Elsevier

Thrombosis Research

Volume 91, Issue 5, September 1998, Pages 229-235
Thrombosis Research

REGULAR ARTICLE
A New Thromboxane Receptor Antagonist, Z-335, Ameliorates Experimental Thrombosis without Prolonging the Rat Tail Bleeding Time

https://doi.org/10.1016/S0049-3848(98)00103-0Get rights and content

Abstract

We investigated the antithrombotic activity of Z-335, a new thromboxane A2 receptor antagonist, using experimental thrombosis models, and also tested its effect on the rat tail bleeding time. Z-335 (0.1, 0.3, and 1 mg/kg, p.o.) dose-dependently prevented the occurrence of arachidonic acid-induced pulmonary thromboembolism in mice. During photochemically induced thrombosis in the femoral artery of guinea pigs, Z-335 (0.3, 1, and 3 mg/kg, i.v.) dose-dependently prolonged the time required to form thrombi. Moreover, Z-335 (10 mg/kg/day, p.o.) strongly suppressed lauric acid-induced hind limb injury in rats. Z-335 (0.3, 3, 30, and 300 mg/kg, p.o.) did not prolong the tail bleeding time in rats. These results strongly suggest that Z-335 ameliorates experimental thrombosis without prolonging the rat tail bleeding time, and may therefore be a useful antithrombotic drug.

Section snippets

Animals

Male ICR mice (4 weeks old; Charles River, Japan), male Sprague-Dawley rats (8 weeks old; Charles River, Japan) and male Hartley guinea pigs (4 weeks old; Nihon SLC, Japan) were used in this study. These animals were housed in a temperature-controlled room for at least 5 days before starting the experiments, which were approved by the Committee for the Use of Laboratory Animals of the Central Research Laboratories of Zeria Pharmaceutical Co., Ltd..

Drugs

Z-335 ((±)-sodium

Inhibitory Effect of Z-335 on Arachidonic Acid-induced Pulmonary Thromboembolism in Mice

Z-335 (0.1, 0.3, and 1 mg/kg, p.o.) dose-dependently prevented the occurrence of sudden death. Vapiprost (10 mg/kg, p.o.), daltroban (1 mg/kg, p.o.), and cilostazol (100 mg/kg, p.o.) also decreased lethality (Table 1).

Inhibitory Effect of Z-335 on Photochemically Induced Thrombosis in Guinea Pigs

Z-335 (0.3, 1 and 3 mg/kg, i.v.) dose-dependently prolonged the time taken to form thrombi. Vapiprost (1 mg/kg, i.v.) also prolonged this time significantly, while daltroban (3 mg/kg, i.v.) showed a tendency towards prolongation, although its effect failed to reach significance.

Discussion

TxA2 plays an important role in the occurrence of arachidonic acid-induced sudden death 11, 14, 15 and Myers et al. [11] reported that a TxA2 receptor antagonist clearly protected against arachidonic acid-induced acute death in mice. The protective effects of Z-335 and other TxA2 receptor antagonists against arachidonic acid-induced sudden death are probably due to their TxA2 receptor antagonistic effects on platelets and vascular smooth muscle cells. Cilostazol, a popular antiplatelet drug in

Acknowledgements

We wish to thank Mr. Yosuke Nomura for his excellent technical assistance, and Dr. Katsuo Shinozaki, Mr. Kiyoto Maeda and Mr. Nobuo Kawase for providing us with vapiprost, daltroban, and cilostazol.

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