enalaprilat-anhydrous and Myocardial-Ischemia

Cardioprotection due to angiotensin enzyme inhibitors is attributed, at least in part, to the inhibition of bradykinin breakdown and the preconditioning effect of the elevated endogenous bradykinin level. We have previously shown that in patients undergoing percutaneous coronary intervention, one 120-second balloon inflation is insufficient to precondition the heart. The objective of the present study was to examine whether the administration of enalaprilat to these patients results in protection. Twenty patients underwent two 120-second coronary artery occlusions separated by a reperfusion interval of 10 min. Ten patients were given 50 microg x min-1 enalaprilat in an intracoronary infusion between the balloon inflations, whereas the others received an infusion of saline. In the latter control patients, there were no significant differences in ST-segment elevation between the consecutive occlusions (peak ST: 1.61 +/- 0.17 vs. 1.61 +/- 0.16 mV; time to reach 0.5 mV ST elevation: 16 +/- 4 vs. 22 +/- 7 s; mean ST: 1.03 +/- 0.12 vs. 1.02 +/- 0.11 mV). In the patients who received enalaprilat before the second balloon inflation, the ST-segment elevation was significantly less pronounced and slower during the second inflation than during the first (peak ST: 1.80 +/- 0.18 vs. 1.41 +/- 0.19 mV; time to reach 0.5 mV ST elevation: 18 +/- 4 vs. 30 +/- 4 s; mean ST: 1.04 +/- 0.11 vs. 0.85 +/- 0.14 mV). We conclude that enalaprilat administered during percutaneous coronary intervention provides protection to patients who do not have a protective response to the initial balloon inflation.

Topics: Aged; Angioplasty, Balloon, Coronary; Angiotensin-Converting Enzyme Inhibitors; Enalaprilat; Female; Humans; Ischemic Preconditioning, Myocardial; Male; Middle Aged; Myocardial Ischemia; Time Factors

Renal dysfunction occurring after open heart surgery is multifactorial in origin but activation of the renin-angiotensin system may have a prominent role. Fourteen patients with ischaemic heart dysfunction scheduled for elective coronary artery bypass graft (CABG) surgery were allocated to a treatment group [enalaprilat for 2 days; ACEI (angiotensin-converting enzyme inhibitor) group, n=7] or a control group (n=7). The cardiac index was significantly higher in ACEI-treated patients than in the controls before and after cardiopulmonary bypass (CPB) (P<0.05) and on postoperative day 2 (P<0.05). The systemic vascular resistance was significantly lower in the ACEI-treated patients than in the controls before and after CPB (P<0.05). Renal plasma flow, measured as [131I]orthoiodohippuran clearance (ClH), was higher in the ACEI group than in the control group before CPB, as was endogenous creatinine clearance after CPB (P<0.05). On post-operative day 7, ClH was significantly higher in the ACEI group than in the control group (P<0.05). Plasma renin activity and vasopressin concentration increased in both groups during CPB (P<0.05). The study demonstrates that administration of an i.v. ACEI, enalaprilat, improves cardiac output during CABG surgery in patients with ischaemic heart dysfunction. Moreover, renal perfusion was better maintained during surgery, and this effect was sustained up to post-operative day 7.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Arginine Vasopressin; Cardiac Output; Coronary Artery Bypass; Double-Blind Method; Enalaprilat; Female; Hemodynamics; Humans; Intraoperative Care; Kidney; Male; Middle Aged; Myocardial Ischemia; Postoperative Period; Renal Circulation; Renin; Treatment Outcome

To evaluate whether clonidine, enoximone, and enalaprilat reduce ischaemia-related myocardial cell damage in cardiac surgery.. Prospective randomised controlled trial.. Clinical investigation in a cardiac anaesthesia department of a university hospital.. 88 consecutive patients undergoing coronary artery bypass surgery.. After induction of anaesthesia patients continuously received the alpha 2 agonist clonidine (group 1, n = 22), the phosphodiesterase (PDE) III inhibitor enoximone (group 2, n = 22), the angiotensin converting enzyme (ACE) inhibitor enalaprilat (group 3, n = 22), or saline solution as placebo (control group, n = 22). The infusion was stopped immediately before the start of cardiopulmonary bypass.. The ST segment was analysed and the activity of creatine kinase isoenzyme MB (CKMB), cardiac troponin T (TnT), and the BB isoenzyme of glycogen phosphorylase (GPBB) were measured before the start of infusion (baseline), after weaning from cardiopulmonary bypass (CPB), at the end of surgery, 5 h after CPB, and on the morning of the first and third postoperative days.. Biometric data and time of cross-clamping were not significantly different in the four groups. Changes in the ST segment indicating ischaemia were least common in the enalaprilat group (P < 0.05). Postoperatively, CKMB activity was significantly higher in the clonidine and the control groups. Both new markers of myocardial cell damage increased more after CPB and postoperatively in the control patients (TnT peak: (mean (SD)) 3.99 (0.35) microgram/1; GPBB peak: 82 (15) ng/ml) and the clonidine-treated group (TnT peak: 3.80 (0.3) microgram/1; GPBB peak: 85 (14) ng/ml). Enalaprilat-treated patients showed the smallest overall changes in standard (CKMB) and new serological markers of myocardial ischaemia (TnT peak: 0.71 (0.1) microgram/1; GPBB peak: 44 (14) ng/ml).. In patients treated with enalaprilat before CPB, both new, more sensitive markers of ischaemic myocardial tissue damage increased significantly less than in an untreated control group. Those treated with enoximone also had lower plasma concentration of TnT and GPBB than the control group, whereas clonidine did not reduce the concentration of these markers of myocardial ischaemia. Pharmacological interventions, such as the continuous infusion of the ACE inhibitor enalaprilat, before start of CPB may help to protect the heart against ischaemia/reperfusion injury.

Topics: Adrenergic alpha-Agonists; Angiotensin-Converting Enzyme Inhibitors; Biomarkers; Cardiac Surgical Procedures; Cardiopulmonary Bypass; Clonidine; Enalaprilat; Enoximone; Humans; Middle Aged; Monitoring, Intraoperative; Myocardial Ischemia; Phosphodiesterase Inhibitors; Prospective Studies

Myocardial perfusion and contraction are closely coupled; however, the effect of recurrent no-flow ischaemia on perfusion-contraction matching remains to be established. In the present studies, we examined the influence of modulating nitric oxide availability on perfusion-contraction matching after recurrent no-flow ischaemia in acute open-chest, anaesthetized dogs. The following three groups were studied: (1) saline; (2) L-NAME (10 mg kg(-1) I.V.); and (3) enalaprilat (1.5 mg kg(-1) I.V.). Regional myocardial blood flow was measured with microspheres and contractile function with piezoelectric crystals to determine systolic wall thickening. Dogs underwent four cycles of 5 min acute ischaemia and 5 min coronary reperfusion; area at risk was similar for all groups. In all dogs, ischaemic zone contractile function was depressed after recurrent no-flow ischaemia despite increased myocardial blood flow during reperfusion; contractile function was further depressed during L-NAME and was partly restored with enalaprilat. Within the ischaemic region, blood flow in subendocardial and subepicardial layers increased significantly compared with baseline during each reperfusion period independently of treatment. Our findings suggest that reduced NO availability can significantly impair myocardial perfusion-contraction matching, which is partly restored by administration of an NO donor.

Topics: Animals; Coronary Circulation; Dogs; Enalaprilat; Female; Heart Rate; Hemodynamics; Male; Myocardial Contraction; Myocardial Ischemia; Myocardial Reperfusion; NG-Nitroarginine Methyl Ester; Nitric Oxide

Angiotensin-converting enzyme (ACE) inhibitors have been shown to have beneficial effects on ischemic myocardium. We examined whether the ACE inhibitor, enalaprilat (EN), improves intracellular sodium homeostasis during myocardial ischemia and the relationship of this effect to bradykinin.. EN (3.2 nM) was administered to isolated rat hearts that were subjected to ischemia and reperfusion. Intracellular sodium and pH were monitored using magnetic resonance spectroscopy (MRS). The specific bradykinin B2 receptor antagonist, HOE 140 (10 nM), was administered with EN in some hearts to determine the effect of bradykinin blockade on EN-mediated effects.. EN blunted the rise in ischemic intracellular sodium, measured using MRS. With reperfusion, EN-treated hearts recovered 80% of their preischemic ventricular function, compared with negligible recover, in controls. These beneficial effects of EN were blocked when the bradykinin receptor antagonist, HOE 140, was coadministered with EN. HOE 140 also blocked EN-mediated attenuation of ischemic intracellular acidosis.. These results suggest that EN exerts beneficial effects on ischemic intracellular sodium and pH homeostasis via the bradykinin receptor. These effects of EN may provide a mechanism for the beneficial actions of this agent during ischemia.

Topics: Animals; Bradykinin; Culture Techniques; Enalaprilat; Homeostasis; Intracellular Fluid; Magnetic Resonance Spectroscopy; Male; Myocardial Ischemia; Rats; Rats, Wistar; Receptors, Bradykinin; Sodium

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Capillary Permeability; Enalaprilat; Microcirculation; Myocardial Ischemia; Myocardial Reperfusion Injury; Rats; Rats, Wistar

Hemodynamic effects of valsartan ((S)-N-valeryl-N-¿[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]meth yl¿valine, CAS 137862-53-4, CGP 48933), a non-peptide angiotensin II type 1 receptor antagonist were examined in dogs with heart failure induced acutely by coronary artery ligation and chronically by rapid-ventricular pacing. Coronary artery ligation induced decrease in cardiac output and increase in left ventricular end-diastolic pressure. Valsartan at 10 mg/kg i.v. reduced blood pressure, heart rate, left ventricular pressure, left ventricular end-diastolic pressure and total systemic resistance. Similar changes were observed with enalaprilat at 0.1 mg/kg i.v. Rapid left ventricular pacing for 2 weeks reduced cardiac contractility. Valsartan, administered at a dose of 100 mg/kg/d p.o. for 2 weeks, lowered left ventricular end-diastolic pressure. Valsartan reduced preload and afterload in these two dog heart failure models.

Topics: Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Blood Pressure; Cardiac Output; Coronary Vessels; Dogs; Enalaprilat; Female; Heart Rate; Hemodynamics; Male; Myocardial Ischemia; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Stroke Volume; Tetrazoles; Valine; Valsartan; Vascular Resistance; Ventricular Function, Left

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

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