Antagonism of thromboxane A2/prostaglandin H2 by 13-azaprostanoic acid prevents platelet deposition to the de-endothelialized rabbit aorta in vivo.
The present study evaluated the direct involvement of thromboxane A2/prostaglandin H2 (TXA2/PGH2) in the process of thrombus formation at a site of vascular damage. De-endothelialization of the rabbit aorta was performed by a balloon catheter technique. Platelet deposition to the injured vessel was measured using 111Indium-labeled autologous platelets. Studies using the radiolabeled TXA2/PGH2 antagonist, 13-azaprostanoic acid (13-APA), indicated that 13-APA has an in vivo half-life of approximately 35 min and is excreted by the kidney in the metabolized form. Addition of 13-APA to rabbit plasma samples in vitro produced a dose-dependent inhibition of arachidonic acid-induced platelet aggregation. When comparable plasma levels of 13-APA were achieved by infusion of 13-APA (300 micrograms/kg/min for 90 min), a similar dose-dependency of inhibition of ex vivo aggregation was observed. Furthermore, at a plasma concentration of 40 microM, 13-APA was found to inhibit platelet deposition to the de-endothelialized rabbit aorta by 45%. Because 13-APA does not interfere with arachidonic acid metabolism, the ability of 13-APA to suppress thrombus formation is presumably due to direct antagonism of TXA2/PGH2 at the platelet receptor level. These findings, therefore, provide evidence that TXA2 and/or PGH2 have a major role in platelet deposition at a site of vascular damage.
D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000037:antagonists & inhibitors; D001792:Blood Platelets / Q000187:drug effects*; D005227:Fatty Acids / Q000494:pharmacology*; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects; D011449:Prostaglandin Endoperoxides / Q000037:antagonists & inhibitors*; D011450:Prostaglandin Endoperoxides, Synthetic / Q000037:antagonists & inhibitors*; D044262:Prostaglandin H2; D011463:Prostaglandins H / Q000037:antagonists & inhibitors*; D011466:Prostanoic Acids / Q000097:blood / Q000494:pharmacology*; D011817:Rabbits; D013927:Thrombosis / Q000473:pathology*; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors*; D013931:Thromboxanes / Q000037:antagonists & inhibitors*
D001095:Arachidonic Acids; D005227:Fatty Acids; D011449:Prostaglandin Endoperoxides; D011450:Prostaglandin Endoperoxides, Synthetic; D011463:Prostaglandins H; D011466:Prostanoic Acids; D013931:Thromboxanes; D016718:Arachidonic Acid; D044262:Prostaglandin H2; D013928:Thromboxane A2; C022574:13-azaprostanoic acid