The effect of enclothelin-l (ET-1) on thrombus formation in vivo was evaluated in two well-established canine models of coronary artery thrombosis. First, the possible antithrombotic effect of ET-1 was examined using the cyclic flow reduction (CFR) model of coronary artery stenosis, vascular endothelial cell and intimal smooth muscle cell injury, and 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 μg/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 and U-46619 by 30-60%. When aspirin was administered at 5 mg/kg prior to ET-1 administration at 0.5 pg/kg, ET-1 produced a CFR rating of 2.7 ± 0.2 (n = 6). However, higher dose aspirin (30 mg/kg, i.v.) significantly inhibited the antithrombotic effect of ET-1 (0.5 ± 0.5, n = 4). The antithrombotic effect of ET-1 was also examined using an electrolytic injury model of arterial thrombosis. The time required to produce an occlusive thrombus during the experiments in which ET-1 was administered 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 not significantly different between dogs given ET-1 and those given vehicle, suggesting that elevated plasma levels of ET-1 did not exacerbate the adverse effects of coronary occlusion. In addition, plasma ET-1 levels were elevated significantly after occlusion in the dogs given vehicle (from 7.4 to 12.4 pg/ml). Taken together, these data provide further evidence to support the notion that ET-1 release during ischemia may be involved in a protective mechanism that impedes thrombus formation in the stenosed coronary artery.
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