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Drug design for cardiac treatment by control of K channel

Research Project

Project/Area Number 10044259
Research Category

Grant-in-Aid for Scientific Research (B).

Allocation TypeSingle-year Grants
Section一般
Research Field Circulatory organs internal medicine
Research InstitutionNagoya University

Principal Investigator

KAMIYA Kaichiro  Nagoya Univ. Res. Inst. of Environ. Med., Associate Professor, 環境医学研究所, 助教授 (50194973)

Co-Investigator(Kenkyū-buntansha) YASUI Kenji  Nagoya Univ. Res. Inst. of Environ. Med., Assistant Professor, 環境医学研究所, 助手 (70283471)
MICHAEL Sang  アメリカ合衆国, ユタ大学・内科学, 教授
Project Period (FY) 1998 – 1999
Project Status Completed (Fiscal Year 1999)
Budget Amount *help
¥5,100,000 (Direct Cost: ¥5,100,000)
Fiscal Year 1999: ¥2,300,000 (Direct Cost: ¥2,300,000)
Fiscal Year 1998: ¥2,800,000 (Direct Cost: ¥2,800,000)
Keywordsion channels / antiarrhythmic drugs / K channel blocker / 突然死 / QT延長症候群
Research Abstract

The delayed rectifier KィイD1+ィエD1 current (IィイD2KィエD2) is one of the most important currents responsible for repolarization of cardiac action potential. IィイD2KィエD2 is composed of two distinctive components : a rapidly activating component, IィイD2KrィエD2, and a slowly activating component, IィイD2KsィエD2. Most of the Class III drugs currently used, such as d-sotalol, dofetilide, sematilide and MS-551 preferentially block IィイD2KrィエD2. Potassium channel genes which encode IィイD2KrィエD2 and IィイD2KsィエD2, are HERG and KVLQT1/minK, respectively. In this study, we examined the modulation of various class III antiarrhythmic drugs on HERG and KVLQT1/minK currents.
We have previously shown that vesnarinone, a cardiotonic agent, produced a frequency-dependent prolongation of action potential duration (APD) in rabbit ventricular myocytes. This favorable property as a class III antiarrhythmic agent has not been reported with other class III drugs. To elucidate the underlying mechanisms, we studied the effects of vesnarinone on HERG channels, and KVLQT1/minK channels in Xenopus oocytes. Vesnarinone provided a concentration-dependent inhibition on HERG current with an ICィイD250ィエD2 of 58.7±9.3 μM + 50mV (n=5). The onset of HERG block by 100μM vesnarinone at +10mV developed with a time constant of 178±15 msec (n=3). Vesnarinone at 300 M produced a minimal reduction in KVLQT1/minK current. These results suggest that 1) the prolongation in APD by vesnarinone is caused by block of HERG, but not KVLQT1/minK channels, 2) frequency-dependent prolongation of APD by vesnarinone results from the voltage-dependent binding and unbinding of the drug to HERG channels with moderate time constants, 3) inactivation gate may not interfere neither the drug binding nor unbinding when membrane voltage was altered.

Report

(3 results)
  • 1999 Annual Research Report   Final Research Report Summary
  • 1998 Annual Research Report
  • Research Products

    (27 results)

All Other

All Publications (27 results)

  • [Publications] KAMIYA Kaichiro, GUO Weinong, YASUI Kenji, TOYAMA Junji: "Hypoxia inhibits the changes in action potentials and ion channels during primary culture of neonatal rat ventricular myocytes"Journal of Molecular and Cellular Cardiology. 31. 1591-1598 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] CHENG Jianhua, NIWA Ryoko, KAMIYA Kaichiro, et al.: "Carvedilol blocks repolarizing K+ currents and the L-type Ca2+ current in rabbit ventricular myocytes"European Journal of Pharmacology. 376. 189-201 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] CHENG Jianhua, KAMIYA Kaichiro, LIU Weiran, TSUJI Yukiomi, et al.: "Heterogeneous distribution of the two components of delayed rectifier K+ current : a potential mechanism of the proarrhythmic effects of methanesulfonanilide class III agents"Cardiovascular Research. 43. 135-147 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] LEE Jong-Kook, NISHIYAMA Atsushi, KAMBE Fukushi, SEO Hisato, TAKEUCHI Susumu, KAMIYA Kaichiro: "Downregulation of voltage-gated K+ channels in rat heart with right ventricular hypertrophy"American Journal of Physiology. 277. 1725-1731 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] KADA Kenji, YASUI Kenji, NARUSE Kenji, KAMIYA Kaichiro, et al.: "Orientation change change of cardiocytes induced by cyclic stretch stimulation : Time dependency and involvement of protein kinases"Journal of Molecular and Cellular Cardiology. 31. 247-259 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] LIU Weiran, YASUI Kenji, ARAI Akio, KAMIYA Kaichiro, et al.: "Beta-adrenergic modulation of L-type Ca2+-channel currents in early-stage embryonic mouse heart"American Journal of Physiology. 276. 608-613 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] GUO Weinong, KAMIYA Kaichiro, YASUI Kenji, KODAMA Itsuo, TOYAMA Junji: "Paracrine hypertrophic factors from cardiac non-myocyte cells downregulate the transient outward current density and Kv4.2 K+ channel expression in cultured rat cardiomyocytes"Cardiovascular Research 41 : 157-165, 1999. 41. 157-165 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] 神谷香一郎: "頻脈性不整脈の電気生理学的機序"Heart View. 5 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] 神谷香一郎: "循環器病への挑戦シリーズXVIII,「心房細動の最近の話題」"ライフメディコム. 13 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] KAMIYA Kaichiro, GUO Weinong, YASUI Kenji, TOYAMA Junji: "Hypoxia inhibits the changes in action potentials and ion channels during primary culture of neonatal rat ventricular myocytes"Journal of Molecular and Cellular Cardiology. 31. 1591-1598 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] CHENG Jianhua, NIWA Ryoko, KAMIYA Kaichiro, TOYAMA Junji, KODAMA Itsuo: "Carvedilol blocks repolarizing K+ currents and the L-type Ca2+ current in rabbit ventricular myocytes"European Journal of Pharmacology. 376. 189-201 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] CHENG Jianhua, KAMIYA Kaichiro, LIU Weiran, TSUJI Yukiomi, TOYAMA Junji, KODAMA Itsuo: "Heterogeneous distribution of the two components of delayed rectifier K+ current : a potential mechanism of the proarrhythmic effects of methanesulfonanilide class III agents"Cardiovascular Research. 43. 135-147 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] LEE Jong-KooK, NISHIYAMA Atsushi, KAMBE Fukushi, SEO, Hisao, TAKEUCHI Susumu, KAMIYA Kaichiro, KODAMA Itsuo, TOYAMA Junji: "Downregulation of voltage-gated K+ channels in rat heart with right ventricular hypertrophy"American Journal of Physiology 277 (Heart Circ. Physiol. 46). H1725-1731 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] KADA Kenji, YASUI Kenji, NARUSE Keiji, KAMIYA Kaichiro, KODAMA Itsuo, TOYAMA Junji: "Orientation change of cardiocytes induced by cyclic stretch stimulation : Time dependency and involvement of protein kinases"Journal of Molecular and Cellular Cardiology. 31. 247-259 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] LIU Weiran, YASUI Kenji, ARAI Akio, KAMIYA Kaichiro, CHENG Jianhua, KODAMA Itsuo, TOYAMA Junji: "Beta-adrenergic modulation of L-type Ca2+-channel currents in early-stage embryonic mouse heart"American Journal of Physiology 276 (Heart Circ. Physiol. 45). H608-613 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] GUO Weinong, KAMIYA Kaichiro, YASUI Kenji, KODAMA Itsuo, TOYAMA Junji: "Paracrine hypertrophic factors from cardiac non-myocyte cells downregulate the transient outward current density and Kv4.2 K+ channel expression in cultured rat cardiomyocytes"Cardiovascular Research. 41. 157-165 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] KAMIYA Kaichiro: "Electrophysiological mechanisms of tachyarrhythmias"Heart View. 31. 8-13 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] KAMIYA Kaichiro: "Atrial fibrillation and cardiac remodeling"Topics on atrial fibrillation. 18. 17-29 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] KAMIYA Kaichiro,GUO Weinong,YASUI Kenji,TOYAMA Junji: "Hypoxia inhibits the changes in action potentials and ion channels during primary culture of neonatal rat ventricular myocytes."Journal of Molecular and Cellular Cardiology. 31. 1591-1598 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] CHENG Jianhua,NIWA Ryoko,KAMIYA Kaichiro,et al.: "Carvedilol blocks repolarizing K+ currents and the L-type Ca2+ current in rabbit ventricular myocytes."European Journal of Pharmacology. 376. 189-201 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] CHENG Jianhua,KAMIYA Kaichiro,LIU Weiran,TSUJI Yukiomi,et al.: "Heterogeneous distribution of the two components of delayed rectifier K+ current: a potential mechanism of the proarrhythmic effects of methanesulfonanilide class III agents."Cardiovascular Research. 43. 135-147 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] LEE Jong-Kook,NISHIYAMA Atsushi,KAMBE Fukushi,SEO Hisao,TAKEUCHI Susumu,KAMIYA Kaichiro: "Downregulation of voltage-gated K+ channels in rat heart with right ventricular hypertrophy"American Journal of Physiology. 277. 1725-1731 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] KADA Kenji,YASUI Kenji,NARUSE Kenji,KAMIYA Kaichiro,et al.: "Orientation change of cardiocytes induced by cyclic stretch stimulation: Time dependency and involvement of protein kinases"Journal of Molecular and Cellular Cardiology. 31. 247-259 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] LIU Weiran,YASUI Kenji,ARAI Akio,KAMIYA Kaichiro,et al.: "Beta-adrenergic modulation of L-type Ca2+-channel currents in early-stage embryonic mouse heart."American Journal of Physiology. 276. 608-613 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] GUO Weinong,KAMIYA kaichiro,YASUI kenji,KODAMA Itsuo,TOYAMA Junji: "Paracrine hypertrophic factors from cardiac non-myocyte cells downregulate the transient outward current density and Kv4.2 K+ channel expression in cultured rat cardiomyocytes"Cardiovascular Research. 41. 157-165 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] 神谷 香一郎: "頻脈性不整脈の電気生理学的機序"Heart View. 5 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] 神谷 香一郎: "循環器病への挑戦シリーズXIII,「心房細動の最近の話題」"ライフメディコム. 13 (1999)

    • Related Report
      1999 Annual Research Report

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Published: 1998-04-01   Modified: 2016-04-21  

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