enalaprilat-anhydrous and Myocardial-Infarction

Topics: Angina Pectoris; Angiotensin-Converting Enzyme Inhibitors; Captopril; Coronary Disease; Enalaprilat; Hemodynamics; Humans; Hypertension; Myocardial Infarction

Reperfusion after myocardial ischaemia is associated with a distinct ischaemia/reperfusion injury. Since ACE-inhibition, beyond its influence on cardiac angiotensin II formation and kinin metabolism, has been shown to be cardioprotective by decreasing leucocyte adhesion and endothelin-1 (ET-1) release, we investigated the effects of intracoronary (i.c.) enalaprilat during primary angioplasty in acute myocardial infarction.. Twenty-two patients were randomized to receive i.c. enalaprilat (50 micro g) or placebo immediately after reopening of the infarct-related artery (IRA). Plasma concentrations of soluble L-selectin, P-selectin, intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), ET-1 and nitric oxide metabolite concentrations (NOx) were measured in pulmonary arterial blood. Coronary blood flow was assessed using corrected thrombolysis in myocardial infarction (TIMI) frame counts (CTFC). During reperfusion, there was a significant increase in sL-selectin, sP-selectin and ET-1 in the placebo group, which was greatly diminished by enalaprilat. Levels of sVCAM-1 and sICAM-1 were not affected in either group. CTFC in the placebo group remained higher than normal in both the IRA and nonculprit vessels, whereas myocardial blood flow improved with enalaprilat.. Enalaprilat as adjunct to primary angioplasty might be a protective approach to prevent leucocyte adhesion and the release of ET-1, thereby improving coronary blood flow.

Topics: Aged; Analysis of Variance; Angioplasty, Balloon, Coronary; Angiotensin-Converting Enzyme Inhibitors; Biomarkers; Combined Modality Therapy; Coronary Vessels; Enalaprilat; Endothelin-1; Female; Humans; Injections; L-Selectin; Male; Middle Aged; Myocardial Infarction; Myocardial Reperfusion; Nitric Oxide; Norepinephrine; P-Selectin; Pulmonary Artery; Recurrence; Vascular Cell Adhesion Molecule-1

Data from animal models suggest that inhibition of angiotensin converting enzymes result in an increased ventricular electrical stability after reperfusion in acute myocardial infarction (MI). As electrical stability is largely dependent on ventricular repolarization, we sought to determine the impact of low-dose intracoronary (i.c.) application of enalaprilat (EN) as an adjunct to direct primary coronary intervention (PCI) on QT dynamics in the acute phase of MI.. Twenty-two consecutive patients with a first acute MI who underwent successful direct PCI (TIMI 3 flow) were randomized to i.c. EN (50 microg) or placebo/saline (PL), given immediately after reopening of the infarct vessel. On hospital admission, a 24-hour-Holter-electrocardiogram (ECG) was initiated. Slopes of the linear QT/RR regression were determined for the time intervals before reperfusion and after reperfusion.. A total of 7 patients in the EN group and 8 patients in the PL group had valid ECG recordings for beat-to-beat QT analysis. Mean RR interval and mean QT interval were not significantly different between the EN and the PL groups both before and after PCI. There were also no significant differences regarding QT/RR slopes between EN and PL groups before PCI. After PCI, QT/RR slopes significantly decreased in the EN group (0.169 +/- 0.04 to 0.121 +/- 0.03; P < 0.01), whereas there were no significant alterations in the PL group (0.175 +/- 0.04 to 0.171 +/- 0.03; P = ns).. Intracoronary EN therapy as an adjunct to direct PCI significantly decreases QT/RR slopes, suggesting a normalization of the coupling between heart rate and repolarization by improving electrical restitution. Thus, our findings offer new insights into possible beneficial effects of ACE inhibition on cardiac electrical stability in acute MI.

Topics: Analysis of Variance; Angioplasty, Balloon, Coronary; Angiotensin-Converting Enzyme Inhibitors; Combined Modality Therapy; Electrocardiography, Ambulatory; Enalaprilat; Female; Humans; Male; Middle Aged; Myocardial Infarction; Statistics, Nonparametric; Treatment Outcome

Bradykinin accumulation is a potent cardioprotective mechanism underlying angiotensin-converting enzyme (ACE) inhibition in ischemia and/or reperfusion injury. There is, however, concern about treatment with ACE inhibitors in the very early phase of acute myocardial infarction (AMI) due to adverse systemic hemodynamic effects. We tested the hypothesis that cardiac bradykinin metabolism can be influenced by very low doses of intracoronary ACE inhibitors without harmful systemic effects in patients with AMI. Twenty-two patients with AMI in Killip classes II to III who underwent primary percutaneous transluminal coronary angiography (PTCA) were randomized to intracoronary enalaprilat (50 microg) or saline, given immediately after reopening of the infarct-related artery. Hemodynamics and electrocardiograms were monitored continuously and samples for determination of ACE activity, angiotensin II, bradykinin, kininogen, and cardiac marker proteins were collected from pulmonary arterial and central venous blood. Enalaprilat had no adverse effects on systemic hemodynamics, but rather stabilized arterial pressure and cardiac rhythm during reperfusion. Enalaprilat induced a 70% reduction of ACE activity and a significant increase of bradykinin in pulmonary arterial blood. Angiotensin II was not significantly affected by enalaprilat either in pulmonary arterial or in central venous blood. Myoglobin release was lower and the duration of reperfusion arrhythmias was significantly reduced in the enalaprilat group (p <0.05). Thus, in this pilot study, intracoronary enalaprilat infusion in the infarct-related artery is feasible in the setting of primary angioplasty and is safe and well tolerated. Effective cardiac ACE inhibition can be achieved by low-dose intracoronary enalaprilat, which primarily causes a potentiation of bradykinin.

Topics: Angioplasty, Balloon, Coronary; Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Drug Synergism; Electrocardiography; Enalaprilat; Hemodynamics; Humans; Infusions, Intravenous; Myocardial Infarction; Pilot Projects; Rats; Ventricular Function, Left

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Double-Blind Method; Electrophysiology; Enalapril; Enalaprilat; Humans; Male; Membrane Potentials; Middle Aged; Myocardial Infarction; Ventricular Function, Left

Neurohormonal activation may provide a pathophysiological link between acute myocardial infarction and chronic congestive heart failure, and modulation of neurohormonal activity may be an important therapeutic target in these conditions. Plasma neurohormones were studied in 55 patients with acute myocardial infarction. Angiotensin II, noradrenaline and ANP were elevated in the early phase but tended to normalize during the first week in patients without signs of heart failure. In patients with heart failure angiotensin II and noradrenaline remained elevated for 1 month and ANP for 4-6 months. During head-up tilt, angiotensin II and noradrenaline increased most in patients with heart failure. In patients with a first myocardial infarction there was a positive correlation between sustained neurohormonal activity and infarct size. Almost complete suppression of plasma ACE activity was achieved within 30 min in 48 patients treated with intravenous enalaprilat, initiated within 24 h from the onset of infarction. The drug was tolerated in dosages of 1.0-1.2 mg given over 1-2h. Patients with systolic blood pressure between 100 and 110 mmHg incurred a greater risk of hypotension than those with higher blood pressure at baseline. Tolerance was not worse among patients treated with intravenous diuretics, metoprolol or nitroglycerin. A total of 98 patients were randomized to treatment with enalapril or placebo, initiated within 24 h from onset of infarction and continued for 4-6 months. During treatment there were no significant differences in plasma levels of angiotensin II, aldosterone, ANP or catecholamines between groups. Echocardiographic recordings were performed in 28 patients. Among patients on placebo there was a positive correlation between plasma levels of noradrenaline at days 5-7 and the increase in left ventricular volumes during the study period, and an inverse correlation between plasma aldosterone at days 5-7 and the increase in left ventricular ejection fraction during the study. No such correlation was found among patients on enalapril. ANP levels at 1 month correlated inversely with the left ventricular ejection fraction at the same time. Plasma neurohormones were measured in 223 patients with mild or moderately severe chronic heart failure, randomized to treatment with ramipril or placebo for 3 months. There was wide variation in hormone levels. Noradrenaline and aldosterone correlated inversely with exercise duration at baseline. Noradrenaline

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Atrial Natriuretic Factor; Blood Pressure; Enalapril; Enalaprilat; Exercise; Female; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Myocardial Infarction; Neurosecretory Systems; Norepinephrine; Peptidyl-Dipeptidase A; Ramipril; Ventricular Function, Left

To evaluate the acute effects of intravenous enalaprilat infusion in critically ill patients with intractable heart failure after acute myocardial infarction.. Prospective, consecutive sample, before-after trial.. Medical intensive care unit in a university hospital.. Eight consecutive patients with intractable acute heart failure after acute myocardial infarction. All study patients continued receiving inotropic, vasodilating, and diuretic medication at a constant rate. Six patients received steady intermittent mandatory ventilation and two patients were on a continuous positive airway pressure mask during the investigation, all with constant positive end-expiratory pressure. Heart failure was defined as intractable if the pulmonary artery occlusion pressure remained > 20 mm Hg despite this conventional therapy.. Enalaprilat was infused at a rate of 1 mg/hr until the pulmonary artery occlusion pressure decreased by > or = 20%.. Central hemodynamics, oxygenation, and hormonal regulation (plasma renin activity, plasma norepinephrine, epinephrine, endothelin, atrial natriuretic peptide, and vasopressin concentrations, serum angiotensin-converting enzyme activity, and serum concentrations of aldosterone) were assessed at baseline before enalaprilat infusion, and repeatedly during 2 hrs after the infusion. The statistical analysis was performed with analysis of variance for repeated measurements. Enalaprilat infusion (median dose 0.3 mg and infusion time 21 mins) caused significant but short-lasting decreases in pulmonary artery occlusion pressure (p = .007), mean arterial pressure (p = .003), mean pulmonary arterial pressure, and rate pressure product. These findings coincided with inhibition of serum angiotensin-converting enzyme activity, an increase in plasma renin activity, and a decrease in plasma endothelin concentrations (p = .041). Enalaprilat had no significant effects on the other hormones studied. Cardiac output and stroke volume index, venous admixture, oxygen extraction ratio, and mixed venous and arterial oxygen saturations remained unchanged.. Adding enalaprilat to conventional therapy makes it possible to transiently relieve pulmonary congestion while maintaining cardiac function and systemic oxygenation. The decrease in plasma endothelin concentrations may have further clinical implications, because endothelin is known to have potent vasoconstricting effects on the coronary circulation and it may also contribute to the extension of myocardial infarction. Whether these observed benefits can be maintained with repeated bolus injections or with continuous infusion of enalaprilat, remains to be settled.

Topics: Acute Disease; Aged; Combined Modality Therapy; Enalaprilat; Female; Finland; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Myocardial Infarction; Prospective Studies; Statistics as Topic; Time Factors

We treated 48 patients with intravenous enalaprilat within 24 hours from the onset of acute myocardial infarction. Concomitant therapy included thrombolytic treatment (29), intravenous metoprolol (34), intravenous nitroglycerin (16) and intravenous furosemide (15). The first 40 patients included had systolic blood pressure at baseline greater than or equal to 110 mmHg. Intravenous bolus injections of 0.2-1.2 mg (mean 1.0 mg) enalaprilat in one hour were given to 20 patients and an intravenous infusion of 1 mg over two hours was administered to another 20 patients, as well as to a separate group of 8 patients with systolic blood pressure between 100-109 mmHg at baseline. The infusion was stopped in five cases when the systolic blood pressure fell below 100 and 90 mmHg, respectively, in the two infusion groups. No hypotensive reactions were symptomatic. Blood pressure decreased from a mean of 134/82, 131/79 and 106/72 mmHg to a minimum of 117/71, 118/73 and 97/63 mmHg, respectively, in the three groups. Almost complete suppression of plasma angiotensin converting enzyme activity was achieved within 30 minutes. No significant changes were found in plasma levels of angiotensin II, renin activity or atrial natriuretic peptide between baseline and 24 hours. Treatment was continued with oral enalapril 2.5-10 mg/day, which was generally well tolerated. We conclude that intravenous and oral enalapril added to conventional therapy in the early phase of acute myocardial infarction is well tolerated in selected patients, but should be carefully titrated.

Topics: Aged; Blood Pressure; Enalaprilat; Female; Furosemide; Humans; Infusions, Intravenous; Injections, Intravenous; Male; Metoprolol; Middle Aged; Myocardial Infarction; Nitroglycerin; Renin-Angiotensin System; Thrombolytic Therapy

Cell therapy repair strategies using adult mesenchymal stromal cells have shown promising evidence to prevent cardiac deterioration in rodents even in the absence of robust differentiation of the cells into cardiomyocytes. We tested whether increasing doses of porcine adipose-tissue derived mesenchymal stem cells (pASCs) increase cardiac tissue perfusion in pigs post-myocardial infarction (MI) receiving angiotensin-converting-enzyme inhibitor (ACE inhibitors) and Beta-blockers similarly to patients. Female pigs were subjected to MI induction by sponge permanent occlusion of left circumflex coronary artery (LCx) generating approximately 10% of injured LV area with minimum hemodynamic impact. We assessed tissue perfusion by real time myocardial perfusion echocardiography (RTMPE) using commercial microbubbles before and following pASCs treatment. Four weeks after the occlusion of the left circumflex artery, we transplanted placebo or pASCs (1, 2 and 4x106 cells/Kg BW) into the myocardium. The highest dose of pASCs increased myocardial vessel number and blood flow in the border (56% and 3.7-fold, respectively) and in the remote area (54% and 3.9-fold, respectively) while the non-perfused scar area decreased (up to 38%). We also found an increase of immature collagen fibers, although the increase in total tissue collagen and types I and III was similar in all groups. Our results provide evidence that pASCs-induced stimulation of tissue perfusion and accumulation of immature collagen fibers attenuates adverse remodeling post-MI beyond the normal beneficial effects associated with ACE inhibition and beta-blockade.

Topics: Adipose Tissue; Animals; Coronary Circulation; Enalaprilat; Female; Hemodynamics; Mesenchymal Stem Cell Transplantation; Metoprolol; Myocardial Infarction; Swine; Transplantation, Homologous; Ventricular Remodeling

Translocation and activation of protein kinase C (PKC) has been shown to occur in the ischemic heart. It is, however, controversial if this activation process occurs also in the non-ischemic, remote area of an infarcted heart early after infarction. Furthermore, the mechanisms contributing to the translocation process induced by acute myocardial ischemia in both areas are not fully elucidated.. Regional myocardial infarction was induced by left anterior descending coronary artery (LAD-) ligation in situ for 2.5 min in rats or in pigs. To evaluate the influence of angiotensin and bradykinin signaling, ramiprilat, candesartan, or the bradykinin-receptor antagonist HOE 140 was given. In biopsies from the ischemic and the non-ischemic remote area, PKC activity and intracellular isozyme distribution were determined.. Translocation and activation of PKC could be demonstrated for the first time in the myocardium remote from the infarcted area. This activation was conserved both in pigs and in rats. All major cardiac isozymes of PKC were involved. Whereas bradykinin-receptor blockade had no effect, both angiotensin-converting enzyme inhibition (ACEI) and angiotensin receptor could effectively block this activation process of PKC.. In the area remote from a myocardial infarction, the activation of PKC could be detected for the first time as early as 2.5 min after LAD ligation. This newly characterized activation in the non-infarcted area can be prevented by ACEI via an angiotensin-AT1-receptor-dependent mechanism. It is supposed that this newly characterized activation process of PKC plays an important role in the signal transduction in the remote myocardium in acute myocardial infarction as a trigger for the late development of hypertrophy and heart failure.

Topics: Angiotensin I; Angiotensin-Converting Enzyme Inhibitors; Animals; Enalaprilat; Enzyme Activation; Isoenzymes; Ligation; Male; Myocardial Infarction; Myocardium; Protein Kinase C; Rats; Rats, Wistar; Receptors, Angiotensin; Swine; Time Factors

Angiotensin-converting enzyme (ACE) inhibitors differ in their ability to inhibit tissue ACE. This study was, therefore, undertaken to determine whether high tissue affinity ACE inhibitors would improve endothelial function and thereby decrease tissue necrosis during ischemia.. In a porcine model, the second and third diagonal vessels were occluded for 90 minutes, followed by 45 minutes of cardioplegic arrest and 180 minutes of reperfusion. During the period of coronary occlusion, 10 pigs received enalaprilat (low affinity tissue ACE inhibitor), 0.05 mg/kg intravenously, 10 received quinaprilat (high affinity tissue ACE inhibitor), 10 mg intravenously, and 10 others received no ACE inhibitor.. Wall motion scores (4, normal, to -1, dyskinesia) were higher in animals treated with ACE inhibitors (3.20+/-0.15 SE enalaprilat versus 3.08+/-0.23 quinaprilat versus 1.52+/-0.07 no ACE; both p < 0.0001 from no ACE). Endothelial-dependent relaxation to bradykinin was best preserved in the quinaprilat-treated hearts (32.1%+/-7.6% enalaprilat versus 65.8%+/-12.6% quinaprilat versus 30.6%+/-10.7% no ACE; p < 0.0001 from no ACE; p < 0.005 from enalaprilat). This was associated with a greater reduction in infarct size: area necrosis/area risk 24.3%+/-0.8% enalaprilat (p < 0.0001 from no ACE) versus 14.3%+/-3.2% quinaprilat (p < 0.0001 from no ACE; p < 0.005 from enalaprilat) versus 40.0%+/-1.7% no ACE.. ACE inhibitors with higher affinity to tissue ACE result in better preservation of endothelial function and less tissue necrosis during coronary revascularization.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Enalaprilat; Endothelium, Vascular; Infusions, Intravenous; Isoquinolines; Myocardial Contraction; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Necrosis; Swine; Tetrahydroisoquinolines

The respective role of angiotensin-converting enzyme (ACE) and neutral endopeptidase 24.11 (NEP) in the degradation of bradykinin (BK) has been studied in the infarcted and hypertrophied rat heart. Myocardial infarction (MI) was induced in rats by left descendant coronary artery ligature. Animals were killed, and hearts were sampled 1, 4, and 35 days post-MI. BK metabolism was assessed by incubating synthetic BK with heart membranes from sham hearts and infarcted (scar) and noninfarcted regions of infarcted hearts. The half-life (t1/2) of BK showed significant differences among the three types of tissue at 4 days [sham heart (114 +/- 7 s) > noninfarcted region (85 +/- 4 s) > infarcted region (28 +/- 2 s)] and 35 days post-MI [sham heart (143 +/- 6 s) = noninfarcted region (137 +/- 9 s) > infarcted region (55 +/- 4 s)]. No difference was observed at 1 day post-MI. The participation of ACE and NEP in the metabolism of BK was defined by preincubation of the membrane preparations with enalaprilat, an ACE inhibitor, and omapatrilat, a vasopeptidase inhibitor that acts by combined inhibition of NEP and ACE. Enalaprilat significantly prevented the rapid degradation of BK in every tissue type and at every sampling time. Moreover, omapatrilat significantly increased the t1/2 of BK compared with enalaprilat in every tissue type and at every sampling time. These results demonstrate that experimental MI followed by left ventricular dysfunction significantly modifies the metabolism of exogenous BK by heart membranes. ACE and NEP participate in the degradation of BK since both enalaprilat and omapatrilat have potentiating effects on the t1/2 of BK.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Cell Membrane; Chromatography, High Pressure Liquid; Enalaprilat; Hypertrophy, Left Ventricular; In Vitro Techniques; Male; Myocardial Infarction; Myocardium; Neprilysin; Peptidyl-Dipeptidase A; Pyridines; Rats; Rats, Wistar; Thiazepines; Ventricular Function, Left

There is no agreement on the effect of angiotensin II receptor blockade in the setting of ischemic reperfusion. Our aim was to assess the acute effects of angiotensin-converting enzyme (ACE) inhibition and angiotensin II AT1-subtype receptor blockade in pig heart. Five groups of open-chest pigs received 1 hour of left anterior descending (LAD) coronary artery occlusion and 2 hours of reperfusion. Left ventricular pressure was monitored by an intraventricular catheter, and regional segment shortening (%SS) in the LAD-supplied territory was measured by ultrasonic crystals implanted in the subendocardium. Group 1 (n = 6) served as the control; groups 2 (n = 6) and 3 (n = 6) received the angiotensin II receptor blocker, EXP 3174 (C22H21Cl1N6O2), and the ACE inhibitor, enalaprilat, respectively, prior to LAD occlusion; group 4 (n = 6) was preconditioned with two cycles of 10 minutes of coronary occlusion and 30 minutes of reperfusion; and group 5 (n = 6) underwent preconditioning with additional administration of EXP 3174 prior to the 60-minute occlusion period. Infarct sizes were measured by p-nitrobluetetrazolium staining and were expressed in percent of the ischemic area of risk. The angiotensin II receptor blocker EXP 3174 and enalaprilat reduced infarct sizes significantly (35.3 +/- 17.1% and 40.1 +/- 15.1%, respectively) compared with controls (71.2 +/- 12.8%, P < 0.05), and EXP 3174 augmented the infarct size-limiting effects of preconditioning by ischemia (10.5 +/- 6% vs. 28.6 +/- 5.3%, P < 0.05). Regional contractile dysfunction during reperfusion demonstrated no changes after angiotensin II receptor blockade. Angiotensin II receptor blockade reduced infarct size comparable with that obtained with angiotensin converting-enzyme inhibition. The infarct size-limiting effects of ischemic preconditioning were augmented by administration of the angiotensin II receptor antagonist EXP 3174. These data support the concept that blockade or inhibition of angiotensin II before coronary occlusion is protective in a swine model of acute ischemia and reperfusion.

Topics: Angiotensin Receptor Antagonists; Animals; Enalaprilat; Hemodynamics; Imidazoles; Losartan; Male; Myocardial Infarction; Myocardium; Swine; Tetrazoles

In this study, the acute haemodynamic effects of angiotensin converting enzyme (ACE) inhibition with intravenous enalaprilat alone or in combination with preload restoration were determined in patients with severe heart failure complicating acute myocardial infarction. Ten patients with raised pulmonary arterial wedge pressure (PAWP > or = 18 mmHg) were first studied during constant conventional vasodilation with diuretic and inotropic medication, by monitoring central haemodynamics and arterial blood gases. The same variables were measured before enalaprilat infusion, after preload reduction with enalaprilat (1 mg.h-1, rate doubled every 30 min until PAWP decreased > or = 25% or up to total cumulative dose of 10 mg) and after preload restoration with fluid loading (4% albumin given 15 ml.min-1 to restore PAWP to baseline) during continuous low dose enalaprilat infusion. Enalaprilat alone (median dose 0.9 mg) reduced significantly the PAWP (from 25 to 17 mmHg; P = 0.004), the mean arterial pressure (from 87 to 83 mmHg; P = 0.008), the mean pulmonary arterial pressure and the right atrial pressure. The cardiac index, stroke volume index and systemic vascular resistance index remained unchanged. Preload restoration during continuous enalaprilat infusion (median dose of 4% albumin 230 ml, and enalaprilat 0.2 mg) did not further enhance left ventricular function; rather, there was a nearly significant decrease in myocardial perfusion pressure. Arterial oxygenation remained unchanged throughout the study. In conclusion, adding intravenous enalaprilat to conventional therapy makes it possible to relieve pulmonary congestion while maintaining the cardiac function and arterial oxygenation. Preload restoration during continuous ACE inhibition offers no further advantages, and may have adverse effects, since the myocardial perfusion pressure may fall.

Topics: Aged; Enalaprilat; Female; Heart; Heart Failure; Hemodynamics; Humans; Infusions, Intravenous; Male; Middle Aged; Myocardial Infarction; Pulmonary Circulation; Pulmonary Wedge Pressure

1. In order to determine whether the renin-angiotensin system is involved in myocardial ischaemia-reperfusion injury, we investigated and compared the effects on infarct size of two different drugs which interfere with this system, i.e., an angiotensin II (AT1) antagonist, EXP3174, and an angiotensin I-converting enzyme inhibitor (ACEI), enalaprilat in a canine model of ischaemia-reperfusion. 2. EXP3174 (0.1 mg kg-1, i.v. followed by 0.02 mg kg-1 h-1 for 5.5 h) and enalaprilate (0.3 mg kg-1, i.v. followed by 0.06 mg kg-1 h-1 for 5.5 h) were used in doses inducing a similar level of inhibition (87 +/- 4 and 91 +/- 3%, respectively) of the pressor responses to angiotensin I. Control animals received saline. 3. Infarct size and area at risk were quantified by ex vivo dual coronary perfusion with triphenyltetrazolium chloride and monastral blue dye. Regional myocardial blood flows (ischaemic and nonischaemic, endocardial, epicardial) were assessed by the radioactive microsphere technique. 4. Both EXP3174 and enalaprilat induced a decrease in mean arterial blood pressure. However, non significant changes in regional myocardial blood flows, whether ischaemic or nonischaemic, were observed after administration of either the ACEI or the AT1 antagonist. 5. The size of the area at risk was similar in the three groups. By direct comparison, there were no significant differences between infarct sizes in the three groups. Furthermore, there was a close inverse relationship between infarct size and transmural mean collateral blood flow in controls, and none of the treatments altered this correlation. Thus, neither EXP3174 nor enalaprilat limited infarct size. 6. These results indicate that activation of the renin-angiotensin system does not contribute to myocyte death in this canine ischaemia/reperfusion model.

Topics: Anesthesia; Angiotensin I; Angiotensin II; Animals; Antihypertensive Agents; Blood Pressure; Coronary Circulation; Disease Models, Animal; Dogs; Enalaprilat; Female; Furosemide; Heart Rate; Imidazoles; Injections, Intravenous; Losartan; Male; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Renin-Angiotensin System; Tetrazoles

Both circulating and local renin-angiotensin systems (RAS) may contribute to cardiovascular homeostasis under normal and pathophysiologic conditions. They may also play a role in the effects of angiotensin-converting enzyme (ACE) inhibitors. In the present study, we compared systemic and regional hemodynamic effects of nonhypotensive doses of captopril and enalaprilate in normal rats, spontaneously hypertensive rats (SHR), and rats with heart failure due to myocardial infarction (MI). Enalaprilate (0.1 mg/kg) or captopril (3 mg/kg) was injected intravenously (i.v.) in conscious rats equipped with miniature Doppler flow probes on renal and mesenteric artery and abdominal aorta or an electromagnetic flow probe on the ascending aorta to measure cardiac output (CO). This resulted in a shift of the angiotensin-I (ANG I) dose-pressor curve (ED50 of ANG I after saline 0.21 +/- 0.33 micrograms, enalaprilate 1.45 +/- 0.26 micrograms, captopril 2.38 +/- 0.73 micrograms; mean +/- SEM; n = 6-12). In the systemic hemodynamic groups, no significant changes in mean arterial pressure (MAP), CO, or total peripheral resistance (TPR) were observed. In the regional hemodynamic groups, enalaprilate caused a slight (-8 +/- 1 mm Hg) reduction in MAP in normal rats. Resistance in the hindquarters was not affected by ACE inhibitors, whereas only enalaprilate reduced mesenteric resistance in MI rats. In contrast, renal resistance was reduced and renal blood flow (RBF) increased after captopril in normal and MI rats and after enalaprilate in MI rats. Effects were greatest in MI rats (RBF: saline -0.05 +/- 1.9%, enalaprilate 10.3 +/- 2.4%, captopril 10.1 +/- 2.0%).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Captopril; Cardiac Output; Enalaprilat; Heart Failure; Hemodynamics; Hypertension; Injections, Intravenous; Male; Myocardial Infarction; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renal 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

A model of congestive heart failure (CHF) was produced in rats approximately 76 days following surgical occlusion of the left coronary artery. In rats with healed myocardial infarction (MI size = 45% LV), hemodynamic variables were predictably elevated (LVEDP greater than 20 mm Hg) or depressed LV dP/dtmax (5200 mm Hg/sec). The hemodynamic response (MAP, HR, LVEDP, and dP/dtmax) to intravenous infusion of Mil (54 to 347 micrograms/kg) was measured on two occasions, separated by a 7-12 day period of oral treatment (2 mg/kg/day). Enalaprilat was tested in a similar design with the infusion phase (70 micrograms/kg, total dose) separated by oral enalapril (Enal), 1 mg/kg/day. The hemodynamic response to Mil was also examined in rats treated with the ACE inhibitor. At low doses, Mil modestly elevated HR (+17 beats/min) and dose-dependently increased (P less than 0.05) LV contractility by approximately 25%. Higher doses of Mil reduced preload (LVEDP) and afterload (MAP). Oral Mil produced little hemodynamic improvement except modest elevation (+9%) in LV contractility. There was no evidence of tachyphylaxis to i.v. Mil. In contrast, enalaprilat reduced MAP and preload without altering HR or contractility, effects observed after oral treatment. In the presence of the ACE inhibitor, Mil's hemodynamic actions were not enhanced. These experiments demonstrate that ACE inhibition improves ventricular performance by reducing preload and afterload. In this model, Mil improves performance by a direct inotropic mechanism as well as a reduction in afterload.

Topics: Animals; Antihypertensive Agents; Drug Therapy, Combination; Enalapril; Enalaprilat; Heart Failure; Hemodynamics; Milrinone; Myocardial Contraction; Myocardial Infarction; Pyridones; Rats; Vasodilator Agents

Enalaprilic acid (MK-422), the biologically active diacid of the converting enzyme inhibitor enalapril, was studied in myocardial ischemia (MI). Acute left coronary artery ligation was produced in 62 male Sprague-Dawley rats, and infarct size was determined by left ventricular free wall (LVFW) creatine kinase (CK) activity. Administration of enalaprilic acid (2 mg/kg) 2 minutes and 24 hours after MI significantly blunted the reduction in LVFW CK activity at 48 hours after ligation, when compared to the MI rats given vehicle (6.4 +/- 0.5 vs 4.7 +/- 0.2 IU/mg protein, respectively; p less than 0.01). The percentage of LVFW spared was significantly (p less than 0.01) increased from 28 +/- 2% to 45 +/- 5% by MK-422. MK-422 also significantly blunted the loss of LVFW CK activity 48 hours after a coronary ligation (10 minutes) followed by reperfusion, when compared to vehicle (10.1 +/- 0.6 vs 8.3 +/- 0.6 IU/mg protein, respectively; p less than 0.05). This represents a significant increase in the percentage of LVFW spared, 65 +/- 5% vs 85 +/- 6% (p less than 0.05). These data indicate a significant protective action afforded by MK-422 in two different protocols of ischemic damage to the myocardium and suggest a role for the renin-angiotensin system in the extension of ischemic damage.

Topics: Angiotensin II; Animals; Coronary Circulation; Creatine Kinase; Dipeptides; Enalaprilat; Heart Ventricles; Male; Myocardial Infarction; Rats; Rats, Inbred Strains; Renin-Angiotensin System