in heart rate (HR) suggests that these therapies may have definite haemodynamic advantages over the hydralazine/ISDN combination.

Topics: Adrenergic alpha-Antagonists; Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Cardiac Output, Low; Doxazosin; Drug Therapy, Combination; Enalaprilat; Heart Rate; Hemodynamics; Humans; Hydralazine; Injections, Intravenous; Isosorbide Dinitrate; Male; Middle Aged; Myocardial Infarction; Prazosin; Pulmonary Wedge Pressure; Vasodilator Agents; Ventricular Function, Left

Regional cerebral blood flow (rCBF) was studied in anesthetized dogs subjected to acute left ventricular failure and its treatment with enalaprilat (MK-422). When failure was induced a reduction in rCBF paralleling the reduction in systemic blood pressure was observed. After treatment rCBF did not change in spite of further blood pressure reduction. The results are explained by changes in vascular resistance of larger cerebral arteries. Vasoconstriction in these vessels during failure was counteracted by enalaprilat through reduction in circulating angiotensin II.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Cardiac Output, Low; Cerebrovascular Circulation; Dogs; Enalapril; Enalaprilat; Heart Ventricles; Hemodynamics; Vascular Resistance