Mechanism of antagonism of thromboxane receptors in vascular smooth muscle.

The mechanism and profile of antagonism of thromboxane receptors were studied in isolated perfused cat coronary arteries and in rat aortic rings. In cat coronary arteries, the thromboxane receptor antagonist (TxRA) BM-13,505 at concentrations from 3 to 300 ng/ml, significantly attenuated the vasoconstrictor effects of both a thromboxane A2 analog (CTA2) and an endoperoxide analog (U-46,619) and did not alter the constrictor responses to leukotriene D4, arginine vasopressin, or angiotensin II. In rat aortic rings precontracted by CTA2 or U-46,619, the effective threshold concentration of BM-13,505 for relaxation was 5 ng/ml. Lower concentrations of BM-13,505 exerted no relaxation, and higher concentrations exhibited faster relaxation to the precontracted baseline levels. This relaxation was not observed in aortic rings precontracted by norepinephrine or angiotensin II. The action of TxRA was not influenced by the absence of the endothelium or by pretreatment with a selective guanylate cyclase inhibitor, methylene blue. Also, thromboxane receptor antagonists do not appear to block thromboxane induced constriction by action as free radical scavengers. It can be concluded that replacing thromboxane A2 on the vascular receptor by a TxRA is the main factor responsible for the antagonism of thromboxane induced vasoconstriction in vascular smooth muscle preparations, not, the presence of the endothelium, activation of guanylate cyclase, or scavenging of superoxide free radicals.