enalaprilat-anhydrous and Cardiomyopathy--Dilated

Cytochrome P450 family 2 subfamily E member 1 (CYP2E1) is a member of the cytochrome P450 enzyme family and catalyzes the metabolism of various substrates. CYP2E1 is upregulated in multiple heart diseases and causes damage mainly via the production of reactive oxygen species (ROS). In mice, increased CYP2E1 expression induces cardiac myocyte apoptosis, and knockdown of endogenous CYP2E1 can attenuate the pathological development of dilated cardiomyopathy (DCM). Nevertheless, targeted inhibition of CYP2E1 via the administration of drugs for the treatment of DCM remains elusive. Therefore, the present study aimed to investigate whether diallyl sulfide (DAS), a competitive inhibitor of CYP2E1, can be used to inhibit the development of the pathological process of DCM and identify its possible mechanism. Here, cTnT

Topics: Allyl Compounds; Angiotensin-Converting Enzyme Inhibitors; Animals; Apoptosis; Cardiomyopathy, Dilated; Cardiotonic Agents; Cell Line; Cytochrome P-450 CYP2E1; Disease Models, Animal; Enalaprilat; Female; Male; Mice, Transgenic; Mitochondria; Oxidative Stress; Rats; Sulfides; Troponin T

ACE inhibitors have been used extensively in heart failure, where they induce systemic vasodilatation. ACE inhibitors have also been shown to reduce ischemic events after myocardial infarction, although their mechanisms of action on the coronary circulation are less well understood. The purpose of the present study was to determine the effects and the mechanism of action of the ACE inhibitor enalaprilat and the AT1 antagonist losartan on regional myocardial perfusion and coronary flow and vasodilator reserve in conscious dogs with pacing-induced dilated cardiomyopathy (DCM).. Twenty-seven conscious, chronically instrumented dogs were studied during advanced stages of dilated cardiomyopathy, which was induced by rapid pacing. Enalaprilat (1.25 mg IV) improved transmural distribution (endocardial/epicardial ratio) at rest (baseline, 0.91+/-0.11; enalaprilat, 1.02+/-0.07 mL/min per g; P<0.05) and during atrial pacing (baseline, 0.82+/-0.11; enalaprilat, 0.98+/-0.07; P<0.05). Enalaprilat also restored subendocardial coronary flow reserve (CFR) (baseline CFR, 1.89+/-0.11; enalaprilat CFR, 2.74+/-0.33; P<0.05) in DCM. These effects were abolished by pretreatment with the NO synthase inhibitor nitro-L-arginine. The effects were recapitulated by the bradykinin(2) receptor agonist cereport but not by the AT1 antagonist losartan.. The ACE inhibitor enalaprilat improves transmural myocardial perfusion at rest and after chronotropic stress and restores impaired subendocardial coronary flow and vasodilator reserve in DCM. The effects of enalaprilat were bradykinin mediated and NO dependent and were not recapitulated by losartan. These data suggest beneficial effects of ACE inhibitors on the coronary circulation in DCM that are not shared by AT1 receptor antagonists.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Cardiomyopathy, Dilated; Coronary Circulation; Dogs; Dose-Response Relationship, Drug; Enalaprilat; Enzyme Inhibitors; Hemodynamics; Kinetics; Losartan; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Receptor, Angiotensin, Type 1; Receptor, Bradykinin B2; Receptors, Bradykinin; Regional Blood Flow; Vasodilator Agents

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

Coronary flow reserve is reduced in patients with idiopathic dilated cardiomyopathy (DCM). We examined acute effects of intracoronary enalaprilat on metabolic coronary vasodilation during pacing tachycardia in patients. Coronary blood flow (Doppler guidewire) and diameter (quantitative angiography) were measured in seven patients with DCM and seven control subjects. In the DCM group, tachypacing increased coronary blood flow by 37 +/- 22% from the baseline before enalaprilat and by 65 +/- 22% (p < 0.01 vs. before treatment) after enalaprilat (0.5 microg/kg/min for 5 min, i.c.) at comparable double product. Pacing-induced dilation of the epicardial coronary artery also was greater after enalaprilat (p < 0.05). Effects of enalaprilat on coronary blood flow and diameter during pacing tachycardia were abolished by pretreatment with intracoronary administration of the nitric oxide (NO) synthesis inhibitor, N(G)-monomethyl-L-arginine. These beneficial effects of enalaprilat on large and small coronary vasodilation were not observed in control patients. Thus, intracoronary enalaprilat acutely augmented dilator responses of the large and small coronary arteries to pacing tachycardia in patients with DCM, and NO appeared to play an important role in mediating the effects of enalaprilat. These favorable effects of enalaprilat on the coronary circulation may be of clinical significance in patients with heart failure due to nonischemic DCM. Further long-term studies of the effects of angiotensin-converting enzyme inhibition on coronary vasodilation will be needed in this population.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Cardiomyopathy, Dilated; Coronary Vessels; Drug Interactions; Enalaprilat; Enzyme Inhibitors; Female; Hemodynamics; Humans; Infusions, Intra-Arterial; Male; Middle Aged; Nitric Oxide; omega-N-Methylarginine; Tachycardia; Vasodilation; Vasodilator Agents

Cardiac hypertrophy is associated with elevated intracardiac angiotensin-converting enzyme activity, which may contribute to diastolic dysfunction.. We infused enalaprilat (0.05 mg/min) for 15 minutes into the left coronary arteries of 20 adult patients with left ventricular (LV) hypertrophy due to aortic stenosis (mean aortic valve area, 0.7 +/- 0.2 cm2) and 10 patients with dilated cardiomyopathy (mean ejection fraction, 35 +/- 4%) and assessed (1) simultaneous changes in LV micromanometer pressure and dimensions, (2) LV regional wall motion analyzed by the area method, and (3) Doppler flow-velocity profiles. Systemic neurohormonal activation did not occur with the selective left coronary artery infusion; there were no changes in plasma renin activity, angiotensin-converting enzyme activity, or atrial natriuretic peptide. In patients with aortic stenosis, LV end-diastolic pressure declined from 25 +/- 2 to 20 +/- 2 mm Hg (P < .05). LV pressure-volume and LV pressure-dimension relations showed downward shifts by ventriculography and echocardiography, respectively, indicating improved diastolic distensibility. Regional area change during isovolumic relaxation increased in the anterior segments perfused with enalaprilat but decreased in the inferior segments, indicating acceleration of isovolumic relaxation in the anterior segments and reciprocal shortening in the inferior segments. Regional peak filling rate increased in the anterior segments but not in the inferior segments, and the regional area stiffness constant decreased in the anterior segments but not in the inferior segments. There were no changes in heart rate, cardiac output, or right atrial pressure, excluding alterations in right ventricular/pericardial constraint. In contrast, in the patients with dilated cardiomyopathy the decrease in LV end-diastolic pressure from 22 +/- 2 to 18 +/- 2 mm Hg (P < .05) was accompanied by a significant fall in right atrial pressure (9 +/- 1 to 6 +/- 1 mm Hg), implicating alterations in pericardial constraint. The patients with dilated cardiomyopathy showed no improvement in regional diastolic relaxation, filling, or distensibility.. Intracoronary enalaprilat at a dosage that did not cause systemic neurohormonal activation improved LV diastolic chamber distensibility and regional relaxation and filling in patients with LV hypertrophy due to aortic stenosis. In contrast, these effects of intracoronary enalaprilat on diastolic function were not observed in patients with dilated cardiomyopathy who did not have concentric hypertrophy. These observations support the hypothesis that the cardiac renin-angiotensin system is activated in patients with concentric pressure-overload hypertrophy and that this activation may contribute to impaired diastolic function.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Aortic Valve Stenosis; Cardiomyopathy, Dilated; Coronary Vessels; Diastole; Enalaprilat; Female; Heart; Hemodynamics; Humans; Hypertrophy, Left Ventricular; Injections, Intra-Arterial; Male; Middle Aged

Although indicated by several experimental studies, the presence of a renin-angiotensin system has not been demonstrated in the human heart. The influence of a local renin-angiotensin system on the coronary vessels may be difficult to establish after oral or intravenous administration of an angiotensin converting-enzyme inhibitor, since coronary blood flow depends greatly on the loading conditions of the left ventricle. To avoid such a situation, our study consisted in a direct bilateral intracoronary infusion of enalaprilat in patients with dilated cardiomyopathy and normal coronary arteries (mean ejection fraction = 32 +/- 11%, n = 12). This intracoronary infusion (0.05 mg min-1, 1 ml min-1 in each coronary artery) resulted in no significant change of the systemic resistances (20.6 +/- 5.6 to 22.0 +/- 5.1 mmHg l-1 min), rate-pressure product (10,974 +/- 2630 to 10,214 +/- 2486) or myocardial oxygen consumption (21.08 +/- 6.37 to 22.10 +/- 6.42 ml min-1). Despite these steady haemodynamic conditions, intracoronary enalaprilat provoked a significant elevation of coronary sinus blood flow (181 +/- 73 to 214 +/- 79 ml min-1, P less than 0.001) with a reduction of coronary resistance (0.51 +/- 0.17 to 0.41 +/- 0.15 mmHg ml-1 min, P less than 0.001), and no significant alteration in plasma renin activity or plasma aldosterone. The results of this intracoronary infusion of enalaprilat demonstrate that this angiotensin converting-enzyme inhibitor has significant coronary vasodilator properties, which can be evidenced without stimulating the peripheral renin-angiotensin system.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Cardiomyopathy, Dilated; Coronary Circulation; Coronary Vessels; Enalaprilat; Hemodynamics; Humans; Infusions, Intra-Arterial; Oxygen Consumption; Renin-Angiotensin System; Vascular Resistance; Vasodilation

Angiotensin II elicits contractile responses in the coronary arteries and myocardial tissue, which suggests that blockade of the renin-angiotensin system by specific agents should lead to both coronary vasodilation and an alteration of left ventricular inotropism. The present work was designed to delineate--independently from its systemic effects--the intrinsic actions of an angiotensin converting-enzyme inhibitor on the coronary circulation and left ventricular function. To minimize peripheral effects, a bilateral intracoronary infusion of enalaprilat (0.05 mg.min-1, 1 ml.min-1 in each coronary artery) was performed in 16 patients with dilated cardiomyopathy. All patients had normal coronary arteriograms. In 12 patients (group I) the intracoronary infusion of enalaprilat resulted in minimal peripheral changes, with a 5% reduction in the mean aortic pressure (p less than .05) and no significant alteration in indexes of preload, i.e., left ventricular end-diastolic pressure and volume, or of afterload, i.e., left ventricular end-systolic stress and systemic resistances. Myocardial oxygen consumption was also unaffected by the intracoronary infusion of enalaprilat. Coronary vasodilation was demonstrated by a significant elevation of coronary sinus blood flow (+19%, from 181 +/- 73 to 214 +/- 79 ml.min-1, p less than .001) and a reduction of coronary resistance (-18%, from 0.51 +/- 0.17 to 0.41 +/- 0.15 mm Hg.ml-1.min, p less than .001), with a parallel increase in coronary sinus oxygen content and pressure (both p less than .05). Oxygen extraction by the myocardium was reduced (p less than .01).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Cardiac Catheterization; Cardiomyopathy, Dilated; Coronary Circulation; Coronary Vessels; Enalapril; Enalaprilat; Female; Heart Ventricles; Hemodynamics; Humans; Infusions, Intravenous; Male; Middle Aged; Myocardial Contraction; Oxygen Consumption