Z-335, a new thromboxane A(2) 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 cilostazol (100 mg/kg, p.o.), a selective phosphodiesterase type III inhibitor. The effect of Z-335 (3 mg/kg, p.o.), but not cilostazol, persisted for 16 h. Z-335, but not cilostazol, inhibited platelet aggregation induced by U-46619 (a TP-receptor agonist, 9, 11-dideoxy-9alpha,11alpha-methanoepoxy prostaglandin F(2alpha)) 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.
Tanaka
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Central Research Laboratories, ZERIA Pharmaceutical Co. Ltd., 2512-1 Oshikiri, Kohnan-machi, Ohsato-gun, Saitama, 360-0111, Japan.
Sato
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Kurimoto
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D000284:Administration, Oral; D000818:Animals; D001012:Aorta, Abdominal / Q000187:drug effects / Q000473:pathology; D002712:Chlorides; D000077407:Cilostazol; D004305:Dose-Response Relationship, Drug; D005290:Ferric Compounds / Q000009:adverse effects*; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D007189:Indans / Q000494:pharmacology*; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D013777:Tetrazoles / Q000494:pharmacology; D013927:Thrombosis / Q000139:chemically induced / Q000517:prevention & control*; D013997:Time Factors
D002712:Chlorides; D005290:Ferric Compounds; D005343:Fibrinolytic Agents; D007189:Indans; D010975:Platelet Aggregation Inhibitors; D017482:Receptors, Thromboxane; D013777:Tetrazoles; C115527:Z 335; D000077407:Cilostazol; C024555:ferric chloride