Effects of losartan, captopril and angiotensin II Type 2 receptor agonist (CGP42112A) on myocardial ischemia-reperfusion necrosis in in vivo rat

BACKGROUND: Myocardial ischemia?reperfusion (MI/R) represents a clinically relevant problem associated with thrombolysis, angioplasty and coronary bypass surgery. Angiotensin II (Ang II) elicits several pathophysiological effects that exacerbate ischemia-reperfusion (I/R) injury. The cardioprotective efficacy of strategies that decrease Ang II production and receptor?s stimulation has been investigated in models of I/R injury. The aim of this study was to examine the effects of ACE inhibitor captopril, AT1 receptor blocker losartan and AT2 receptor agonist CGP42112A, on ischemia-reperfusion-induced myocardial infarct size in an in vivo rat model. MATERIAL AND METHODS: To produce necrosis, a branch of the descending left coronary artery was occluded for 30 min followed by two hours reperfusion. ECG changes, blood pressure and heart rate were measured during all experiment. Captopril (3mg/kg), losartan (2mg/kg) and CGP42112A (1mg/kg/min) were given I.V. 10 min before ischemia and continued during ischemia. Infarction was measured triphenyl tetrazolium staining. The volume of infarct and the risk zone was calculated by Image Tool 2.0 program. RESULTS: Compared to the control group (%64±6) captopril (%46±4, p<0.05), losartan (%43±2, p<0.05), CGP42112A (%41±4, p<0.05), CGP42112A+captopril (%38±7, p<0.05) and CGP42112A+losartan (%44±3, p<0.05). There was no statistical difference among the risk zone. CONCLUSION: Our results indicate that, blockage of Ang II produce by captopril or AT1 receptor antagonist losartan and AT2 receptor agonist CGP42112A exert cardioprotective activity after I/R injury. The therapeutic success of these drugs is related to their unique involving both a reduction of plasma and tissue Ang II concentrations and blockage of Ang II harmful effects by AT1 receptor or AT2 receptor activation. Also, the infarct size reduction by losartan was abolished with blockade of the AT2 receptor, suggesting a cardioprotective action of losartan through a signal cascade of AT2 receptor activation, bradykinin and prostaglandins. Key Words: Angiotensin II, captopril, losartan, AT2 receptor, CGP42112A, myocardial ischemia-reperfusion, necrosis.