ANTITHROMBOTIC EFFECTS OF A NITRIC OXIDE-RELEASING, GASTRIC-SPARING ASPIRIN DERIVATIVE

Effects of a nitroxybutylester derivative of aspirin (NCX 4215) on pla telet aggregation and prostanoid synthesis were compared to the effect s of aspirin, NCX 4215 was approximately seven times more potent than aspirin as an inhibitor of thrombin-induced human platelet aggregation in vitro, but did not inhibit platelet thromboxane synthesis or gastr ic prostaglandin synthesis, NCX 4215 released nitric oxide when incuba ted in the presence of platelets and increased platelet levels of cGMP within 10 min of exposure, while aspirin did not. The anti-aggregator y effects of NCX 4215 in vitro were significantly attenuated by 10 mu M hemoglobin, In ex vivo studies of ADP- or collagen- or thrombin-indu ced rat platelet aggregation, aspirin and NCX 4215 had comparable inhi bitory effects 3 h after administration, Aspirin (10-120 mg/kg) caused extensive hemorrhagic erosion formation in the stomach of the rat wit hin 3 h of oral administration, while NCX 4215 did not produce signifi cant damage at doses of up to 300 mg/kg, nor when given daily for two weeks at 166 mg/kg, NCX 4215 did not alter systemic arterial blood pre ssure when administered intravenously to the rat, These studies demons trate that NCX 4215 has comparable or enhanced anti-thrombotic activit y to that of aspirin, but does not cause gastric damage or alter syste mic blood pressure, The anti-thrombotic actions of NCX 4215 are, at le ast in part, due to generation of nitric oxide.