Protective actions of a new potent thromboxane receptor antagonist in arachidonate induced sudden death.

Sodium arachidonate (NaAr) at a dose of 1.1 mg/kg injected i.v. is uniformly lethal in rabbits within 5 min. This sudden death is typified by a precipitous drop in mean arterial blood pressure, a dramatic decrease in the circulating platelet count, and by a marked rise in plasma thromboxane A2 (TxA2) concentration as measured by radioimmunoassay of its breakdown product, TxB2. Pretreatment with S-145, a new thromboxane receptor antagonist, at doses ranging from 50 to 500 micrograms/kg resulted in 100% survival of all the rabbits subjected to sodium arachidonate injection. However, at 20 micrograms/kg S-145 only 25% of the rabbits challenged with NaAr survived. S-145 pretreatment also inhibited the decreases in circulating platelet count and in blood pressure associated with the i.v. injection of sodium arachidonate (NaAr). S-145 blunted the rise in plasma TxB2 concentration at all doses. S-145 was also shown to be a potent and long-lasting antagonist of TxA2 receptors in isolated rabbit aortic rings. Our data show that S-145 is a very effective protective agent against NaAr-induced sudden death in rabbits.