Thromboxane A2 (TxA2) or its stable mimetic U-46,619 can increase the generation of arachidonate metabolites. Therefore, these studies were designed to investigate the role of prostaglandins, TxA2, and leukotrienes in the renal vascular response to U-46,619. Anesthetized rats were studied during a basal period and during an intra-aortic infusion of vehicle or U-46,619 (1 micrograms/kg per minute). U-46,619 reduced the GFR and the RBF without changing the mean arterial pressure or the femoral vascular resistance. All of the effects of U-46,619 were blocked by pretreatment with the TxA2/prostaglandin H2 receptor antagonist SQ-29,548. Pretreatment with the cyclo-oxygenase inhibitor indomethacin did not modify the renal vascular response to U-46,619. However, pretreatment with the TxA2 synthesis inhibitor UK-38,485 or with the leukotriene D4/E4 antagonist LY-163,443 markedly blunted the U-46,619-induced increase in renal vascular resistance and the decrease in GFR. These results indicate that the renal vascular response to U-46,619 is receptor mediated and is promoted by TxA2 and leukotriene D4/E4.