INHIBITION OF THROMBUS FORMATION BY ENDOTHELIN-1 IN CANINE MODELS OF ARTERIAL THROMBOSIS

The effect of endothelin-l (ET-I) on thrombus formation in vivo was ev aluated in two well-established canine models of coronary artery throm bosis. First, the possible antithrombotic effect of ET-1 was examined using the cyclic flow reduction (CFR) model of coronary artery stenosi s, vascular endothelial cell and intimal smooth muscle cell injury, an d periodic acute platelet thrombus formation. Using a rating system of 0 (no inhibition) to 3 (complete inhibition), ET-1 administration at 0.1, 0.5, and 1.0 mu g/kg, i.v. bolus, produced scores of 1.0 +/- 0.2 (n = 10), 1.8 +/- 0.4 (n = 8), and 2.1 +/- 0.3 (n = 7), respectively. ET-1 injection inhibited ex vivo platelet aggregation induced by ADP a nd U-46619 by 30-60%. When aspirin was administered at 5 mg/kg prior t o ET-I administration at 0.5 mu g/kg, ET-1 produced a CFR rating of 2. 7 +/- 0.2 (n = 6). However, higher dose aspirin (30 mg/kg, i.v.) signi ficantly inhibited the antithrombotic effect of ET-I (0.5 +/- 0.5, n = 4). The antithrombotic effect of ET-1 was also examined using an elec trolytic injury model of arterial thrombosis. The time required to pro duce an occlusive thrombus during the experiments in which ET-I was ad ministered at 10 and 20 ng kg(-1) min(-1) was 77 +/- 15 (p <0.08) and 105 +/- 16 min (p <0.05), respectively, compared to 44 +/- 5 min when vehicle was infused. Cardiovascular changes following occlusion were n ot significantly different between dogs given ET-I and those given veh icle, suggesting that elevated plasma levels of ET-I did not exacerbat e the adverse effects of coronary occlusion. In addition, plasma ET-1 levels were elevated significantly after occlusion in the dogs given v ehicle (from 7.4 to 12.4 pg/ml). Taken together, these data provide fu rther evidence to support the notion that ET-1 release during ischemia may be involved in a protective mechanism that impedes thrombus forma tion in the stenosed coronary artery.