Inhibition of platelet aggregation and the release of P-selectin from platelets by cilostazol

To evaluate the in vitro effects of cilostazol, a phosphodiesterase III inhibitor, on platelet responses, we measured platelet aggregation and the levels of soluble P-selectin, a glycoprotein present on the oc-granule membrane in resting platelets, and cAMP. Platelet-rich plasma and washed platelets from healthy human volunteers were treated with cilostazol (5, 25 and 50 CIM) Platelet-rich plasma was stimulated by ADP (1 and 5 muM) or collagen (5 mug/ml). Washed platelets were stimulated by thrombin (4 U/ml) in the presence or absence of 1 CIM forskolin. In vehicle-treated samples, soluble P-selectin levels in response to 1 muM ADP-induced primary aggregation were similar to those of circulating levels of healthy volunteers but the levels in response to 5 muM ADP-induced secondary aggregation and collagen-induced aggregation increased markedly compared to those in response to primary aggregation. This result suggests that P-selectin is released from platelets according to the extent of platelet aggregation. Cilostazol inhibited platelet aggregation as well as P-selectin release in a concentration-dependent manner. Cilostazol inhibited completely thrombin-induced aggregation in the presence of 1 muM forskolin, when cAMP levels were two-fold higher than those in the absence of forskolin. Cilostazol, which increases intracellular cAMP in platelets, may be useful in the treatment of arterial occlusive diseases. (C) 2001 Elsevier Science Ltd. All rights reserved.