Antiplatelet and antithrombotic activity of cilostazol is potentiated by dipyridamole in rabbits and dissociated from bleeding time prolongation.
OBJECTIVE
To determine the antiplatelet effect of cilostazol (Pletal) and its interaction with dipyridamole in in vitro and in vivo rabbit models, and to see if it can be dissociated from bleeding time prolongation.


METHODS
In vitro collagen-induced platelet aggregation was measured by an impedance-based aggregometer. The in vivo antithrombotic effect was evaluated in a rabbit carotid artery cyclic flow reduction (CFR) model, in which repetitive thrombosis was induced by mechanical injuries of the artery and stenosis. Template bleeding time was determined in rabbit ear arterioles and hindlimb nail cuticles.


RESULTS
In vitro platelet aggregation was slightly inhibited by 4 microM cilostazol (22 +/- 6%), and modestly by 13 microM (57 +/- 3% of aggregation). While dipyridamole itself up to 13 microM had no significant inhibition, it potentiated the effect from cilostazol: in the presence of 4 microM dipyridamole, 4 microM cilostazol inhibited aggregation by 47 +/- 6%. Dipyridamole also potentiated the CFR reducing effect of cilostazol: combination of dipyridamole (no effect by itself) and cilostazol at 1 microM decreased CFRs to levels achieved by 3-4 microM cilostazol alone. Bleeding times were similar in controls and animals treated with cilostazol, or with cilostazol and dipyridamole. In contrast, aspirin (4 mg/kg), while reducing CFRs, significantly increased bleeding time.


CONCLUSIONS
These results suggest that dipyridamole potentiates the antiplatelet effect of cilostazol without prolongation of the bleeding time, implying a potential novel combination antithrombotic therapy.
Li
Haiquan
H
Department of Cardiology, Otsuka Maryland Medicinal Laboratories, LLC, 9900 Medical Center Drive, Rockville, Maryland 20850, USA.
Cone
James
J
Fong
Miranda
M
Kambayashi
Junichi
J
Yoshitake
Masuhiro
M
Liu
Yongge
Y
D000818:Animals; D001760:Bleeding Time; D002341:Carotid Artery Thrombosis / Q000097:blood / Q000188:drug therapy*; D000077407:Cilostazol; D004176:Dipyridamole / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004357:Drug Synergism; D066298:In Vitro Techniques; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011817:Rabbits; D013777:Tetrazoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*
D010975:Platelet Aggregation Inhibitors; D013777:Tetrazoles; D004176:Dipyridamole; D000077407:Cilostazol