15-hydroxy-11-alpha-9-alpha-(epoxymethano)prosta-5-13-dienoic-acid and 2-methyl-3-(4-(3-pyridinylmethyl)phenyl)-2-propenoic-acid

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.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Blood Platelets; Collagen; Humans; In Vitro Techniques; Indomethacin; Inositol Phosphates; Methacrylates; Platelet Activating Factor; Prostaglandin Endoperoxides; Prostaglandin Endoperoxides, Synthetic; Serotonin; Sulfonamides; Thromboxane A2; Thromboxane-A Synthase

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acrylates; Animals; Arachidonic Acid; Arachidonic Acids; Bridged Bicyclo Compounds, Heterocyclic; Cats; Dinoprost; Fatty Acids, Unsaturated; Hydrazines; Lung; Methacrylates; Prostaglandin Endoperoxides, Synthetic; Respiratory Function Tests; Thromboxane A2; Thromboxane-A Synthase

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acrylates; Animals; Arachidonic Acid; Arachidonic Acids; Cats; Chromatography, Thin Layer; Female; Indomethacin; Male; Methacrylates; Oxidoreductases; Prostaglandin Endoperoxides, Synthetic; Prostaglandin H2; Prostaglandins H; Pulmonary Artery; Thromboxane A2; Thromboxane-A Synthase; Thromboxanes; Vasoconstriction; Vasodilation

The effects of the stable thromboxane agonist, U46619, and sodium arachidonate were tested by i.v. injection into male and female mice. U46619 produced dose-dependent mortality in both sexes equally, in contrast to the gender-differentiated effects of arachidonic acid. The thromboxane receptor antagonist, SQ 26,536, protected in a dose-dependent manner against both arachidonate and U46619. The thromboxane antagonist was more effective against arachidonate toxicity in male than in female mice, but was equiactive against U46619 in both sexes. Neither the thromboxane synthetase inhibitor, OKY-1581, nor the cyclooxygenase inhibitor, indomethacin, protected against U46619-induced sudden death. However, cortisone acetate increased survival of mice challenged with U46619. The results support the hypothesis that thromboxane A2 mediates arachidonate-induced sudden death. The effects of arachidonate can be mimicked by the thromboxane agonist and are attenuated by the thromboxane antagonist. The gender difference in arachidonate toxicity is apparently not due to differences in sensitivity to thromboxane A2, as the thromboxane agonist was equally toxic in males and females. The greater protective effect of the thromboxane antagonist against arachidonate toxicity in males suggests that thromboxane A2 is a more important mediator of arachidonate-induced sudden death in males compared to female mice.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Arachidonic Acids; Cortisone; Fatty Acids, Monounsaturated; Fatty Acids, Unsaturated; Female; Indomethacin; Male; Methacrylates; Mice; Prostaglandin Endoperoxides, Synthetic; Sex Factors; Thromboxane A2; Thromboxanes