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Intrinsic mechanisms of the ion channels associated with life threatening arrhythmia

Research Project

Project/Area Number 17590194
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field General physiology
Research InstitutionUniversity of Occupational and Environmental Health, Japan

Principal Investigator

NAGATOMO Toshihisa  University of Occupational and Environmental Health, Japan, University Hospital, Associate Professor (50258604)

Co-Investigator(Kenkyū-buntansha) ABE Haruhiko  University of Occupational&Environmental Health, Japan, School of Medicine, Lecturer (70231967)
Project Period (FY) 2005 – 2007
Project Status Completed (Fiscal Year 2007)
Budget Amount *help
¥3,730,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥330,000)
Fiscal Year 2007: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2006: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2005: ¥1,200,000 (Direct Cost: ¥1,200,000)
KeywordsElectrophysiology / long QT syndrome / Sodium channel / Potassium channel / hERG channel / Gene / Protein trafficking / Signal transduction / 生理学 / 循環器・高血圧
Research Abstract

1. Congenital long QT syndrome (Na^+ channel mutation)
Type 3 of the long QT syndrome (LQT3) is caused by mutations in SCN5A, the gene that encodes the α-subunit of the human voltage-dependent cardiac Na^+ channel. Previous functional studies of SCN5A mutants indicated that most LQT3 mutations cause increased late sodium current (I_<Na>). Ventricular tachyarrhythmias and sudden cardiac death in patients with LQT3 tend to occur during sleep or at rest when the heart rate is slow. However, the intrinsic mechanism (s) that might explain why arrhythmia attack is most prevalent at slower heart rates has not been investigated. The intrinsic kinetic property of the I^<Na> in the LQT3 R1623Q mutant, preferential rate-dependent reduction of phase 3 'Na under non-equilibrium condition, accounted for the enhanced shortening of QT interval at faster heart rates. On the other hand, β-adrenergic agents were ineffective in reducing the late I_<Na>. Different intrinsic mechanisms are involved in QT int … More erval shortening induced by pacing and ii-adrenergic stimulation. The mechanism of QT shortening by overdrive pacing might mainly include a frequency-dependent reduction of the late and phase 3 I_<Na> in R1623Q mutant channels, while a balance of inward and outward currents might explain the QT interval shortening by β-adrenergic stimulation.
2. Acquired long QT syndrome (Cardiac hERG K^+ channel)
Many drugs associated with acquired long QT syndrome (LQTS) directly block human ether-a-go-go-related gene (hERG) cardiac K+ channels. Recently, disrupted trafficking of the hERG channel protein was proposed as a new mechanism underlying LQTS, but whether this defect coexists with the hERG current block remains unclear. This study investigated how ketoconazole, a direct hERG current inhibitor, affects the trafficking of hERG channel protein. Therapeutic ketoconazole caused acquired LQTS by direct blocking of the hERG channel current and by disrupting hERG protein trafficking. Common drug-binding sites (Y652, F656) were involved in the direct hERG channel block, but not in the hERG trafficking defect. These findings should be considered when evaluating new drugs. Less

Report

(4 results)
  • 2007 Annual Research Report   Final Research Report Summary
  • 2006 Annual Research Report
  • 2005 Annual Research Report
  • Research Products

    (21 results)

All 2008 2007 2006 2005

All Journal Article (14 results) (of which Peer Reviewed: 6 results) Presentation (6 results) Book (1 results)

  • [Journal Article] Coexistence of hERG current block and disruption of protein trafficking in ketoconazole-induced long QT syndrome2008

    • Author(s)
      Takemasa H, Nagatomo T, et. al.
    • Journal Title

      Br J Pharmacol 153

      Pages: 439-447

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Coexistence of hERO current block and disruption of protein trafficking in ketoconazole-induced long QT syndrome.2008

    • Author(s)
      Takemasa H, Nagatomo T, Abe H, Kawakami K, Igarashi T, Tsurugi T, Kabashima N, Tamura M, Okazaki M, Delisle BP, January CT, Otsuji Y
    • Journal Title

      Br J Pharmacol 153

      Pages: 439-447

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Coexistence of hERG current block and disruption of proteintrafficking in ketoconazole-induced long QT syndrome2008

    • Author(s)
      Takemasa H., et. al.
    • Journal Title

      Br J Pharmacol 153

      Pages: 439-447

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Angiotensin receptor blocker improves coronary flow velocity reserve in hertensive patients:comarison with calcium channel blocker2007

    • Author(s)
      Kamezaki E, et. al.
    • Journal Title

      Hypertens Res 30

      Pages: 699-706

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Non-phammacological management in neurocardiogenic syncope2007

    • Author(s)
      Abe H, et. al.
    • Journal Title

      J Arrhythmia 23

      Pages: 21-24

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Effects of atrial tachypacing on symptoms and blood pressure in severe orthostatic hypotension.2007

    • Author(s)
      Kohno R., et al.
    • Journal Title

      Pacing Clin Electrophysiol 30

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Comparison of HERG channel blocking effects of various β-blockers-implication for clinical strategy2006

    • Author(s)
      Kawakami K., Nagatomo T, et. al.
    • Journal Title

      Br J Pharmacol 147

      Pages: 642-52

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Comparison of HERG channel blocking effects of various β-blockers-implication for clinical strategy.2006

    • Author(s)
      Kawakami K, Nagatomo T, Abe H, Kikuchi K, Takemasa H, Anson BD, Delisle BP, January CT, Nakashima Y
    • Journal Title

      Br J Pharmacol 147

      Pages: 642-652

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Comparison of HERG channel blocking effects of various β-blockers - implication for clinical strategy.2006

    • Author(s)
      Kawakami K., et al.
    • Journal Title

      Br J Pharmacol 147

      Pages: 642-52

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Intrinsic mechanism of the enhanced rate-dependent QT shortening in the R1623Q mutant of the LQT3 syndrome2005

    • Author(s)
      Oginosawa Y, Nagatomo T, et. al.
    • Journal Title

      Cardiovasc Res 65

      Pages: 138-147

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Intrinsic mechanism of the enhanced rate-dependent QT shortening in the R1623Q mutant of the LQT3 syndrome.2005

    • Author(s)
      Oginosawa Y, Nagatomo T, Abe H, Makita N, Makielski JC, Nakashima Y.
    • Journal Title

      Cardiovasc Res 65

      Pages: 138-47

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Blockade of HERG cardiac K^+ current by antifungal drug miconazole.2005

    • Author(s)
      Kikuchi K, Nagatomo T, Abe H, Kawakami K, Duff HJ, Makielski JC, Januaiy CT, Nakashima Y
    • Journal Title

      Br J Pharmacol 144

      Pages: 840-848

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Intrinsic mechanism of the enhanced rate-dependent QT shortening in the R1623Q mutant of the LQT3 syndrome.2005

    • Author(s)
      Oginosawa Y, et al.
    • Journal Title

      Cardiovasc Res 65

      Pages: 138-147

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Blockade of HERG cardiac K^+ current by antifungal drug miconazole.2005

    • Author(s)
      Kikuchi K, et al.
    • Journal Title

      Br J Pharmacol 144

      Pages: 840-848

    • Related Report
      2005 Annual Research Report
  • [Presentation] Coexistence of HERG current block and protein trafficking defect in the drug-induced acquired long QT syndrome2007

    • Author(s)
      Takemasa H, Nagatomo T, et. al.
    • Organizer
      ESC Congress 2007
    • Place of Presentation
      Vienna,Austria
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Coexistence of HERG current block and protein trafficking defect in the drug-induced acquired long QT sylldrome.2007

    • Author(s)
      Takemasa H, Nagatomo H, Abe H, Kolmo R, Kawakami K, Tsumgi T, Otsuji Y
    • Organizer
      ESC Congress 2007
    • Place of Presentation
      Viema, Austria
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Modulation of cardiac sodium channel gating by cAMP in the R1623Q mutamt of the LQT3 syndrome.2006

    • Author(s)
      Tsurugi T, Nagatomo T, Abe H, Takemasa H, Kohno R, Nakashima Y
    • Organizer
      27th Annual Scientific Session of the Heart khythm Society
    • Place of Presentation
      Boston, USA
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Coexistence of HERG current block and protein trafficking defect in the drug-induced acquired long QT syndrome.2006

    • Author(s)
      Takemasa H, Nagatomo T, Abe H, Tsurugi T, Kohno R, Otsuji Y
    • Organizer
      27th Annual Scientific Session of the Heart khythm Society
    • Place of Presentation
      Boston, USA
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Novel intrinsic mechanism of the enhanced rate-dependent QT shorteing in Rl623Q mutant of the LQT3 Syndrome.2005

    • Author(s)
      Nagatomo T, Oginosawa Y, Abe H, Tsurgi T, Kikuchi K, Kawakami K, Nakashima Y
    • Organizer
      26th Annual Scientific Session of the Heart Rhythm Sociely
    • Place of Presentation
      New Orleans, USA
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Comparison of HERG channel blocking effects byβ-blockers-Implication for clinical strategy-2005

    • Author(s)
      Kawakami K, Nagatomo T, Kikuchi K, Takemasa H, Oginosawa Y, Tsumgi T, Abe H, Nakashima Y
    • Organizer
      26th Annual Scientific Session of the Heart Rhythm Society
    • Place of Presentation
      New Orleans, USA
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Book] β_1-selective antagonist are more effective for the treatment of type 1 long QT Syndrome. Advances in electrocardiology 2004 (edited by Hiraoka M.et al.)2005

    • Author(s)
      Kawakami K, et al.
    • Total Pages
      4
    • Publisher
      World Scientific Publishing
    • Related Report
      2005 Annual Research Report

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Published: 2005-04-01   Modified: 2016-04-21  

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