Endothelin-receptor antagonist FR 139317 reduces infarct size in a rabbit model when given before, but not after, coronary artery occlusion

Endothelins are potent vasoactive peptides that exist as isoforms having different affinities for two main receptor subtypes, ET(A) and ET(B). Based on their potential to produce adverse effects as a result of marked vasoconstrictor actions, these mediators have been widely studied to investigate their role in disease states involving the cardiovascular system. In this study, we examined the effect of a selective ET(A)-receptor antagonist, FR 139317, on myocardial infarct size by using a rabbit arterial-occlusion model. The main coronary artery of 32 New Zealand white rabbits was occluded for 60 min, followed by 3 h of reperfusion. Sixteen animals received FR 139317 (5.0 mg/kg as a bolus+30 mg/kg given over a 90-min period), whereas the remaining 16 control rabbits received the drug vehicle. Treatment began at 15 min before coronary artery occlusion and ended at 15 min after the start of tissue reperfusion. Infarct size, expressed as a percentage of the area at risk of infarction, was 64+/-4% in the control group and 41+/-2% in the treated animals (p <0.001). In a second set of rabbits, five animals received the same treatment regimen and were compared with five controls; however, unlike the initialprotocol, treatment was initiated 45 min after coronary artery occlusion (15 min before reperfusion) and ended after 75 min of reperfusion. In this case, infarct size was 65+/-4% in the control group and 56+/-10% in the animals that received FR 139317 CNS). The results suggest that endothelin is involved in the extension of myocardial infarction in this rabbit model and that its primary action is manifest during occlusion of the coronary artery.