Analysis of cardiac Ca2+ homeostasis in septic shock

• Project/Area Number: 17K11047
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Anesthesiology
• Research Institution: University of Shizuoka (2020-2021); Hamamatsu University School of Medicine (2017-2019)
• Principal Investigator: Watanabe Yasuhide 静岡県立大学, 薬学部, 客員教授 (50305380)
• 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) ; 松田 直之 名古屋大学, 医学系研究科, 教授 (50332466)
• Project Period (FY): 2017-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: Na/Ca交換輸送体 / 心室筋細胞 / パッチクランプ法 / 敗血症 / 心筋Ca動態 / マウス敗血症モデル / sepsis / heart / Na/Ca exchanger (NCX) / patch clamp / Na/Ca交換電流 / 敗血症モデルマウス / 心筋細胞Ca動態 / Caチャネル / 心機能 / 薬理学 / 生理学

Outline of Final Research Achievements

We investigate cardiomyocyte Ca2+ kinetics and cardiac Na+/Ca2+ exchanger function in sepsis shock.Our collaborators reported dobutamine showed a positive inotropic effect on septic model mice (Sakai et al., 2017). We reported that carvedilol inhibited INCX in guinea-pig cardiac ventricular myocytes (Tashiro et al., 2017) and flecainide suppressed INCX (Kuroda et al., 2017). We reported that the effects of levosimendan and milrinone on hearts of septic mice (Yamashita et al., 2018) and our collaborators reported the elucidation on pathophysiologic mechanisms of septic shock and its application of new treatments (Suzuki et al., 2018). We reported that pinacidil enhanced INCX current in a NO-cGMP-PKG pathway (Iguchi et al., 2019) and summarized the mechanisms of cardioprotective drugs which enhanced NCX1 function (Watanabe, 2019).In 2020 and 2021,we researched in collaboration with the University of Shizuoka on cardiac contractility in septic shock.

Academic Significance and Societal Importance of the Research Achievements

敗血症ショックは、体末梢血管抵抗低下および心筋収縮性低下を主体として急性循環不全をきたす病態である。初期は末梢循環の維持された“warm shock”となりやすいが，血管内皮傷害と並行して“cold shock”へ移行し，心機能低下が具現化しやすい。しかしながら、現在のところ効果がある敗血症治療薬は見出されていない。
心筋のCa動態を調節する心筋Na+/Ca2+交換輸送体について解析し、敗血症治療薬の発見の手助けになることを期待する。今回の研究を通してNCX機能を増強するKATP開口薬のニコランジルやピナシジル、PDE抑制薬のシルデナフィルなどが発見され、今後さらなる研究成果が期待される。

Research Products

• [Journal Article] Cardiac Na+/Ca2+ exchange stimulators among cardioprotective drugs. (2019)
  • Author(s): Yasuhide Watanabe
  • Journal Title: Journal Physiological Science Volume: 69 Issue: 6 Pages: 837-849
  • DOI: 10.1007/s12576-019-00721-5
  • Peer Reviewed / Open Access
• [Journal Article] Pinacidil, a KATP channel opener, stimulates cardiac Na+/Ca2+ exchanger function through the NO/cGMP/PKG signaling pathway in guinea pig cardiac ventricular myocytes. (2019)
  • Author(s): Iguchi K, Saotome M, Yamashita K, Hasan P, Sasaki M, Maekawa Y, Watanabe Y.
  • Journal Title: Naunyn Schmiedebergs Arch Pharmacol. Volume: 392 Issue: 8 Pages: 949-959
  • DOI: 10.1007/s00210-019-01642-1
  • Peer Reviewed
• [Journal Article] Cardioprotective and functional effects of levosimendan and milrinone in mice with cecal ligation and puncture-induced sepsis (2018)
  • Author(s): Yamashita S, Suzuki T, Iguchi K, Sakamoto T, Tomita K, Yokoo H, Sakai M, Misawa H, Hattori K, Nagata T, Watanabe Y, Matsuda N, Yoshimura N, Hattori Y
  • Journal Title: Naunyn Schmiedebergs Arch Pharmacol Volume: 391 Issue: 9 Pages: 1021-1032
  • DOI: 10.1007/s00210-018-1527-z
  • Peer Reviewed
• [Presentation] The effects of pinacidil, an ATP-sensitive K+ channel opener on cardiac Na＋/Ca²＋ exchanger function in guinea pig cardiomyocytes. (2019)
  • Author(s): Iguchi K, Saotome M, Yamashita K, Ikoma T, Hasan P, Maekawa Y, Watanabe Y.
  • Organizer: 63RD ANNUAL MEETING OF THE BIOPHYSICAL SOCIETY, Baltimore
  • Int'l Joint Research
• [Presentation] Pinacidil, a KATP channel opener stimulate a cardiac Na＋/Ca²＋ exchanger function through NO/cGMP/PKG pathways in guinea-pig cardiac myocytes． (2018)
  • Author(s): 33.Iguchi K, Watanabe Y, Saotome M, Yamashita K, Sasaki M, Maekawa Y．
  • Organizer: WCP2018 (18th WORLD CONGRESS OF BASIC AND CLINICAL PHARMACOLOGY)
  • Int'l Joint Research
• [Book] コメディカルのための薬理学 第三版 (2018)
  • Author(s): 渡邊泰秀、安西尚彦、桜田香（編）
  • Total Pages: 250
  • Publisher: 朝倉書店
  • ISBN: 9784254330106