Interactions of dihydropyridine Ca2+ channel agonists with the human platelet thromboxane A2/prostaglandin H2 receptor.

The specific interactions at the human platelet thromboxane A2/prostaglandin H2 (TXA2/PGH2) receptor by four 1-4 dihydropyridine (DHP) agonists were studied. Using competition equilibrium binding assays with the TXA2/PGH2 receptor agonist [125I]BOP and the antagonist [125I]PTA-OH, the affinities of racemic BAY K 8644 (BAY), racemic CGP 28392 (CGP) and (+) and (-) SDZ 202-791 (SDZ) for the TXA2/PGH2 receptor were determined. The rank order potencies for competition were BAY greater than (-)SDZ greater than CGP greater than or equal to (+)SDZ. Bay, CGP and SDZ (stereoselectively) inhibited specific incorporation of the TXA2/PGH2 receptor photoaffinity probe [125I]PTA Azido into three proteins associated with the TXA2/PGH2 receptor with Mr of 43, 39 and 27 kDa as assessed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis autoradiography. Using the fluorescent Ca2+ probe Fura-2, it was observed that I-BOP failed to stimulate classical divalent cation channels. However, SDZ stereoselectively inhibited the rise in [Ca2+]i induced by I-BOP while not affecting that induced by thrombin. Although DHPs specifically and stereoselectively interact with the TXA2/PGH2 receptor on human platelets, the TXA2/PGH2 receptor-mediated rise in [Ca2+]i is not through stimulation of a classical divalent cation channel.