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 B(2) 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 B(2) receptor-mediated pathway.
Hoshida
S
S
Division of Cardiology, the First Department of Medicine, Osaka University School of Medicine, Suita 565-0871, and Cardiovascular Division, Osaka Rosai Hospital, Sakai, Osaka, Japan. hoshidas@orh.go.jp
Yamashita
N
N
Kuzuya
T
T
Hori
M
M
D000704:Analysis of Variance; D000818:Animals; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D004195:Disease Models, Animal; D004656:Enalapril / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology; D006439:Hemodynamics / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology* / Q000503:physiopathology; D015425:Myocardial Reperfusion; D011336:Probability; D011817:Rabbits; D012016:Reference Values; D012084:Renin-Angiotensin System / Q000187:drug effects*; D015996:Survival Rate; D013777:Tetrazoles / Q000494:pharmacology*
D002791:Cholesterol, Dietary; D007093:Imidazoles; D013777:Tetrazoles; C070967:L 158809; D004656:Enalapril