Endothelin ETA receptor antagonist reduces myocardial infarction induced by coronary artery occlusion and reperfusion in the rat.

Abstract

The effect of the endothelin ETA receptor antagonist FR 139317 on myocardial 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 continuously infused i.v. starting approximately 30 min before coronary artery occlusion 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 percent of AAR. The IZ/AAR (%) was significantly reduced in rats treated with 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 reperfusion, 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 ETA receptor-mediated effects of ET in the pathophysiology of myocardial infarction. ETA receptor antagonism may provide a novel therapeutic approach for cardioprotection in myocardial infarction.