Thromboxane-mediated activation of platelets and enhancement of platelet uptake onto collagen-coated glass or deendothelialized rabbit aorta. Comparative effects of a thromboxane antagonist (EPO45) and a thromboxane synthetase inhibitor (dazoxiben).
The effects of a cyclooxygenase inhibitor (indomethacin), a thromboxane synthetase inhibitor (dazoxiben), and a thromboxane antagonist (EPO45) on rabbit platelet aggregation induced by collagen were studied and compared with effects on platelet uptake both by damaged rabbit aorta and by collagen-coated glass. Platelet aggregation and associated release of serotonin were inhibited to a similar extent both by indomethacin and EPO45. Dazoxiben had a minimal inhibitory effect on aggregation but reduced the release of serotonin by about 40% compared with control. Platelet uptake onto collagen-coated glass was markedly reduced both by indomethacin and EPO45 but not by dazoxiben. In contrast, EPO45 and dazoxiben were equally effective in reducing platelet adhesion to damaged rabbit aorta. At the concentrations used for adhesion studies the formation of thromboxane B2 was reduced both by dazoxiben and by indomethacin (both greater than 95% inhibition compared with control) and to a lesser extent by EPO45 (less than 40% inhibition). The results indicate that thromboxane A2 (and cyclic endoperoxide) released by adherent platelets may enhance thromboxane synthesis and promote platelet uptake both onto collagen-coated glass and onto damaged rabbit aorta. In the presence of vascular tissue, cyclic endoperoxides are readily metabolized and thereby removed. The potential antithrombotic activity of TXA2 synthetase inhibitors could be impaired in situations in which endoperoxide clearance is limited (e.g., accompanying platelet uptake onto artificial surfaces) but not at the damaged vessel wall. Thus, both inhibitors and antagonists are likely to have similar potency as antithrombotic agents in vivo.
D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood; D000818:Animals; D003094:Collagen / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D010973:Platelet Adhesiveness / Q000187:drug effects*; D010974:Platelet Aggregation / Q000187:drug effects*; D011465:Prostaglandins, Synthetic / Q000494:pharmacology*; D011817:Rabbits; D012701:Serotonin / Q000097:blood; D013929:Thromboxane B2 / Q000097:blood
D007093:Imidazoles; D011465:Prostaglandins, Synthetic; C029166:dazoxiben; D012701:Serotonin; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; C034549:EP 045; D003094:Collagen; D007213:Indomethacin