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

• Published in: Journal of lipid mediators and cell signalling 1996-01, Vol.13 (1), p.1-8
• Main Authors: Terashita, Z, Imura, Y, Nishikawa, K
• Format: Article
• Language: English
• Subjects: 6-Ketoprostaglandin F1 alpha - metabolism; Animals; Aorta - enzymology; Arachidonic Acid - antagonists & inhibitors; Arachidonic Acid - pharmacology; Aspirin - pharmacology; Cytochrome P-450 Enzyme System - metabolism; Enzyme Inhibitors - pharmacology; Epoprostenol - biosynthesis; Fatty Acids, Monounsaturated - pharmacology; In Vitro Techniques; Intramolecular Oxidoreductases; Isomerases - metabolism; Male; Platelet Aggregation - drug effects; Platelet Aggregation Inhibitors - pharmacology; Prostaglandins - metabolism; Pyridines - pharmacology; Rabbits; Rats; Rats, Sprague-Dawley; Thromboxane A2 - metabolism; Thromboxane-A Synthase - antagonists & inhibitors
• ISSN: 0929-7855
• DOI: 10.1016/0929-7855(95)00009-7

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.