Mechanism of the protective action of Bay-u-3405, a new specific thromboxane receptor antagonist, in arachidonate-induced sudden death

Abstract

Injection of sodium arachidonate (NaAr) intravenously at a dose of 2 mg/kg is uniformly lethal in rabbits within 3 min. This sudden death is characterized by a precipitous drop in mean blood pressure within 2 min after injection of NaAr, a marked decrease in the circulating platelet count, a significant increase in intratracheal pressure and in plasma thromboxane A2 (TxA2) concentration as measured by radioimmunoassay of its stable breakdown product, TxB2. Pretreatment with Bay-u-3405, a new specific thromboxane receptor antagonist, at a dose of 1 or 10 mg/kg dramatically protected rabbits against sudden death induced by injection of NaAr. All of the rabbits treated with either of these two doses of Bay-u-3405 survived, and their thrombocytopenia, elevated plasma TxB2 concentration and bronchoconstriction were significantly attenuated. However, administration of 0.1 mg/kg Bay-u-3405 exerted no protective effect in this lethal model. Bay-u-3405 was shown to be a potent and specific inhibitor of thromboxane-mimetic induced platelet aggregation in vitro. Our data clearly show that Bay-u-3405 is a very effective protective agent against NaAr-induced sudden death in rabbits, blocking all of the known deleterious effects of TxA2.