REDUCTION OF MYOCARDIAL INFARCT SIZE IN RABBITS BY RAMIPRILAT - REVERSAL BY THE BRADYKININ ANTAGONIST HOE-140

We wished to determine, using a novel specific antagonist of BK2, HOE 140, (a) if the angiotensin-converting enzyme (ACE) inhibitor, ramipri lat, reduces myocardial infarct size in a well-established animal mode l of ischemia/reperfusion with minimal coronary collateralization, and (b) if the reduction in myocardial infarct size occurred through a br adykinin-dependent mechanism Saline vehicle, ramiprilat, HOE 140, or r amiprilat plus HOE 140 (n = 6 each group), was administered intravenou sly (i.v.) in intact animal preparations of experimentally induced acu te myocardial ischemia. Anesthetized, open-chest rabbits were instrume nted for measurement of systemic hemodynamics and left ventricular pre ssure (LVP), from which LV + dP/dt(max) was derived. Animals were subj ected to 30-min left main coronary artery occlusion (marginal branch) followed by 2-h reperfusion. Ramiprilat (50 mug/kg) or saline was admi nistered before reperfusion, and rabbits receiving HOE 140 were pretre ated before occlusion (1 mug/kg). In separate duration of action exper iments (n = 6 each group), the above doses of ramiprilat or HOE 140 ha d significant vascular antagonism of sufficient duration against seria l challenge with angiotensin I (AI) or bradykinin, respectively. After reperfusion, myocardial infarct size (IS) was determined by tetrazoli um staining and expressed as a percentage of area at risk (AR). IS/AR% was significantly reduced in rabbits that received ramiprilat (20 +/- 6%, p < 0.05) as compared with those that received saline (41 +/- 6%) , ramiprilat plus HOE 140 (47 +/- 2%), or HOE 140 alone (43 +/- 4% mea n +/- SEM). AR as a percentage of total LV mass was not different betw een any of the four treatment groups. Tachycardia was observed during early reperfusion in each group treated with ramiprilat. Sustained hyp otension (15-20 mm Hg) and a significant reduction in LV + dP/dt(max) were evident in all groups throughout reperfusion, except in rabbits t reated only with HOE 140, in which hemodynamics were maintained. The e ffect of ramiprilat to reduce infarct size is abolished by pretreatmen t with the specific bradykinin-2 antagonist, HOE 140, suggesting that bradykinin plays an important role in the myocardial protective action of ramiprilat.