Inhibitory Effect of KW-3635, a New Thromboxane A2-Receptor Antagonist, on Arterial Thrombosis in Guinea Pigs

Higo, Katsuya; Karasawa, Akira

doi:10.1254/jjp.63.521

Cited by 3 publications

(2 citation statements)

References 7 publications

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“…In the endothelium-intact aorta, aspirin not only at 100 mg/kg, but even at 3 mg/kg reduced the production of PGI2. Aspirin at 3 mg/kg, does not inhibit the ex vivo platelet aggregation induced by either sodium arachidonate (100 pM) or collagen (3 pg/ml) (18). Thus, the present result implies that aspirin even at the low dose, which does not affect platelet aggregation, could at tenuate the ability of the endothelium to produce PGI2.…”

Section: Discussionmentioning

confidence: 48%

“…The doses of aspirin were determined according to the previous report (18): we used a low dose, 3 mg/kg, that did not inhibit sodium arachidonate (100 tM)-induced ex vivo platelet aggrega tion in guinea pigs 2 hr after administration and a high dose, 100 mg/kg, that completely inhibits the aggrega tion. The dose of KW-3635 examined, 10 mg/kg, was the minimum effective dose to inhibit the aggregation (18). The dose of OKY-046 was determined by a preliminary study examining the TXB2 concentration in the serum.…”

Section: Methodsmentioning

confidence: 99%

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Effects of a Thromboxane A2-Receptor Antagonist, a Thromboxane Synthetase Inhibitor and Aspirin on Prostaglandin I2 Production in Endothelium-Intact and -Injured Aorta of Guinea Pigs

Higo

Karasawa

1994

Japanese Journal of Pharmacology

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ABSTRACT-We examined the effects of KW-3635, a thromboxane (TX) A2-receptor antagonist, and OKY-046, a TX synthetase inhibitor, on the prostaglandin (PG) 12 production in endothelium-intact and -in jured guinea pig aorta and compared them with those of aspirin. In the endothelium-intact aorta, both the low (3 mg/kg) and the high (100 mg/kg) dose of aspirin similarly reduced the PGI2 production, as measured ex vivo 1 hr after the injury. In contrast, neither KW-3635 (10 mg/kg) nor OKY-046 (30 mg/kg) inhibited the PGI2 production. The endothelial injury, induced by balloon catheterization, caused a reduction of PGI2 production in the aorta and decline of plasma PGI2/TXA2 ratio. In the endothelium-injured animals, the high dose of aspirin further reduced the PGI2 production in the aorta, whereas KW-3635 and OKY-046 did not affect it. KW-3635 and OKY-046 also ameliorated the reduced ratio of PGI2/TXA2 in the plasma. The present results demonstrate that aspirin, but not KW-3635 or OKY-046, reduces the PGI2 production in the aorta either in the endothelium-intact or -injured state. It is thus suggested that the TXA2-receptor an tagonist and the TX synthetase inhibitor have some advantages over aspirin when used for the prevention of acute thrombosis after percutaneous transluminal angioplasty.

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Section: Discussionmentioning

confidence: 48%

Section: Methodsmentioning

confidence: 99%

Effects of a Thromboxane A2-Receptor Antagonist, a Thromboxane Synthetase Inhibitor and Aspirin on Prostaglandin I2 Production in Endothelium-Intact and -Injured Aorta of Guinea Pigs

Higo

Karasawa

1994

Japanese Journal of Pharmacology

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Antithrombotic effects in a rat model of aspirin-insensitive arterial thrombosis of desethyl KBT-3022, the main active metabolite of a new antiplatelet agent, KBT-3022

Shimazawa

Takiguchi

Umemura

et al. 1997

European Journal of Pharmacology

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The antithrombotic effect of desethyl KBT-3022, which is the main active metabolite of the new antiplatelet agent, KBT-3022 (ethyl 2-[4,5-bis(4-methoxyphenyl)thiazol-2-yl] pyrrol-1-ylacetate; a cyclooxygenase inhibitor), was determined using a photochemically induced arterial thrombosis model in the rat femoral artery. Pretreatment with desethyl KBT-3022 (0.1, 0.3 and 1 mg/kg, i.v.) prolonged the time required to achieve thrombotic occlusion in the femoral artery and inhibited collagen-induced platelet aggregation in whole blood ex vivo, each in a dose-dependent manner. In all 6 rats used, particularly at the highest dose (1 mg/kg, i.v.) tested, cyclic variations in blood flow were hardly ever observed and complete cessation of blood flow did not occur during the 30-min observation time. BM-13505 (1, 3 and 10 mg/kg, i.v.), a thromboxane A2 receptor antagonist, also prolonged the time to occlusion, but cyclic variations in blood flow did occur. On the other hand, aspirin (10 and 30 mg/kg, i.v.) had little effect in terms of preventing thrombosis, although it inhibited collagen-induced platelet aggregation to the same extent as did desethyl KBT-3022. Desethyl KBT-3022 inhibited the thrombin-induced aggregation of washed platelets in a concentration-dependent manner (1-40 microM), whereas aspirin and BM-13505 did not. These findings suggest that the potent antithrombotic effect of desethyl KBT-3022 may be attributable in part to its additional ability to inhibit thrombin-induced platelet aggregation. Accordingly, thromboxane A2 and thrombin may be important thrombotic mediators in this rat model.

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

Tanaka

Ito

Higashino

et al. 1998

Thrombosis Research

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Inhibitory Effect of KW-3635, a New Thromboxane A2-Receptor Antagonist, on Arterial Thrombosis in Guinea Pigs

Cited by 3 publications

References 7 publications

Effects of a Thromboxane A2-Receptor Antagonist, a Thromboxane Synthetase Inhibitor and Aspirin on Prostaglandin I2 Production in Endothelium-Intact and -Injured Aorta of Guinea Pigs

Effects of a Thromboxane A2-Receptor Antagonist, a Thromboxane Synthetase Inhibitor and Aspirin on Prostaglandin I2 Production in Endothelium-Intact and -Injured Aorta of Guinea Pigs

Antithrombotic effects in a rat model of aspirin-insensitive arterial thrombosis of desethyl KBT-3022, the main active metabolite of a new antiplatelet agent, KBT-3022

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

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