Protective effects of KW-3635, a thromboxane A2 antagonist, on arachidonic acid-induced transient cerebral ischemia in dogs.
We investigated the effect of KW-3635, a selective thromboxane (TX) A2-receptor antagonist, on the arachidonic acid (AA)-induced transient cerebral ischemia in anesthetized dogs. Intracarotid-arterial injection of AA (0.25-1 mg/kg) produced a transient and reversible decrease in electroencephalographic (EEG) activity. The reduction of EEG power was inhibited by the intravenous injection of KW-3635 or aspirin, a cyclooxygenase inhibitor. Local cortical perfusion (LCP) measured by a laser-doppler flow meter was also reduced concomitantly with the reduction of EEG power. Although KW-3635 at 1 and 3 mg/kg (i.v.) did not affect the maximum reduction of LCP, the duration of the reduction period of LCP was significantly shortened by KW-3635. On the other hand, aspirin at 1 and 3 mg/kg (i.v.) inhibited both the maximum and the delay of LCP reduction. The intravenous administration of KW-3635 or aspirin caused dose-dependent inhibition of ex vivo platelet aggregation stimulated by AA (150 microM) at the doses that improve the EEG activity. These data suggest that TXA2 is one of the important factors in the AA-induced transient reduction of EEG activity in anesthetized dogs. The TXA2-receptor antagonist may be useful for protection against the ischemic brain damage following transient ischemic attack.
Satoh
H
H
Department of Pharmacology, Kyowa Hakko Kogyo Co., Ltd., Shizuoka, Japan.
Kobayashi
T
T
Higo
K
K
Karasawa
A
A
D000818:Animals; D016718:Arachidonic Acid / Q000008:administration & dosage; D001241:Aspirin / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology*; D001584:Benzoxepins / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002339:Carotid Arteries; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004285:Dogs; D004569:Electroencephalography / Q000187:drug effects; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D007269:Injections, Intra-Arterial; D002546:Ischemic Attack, Transient / Q000139:chemically induced / Q000517:prevention & control*; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors*
D001562:Benzimidazoles; D001584:Benzoxepins; D016718:Arachidonic Acid; D013928:Thromboxane A2; D001241:Aspirin; C065729:KW 3635