Synergistic effect of cilostazol and dipyridamole mediated by adenosine on shear-induced platelet aggregation.
BACKGROUND
The Cilostazol 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 cilostazol 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 dipyridamole, an inhibitor of cellular adenosine reuptake, in combination with cilostazol in vitro.


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 microM) 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 cilostazol 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.
Nakamura
Tomomi
T
Department of Neurology, Neurological Institute, Tokyo Women's Medical University, Tokyo, Japan. tnakamur@nij.twmu.ac.jp
Uchiyama
Shinichiro
S
Yamazaki
Masako
M
Iwata
Makoto
M
D000241:Adenosine / Q000097:blood / Q000494:pharmacology*; D000328:Adult; D000077407:Cilostazol; D004176:Dipyridamole / Q000097:blood / Q000494:pharmacology*; D004357:Drug Synergism; D006801:Humans; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects* / Q000502:physiology*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D033081:Shear Strength; D013777:Tetrazoles / Q000097:blood / Q000494:pharmacology*
D010975:Platelet Aggregation Inhibitors; D013777:Tetrazoles; D004176:Dipyridamole; D000241:Adenosine; D000077407:Cilostazol