enalaprilat-anhydrous and Ventricular-Dysfunction--Left

Angiotensin-converting enzyme inhibitors are an effective therapy for all stages of heart failure due to reduced systolic left ventricular function. Because sufficient data on intravenous angiotensin-converting enzyme inhibitors following coronary artery bypass surgery complicated by postoperative left ventricular dysfunction are unavailable, the efficacy and safety of intravenously administered enalaprilat were evaluated.. A placebo-controlled, randomized, double-blind protocol.. Postoperative intensive care unit at the German Heart Institute Berlin.. Forty patients with a left ventricular ejection fraction <35% following coronary artery bypass surgery on the second postoperative day or after weaning from intra-aortic balloon counterpulsation.. A loading dose of enalaprilat 0.625 mg infused over 1 hr was followed by 5 mg/24 hrs administered continuously for up to 72 hrs.. Systemic and pulmonary hemodynamic variables, blood gases, hormonal variables, renal function, and electrolytes were measured before and repeatedly during therapy. Acute effects were as follows: At 1 hr, enalaprilat increased the cardiac index (p <.001), stroke volume index (p <.001), and right ventricular stroke work index (p <.03) compared with placebo, whereas mean arterial pressure (p <.008) and both systemic (p <.001) and pulmonary (p <.02) vascular resistance decreased. Continuous effects were as follows: Over 72 hrs, enalaprilat decreased diastolic pulmonary artery pressure (p <.019), pulmonary artery occlusion pressure (p <.02), and central venous pressure (p <.02). The cardiac and stroke volume indexes were consistently higher in the enalaprilat group, whereas systemic and pulmonary vascular resistances were lower. The arterial blood-pressure lowering effect was blunted and heart rate remained unchanged. Mixed venous oxygenation (p <.02) was higher and arterial oxygenation was not modified. Finally, enalaprilat increased creatinine clearance (p <.002) and decreased creatinine (p <.02) and urea (p <.03).. Intravenous enalaprilat safely and effectively improves cardiac and renal function following coronary artery bypass surgery complicated by postoperative left ventricular dysfunction.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Gas Analysis; Blood Urea Nitrogen; Coronary Artery Bypass; Creatinine; Double-Blind Method; Drug Monitoring; Enalaprilat; Female; Hemodynamics; Humans; Infusions, Intravenous; Kidney; Male; Metabolic Clearance Rate; Middle Aged; Postoperative Care; Safety; Time Factors; Treatment Outcome; Ventricular Dysfunction, Left

Left ventricular (LV) diastolic function and coronary flow are impaired in hypertrophic obstructive cardiomyopathy (HOCM). This study was designed to evaluate the impact of cardiac and circulatory ACE inhibition on such derangements.. Twenty patients with HOCM underwent cardiac ACE inhibition with intracoronary (IC) enalaprilat (0.05 mg/min infused into the left anterior descending coronary artery for 15 minutes) followed by circulatory ACE inhibition with 25 mg sublingual (SL) captopril. Contrast ventriculography, pressure, and coronary flow measurements were performed at baseline, after IC enalaprilat infusion, and 45 minutes after SL captopril. Heart rate was not affected by the respective interventions (75+/-11 versus 76+/-13 versus 75+/-10 bpm; P=NS), whereas mean aortic pressure dropped slightly after IC enalaprilat and significantly after SL captopril (90+/-8 versus 85+/-10 versus 74+/-9 mm Hg; P<.05). Compared with baseline, IC enalaprilat resulted in a decrease in LV end-diastolic pressure (17.6+/-5.9 versus 14.4+/-4.9 mm Hg; P<.05), time constant of isovolumic LV pressure relaxation (tauG) (69+/-9 versus 52+/-10 ms; P<.05), and outflow gradient (45.2+/-6.9 versus 24.4+/-3.7 mm Hg; P<.05) and in an increase in coronary blood flow (107+/-10 versus 127+/-12 mL/min; P<.05) and coronary flow reserve (2.2+/-0.4 versus 2.6+/-0.3; P<.05). After SL captopril, tauG was prolonged (60+/-13 ms; P<.05 versus IC enalaprilat), and LV outflow gradient, coronary blood flow, and coronary flow reserve values returned to baseline (45.5+/-5.3 mm Hg, 107+/-12 mL/min, and 2.2+/-0.5, respectively; P=NS versus baseline).. Activation of the cardiac renin-angiotensin system contributes to LV diastolic dysfunction as well as to the decreased coronary blood flow and coronary flow reserve in HOCM. Cardiac ACE inhibition restores and circulatory ACE inhibition aggravates the above derangements.

Topics: Adult; Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Captopril; Cardiomyopathy, Hypertrophic; Coronary Circulation; Diastole; Echocardiography; Enalaprilat; Female; Heart; Hemodynamics; Humans; Infusions, Parenteral; Male; Middle Aged; Prospective Studies; Ventricular Dysfunction, Left

Fifty patients with left ventricular diastolic heart failure (LVDHF), and 35 patients with left ventricular systolic heart failure (LVSHF) diagnosed by clinical manifestation and radionuclide ventriculography were studied and 20 normal persons served as controls. Plasma renin activity (PRA), angiotensin I (AT I), aldosterone (ALD), endothelin (ET) and atrial natriuretic peptide (ANP) concentrations were measured by radioimmunoassay. Fifty patients with LVDHF were divided into treatment group and control group in a randomized, double blind, control method. Enalpril, CoQ10 and VitE were given in treatment group while only CoQ10 and VitE were given in control group. The therapeutic efficacy was evaluated after 8 weeks of treatment. The results showed that plasma concentration of PRA, AT I, ALD, ET and ANP were increased in LVDHF, but lower than those in LVSHF. After treatment with enalapril plasma PRA was increased while AT I, ALD and ET level were decreased significantly but ANP level had no change in treatment group.

Topics: Adult; Aged; Aldosterone; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Atrial Natriuretic Factor; Double-Blind Method; Enalaprilat; Endothelins; Female; Humans; Male; Middle Aged; Renin; Ventricular Dysfunction, Left

Topics: Angiotensin-Converting Enzyme Inhibitors; Coronary Artery Bypass; Enalaprilat; Humans; Infusions, Intravenous; Research Design; Stroke Volume; Ventricular Dysfunction, Left

This study tested the hypothesis that angiotensin-converting enzyme (ACE) inhibitors attenuate beta-adrenergic contractility in patients with idiopathic dilated cardiomyopathy (DCM) through nitric oxide (NO) myocardial signaling.. The ACE inhibitors increase bradykinin, an agonist of NO synthase (NOS). Nitric oxide inhibits beta-adrenergic myocardial contractility in patients with heart failure.. The study patients were given the angiotensin-1 (AT-1) receptor antagonist losartan for one week. The hemodynamic responses to intravenous dobutamine were determined before and during intracoronary infusion of enalaprilat (0.2 mg/min) with and without the NOS inhibitor N(G)-monomethyl-L-arginine (L-NMMA, 5 mg/min).. In patients with DCM (n = 8), dobutamine increased the peak rate of rise of left ventricular pressure (+dP/dt) by 49 +/- 8% (p < 0.001) and ventricular elastance (Ecs) by 53 +/- 16% (p < 0.03). Co-infusion with enalaprilat decreased +dP/dt to 26 +/- 12% and Ecs to -2 +/- 17% above baseline (p < 0.05), and this anti-adrenergic effect was reversed by L-NMMA co-infusion (p < 0.05 vs. enalaprilat). In addition, intracoronary enalaprilat reduced left ventricular end-diastolic pressure (LVEDP), but not left ventricular end-diastolic volume, consistent with increased left ventricular distensibility. Infusion with L-NMMA before enalaprilat in patients with DCM (n = 5) prevented the reduction in +dP/dt, Ecs and LVEDP. In patients with normal left ventricular function (n = 5), enalaprilat did not inhibit contractility or reduce LVEDP during dobutamine infusion.. Enalaprilat attenuates beta-adrenergic contractility and enhances left ventricular distensibility in patients with DCM, but not in subjects with normal left ventricular function. This response is NO modulated and occurs in the presence of angiotensin receptor blockade. These findings may have important clinical and pharmacologic implications for the use of ACE inhibitors, AT-1 receptor antagonists and their combination in the treatment of heart failure.

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Cardiomyopathy, Dilated; Compliance; Depression, Chemical; Diastole; Dobutamine; Enalaprilat; Enzyme Inhibitors; Female; Heart; Hemodynamics; Humans; Losartan; Male; Middle Aged; Myocardial Contraction; Myocardium; Nitric Oxide; omega-N-Methylarginine; Ventricular Dysfunction, Left

The pump function during exercise can be disturbed not only in hypertensives with coronary artery disease (CAD), but also in those with a normal angiogram.. In 10 hypertensive patients (group 1; aged 52+/-4 years, 1 men, 9 women) with ST segment depression during exercise and concomitant angina pectoris but normal coronary angiograms (microangiopathy) and without left ventricular hypertrophy (LVMI <110 g/m2), the left ventricular function at rest and during exercise was studied by cardiac catheterization and compared with 10 hypertensives with CAD (group 2; aged 57.6+/-4 years, 7 men, 3 women) and 10 hypertensives without ST segment depression (group 3; aged 51.8+/-5 years, 10 men) before and after intravenous administration of 1.25 mg enalaprilat.. The pulmonary capillary wedge pressure (PCWP) was normal at rest and pathologically increased at 60+/-13 W only in groups 1 and 2 (27.2+/-3 and 32.2+/-8 mm Hg, respectively), but not in group 3 (12.2+/-4 mm Hg; p<0.001). At the identical load level, the PCWP in patients with microangiopathy (group 1) was significantly (p<0.01) reduced after enalaprilat (-21.7%) and even normalized in 5 of 10 patients. This was accompanied by a significant (p>0.01) decrease in ST segment depression (-73.9%) and in the occurrence of angina pectoris, despite the fact that the rate-pressure product as a measure of myocardial oxygen consumption was significantly (p<0.05) increased. Also in patients with CAD enalaprilat had a significant effect on PCWP (p<0.01), ST segment depression (p<0.01), occurrence of angina pectoris (p<0.001), cardiac index (p<0.05), and stroke index (p<0.05) during exercise. In group 3 there were no significant changes in PCWP, cardiac index, and stroke index after enalaprilat either at rest or during exercise.. The functional improvement under the action of enalaprilat suggests that the advantages of the drug may be mediated mainly through an increase in myocardial blood flow and that angiotensin II might be involved in the restricted increase in coronary blood flow during dynamic exercise in hypertensives with coronary microangiopathy.

Topics: Angina Pectoris; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Coronary Disease; Enalaprilat; Exercise Test; Female; Hemodynamics; Humans; Hypertension; Male; Microcirculation; Middle Aged; Ventricular Dysfunction, Left

To study the acute effects of angiotensin-converting enzyme inhibition by intravenous enalaprilat infusion in patients with left ventricular dysfunction after cardiac surgery.. Prospective, consecutive sample, before-after trial.. Surgical intensive care unit in a tertiary care university hospital.. Eight patients with left ventricular dysfunction after cardiac surgery. Patients were defined as having left ventricular dysfunction if the pulmonary capillary wedge pressure persisted above 18 mmHg in spite of conventional vasoactive medication (inotropic or vasodilating and diuretic drugs) and intermittent mandatory ventilation during the first postoperative week.. Enalaprilat was infused initially at 1 mg/ hour. The rate was doubled every 30 minutes until pulmonary capillary wedge pressure decreased at least 20% or until a maximum total dose of 10 mg was achieved.. Central hemodynamics, systemic oxygenation, and hormonal regulation of circulation (plasma renin activity, plasma endothelin, atrial natriuretic peptide, norepinephrine, epinephrine, and vasopressin concentrations, serum angiotensin-converting enzyme activity, and serum levels of aldosterone) were assessed at baseline before enalaprilat infusion, and repeatedly over 2 hours after the infusion. Enalaprilat infusion (median dose, 2.0 mg; infusion time, 48 minutes) caused a significant decrease in pulmonary capillary wedge pressure (p = 0.004), lasting until the end of the 2 hours' follow-up. This coincided with inhibition of serum angiotensin-converting enzyme activity (p < 0.001), an increase in plasma renin activity (p = 0.022), and decreases in plasma endothelin (p = 0.035), atrial natriuretic peptide (p = 0.005), and serum aldosterone (p = 0.001) concentrations. Cardiac output, venous admixture, and oxygen delivery and consumption remained unchanged.. Adding enalaprilat to conventional therapy makes it possible to unload the left ventricle and to relieve overt neurohormonal activation temporarily while maintaining cardiac function and systemic oxygenation.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Atrial Natriuretic Factor; Cardiac Surgical Procedures; Enalaprilat; Endothelins; Female; Humans; Male; Middle Aged; Prospective Studies; Ventricular Dysfunction, Left

Vasodilator drugs have variable effects on veins and arteries. However, direct measurements of their effects on the splanchnic veins, perhaps the most important volume reservoir, have not been reported. We assessed the effect of acute heart failure and the subsequent administration of hydralazine, enalaprilat, and nitroglycerin on the splanchnic venous pressure-volume relation in intact dogs.. Experimental acute ischemic heart failure was induced in 19 splenectomized dogs by microsphere embolization of the left main coronary artery. Embolization was repeated until left ventricular end-diastolic pressure (LVEDP) reached 20 mm Hg and cardiac output decreased by 50%. The splanchnic vascular pressure-volume relation was determined by radionuclide plethysmography during the control stage, after acute heart failure had been established, and after administration of a vasodilator (hydralazine, enalaprilat, or nitroglycerin) at a dose sufficient to reduce mean aortic pressure by approximately 20%. Induction of acute heart failure was associated with a decrease in the splanchnic vascular volume from 100% to 86 +/- 2% and an increase in LVEDP from 6 +/- 1 to 21 +/- 1 mm Hg (P < .001). There was a parallel leftward shift of the splanchnic vascular pressure-volume curve. After the administration of hydralazine, enalaprilat, and nitroglycerin, the splanchnic vascular volumes increased from 86% to 88 +/- 3%, 96 +/- 3%, and 113 +/- 3%, respectively (P = NS, P < .01, and P < .001, respectively, versus heart failure). After drug administration, the LVEDPs were 18 +/- 2, 16 +/- 1, and 13 +/- 1 mm Hg (P = NS, P < .05, and P < .001, respectively, versus heart failure).. Acute heart failure was associated with a parallel leftward shift of the splanchnic venous pressure-volume relation (venoconstriction). Splanchnic (systemic) venoconstriction may in part explain the increased LVEDP during acute heart failure by displacement of blood to the central compartment. Subsequently administered enalaprilat and, to a greater degree, nitroglycerin produced splanchnic venodilation, thereby lowering LVEDP. Hydralazine had no significant effect on the splanchnic veins and only a modest effect on LVEDP. In this model, splanchnic capacitance changes appear to modulate change in left ventricular preload.

Topics: Animals; Dogs; Enalaprilat; Heart Failure; Hydralazine; Mesenteric Veins; Nitroglycerin; Plethysmography; Radionuclide Imaging; Splanchnic Circulation; Venous Pressure; Ventricular Dysfunction, Left; Ventricular Function, Left