Bay 60-7550, a PDE2 inhibitor, exerts positive inotropic effect of rat heart by increasing PKA-mediated phosphorylation of phospholamban.

Item request has been placed! ×
Item request cannot be made. ×
loading   Processing Request
Read More Add to Saved list
  • Additional Information
    • Source:
      Publisher: Elsevier Science Country of Publication: Netherlands NLM ID: 1254354 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1879-0712 (Electronic) Linking ISSN: 00142999 NLM ISO Abbreviation: Eur J Pharmacol Subsets: MEDLINE
    • Publication Information:
      Publication: 2005- : Amsterdam : Elsevier Science
      Original Publication: Amsterdam, North Holland Pub. Co.
    • Subject Terms:
      Calcium-Binding Proteins/*metabolism ; Cardiotonic Agents/*pharmacology ; Cyclic Nucleotide Phosphodiesterases, Type 2/*antagonists & inhibitors ; Imidazoles/*pharmacology ; Phosphodiesterase Inhibitors/*pharmacology ; Triazines/*pharmacology; Animals ; Blood Pressure/drug effects ; Calcium/metabolism ; Hemodynamics/drug effects ; In Vitro Techniques ; Male ; Myocardial Contraction/drug effects ; Myocytes, Cardiac/drug effects ; Phosphorylation ; Rats ; Rats, Sprague-Dawley ; Sarcoplasmic Reticulum Calcium-Transporting ATPases/drug effects ; Sarcoplasmic Reticulum Calcium-Transporting ATPases/metabolism ; Vascular Resistance/drug effects ; Ventricular Function, Left/drug effects
    • Abstract:
      This study investigated the hemodynamic effect of Bay 60-7550, a phosphodiesterase type 2 (PDE2) inhibitor, in healthy rat hearts both in vivo and ex vivo and its underlying mechanisms. In vivo rat left ventricular pressure-volume loop, Langendorff isolated rat heart, Ca 2+ transient of left ventricular myocyte and Western blot experiments were used in this study. The results demonstrated that Bay 60-7550 (1.5 mg/kg, i. p.) increased the in vivo rat heart contractility by enhancing stroke work, cardiac output, stroke volume, end-diastolic volume, heart rate, and ejection fraction. The simultaneous aortic pressure recording indicated that the systolic blood pressure was increased and diastolic blood pressure was decreased by Bay 60-7550. Also, the arterial elastance which is proportional to the peripheral vessel resistance was significantly decreased. Bay 60-7550 (0.001, 0.01, 0.1, 1 μmol/l) also enhanced the left ventricular development pressure in non-paced and paced modes with a decrease of heart rate in non-paced model. Bay 60-7550 (1 μmol/l) increased SERCA2a activity and SR Ca 2+ content and reduced SR Ca 2+ leak rate. Furthermore, Bay 60-7550 (0.1 μmol/l) increased the phosphorylation of phospholamban at 16-serine without significantly changing the phosphorylation levels of phospholamban at 17-threonine and RyR2. Bay 60-7550 increased the rat heart contractility and reduced peripheral arterial resistance may be mediated by increasing the phosphorylation of phospholamban and dilating peripheral vessels. PDE2 inhibitors which result in a positive inotropic effect and a decrease in peripheral resistance might serve as a target for developing agents for the treatment of heart failure in clinical settings.
      (Copyright © 2021 Elsevier B.V. All rights reserved.)
    • Contributed Indexing:
      Keywords: Bay 60-7550; Ca(2+) transient; PDE 2; Phospholamban; P–V loop
    • Accession Number:
      0 (2-(3,4-dimethoxybenzyl)-7-(1-(1-hydroxyethyl)-4-phenylbutyl)-5-methylimidazo(5,1-f)(1,2,4)triazin-4 (3H)-one)
      0 (Atp2a2 protein, rat)
      0 (Calcium-Binding Proteins)
      0 (Cardiotonic Agents)
      0 (Imidazoles)
      0 (Phosphodiesterase Inhibitors)
      0 (Triazines)
      0 (phospholamban)
      EC 3.1.4.17 (Cyclic Nucleotide Phosphodiesterases, Type 2)
      EC 3.6.3.8 (Sarcoplasmic Reticulum Calcium-Transporting ATPases)
      SY7Q814VUP (Calcium)
    • Publication Date:
      Date Created: 20210402 Date Completed: 20210518 Latest Revision: 20210518
    • Publication Date:
      20221213
    • Accession Number:
      10.1016/j.ejphar.2021.174077
    • Accession Number:
      33798601