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 alpha-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 microM). Platelet-rich plasma was stimulated by ADP (1 and 5 microM) or collagen (5 microg/ml). Washed platelets were stimulated by thrombin (4 U/ml) in the presence or absence of 1 microM forskolin. In vehicle-treated samples, soluble P-selectin levels in response to 1 microM ADP-induced primary aggregation were similar to those of circulating levels of healthy volunteers but the levels in response to 5 microM 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 microM 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.
Kariyazono
H
H
Department of Hospital Pharmacy, Faculty of Medicine, Kagoshima University, Kagoshima, Japan. kariya@khosp3.kufm.kagoshima-u.ac.jp
Nakamura
K
K
Shinkawa
T
T
Yamaguchi
T
T
Sakata
R
R
Yamada
K
K
D000244:Adenosine Diphosphate / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D000077407:Cilostazol; D003094:Collagen / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D019007:P-Selectin / Q000378:metabolism*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects*; D013777:Tetrazoles / Q000494:pharmacology*
D019007:P-Selectin; D010726:Phosphodiesterase Inhibitors; D013777:Tetrazoles; D000244:Adenosine Diphosphate; D003094:Collagen; D000242:Cyclic AMP; D000077407:Cilostazol