Potentiation of antiaggregating activity of adenosine by a phosphodiesterase inhibitor, EG626 (oxagrelate), in human platelets in vitro.

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Abstract
EG626 (oxagrelate), a specific inhibitor of cAMP phosphodiesterase, produced in vitro a concentration-dependent inhibition of platelet aggregation induced by collagen and ADP in human platelets. When adenosine was added to the platelet rich plasma (PRP) in the presence of a threshold concentration of EG262, the potency of adenosine in inhibiting platelet aggregation was markedly potentiated. This potentiating effect of EG262 proved to be synergistic, but not additive and was accompanied by a marked accumulation of cAMP in the platelets. The antiaggregating and cAMP increasing activities of adenosine were little affected by S-(p-nitrobenzyl)-6-thioguanosine (6TG), an uptake inhibitor of adenosine, or 2''-deoxycoformycin, an inhibitor of adenosine deaminase. The incorporation of adenosine into platelets was abolished by 6TG. Incorporation of adenosine into platelets is evidently no required for inhibition of aggregation or an increase in cAMP and the site of action of adenosine is probably extracellular. The synergistic action by EG626 is apparently not the result of an inhibition of adenosine uptake and/or adenosine deaminase; EG626 also potentiates the antiaggregating activity of 2-chloroadenosine. Antiaggregating activity of prostaglandin E1, an activator of adenylate cyclase, was markedly potentiated in combination with EG626. Dibutyryl cAMP showed a time-dependent inhibition of the platelet aggregation and the inhibitory action was markedly potentiated by EG626. Qualitatively similar results were obtained with another phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (IBMX). The synergistic potentiation of the antiaggregating activity of adenosine by EG626 might be due to the synergistic accumulation of cAMP in the platelets. This action is mediated through activation of adenylate cyclase by adenosine in combination with the inhibition of cAMP phosphodiesterase by EG626.