MODE OF ACTION OF DIPYRIDAMOLE ON HUMAN-PLATELETS

The effects of dipyridamole were investigated on platelet aggregation, (14C)-5 hydroxytryptamine release, cyclic nucleotide metabolism and malonyldialdehyde and thromboxane B2 production. Pre-incubation of platelet-rich plasma with dipyridamole inhibited platelet aggregation in response to ADP, epinephrine, an epoxymethano prostaglandin endoperoxide analogue and collagen, and potentiated the inhibitory effect of prostacyclin on platelet aggregation. A small inhibition of 5-hydroxytryptamine release was also found. Dipyridamole potentiated the stimulation of platelet cyclic AMP accumulation by prostacyclin, and also potentiated the stimulatory effect of both arachidonic acid and dihomo-γ-linoleic acid on cyclic GMP accumulation. An inhibitory effect of the drug was observed on both cyclic AMP and cyclic GNP phosphodiesterase activities, particularly at high substrate concentrations. In addition, a slight stimulation of platelet membrane adenylate cyclase activity was found. The inhibition of platelet aggregation induced by collagen and arachidonic acid by the drug was accompanied by a reduction in the thromboxane B2 production. The inhibition of thromboxane B2 formation was also apparent in human platelet-rich plasma containing EDTA and in an isolated bovine platelet microsome preparation indicating that dipyridamole has a dose-dependent inhibitory effect on thromboxane synthesis which was independent of aggregation. Dipyridamole also inhibited malonyldialdehyde production in response to both thrombin and arachidonic acid. Thus dipyridamole may inhibit platelet function not only by increasing platelet cyclic AMP but may also exert a minor effect on platelet thromboxane biosynthesis. © 1979.