Studies on the antiplatelet effect of the stable epoprostenol analogue beraprost sodium and its mechanism of action in rats.

Baraprost sodium (sodium (+/-)-(1R*,2R*,3aS*,8bS*)-2,3,3a.8b- tetrahydro-2-hydroxy-1-[(E)-(3S*)-3-hydroxy-4-methyl-1-octen-6- 1H-cyclopenta[b]benzo-furan-5-butyrate, TRK-100) is a novel stable epoprostenol (prostaglandin I2, PGI2) analogue having antiplatelet and vasodilating actions. Its effect on platelet aggregation in whole blood ex vivo and platelet suspension in vitro, formation of cyclic AMP(cAMP), production of malondialdehyde(MDA), and 45Ca++-influx into platelets were studied in rats. Oral administration of TRK-100 (0.3-1 mg/kg) showed a dose-dependent inhibition of platelet aggregation induced by ADP and collagen in whole blood and also inhibited in vitro thrombin-induced aggregation of platelet suspension in the presence or absence of external Ca++. Oral TRK-100 (0.3-3 mg/kg) dose-dependently increased plasma cAMP levels and this action was confirmed in vitro with platelet rich plasma in the presence or absence of theophylline. 45Ca++-influx into platelets stimulated by thrombin was dose-dependently inhibited by TRK-100 (3-100 nmol/l). TRK-100 (3-100 nmol/l) also suppressed MDA production induced by thrombin in platelet suspension but not that induced by arachidonic acid. From these results, TRK-100 which is orally active was suggested to exert its antiplatelet action through the increase of cAMP in platelets by activation of adenylate cyclase, concomitantly followed by the inhibition of Ca++-influx and thromboxane A2 formation.