Z-335, a thromboxane A2 receptor antagonist, suppresses the progression of arachidonic acid-induced hind limb gangrene in rats.
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 collagen-induced 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 against arachidonic acid-induced hind limb gangrene in rats. Our experiments suggest that Z-335 may be beneficial in the prevention of gangrenous peripheral vascular disease.
Tanaka
T
T
Central Research Laboratories, Zeria Pharmaceutical Co., Ltd., Saitama, Japan.
Fukuta
Y
Y
Fukuda
Y
Y
Higashino
R
R
Ito
S
S
Takei
M
M
Tamaki
H
H
Kurimoto
T
T
Suzuki
Y
Y
D000818:Animals; D016718:Arachidonic Acid; D000077407:Cilostazol; D005343:Fibrinolytic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D005734:Gangrene / Q000139:chemically induced / Q000517:prevention & control*; D006614:Hindlimb; D007189:Indans / Q000494:pharmacology / Q000627:therapeutic use*; D007869:Leg Injuries / Q000473:pathology; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use
D005343:Fibrinolytic Agents; D007189:Indans; D010975:Platelet Aggregation Inhibitors; D017482:Receptors, Thromboxane; D013777:Tetrazoles; C115527:Z 335; D016718:Arachidonic Acid; D000077407:Cilostazol