Inhibitory effects of the selective thromboxane receptor antagonist BM 13.177 on platelet aggregation, vasoconstriction and sudden death.
BM 13.177 (0.1-100 microM) produced a concentration-dependent reduction of the platelet shape change, aggregation and (3H)serotonin release induced by the stable PGH2 analogues U 46619 and U 44069 or exogenous and endogenous arachidonic acid, the latter mobilized by hydrogen peroxide or collagen. BM 13.177 (100 microM) did not inhibit the primary platelet activation by ADP, serotonin, thrombin or collagen in washed platelets or citrated PRP that had been pre-treated with ASA (acetylsalicylic acid). The formation of TXB2 triggered by 100 microM hydrogen peroxide or 10 microM arachidonic acid was not influenced by BM 13.177 (10 microM). In spiral strips of rat and rabbit aorta, BM 13.117 markedly reduced the vasoconstriction triggered by U 46619 and PGF2 alpha. BM 13.177 did not inhibit the K+-or noradrenaline-induced constriction. The concentration/response curves of the U 46619-stimulated platelet shape change and of the vasoconstriction induced by U 46619 and PGF2 alpha were shifted in parallel to the right by BM 13.177, implicating a competitive antagonism. The pAx values were about the same in these models which indicates that BM 13.177 does not differentiate between the thromboxane receptors in human platelets and rabbit aorta. In mice, BM 13.177 prevented in a dose-dependent fashion the sudden death and the symptoms of respiratory depression and shock induced by i.v. injections of U 46619 or arachidonic acid. BM 13.177 did not exert partial agonist activity in the in vitro and in the animal models.(ABSTRACT TRUNCATED AT 250 WORDS)
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology*; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000494:pharmacology; D001792:Blood Platelets / Q000378:metabolism; D015237:Dinoprost; D006801:Humans; D010974:Platelet Aggregation / Q000187:drug effects*; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D011460:Prostaglandins F / Q000494:pharmacology; D051381:Rats; D011956:Receptors, Cell Surface / Q000187:drug effects*; D011982:Receptors, Prostaglandin / Q000187:drug effects*; D017482:Receptors, Thromboxane; D012701:Serotonin / Q000097:blood; D013449:Sulfonamides / Q000494:pharmacology*; D013931:Thromboxanes / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects*
D001095:Arachidonic Acids; D011450:Prostaglandin Endoperoxides, Synthetic; D011460:Prostaglandins F; D011956:Receptors, Cell Surface; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D013449:Sulfonamides; D013931:Thromboxanes; D016718:Arachidonic Acid; D012701:Serotonin; C028429:U 44069; C040624:sulotroban; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D015237:Dinoprost