SUPERIOR ACTIVITY OF A THROMBOXANE RECEPTOR ANTAGONIST AS COMPARED WITH ASPIRIN IN RAT MODELS OF ARTERIAL AND VENOUS THROMBOSIS

We determined the effects of aspirin and a novel thromboxane A2/prosta glandin endoperoxide (TP)-receptor antagonist, BMS-180291, on thrombos is and bleeding times in skin and mesenteric arteries. In anesthetized rats, occlusive thrombosis was induced in the carotid artery by topic al application of ferrous chloride and in the vena cava by blood flow stasis combined with either infusion of thromboplastin or hypotonic sa line. Aspirin (1, 10, and 50 mg/kg) did not reduce arterial or venous thrombus weight significantly. BMS 180,291 (150 mug/kg/min) decreased arterial thrombus weight and hypotonic saline-induced caval thrombus w eight by 58 and 57%, respectively. BMS-180291 lacked antithrombotic ac tivity at a lower dose (50 mug/kg/min) and failed to inhibit thrombopl astin-induced caval thrombosis. BMS-180291 (150 mug/kg/min) significan tly reduced arterial thrombus weight by 40% when plasma epinephrine co ncentration was increased to 5 ng/ml. BMS-180291 and aspirin produced increases of only less-than-or-equal-to 30% in bleeding times. These r esults demonstrate that BMS-180291 has antithrombotic activity in expe rimental aspirin-resistant arterial and venous thrombosis. Both aspiri n and BMS-180291 have only modest effects on small artery hemostasis i n rats.