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Effects of Tolvaptan via vasopressin V2 receptor-independent pathway on adrenal aldosterone synthesis.

Research Project

Project/Area Number 18K08066
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 53020:Cardiology-related
Research InstitutionMie University

Principal Investigator

Ito Masaaki  三重大学, 医学系研究科, 学長 (00223181)

Co-Investigator(Kenkyū-buntansha) 土肥 薫  三重大学, 医学系研究科, 教授 (50422837)
岡本 隆二  三重大学, 医学部附属病院, 教授 (60378346)
Project Period (FY) 2018-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Keywordsトルバプタン / アルドステロン / 心不全 / CYP11B2 / 自己免疫性心筋炎 / 慢性心不全 / バソプレシンV2受容体拮抗薬 / 副腎
Outline of Final Research Achievements

Tolvaptan, a V2 receptor antagonist, exerts its water diuretic effect by inhibiting V2 receptors in the renal collecting ducts. Experiments using H295R cells, cultured cells derived from the human adrenal cortex and rat models with increased aldosterone production under AngII stimulation, have shown that Tolvaptan suppressed the increase in aldosterone concentration and protein expression of CYP11B2, an aldosterone synthase, by a V2R-independent manner. In addition, tolvaptan suppressed protein expression without suppressing CYP11B2 mRNA expression, and increased DDIT3 protein expression and phosphorylation of eIF2α. These results suggest that tolvaptan could have attenuated CYP11B2 translation and subsequently inhibited the aldosterone biosynthesis, likely in part by promoting the UPR and subsequent inhibition of global protein translation.

Academic Significance and Societal Importance of the Research Achievements

心不全では体液過剰に対する治療に利尿薬が用いられる。ナトリウム利尿を起こす利尿薬ではレニン-アンジオテンシン-アルドステロン(RAA)系や交感神経系の活性、腎集合管での自由水再吸収亢進が引き起こされ、心筋リモデリングやナトリウム・水分貯留の原因となる。近年臨床応用された選択的V2R拮抗薬トルバプタンは腎集合管での自由水再吸収を抑制することにより水利尿を引き起こし、RAA賦活化作用の少ないとされている。今回の研究でトルバプタンの分子薬理機序が解明され、トルバプタンの心不全におけるより有効な治療法やその他の病態への応用に結び付き、さらには新しいアルドステロン阻害薬の開発に繋がることが期待される。

Report

(5 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (2 results)

All 2019 2018

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

  • [Journal Article] Novel molecular mechanisms in the inhibition of adrenal aldosterone synthesis: Action of tolvaptan via vasopressin V(2) receptor-independent pathway.2019

    • Author(s)
      Ali Y, Dohi K, Okamoto R, Katayama K, Ito M
    • Journal Title

      Br J Pharmacol.

      Volume: 176(9) Issue: 9 Pages: 1315-1327

    • DOI

      10.1111/bph.14630

    • Related Report
      2019 Research-status Report 2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Tolvaptan Inhibits Aldosterone Production and Blood Pressure Elevation Induced by Angiotensin II in Hypertensive Rat Model2018

    • Author(s)
      Yusuf Ali, Kaoru Dohi, Ryuji Okamoto, Kan Katayama, Masaaki Ito
    • Organizer
      American Heart Association 2018 Scientifc Sessions (AHA)
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research

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Published: 2018-04-23   Modified: 2023-01-30  

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