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 enzyme (ACE) or receptor blockade of angiotensin II type I on the size of myocardial infarcts induced by coronary occlusion-reperfusion in rabbits fed a high-cholesterol or normal diet for 10 weeks. In treated rabbits, myocardial infarction occurred 24 h after the last dose of enalapril or L-158809, an angiotensin II type I receptor antagonist, because of the drugs’ waning effects 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 long-term treatment with enalapril, but not L-158809. The favorable effects of enalapril treatment disappeared after pretreatment with the bradykinin B2 receptor blocker HOE 140. Long-term enalapril or L-158809 administration did not reduce the size of the infarct in rabbits fed a normal diet. ACE activity in ischemic myocardium significantly exceeded that in nonischemic myocardium and was further increased in cholesterol-fed rabbits, but was significantly reduced by long-term enalapril, but not L-158809. Moreover, treatment with enalapril, but not L-158809, restored acetylcholine-induced endothelium-dependent relaxation of aortic rings from cholesterol-fed rabbits. These results demonstrate that long-term ACE inhibition, but not angiotensin II type I receptor blockade, effectively reduces the size of myocardial infarcts in cholesterol-fed rabbits. The favorable effects of enalapril treatment may involve primarily a bradykinin B2 receptor-mediated pathway.