Blockade of Thromboxane and the Prevention of Eicosanoid-Induced Sudden Death in Mice 1

Abstract

Abstract

We studied the effects of thromboxane-receptor antagonism and thromboxane synthetase inhibition in a thrombotic model of sudden death in mice. Intravenous injection of ara-chidonic acid (AA; 80 mg/kg) or the prostaglandin-endoperoxide analog U-46,619 (2.3 mg/kg) results in sudden death in approximately 90% of the animals. Pretreatment with the thromboxane receptor antagonist SQ-29,548 (0.3–10 mg/kg) protects dose-dependently against AA and U-46,619-induced sudden death. In contrast, CGS-13,080, a thromboxane synthetase inhibitor, shows a dose-dependent beneficial effect in AA-induced sudden death only. Although PTA₂ has partial thromboxane agonistic properties in the rabbit, it protected the mice against AA-induced sudden death, thus demonstrating TxA₂ antagonistic properties in this species. These data emphasize the importance of thromboxane A₂ as a major mediator of arachidonic acid-induced sudden death and the effectiveness of thromboxane-receptor antagonists in endoperoxide-induced sudden death.