Effect of thromboxane A2 synthetase inhibition, singly and combined with thromboxane A2/prostaglandin endoperoxide receptor antagonism, on inositol phospholipid turnover and on 5-HT release by washed human platelets.
Differential effects on human platelet function of thromboxane A2 (TXA2) synthetase inhibition singly and of TXA2 synthetase inhibition combined with TXA2/prostaglandin endoperoxide receptor antagonism were revealed, using ridogrel as a probe. Ridogrel combines selective TXA2 synthetase inhibition with TXA2/prostaglandin receptor antagonism in one molecule: in washed human platelets, the compound reduces the production of TXB2 (IC50 = 1.3 X 10(-8) M) and increases that of PGF2 alpha, PGE2, PGD2 from [14C]arachidonic acid. Additionally, at higher concentrations (Ki = 0.52 X 10(-6) M), it selectively antagonizes the breakdown of inositol phospholipids, subsequent to stimulation of TXA2/prostaglandin endoperoxide receptors with U 46619. The latter happens in a competitive way with fast receptor association-dissociation characteristics. At low concentrations (1 X 10(-9)-1 X 10(-7) M) producing single TXA2 synthetase inhibition, ridogrel reduces the collagen-induced formation of TXB2 by washed platelets, but enhances [32P]phosphatidic acid (PA) accumulation and [3H]5-hydroxytryptamine (5-HT) release. At higher concentrations (1 X 10(-6)-1 X 10(-5) M) which additionally block U 46619-induced [32P]PA accumulation, ridogrel inhibits the [32P]PA accumulation and release of [3H]5-HT by human platelets stimulated with collagen. These observations, corroborated by results obtained with OKY 1581, sulotroban, indomethacin and human serum albumin, suggest a causal role for prostaglandin endoperoxides in the stimulation by TXA2 synthetase inhibition of platelet reactions to collagen. They reinforce the concept that TXA2 synthetase inhibition-induced reorientation of cyclic endoperoxide metabolism, away from TXA2 into inhibitory prostanoids, requires additional TXA2/prostaglandin endoperoxide receptor antagonism to achieve optimal anti-platelet effects.
de Chaffoy de Courcelles
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D
Department of Biochemistry, Janssen Research Foundation, Beerse, Belgium.
De Clerck
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F
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D003094:Collagen / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D007295:Inositol Phosphates / Q000097:blood*; D008689:Methacrylates / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000494:pharmacology; D011449:Prostaglandin Endoperoxides / Q000097:blood*; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D012701:Serotonin / Q000097:blood*; D013449:Sulfonamides / Q000494:pharmacology; D013928:Thromboxane A2 / Q000097:blood*; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
D007295:Inositol Phosphates; D008689:Methacrylates; D010972:Platelet Activating Factor; D011449:Prostaglandin Endoperoxides; D011450:Prostaglandin Endoperoxides, Synthetic; D013449:Sulfonamides; D012701:Serotonin; D013928:Thromboxane A2; C040624:sulotroban; C031517:2-methyl-3-(4-(3-pyridinylmethyl)phenyl)-2-propenoic acid; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D003094:Collagen; D013930:Thromboxane-A Synthase; D007213:Indomethacin