988-7 Endothelin ETA/B Receptor Antagonist Reduces Infarct Size: A Novel Therapy for Acute Myocardial Infarction

Abstract

We have previously shown that regional myocardial ischemia foliDwed by reperfusion (rep) significantly enhances cardiac release of the potent vasoconstrictor endothelin (ET). We now examine the association of ET production and myocardial blood flow IMBF) in rabbits (n = 14) undergoing 30 min Df circumflex occlusion and 3 hrs of rep. MBF was measured with radioactive microspheres at baseline, 15 min into occlusion, 1 min, 1 and 3 hrs into rep. Utilizing molecular biology techniques, ET 1 mRNA was measured at 3 hrs and found to be elevated in the central ischemic zone (CIZ) compared to the non ischemic zone INIZ). In a second study we investigated the effects of exogenous ET l and PD145065 (an ET A/B receptor antagonist) on infarct size of rabbits undergoing 30 min of circumflex occlusion and 48 hrs of rep. Drug infusion started with an initial bolus (PD145065 3 mg/kg; n = 10 or ET l 10 -10 m/kg; n = 9) 10 min before occlusion followed by 10 -11 m/kg/min of ET 1 or 0.6 mg/kg/min of PD145065 for 2 hrs and 40 minutes. Control animals (n = 10) received the same volumes in saline. Infarct size (AN) was measured histologically and expressed as percentage of area at risk (AR).Results as Mean ± SEM. 1. Myocardial rep after ischemia is associated with marked reactive hyperemia. This flow decreases significantly in the CIZ at 3 hrs into rep demonstrating for the first time that the “no-reflow phenomenon” exists in the rabbit model. 2. ET 1 mRNA was elevated in the CIZ at 3 hrs, suggesting a cause-effect relationship between ET 1 production and the “no-reflow phenomenon”. 3. Exogenous infusion of ET 1 fails to alter infarct size but antagonism of the ET A/B receptors significantly reduces infarct size in rabbits and this might represent a novel therapy for acute myocardial infarction in man.