title: Interactions of dihydropyridine Ca2+ channel agonists with the human platelet thromboxane A2/prostaglandin H2 receptor.
abstract: 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.
authors.affiliation: Department of Pharmacology, Medical University of South Carolina, Charleston 29425.
authors.forename: P R
authors.initials: PR
authors.lastname: Mayeux
authors.forename: D E
authors.initials: DE
authors.lastname: Mais
authors.forename: P V
authors.initials: PV
authors.lastname: Halushka
mesh_terms: D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000345:Affinity Labels; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D002120:Calcium Channel Agonists / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D004095:Dihydropyridines / Q000494:pharmacology*; D016257:Fura-2; D006801:Humans; D066298:In Vitro Techniques; D007457:Iodine Radioisotopes; D007700:Kinetics; D008345:Manganese / Q000494:pharmacology; D011450:Prostaglandin Endoperoxides, Synthetic / Q000378:metabolism*; D044262:Prostaglandin H2; D011463:Prostaglandins H / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D011869:Radioligand Assay; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors / Q000187:drug effects*; D017482:Receptors, Thromboxane; D013237:Stereoisomerism
chemical_list: D000345:Affinity Labels; D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D007457:Iodine Radioisotopes; D011450:Prostaglandin Endoperoxides, Synthetic; D011463:Prostaglandins H; D011725:Pyridines; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D044262:Prostaglandin H2; D008345:Manganese; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; C040525:CGP 28392; C045796:SAN 202791; D016257:Fura-2