The effect of thromboxane A2 synthesis inhibitors on platelet aggregation in whole blood.
Aggregatory responses to arachidonic acid and collagen in vitro were compared in blood (single platelet counting) and PRP (light aggregometry) from four species. Sensitivity of mouse, rat and rabbit PRP to these agonists was not predictive of respective potency in whole blood, whereas for human platelets, responses in blood did not differ significantly from PRP. Indomethacin (3-300 microM) inhibited arachidonic acid-induced aggregation in each species, and collagen responses in all except mouse. In contrast, the thromboxane synthase inhibitors dazoxiben (3.7-372 microM) and SC 38249 (2.6-260 microM) demonstrated activity only in rabbit and human blood. However, since in many experiments drug efficacy decreased significantly in blood compared to corresponding PRP, the concentrations of each agent necessary to inhibit responses were above those at which selectivity has previously been demonstrated against isolated enzyme preparations or in PRP. A fundamental reappraisal of both the potency and selectivity of these inhibitors in whole blood appears essential before their mechanism of action can be firmly established.
D000328:Adult; D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000502:physiology; D001790:Blood Physiological Phenomena; D003094:Collagen / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010974:Platelet Aggregation / Q000187:drug effects*; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors
D001095:Arachidonic Acids; D016861:Cyclooxygenase Inhibitors; D007093:Imidazoles; C029166:dazoxiben; D016718:Arachidonic Acid; D013928:Thromboxane A2; C053318:1-(2,3-bis((4-methoxyphenyl)methoxy)propyl)-1H-imidazole; D003094:Collagen; D013930:Thromboxane-A Synthase; D007213:Indomethacin