Inhibition of arachidonic acid induced-aggregation of rabbit platelets with CV-4151 (isbogrel), a selective thromboxane A2 (TXA2) synthase inhibitor: modulation of the antiplatelet action and prostanoid metabolism by rat aortic rings.
In rabbit platelet-rich plasma, a specific TXA2 synthase inhibitor, CV-4151 (isbogrel) alone modestly inhibited the platelet aggregation induced by arachidonic acid (AA); even at 10(-4) M the inhibition was less than 50% (IC40 value: 8.1 x 10(-5) M). Aspirin-treated rat aortic rings alone inhibited the AA-induced platelet aggregation by 7%. However, CV-4151 exhibited a potent antiplatelet action in the presence of the aortic rings and its IC40 value was 8.3 x 10(-8) M. Thus, the aortic rings caused 1000-fold enhancement of the antiplatelet action of CV-4151. Next, we investigated the effect of CV-4151 on the production of two highly biologically active prostanoids, TXA2 and PGI2, and the contribution of these prostanoids to the antiplatelet action of CV-4151. TXA2 and PGI2 were measured by a radioimmunoassay of their stable metabolites, TXB2 and 6-keto-PGF1 alpha, respectively. Under the experimental conditions, CV-4151 simultaneously inhibited TXA2 generation and enhanced PGI2 generation. There was a positive linear relationship (r = 0.975, p < 0.01) between % inhibition of platelet aggregation and PGI2 generation and a significant negative linear relationship (r = 0.994, p < 0.001) between % inhibition of platelet aggregation and TXA2 generation. CV-4151 exhibits a potent antiplatelet action in the presence of PGI2 synthase, which is the in vivo situation, by simultaneously inhibiting TXA2 generation and enhancing PGI2 generation.
Terashita
Z
Z
Pharmaceutical Research Laboratories I, Pharmaceutical Group Takeda chemical Industries, Ltd, Osaka, Japan.
Imura
Y
Y
Nishikawa
K
K
D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000201:enzymology; D016718:Arachidonic Acid / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D001241:Aspirin / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D011464:Epoprostenol / Q000096:biosynthesis; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D066298:In Vitro Techniques; D019746:Intramolecular Oxidoreductases; D007535:Isomerases / Q000378:metabolism*; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011453:Prostaglandins / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013928:Thromboxane A2 / Q000378:metabolism; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D005229:Fatty Acids, Monounsaturated; D010975:Platelet Aggregation Inhibitors; D011453:Prostaglandins; D011725:Pyridines; D016718:Arachidonic Acid; D013928:Thromboxane A2; D015121:6-Ketoprostaglandin F1 alpha; D003577:Cytochrome P-450 Enzyme System; D011464:Epoprostenol; D007535:Isomerases; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase; D013930:Thromboxane-A Synthase; C045446:isbogrel; D001241:Aspirin