DUP-753, THE SELECTIVE ANGIOTENSIN-II RECEPTOR BLOCKER, IS A COMPETITIVE ANTAGONIST TO HUMAN PLATELET THROMBOXANE A2 PROSTAGLANDIN-H2 (TP) RECEPTORS

DuP 753 is a potent, selective angiotensin II type I (AT1) receptor antagonist. The possibility was investigated that DuP 753 may crossreact with thromboxane A2/prostaglandin H-2 (TP) receptors. DuP 753 inhibited the specific binding of the TP receptor antagonist [H-3]SQ 29,548 (5 nM) in human platelets with k(d)/slope factor values of 9.6+/-1.4-mu-M /1.1+/-0.02. The AT2-selective angiotensin receptor ligand, PD 123,177 was a very weak inhibitor of specific [H-3]SQ 29,548 binding in platelets (K(d)/Slope factor:200-mu-M/0.86). [H-3]SQ 29,548 saturation binding in the absence and presence of DuP 753 resulted in an increase in equilibrium affinity constant (K(d): 9.3, 22, 33 nM, respectively) without a concentration-dependent reduction in binding site maxima (B(max): 3597, 4597, 3109 fmol/mg protein, respectively). Platelet aggregation induced by the TP receptor agonist U 46,619 was concentration-dependently inhibited by DuP 753 (IC50=46-mu-M). These data indicate for the first time that DuP 753 is a weak but competitive antagonist at human platelet TP receptors.