Differential effects of long-term renin-angiotensin system blockade on limitation of infarct size in cholesterol-fed rabbits

We evaluated the effects of chronic inhibition of angiotensin-converting en zyme (ACE) or receptor blockade of angiotensin II type I on the size of myo cardial infarcts induced by coronary occlusion-reperfusion in rabbits fed a high-cholesterol or normal diet for 10 weeks. In treated rabbits, myocardi al infarction occurred 24 h after the last dose of enalapril or L-158809, a n angiotensin II type I receptor antagonist, because of the drugs' waning e ffects on hemodynamic parameters. The size of the infarct was significantly larger in cholesterol-fed rabbits than in rabbits fed a normal diet. This augmentation of infarct size in cholesterol-fed rabbits was reversed by lon g-term treatment with enalapril, but not L-158809. The favorable effects of enalapril treatment disappeared after pretreatment with the bradykinin B-2 receptor blocker HOE 140. Long-term enalapril or L-158809 administration d id not reduce the size of the infarct in rabbits fed a normal diet. ACE act ivity in ischemic myocardium significantly exceeded that in nonischemic myo cardium and was further increased in cholesterol-fed rabbits, but was signi ficantly reduced by long-term enalapril, but not L-158809. Moreover, treatm ent with enalapril, but not L-158809, restored acetylcholine-induced endoth elium-dependent relaxation of aortic rings from cholesterol-fed rabbits. Th ese results demonstrate that long-term ACE inhibition, but not angiotensin II type I receptor blockade, effectively reduces the size of myocardial inf arcts in cholesterol-fed rabbits. The favorable effects of enalapril treatm ent may involve primarily a bradykinin B-2 receptor-mediated pathway. (C) 2 000 Elsevier Science Ireland Ltd. All rights reserved.