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Drug discovery platform for improvement of positive inotropic effect in septic myocardium

Research Project

Project/Area Number 15K15661
Research Category

Grant-in-Aid for Challenging Exploratory Research

Allocation TypeMulti-year Fund
Research Field Emergency medicine
Research InstitutionNagoya University

Principal Investigator

Matsuda Naoyuki  名古屋大学, 医学系研究科, 教授 (50332466)

Co-Investigator(Kenkyū-buntansha) 服部 裕一  富山大学, 大学院医学薬学研究部(医学), 教授 (50156361)
Project Period (FY) 2015-04-01 – 2017-03-31
Project Status Completed (Fiscal Year 2016)
Budget Amount *help
¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2015: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Keywords敗血症 / β受容体 / ホスホジエステラーゼ / PDE4 / ドブタミン / 心筋 / 細胞内情報伝達 / G蛋白 / アデニール酸シクラーゼ / 心筋細胞 / リボシメンダン / 陽性変力作用
Outline of Final Research Achievements

We weighed the effects of dobutamine and milrinone as inotropes in BALB/c mice with cecal ligation and puncture (CLP)-induced sepsis. Surface expression levels of β1-adrenoceptors and alpha subunits of three main G protein families in myocardium were unaffected by CLP-induced sepsis. Plasma cyclic adenosine monophosphate (cAMP) levels were significantly elevated in both sham-operated and CLP mice in response to milrinone but only in sham-operated controls in response to dobutamine. Of phosphodiesterase (PDE) isoforms, PDE4D, but not PDE3A, both of which are responsible for cardiac cAMP hydrolysis, was significantly upregulated in CLP mouse myocardium. We define a novel mechanism for the impaired responsiveness to dobutamine as an inotrope in sepsis and understanding the role of PDE4D in modulating cardiac functional responsiveness in sepsis may open the potential of PDE4D-targeted therapeutic option in septic patients with low cardiac output who have a need for inotropic support.

Report

(3 results)
  • 2016 Annual Research Report   Final Research Report ( PDF )
  • 2015 Research-status Report
  • Research Products

    (2 results)

All 2017 2015

All Journal Article (2 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 2 results,  Acknowledgement Compliant: 1 results,  Open Access: 1 results)

  • [Journal Article] Diminished Responsiveness to Dobutamine as an Inotrope in Mice with Cecal Ligation and Puncture-Induced Sepsis: Attribution to Phosphodiesterase 4 Upregulation.2017

    • Author(s)
      Sakai M, Suzuki T, Tomita K, Yamashita S, Palikhe S, Hattori K, Yoshimura N, Matsuda N, Hattori Y.
    • Journal Title

      Am J Physiol Heart Circ Physiol

      Volume: 印刷中

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Anti-Inflammatory Profile of Levosimendan in Cecal Ligation-Induced Septic Mice and in Lipopolysaccharide-Stimulated Macrophages.2015

    • Author(s)
      Qiang Wang, Hiroki Yokoo, Michinori Takashina, Kimimasa Sakata, Wakana Ohashi, Lobna A Abdelzaher, Takahiro Imaizumi, Takuya Sakamoto, Kohshi Hattori, Naoyuki Matsuda, Yuichi Hattori
    • Journal Title

      Critical Care Medicine

      Volume: 43巻,11号 Issue: 11 Pages: e508-e520

    • DOI

      10.1097/ccm.0000000000001269

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research

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Published: 2015-04-16   Modified: 2018-03-22  

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