Interference of the thromboxane antagonist SK&F 88046 with platelet activation and subsequent desensitization by arachidonic acid and the thromboxane mimetics U46619 and EP171.
We have investigated the effects of the thromboxane antagonist SK&F 88046 on human platelet activation and desensitization by arachidonic acid (AA) and by the thromboxane A2 mimetics U46619 or EP171. SK&F 88046 inhibited platelet aggregation and secretion induced by AA, U46619, EP171 and thrombin at low (0.05 U/ml) but not at a high (1 U/ml) concentrations. Platelet inhibition was reversed by washing the cells. Platelets pre-exposed to AA, U46619 or EP171 and then disaggregated with prostacyclin, washed and resuspended, failed to respond with aggregation or secretion to a second challenge by either agonist. In the presence of the endoperoxide/thromboxane receptor antagonist L636499 or of SK&F 88046, pre-exposure to AA, U46619 or EP171 failed to prevent subsequent responses to the related agonists. Our results suggest that SK&F 88046 is a selective antagonist of platelet activation and desensitization induced by TxA2 or prostaglandin endoperoxides and that it may have utility as an anti-platelet drug.
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects / Q000648:ultrastructure; D003988:Dibenzothiepins / Q000494:pharmacology; D004347:Drug Interactions; D006801:Humans; D010974:Platelet Aggregation / Q000187:drug effects*; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology*; D011956:Receptors, Cell Surface / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology*; D013928:Thromboxane A2 / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000502:physiology*; D013931:Thromboxanes / Q000037:antagonists & inhibitors*
D001095:Arachidonic Acids; D003988:Dibenzothiepins; D011450:Prostaglandin Endoperoxides, Synthetic; D011956:Receptors, Cell Surface; C034339:SK&F 88046; D013449:Sulfonamides; D013931:Thromboxanes; C053315:EP 171; D016718:Arachidonic Acid; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C047685:L 636499