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

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)487-495
Number of pages9
JournalThrombosis and Haemostasis
Volume105
Issue number3
DOIs
Publication statusPublished - 2011 Mar

Fingerprint

tirofiban
Phosphoric Diester Hydrolases
Phosphodiesterase 3 Inhibitors
Thrombosis
Blood Platelets
von Willebrand Factor
Aspirin
Platelet Aggregation
Collagen
Ristocetin
Bleeding Time
Alprostadil
Hemostatics
Adenylyl Cyclases
Cyclic AMP
Hemorrhage
Ligands

Keywords

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

ASJC Scopus subject areas

  • Hematology

Cite this

Shear-dependent suppression of platelet thrombus formation by phosphodiesterase 3 inhibition requires low levels of concomitant Gs-coupled receptor stimulation. / Yoshida, Hideo; Okamura, Yosuke; Watanabe, Naohide; Ikeda, Yasuo; Handa, Makoto.

In: Thrombosis and Haemostasis, Vol. 105, No. 3, 03.2011, p. 487-495.

Research output: Contribution to journalArticle

Yoshida, Hideo ; Okamura, Yosuke ; Watanabe, Naohide ; Ikeda, Yasuo ; Handa, Makoto. / Shear-dependent suppression of platelet thrombus formation by phosphodiesterase 3 inhibition requires low levels of concomitant Gs-coupled receptor stimulation. In: Thrombosis and Haemostasis. 2011 ; Vol. 105, No. 3. pp. 487-495.
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