Effects of CI-930, a novel phosphodiesterase III inhibitor, on platelet aggregation and arachidonic acid metabolism.
In the platelet-rich plasma of rabbits, 4,5-dihydro-6-[4-(1H-imidazol-1-yl)phenyl]-5-methyl-3(2H)-pyridazinone (CI-930) inhibited platelet aggregation triggered by AA, U-46619, ADP, collagen and PAF, with the IC50 values of 0.91, 0.73, 2.12, 2.35 and 7.15 mumols/L, respectively. The inhibitory effect of CI-930 on AA-induced aggregation was potentiated by PGE1, an adenylate cyclase activator, and antagonized by SQ-22536, an adenylate cyclase inhibitor. The contents of cAMP in washed rabbit platelets were increased by CI-930 5-50 mumols/L. In the concentration range of 0.5-500 mumols/L, CI-930 reduced the synthesis of TXB2 by either washed rat or rabbit platelets or rat pleural neutrophils. At the same time, CI-930 induced a dose-dependent increase of PGE2, PGF2a, and PGD2 biosynthesis by rat platelets and had no significant influence on the formation of 6-keto-PGF1a by the neutrophils. It is showed that CI-930 is an anti-platelet agent with a wide-spectrum activity and its anti-aggregating action may be exerted by dual mechanisms, both increasing cAMP contents and selectively inhibiting TXA2 synthesis in platelets.