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

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  • Author(s): Yoshida H;Yoshida H; Okamura Y; Watanabe N; Ikeda Y; Handa M
  • Source:
    Thrombosis and haemostasis [Thromb Haemost] 2011 Mar; Vol. 105 (3), pp. 487-95. Date of Electronic Publication: 2010 Dec 06.
  • Publication Type:
    Journal Article; Research Support, Non-U.S. Gov't
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: Thieme Country of Publication: Germany NLM ID: 7608063 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2567-689X (Electronic) Linking ISSN: 03406245 NLM ISO Abbreviation: Thromb Haemost Subsets: MEDLINE
    • Publication Information:
      Publication: 2018- : Stuttgart : Thieme
      Original Publication: Stuttgart, Schattauer.
    • Subject Terms:
      Cyclic Nucleotide Phosphodiesterases, Type 3/*metabolism ; GTP-Binding Protein alpha Subunits, Gs/*metabolism; Aspirin/chemistry ; Aspirin/pharmacology ; Cyclic AMP/metabolism ; Cyclic GMP/metabolism ; Dose-Response Relationship, Drug ; Hemostasis ; Humans ; Ligands ; Platelet Aggregation ; Quinolines/pharmacology ; Ristocetin/pharmacology ; Shear Strength ; Tirofiban ; Tyrosine/analogs & derivatives ; Tyrosine/pharmacology ; Urea/analogs & derivatives ; Urea/pharmacology ; von Willebrand Factor/metabolism
    • 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.
    • Accession Number:
      0 (Ligands)
      0 (Quinolines)
      0 (von Willebrand Factor)
      1404-55-3 (Ristocetin)
      42HK56048U (Tyrosine)
      8W8T17847W (Urea)
      E0399OZS9N (Cyclic AMP)
      EC 3.1.4.17 (Cyclic Nucleotide Phosphodiesterases, Type 3)
      EC 3.6.5.1 (GTP-Binding Protein alpha Subunits, Gs)
      GGX234SI5H (Tirofiban)
      H2D2X058MU (Cyclic GMP)
      J9J6NK6W4U (OPC 33509)
      R16CO5Y76E (Aspirin)
    • Publication Date:
      Date Created: 20101208 Date Completed: 20110621 Latest Revision: 20181221
    • Publication Date:
      20221213
    • Accession Number:
      10.1160/TH10-07-0439
    • Accession Number:
      21136009