Z-335, a Thromboxane A2 Receptor Antagonist, Suppresses the Progression of Arachidonic Acid-Induced Hind Limb Gangrene in Rats

• Published in: Biological & pharmaceutical bulletin 1999/12/15, Vol.22(12), pp.1382-1384
• Main Authors: TANAKA, Kakao, FUKUTA, Yoshihisa, FUKUDA, Youichi, HIGASHINO, Raita, ITO, Shigeru, TAKEI, Mineo, TAMAKI, Hajime, KURIMOTO, Tadashi, SUZUKI, Yoshio
• Format: Article
• Language: English
• Subjects: Animals; Arachidonic Acid; Biological and medical sciences; Blood. Blood coagulation. Reticuloendothelial system; Cilostazol; Fibrinolytic Agents - pharmacology; Fibrinolytic Agents - therapeutic use; gangrene; Gangrene - chemically induced; Gangrene - prevention & control; Hindlimb; Indans - pharmacology; Indans - therapeutic use; Leg Injuries - pathology; Male; Medical sciences; peripheral vascular disease; Pharmacology. Drug treatments; Platelet Aggregation - drug effects; Platelet Aggregation Inhibitors - pharmacology; Platelet Aggregation Inhibitors - therapeutic use; Rats; Rats, Sprague-Dawley; Receptors, Thromboxane - antagonists & inhibitors; Tetrazoles - pharmacology; Tetrazoles - therapeutic use; Z-335
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.22.1382

We have developed a new rat model of gangrenous peripheral vascular disease with vascular injury and occlusive thrombi. Rat hind limb gangrene was induced by injecting arachidonic acid (2 mg/leg) into the femoral artery. Using this model, we evaluated the effect of a thromboxane A2 receptor antagonist, Z-335, on the progression of hind limb gangrene. Z-335 (10 mg/kg/d, p.o.) ameliorated arachidonic acid-induced hind limb gangrene. In contrast, daltroban (10 mg/kg/d, p.o.) and cilostazol (100 mg/kg/d, p.o.) tended to improve the hind limb gangrene but their effects failed to reach statistical significance. Z-335 (10 mg/kg. p.o.) inhibited U-46619-induced, but not collagen-induced, platelet aggregation in rat whole blood. Daltroban (10 mg/kg, p.o.) showed a tendency to inhibit U-46619-induced platelet aggregation. Cilostazol (100 mg/kg, p.o.) did not inhibit U-46619- or collageninduced platelet aggregation. Histopathological examination of the injured paws showed that Z-355 (10 mg/kg, p.o.) had partly inhibited the formation of occlusive thrombi. These results indicate that the thromboxane A2 receptor antagonist Z-335 is effective arachidonic acid-induced hind limb gangrene in rats. Our experiments sugggest that Z-335 may be beneficial in the prevention of gangrenous peripheral vascular disease.