YC-1, A NITRIC OXIDE-INDEPENDENT ACTIVATOR OF SOLUBLE GUANYLATE-CYCLASE, INHIBITS PLATELET-RICH THROMBOSIS IN MICE

YC-1 (3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole), a nitric oxide (NO)-independent activator of soluble guanylate cyclase, has been show n to inhibit platelet activation and aggregation in vitro through the generation of cGMP. In the present study, we assessed the antithrombot ic effect of YC-1 in models of experimental thrombosis in mice. YC-1 ( 10, 30 mu g/g, i.p.)-treated mice showed a prolonged tail bleeding tim e 30 min after injection (from control 91.0+/-6.4 s to 208.6+/-22.7 s and 291.8+/-42.4 s, respectively). In contrast, aspirin at a dose of 3 0 mu g/g (i.p.) prolonged the bleeding time to more than 600 s. Platel et-rich thrombus formation was induced by irradiation of the mesenteri c venule with filtered light in mice pretreated intravenously with flu orescein sodium. YC-1 (30 mu g/g, i.p.) markedly prolonged the occlusi on time of irradiated venules (from control 146.1+/-19.0 s to 275.6+/- 24.5 s) in heparinized (1 U/g) mice. In the same condition, aspirin (1 00 mu g/g) only slightly prolonged the time required for occlusion (19 3.2+/-13.2 s). In a model of fatal pulmonary thromboembolism induced b y intravenous injection of ADP (300 mu g/g), YC-1 was effective in red ucing mortality when administered intraperitoneally at doses of 10-30 mu g/g. The antithrombotic effect of YC-1 was correlated with the inhi bition of ADP-induced platelet aggregation ex vivo. In contrast, aspir in (30, 100 mu g/g) did not inhibit ADP-induced pulmonary thromboembol ism in vivo or platelet aggregation ex vivo. YC-1 (3, 10 mu g/g) also exhibited profibrinolytic activity ex vivo, as revealed by shortening of the euglobulin clot lysis time. Therefore, YC-1 is an effective ant ithrombotic agent in preventing thrombosis in animal models, and its a ntiaggregating and additional profibrinolytic effects may be of potent ial clinical benefit in the treatment of thromboembolic diseases.