Relative potencies of dipyridamole and related agents as inhibitors of cyclic nucleotide phosphodiesterases: possible explanation of mechansim of inhibition of platelet function.

The effects of dipyridamole and five related agents (RA233, RA255, RA433, VK744 and VK774) on several aspects of human platelet cyclic nucleotide metabolism were investigated. In platelet-rich plasma VK774 caused a significant increase in total cAMP and a potentiation of adenosine-induced cAMP accumulation. VK744 and RA233 potentiated the adenosine effect while dipyridamole caused a lowering of cAMP levels both in the absence and presence of adenosine. All 6 agents inhibited the cAMP phosphodiesterase of collagen-treated platelets, the high affinity cAMP phosphodiesterase of platelet lysates, and the cGMP phosphodiesterase of membrane-enriched platelet fractions. K_i values for these agents were determined for both the high affinity cAMP and cGMP phosdiestereases. The order of potency of these drugs as inhibitors differed for the two enzymes studied. Neither order showed a clearcut relationship to the reported relative potencies of the drugs in inhibiting a number of other aspects of platelet function. If the relative selectivity of these agents for the two enzymes was however determined, there was a close correspondence between their tendency to promote a relative accumulation of cAMP and their inhibitory effects on platelet adhesion and aggregation. This close correspondence was taken to indicate that these drugs exert many of their effects on platelet function by altering the relative cAMP, cGMP levels and, moreover, supports the contention that platelet aggregation and release are modulated both by cAMP and cGMP.