REDUCTION OF MYOCARDIAL INFARCT SIZE BY RAMIPRILAT IS INDEPENDENT OF ANGIOTENSIN-II SYNTHESIS INHIBITION

The angiotensin-converting enzyme inhibitor ramiprilat, the angiotensi n II receptor antagonist losartan, angiotensin II, ramiprilat plus ang iotensin II, or saline (N = 6 each group), were administered i.v. in a nesthetized, open-chest rabbit preparations of acute myocardial ischem ia. Animals were instrumented for measurement of systemic hemodynamics and left ventricular +dP/dt(max) then subjected to 30 min of left ant erior descending coronary artery occlusion (marginal branch) followed by 2 h of reperfusion. Ramiprilat (50 mug/kg), losartan (10 mg/kg), or saline were administered prior to reperfusion, and angiotensin II (2. 5 ng/kg per min) was infused 15 min prior to occlusion and throughout the remainder of the experiment. Losartan was supplemented (10 mg/kg) after 1 h of reperfusion. These non-hypotensive doses of ramiprilat an d losartan were demonstrated to significantly antagonize the systemic pressor effects of i.v. challenge with angiotensin I (15% of control, maximum) and II (5% of control, maximum), respectively, for the durati on of the experiment. Systemic hemodynamic and +dP/dt(max) changes due to occlusion/reperfusion or drug administration were similar between treatment groups. Infarct size was measured post-experimentally using tetrazolium staining and is reported as a percent of area at risk. Inf arct size/area at risk (%) was significantly lower in rabbits administ ered ramiprilat only (20 +/- 6%) or ramiprilat plus angiotensin II (2 6 +/- 5%), compared to those receiving saline (41 +/- 6%), angiotensi n II (51 +/- 4%), or losartan (52 +/- 4%, mean +/- S.E.M., P < 0.05) . These data indicate that direct angiotensin II receptor stimulation or receptor antagonism does not alter the degree of myocardial necrosi s. The results suggest that ramiprilat protects ischemic/reperfused my ocardium independent of angiotensin II synthesis inhibition.