Coagulation defects and altered hemodynamic responses in mice lacking receptors for thromboxane A(2)

Thromboxane A(2) (TXA(2)) is a labile metabolite of arachidonic acid that h as potent biological effects, Its actions are mediated by G protein-coupled thromboxane-prostanoid (TP) receptors. TP receptors have been implicated i n the pathogenesis of cardiovascular diseases. To investigate the physiolog ical functions of TP receptors, Ne generated TP receptor-deficient mice by gene targeting. Tp(-/-) animals reproduce and survive in expected numbers, and their major organ systems are normal. Thromboxane agonist binding canno t be detected in tissues from Tp(-/-) mice, Bleeding times are prolonged in Tp(-/-) mice and their platelets do not aggregate after exposure to TXA(2) agonists. Aggregation responses after collagen stimulation are also delaye d, although ADP-stimulated aggregation is normal. Infusion of the TP recept or agonist U-46619 causes transient increases in blood pressure followed by cardiovascular collapse in wild-type mice, but U-46619 caused no hemodynam ic effect in Tp(-/-) mice. Tp(-/-) mice are also resistant to arachidonic a cid-induced shock, although arachidonic acid significantly reduced blood pr essure in Tp(-/-) mice. In summary, Tp(-/-) mice have a mild bleeding disor der and altered vascular responses to TXA(2) and arachidonic acid. Our stud ies suggest that most of the recognized functions of TXA(2) are mediated by the single known Tp gene locus.