Shear-dependent suppression of platelet thrombus formation by phosphodiesterase 3 inhibition requires low levels of concomitant Gs-coupled receptor stimulation

Hideo Yoshida; Yosuke Okamura; Naohide Watanabe; Yasuo Ikeda; Makoto Handa

doi:10.1160/TH10-07-0439

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2011; 105(03): 487-495
DOI: 10.1160/TH10-07-0439

Platelets and Blood Cells

Schattauer GmbH

Shear-dependent suppression of platelet thrombus formation by phosphodiesterase 3 inhibition requires low levels of concomitant Gs-coupled receptor stimulation

Hideo Yoshida

¹Tokyo New Drug Research Laboratories, Kowa Company, Ltd., Tokyo, Japan

³Departments of Transfusion Medicine & Cell Therapy, School of Medicine, Keio University, Tokyo, Japan

,

Yosuke Okamura

²Department of Life Science and Medical Bioscience, Graduate School of Advanced Science and Engineering, Waseda University, Tokyo, Japan

³Departments of Transfusion Medicine & Cell Therapy, School of Medicine, Keio University, Tokyo, Japan

,

Naohide Watanabe

³Departments of Transfusion Medicine & Cell Therapy, School of Medicine, Keio University, Tokyo, Japan

,

Yasuo Ikeda

²Department of Life Science and Medical Bioscience, Graduate School of Advanced Science and Engineering, Waseda University, Tokyo, Japan

,

Makoto Handa

³Departments of Transfusion Medicine & Cell Therapy, School of Medicine, Keio University, Tokyo, Japan

› Institutsangaben

Abstract

Summary

Phosphodiesterase (PDE)3 inhibitors exert potent antiplatelet effects through maintaining elevated intracellular cyclic adenosine monophosphate levels, but do not prolong bleeding time. To resolve this discrepancy, we hypothesised that PDE3 inhibitors effectively suppress shear-induced platelet thrombus formation initiated by the interaction of the platelet receptor GPIb/V/IX with its ligand, von Willebrand factor (VWF), since arterial thrombosis is more dependent on shear stress as compared with haemostatic plug formation. To test the hypothesis, we compared the in vitro effects of K-134 (a PDE3 inhibitor), tirofiban (a GPIIb/IIIa inhibitor) and acetylsalicylic acid (ASA) on ristocetin-induced platelet aggregation and platelet thrombus formation on VWF or collagen surfaces under flow conditions. K-134 inhibited GPIIb/IIIa-dependent platelet aggregation to the same extent as tirofiban and more potently than ASA. Likewise, K-134 and tirofiban effectively inhibited stable platelet thrombus formation (platelet firm adhesion and subsequent aggregation) on the VWF or collagen surface under high shear, but ASA only inhibited aggregation. Notably, inhibition by K-134 became evident only when a low concentration of PGE1 was present. These inhibitors did not block shear-induced initial platelet contact with VWF via GPIb/V/IX. In contrast, under low shear, the inhibitory effects of K-134 on platelet aggregation on the collagen surface were lower than tirofiban or ASA. The observed shear-dependent suppression of platelet thrombus formation by PDE3 inhibitor in the presence of low levels of adenylate cyclase stimulator may contribute to high therapeutic benefit with low risk of bleeding.

Keywords

Phosphodiesterase 3 inhibitor - GPIb/V/IX - VWF - shear-induced platelet thrombus formation - PGE1

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Referenzen

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