ENDOTHELIN ET(A) RECEPTOR ANTAGONIST REDUCES MYOCARDIAL-INFARCTION INDUCED BY CORONARY-ARTERY OCCLUSION AND REPERFUSION IN THE RAT

The effect of the endothelin ETA receptor antagonist FR 139317 on myoc ardial infarction was studied in the rat. Under anesthesia, rats were subjected to 30 min of left main coronary artery occlusion and 3 h of reperfusion. FR 139317 (15, 35 and 70 mg/kg total dose) was continuous ly infused i.v. starting similar to 30 min before coronary artery occl usion and continuing throughout occlusion and reperfusion. The area at risk (AAR), determined using phthalocyanine dye, was in the range of 48-63% of the left ventricle (LV). The infarct zone (IZ) was evaluated by tetrazolium staining defect and its size was calculated as a perce nt of AAR. The IZ/AAR (%) was significantly reduced in rats treated wi th FR 139137 (15 mg/kg: 20 +/- 4%, n = 6; 35 mg/kg: 24 +/- 2%, n = 6, and 70 mg/kg: 26 +/- 4%, n = 8) compared to the vehicle group (36 +/- 2%, n = 22) (p<0.05). When rats were treated beginning just prior to r eperfusion, FR 139317 (35 mg/kg) also produced a significant reduction in infarct size (IZ/AAR: 22 +/- 1% for FR 139317, n = 6 vs. 39 +/- 6% for vehicle, n = 6, p<0.05). These data suggest an important role for the ET(A) receptor-mediated effects of ET in the pathophysiology of m yocardial infarction. ET(A) receptor antagonism may provide a novel th erapeutic approach for cardioprotection in myocardial infarction.