Synergistic effect of cilostazol and dipyridamole mediated by adenosine on shear-induced platelet aggregation

Introduction: The Citostazol Stroke Prevention Study found that cilostazol, a phosphodiesterase 3 inhibitor, can reduce the risk of subsequent stroke in Japanese patients with cerebral infarction. Here, we measured the effects of citostazol in vitro on shear-induced platelet aggregation, an important mechanism of thrombosis at arterial bifurcations or stenotic lesions. We also evaluated the influences of intrinsic adenosine on the ability of cilostazol to inhibit shear-induced platelet aggregation by investigating the effect of dipyridamote, an inhibitor of cellular adenosine reuptake, in combination with cilostazol in vitro. Materials and methods: We measured platelet aggregation induced by a shear rate of 10,800 s(-1) in whole blood and in platelet-rich plasma from healthy volunteers using a cone-plate streaming chamber. Results: Both cilostazol and adenosine dose-dependently inhibited shear-induced platelet aggregation in platelet-rich plasma samples. Adding a low concentration of adenosine (0.3 mu M) did not inhibit shear-induced platelet aggregation, but significantly enhanced the inhibitory effect of cilostazol in platelet-rich plasma. Dipyridamole dose-dependently inhibited shear-induced platelet aggregation in whole blood and significantly enhanced the inhibitory effect of cilostazol on shear-induced platelet aggregation, but did not affect shear-induced platelet aggregation in platelet-rich plasma. The inhibitory effects of citostazol combined with dipyridamole in whole blood were almost completely reversed by adenosine deaminase. Conclusions: Dipyridamole appears to synergistically enhance the inhibitory effect of cilostazol on shear-induced platelet aggregation by maintaining high plasma levels of adenosine. (c) 2006 Published by Elsevier Ltd.