Z-335, a new thromboxane A2 receptor antagonist, prevents arterial thrombosis induced by ferric chloride in rats

We examined the antithrombotic effect of Z-335 ((+/-)-sodium [2-(4-chlorophenylsulfonylaminomethyl)indan-5-yl]acetate monohydrate), an orally active thromboxane A(2) receptor (TP-receptor) antagonist that ameliorates experimental gangrene, using a rat arterial thrombosis model. The thrombi were induced by topical application of 50% ferric chloride solution to the rats abdominal artery. Z-335 (0.3-3 mg/kg, p.o.) inhibited thrombus formation in a dose-dependent manner. The antithrombotic effect of Z-335 (1 and 3 mg/kg, p.o.) was almost equivalent with that of eilostazol (100 mg/kg, p.o.), a selective phosphodiesterase type III inhibitor. The effect of Z-335 (3 mg/kg, p.o.), but not eilostazol, persisted for 16 h. Z-335, but not eilostazol, inhibited platelet aggregation induced by U-46619 (a TP-receptor agonist, 9,11-dideoxy-9 alpha,11 alpha-methanoepoxy prostaglandin F-2 alpha) for 16 h in rat whole blood. Histopathological examination also revealed that Z-335 prevented ferric chloride-induced thrombus formation. These results suggest that Z-335 may prevent ferric chloride-induced arterial thrombosis through its antiplatelet action by blocking TP-receptor activation. (C) 2000 Elsevier Science B.V. All rights reserved.