Effects of early angiotensin-converting enzyme inhibition in a pig model of myocardial ischemia and reperfusion.
In a blind, randomized study, the effects of perindopril, a nonsulfhydryl-containing angiotensin-converting enzyme (ACE) inhibitor, were compared with those of placebo in a closed-chest pig model of myocardial infarction. In anesthetized pigs, myocardial ischemia and reperfusion were induced by inflation and deflation of a catheter balloon in the left anterior descending coronary artery (LAD), respectively. Thirty minutes after induction of ischemia and 15 min before reperfusion, a bolus injection of 0.06 mg/kg perindoprilat (n = 12), the active compound of perindopril, or placebo (n = 12) was administered in the pulmonary artery of these animals. After the acute phase of myocardial infarction, treatment with 12 mg/day perindopril or placebo was continued orally for 2 weeks. During the entire treatment period, 7 of 12 animals died in the placebo group versus 2 of 12 animals in the perindopril group (Fisher's exact test p less than 0.04). This beneficial effect of perindopril on mortality could not be attributed to salvage of myocardial tissue because the increases in creatine phosphokinase and coronary venous purine levels were similar in perindopril- and placebo-treated animals. Neither were there any significant between-treatment differences in the hemodynamic and (neuro)humoral parameters during the acute phase of myocardial infarction. The difference in mortality was observed within 24 h after myocardial infarction. Prevention of acute pump failure and, especially, life-threatening ventricular arrhythmias may explain this improvement in survival by perindopril. Retrospectively, logistic regression analysis showed that, irrespective of treatment, survival was inversely correlated to plasma renin activity (PRA) before induction of ischemia (r = -0.33; p less than 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)
van Wijngaarden
J
J
Department of Pharmacology and Clinical Pharmacology, University of Groningen, The Netherlands.
Tobé
T J
TJ
Weersink
E G
EG
Bel
K J
KJ
de Graeff
P A
PA
de Langen
C D
CD
van Gilst
W H
WH
Wesseling
H
H
D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000097:blood / Q000627:therapeutic use*; D000818:Animals; D002395:Catecholamines / Q000097:blood; D003327:Coronary Disease / Q000378:metabolism / Q000517:prevention & control*; D003402:Creatine Kinase / Q000378:metabolism; D004195:Disease Models, Animal; D006439:Hemodynamics / Q000187:drug effects; D007211:Indoles / Q000097:blood / Q000627:therapeutic use; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control*; D020913:Perindopril; D011897:Random Allocation; D012083:Renin / Q000097:blood; D013552:Swine; D013997:Time Factors
D000806:Angiotensin-Converting Enzyme Inhibitors; D002395:Catecholamines; D007211:Indoles; D015121:6-Ketoprostaglandin F1 alpha; D003402:Creatine Kinase; D012083:Renin; D020913:Perindopril