Thromboxane agonism and antagonism in a mouse sudden death model

The effects of the stable thromboxane agonist, U46619, and sodium arachidonate were tested by i.v. injection into male and female mice. U46619 produced dose-dependent mortality in both sexes equally, in contrast to the gender-differentiated effects of arachidonic acid. The thromboxane receptor antagonist, SQ 26,536, protected in a dose-dependent manner against both arachidonate and U46619. The thromboxane antagonist was more effective against arachidonate toxicity in male than in female mice, but was equiactive against U46619 in both sexes. Neither the thromboxane synthetase inhibitor, OKY-1581, nor the cyclooxygenase inhibitor, indomethacin, protected against U46619-induced sudden death. However, cortisone acetate increased survival of mice challenged with U46619. The results support the hypothesis that thromboxane A2 mediates arachidonate-induced sudden death. The effects of arachidonate can be mimicked by the thromboxane agonist and are attenuated by the thromboxane antagonist. The gender difference in arachidonate toxicity is apparently not due to differences in sensitivity to thromboxane A2, as the thromboxane agonist was equally toxic in males and females. The greater protective effect of the thromboxane antagonist against arachidonate toxicity in males suggests that thromboxane A2 is a more important mediator of arachidonate-induced sudden death in males compared to female mice.