Beneficial Effect of OKY-046, a Selective Thromboxane A₂ Synthetase Inhibitor, on Experimental Cerebral Vasospasm

Abstract

Effects of OKY-046, a selective inhibitor of thromboxane (TX)A₂ synthetase and a platelet aggregation inhibitor, on in vitro and in vivo models of cerebral vasospasm were studied. The contraction of the isolated rabbit basilar artery by an exposure to 1.0 ml of whole rabbit blood plus 0.05 or 0.1 units/ml of thrombin was diminished by the treatment with 10^-4 M of OKY-046 and/or 10^-6 M of cinanserin. When the whole blood of rabbits treated intravenously with 1 mg/kg/min of OKY-046 was used, the contraction of the basilar artery was decreased to about half of the control contraction. Angiographically recognized cerebral vasospasm in vivo, by a transorbital injection of 5.0 to 7.0 ml of autologous arterial blood into the cisterna magna of dogs, was suppressed by 0.05 and 0.5 μg of OKY-046. Moreover, the decrease in the regional cerebral blood flow in autologous blood infused-dogs was inhibited by 0.5 μg of OKY-046. The increase in TXB₂ in the cerebrospinal fluid of dogs was significantly inhibited, and the level of 6-keto-PGF_1α was slightly increased by the treatment of OKY-046. The ratio of 6-keto-PGF_1α/TXB₂ was increased from 1.5 to 5.2 in OKY-046-treated dogs. No effect on the basal tone and response to vasoactive agonists such as norepinephrine, KCl and PGE₁ was observed in the isolated spiral thoracic aorta of guinea pigs or rabbits. Taken together with our previous findings, we conclude that the inhibition of cerebral vasospasm in the in vitro and in vivo models by the treatment of OKY-046 might be due to an inhibition of platelet aggregation, an inhibition of TXA₂ generation and an increase in the ratio of PGI₂/TXA₂.