Role of atherosclerosis on myocardial infarction -cross talk of renine-angiotensis system and nitric oxide-

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Drugs which effectively reduce myocardial infarction size in animal exprerimental models could not always be effective in clinical myocardial infarction, partly because coronary atherosclerosis is existing in background of clinical myocardial infarction. Angiotensin converting enzyme inhibitors (ACEI) inhibit the extent of myocardial infarction, together with reduction of atherosclerotic lesion. Because ACEI also inhibit kininase, increase bradykinin concentration and augment NO production, ACEI is assumed to reduce myocardial infarct size when given to atherosclerotic model through regression of atherosclerosis and maintaining NO production. In this study, we applied 1% cholesterol diet to Japanese while rabbit. Myocardial infarct size was markedly enlarged in cholesterol fed rabbits. In these rabbits, myeloperoxidase activity and LTB4 production in ischemic region were increased, suggesting that activation of leukocytes in coronary microcirculation is involved in the mechanism of myocardial injury in the hypercholesterolemic model. Endothelium dependent relaxation was attenuated in hypercholesterolemic rabbits and exogenous NO donnor reduced the extent of myocardial infarction. Therefore, reduction of NO production in atherosclerotic vessel might be responsible for the activation of leukocytes in cholesterol fed animals. In hypercholesterol diet group, ACE activity in vascular wall and angiotensin II level in serum were also increased. ACEI could reduced both the ACE activity and the angiotensin II level, together with reduction of atherosclerotic lesion. These results suggest that (1) activation of renin-angiotensin inhibits NO production in coronary circulation, (2) reduction of NO production activates leukocytes in myocardial tissue and augment myocardial infarct size and (3) ACEI can improve these pathophysiology in atherosclerotic lesion.