Effect of Adenyl-Cyclase Activators, Phosphodiesterase Inhibitors and Pyridoxal-5-Phosphate on Platelet Aggregation and Adenosine-3’-5’-Cyclic Monophosphate Accumulation

Summary

The effect of prostaglandin E₁ (PGE₁) and compound BW245C, adenyl-cyclase activators, theophylline, papaverine and dipyridamole, phosphodiesterase (PDE) inhibitors and pyridoxal- 5-phosphate (PALP) on inhibition of platelet aggregation (PA) and platelet c-AMP accumulation was determined in human platelet-rich plasma (PRP) and washed platelets. PGE₁ at 280 nM and BW245C at 7.7 nM induced a significant PA inhibition in PRP and washed platelets (though less pronounced by PGE₁) concomitant to a very large increase (8-13-fold) in platelet cAMP level both in PRP and washed platelets. At comparable PA inhibition, c-AMP level was not significantly changed by PALP and only moderately (but significantly) increased (2-4.6-fold) by PDE inhibitors. PALP or theophylline potentiated both PGE₁ induced platelet c-AMP accumulation and PA inhibition. Yet PALP potentiated theophylline-induced PA inhibition without affecting platelet c-AMP level.

Our results indicate that 2 c-AMP pools are presumably present in the platelets, since at comparable c-AMP accumulation PDE inhibitors or BW245C were more effective than PGE₁ in PA inhibition in PRP. Morever, this pattern was more pronounced in washed platelets and was also found in the presence of thrombin and adenosine diphosphate which induced a decrease in platelet c-AMP level. The effect of PALP on PA inhibition is presumably mediated by 2 mechanisms: a) a direct effect on the platelet membrane independent from the c-AMP system, b) In the presence of PGE₁, the increment in PA inhibition, is through further indirect activation of the adenyl-cyclase. The mechanism of PA inhibition by BW245C in intact platelets, is most probably through activation of adenyl-cyclase. This study emphasize the importance of c-AMP accumulation in the inhibition of PA.

Keywords

c-AMP - Platelet aggregation inhibition - Pyridoxal-5-phos-phate - Compound BW245C

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