The effect of pyrimidine compounds on the potentiation of adenosine inhibition of aggregation, on adenosine phosphorylation and phosphodiesterase activity of blood platelets.

Abstract

Summary. Three pyrimidine compounds (dipyridamole, RA233 and VK 744) produced variable degrees of direct inhibition as well as potentiation of adenosineinduced inhibition of ADP aggregation of blood platelets. RA233 and VK744 were more potent direct inhibitors of platelet aggregation, whereas RA233 was a more powerful potentiator of adenosine–induced inhibition. A relation between the effect of these compounds on platelet aggregation and on adenosine phosphorylation and phosphodiesterase activity of platelets was looked for in an attempt to elucidate possible modes of action.RA233 and dipyridamole were powerful inhibitors of [14C]adenosine phosphorylation by platelets and VK744 had no effect. There was no correlation with inhibition of platelet aggregation. Adenosine‐induced inhibition of platelet aggregation in the presence of dipyridamole could be maintained for at least 10 min after the rapid clearance of the adenosine with exogenous deaminase. The presence of the pyrimidine so modified the inhibition response that there was no correlation between the concentration of adenosine in the system and the degree or rate of recovery from the inhibition.Dipyridamole, VK744 and RA233 produced 45%, 45% and 55% inhibition of phosphodiesterase activity as measured by the rate of breakdown of [3H]cyclic AMP to AMP in platelet lysates. There was possible correlation between the effect of the three pyrimidine compounds on platelet phosphodiesterase activity and their potentiatory action on adenosine‐induced inhibition of platelet aggregation. These findings suggested that adenosine might induce inhibition of platelet aggregation through the adenyl cyclase, cyclic AMP, phosphodiesterase system.