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Roles of c-kit in development and pathophysiology of smooth muscle

Research Project

Project/Area Number 13670091
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field General pharmacology
Research InstitutionKumamoto University

Principal Investigator

TOKUTOMI Yoshiko  KUMAMOTO University, Grad.Sch.Med.Sci., Instructor, 大学院・医学薬学研究部, 助手 (90253723)

Co-Investigator(Kenkyū-buntansha) TOKUTOMI Naofumi  KUMAMOTO University, Grad.Sch.Med.Sci., Associate Professor, 大学院・医学薬学研究部, 助教授 (30227582)
西 勝英  熊本大学, 医学部, 教授 (00040220)
Project Period (FY) 2001 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2003: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2002: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2001: ¥1,700,000 (Direct Cost: ¥1,700,000)
Keywordssmooth muscle / c-kit / mouse / contraction / intracellular Ca^<2+> / pacemaker / α_1-acid glycoprotein / パッチクランプ法 / 等尺性張力 / ryanodine感受性Ca^<2+>放出 / caffeine / ryanodine / 細胞内Ca^<2+>貯蔵部位
Research Abstract

Drug-induced contraction of gastrointestinal tracts seems to depend upon the extent of their rhythmic contraction that is driven by the activity of gastrointestinal pacemaker cells. In BALB/c mice chronically administered with a neutralizing anti-c-Kit monoclonal antibody (ACK2), rhythmic contraction of gastrointestinal tract was impaired and contractile responses to drugs., including acetylcholine, prostaglandin F_<2α> and bradykinin were anomalously augmented. Histochemical analysis of the c-kit positive cells in the gastrointestinal tract revealed the decreased number of c-kit positive cells in the ACK2-treated animals, which lead to the impaired rhythmic contraction. Since the intestinal c-kit positive cells in primary culture developed Ca^<2+>-dependent rhythmic Cl^-current, the rhythmic current is supposed to be an origin of gastrointestinal pacemakers. The extent of anomaly in drug-induced contraction correlated with the extent of impairment in rhythmic contraction. The anomalou … More s drug-induced contraction in the preparation from ACK2-treated animals, which is accompanied by the impaired rhythmic contraction, was mimicked when the gastrointestinal segments from control animals were superfused with a low temperature organ bath solution at 25℃. These results suggest that rhythmic discharge of excitation of smooth muscle cells, which is triggered by rhythmic excitatory input from c-kit cells, regulates the extent of drug-induced contraction.
We have demonstrated that human α_1-acid glycoprotein produces a transient relaxation in the mouse aorta precontracted with phenylephrine. It is more likely that the α_1-acid glycoprotein-induced relaxation is due to block of Ca^<2+>-entry through VDCC or NSCC in the smooth muscle cells rather than activation of endothelial NO pathway. The transient relaxation induced by α_1-acid glycoprotein might occur as prolonged relaxation in the peripheral blood vessel, which may result in improvement of the blood circulation at tissue with inflammation. Less

Report

(4 results)
  • 2003 Annual Research Report   Final Research Report Summary
  • 2002 Annual Research Report
  • 2001 Annual Research Report
  • Research Products

    (23 results)

All Other

All Publications (23 results)

  • [Publications] Tokutomi Y., et al.: "The properties of ryanodine-sensitive Ca^<2+> release in mouse gastric smooth muscle cells."Br.J.Pharmacol.. 133・1. 125-137 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 徳冨直史, 他: "c-kit機能欠如マウス消化管平滑筋の薬物に対する異常反応"日薬理誌. 119・4. 227-234 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Okuda T., et al.: "Noradrenaline receptor-mediated potentiation of caffeine-induced Ca^<2+>-activated K^+ currents in bovine cillary muscle cells."Curr.Eye Res.. 23・6. 455-462 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Tokutomi Y., et al.: "Effects of α_1-acid glycoprotein on isometric tension of mouse aorta."Eur.J.Pharmacol.. 477・2. 137-141 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Matsumoto K., et al.: "Effects of alpha 1-acid glycoprotein on erythrocyte deformability and membrane stabilization."Biol.Pharm.Bull.. 26・1. 123-126 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 松元 一明, 他: "α_1-酸性糖蛋白質の血液循環系に及ぼす作用"人工血液. 11・2. 144-150 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 徳冨 直史, 他: "c-kit機能欠如マウス消化管平滑筋の薬物に対する異常反応"日薬理誌. 123・3. 163-169 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Tokutomi Y., et al.: "The properties of ryanodine-sensitive Ca^<2+> release in mouse gastric smooth muscle cells."Br.J.Pharmacol.. 133. 125-137 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Tokutomi Y., et al.: "Genetic basis of autonomic gastrointestinal motility and pathophysiological models."Folia Pharmacol.Jpn.. 119. 227-234 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Okuda T., et al.: "Noradrenaline receptor-mediated potentiation of caffeine-induced Ca^<2+>-activated K^+ currents in bovine ciliary muscle cells."Curr.Eye Res.. 23. 455-462 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Tokutomi Y., et al.: "Effects of a_1-acid glycoprotein on isometric tension of mouse aorta."Eur.J.Pharmacol.. 477. 137-141 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Matsumoto K., et al.: "Effects of α_1-acid glycoprotein on blood circulation."Artificial Blood. 11. 144-150 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Tokutomi N., et al.: "Drug-induced anomalous contraction of gastrointestinal tract of mice with impaired c-kit function."Folia Pharmacol.Jpn.. 123. 163-169 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 徳冨 直史, 他: "c-kit機能欠如マウス消化管平滑筋の薬物に対する異常反応"日薬理誌. 123・3(in press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Tokutomi Y., et al.: "Effects of α_1-acid glycoprotein on isometric tension of mouse aorta"Eur.J.Pharmacol.. 477・2. 137-141 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Matsumoto K., et al.: "Effects of alpha 1-acid glycoprotein on erythrocyte deformability and membrane stabilization"Biol.Pharm.Bull.. 26・1. 123-126 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 松元 一明, 他: "α_1-酸性糖蛋白質の血液循環系に及ぼす作用"人工血液. 11・2. 144-150 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Tokutomi, Y., et al.: "The properties of ryanodine-sensitive Ca^<2+> release in mouse gastric smooth muscle cells"Br. J. Pharmacol.. 133. 125-137 (2001)

    • Related Report
      2002 Annual Research Report
  • [Publications] Tokutomi, Y., et al.: "消化管自律運動の遺伝子基盤と病態"日本薬理学雑誌. 119・4. 227-234 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Okuda, T., et al.: "Noradrenaline receptor-mediated potentiation of caffeine-induced Ca^<2+>-activated K^+ currents in bovine ciliary muscle cells"Current Eye Research. 23・6. 455-462 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Tokutomi, Y., et al.: "The properties of ryanodine-sensitive Ca^<2+> release in mouse gastric smooth muscle cells"Br. J. Pharmacol. 133. 125-137 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Tokutomi, Y., et al.: "消化管自律運動の遺伝子基盤と病態"日本薬理学 雑誌. 119・4(in press). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Okuda, S., et al.: "Noradrenaline receptor-mediated potentiation of caffeine-induced Ca^<2+>-activated K^+ currents in bovine ciliary muscle cells"Current Eye Research. (in press). (2002)

    • Related Report
      2001 Annual Research Report

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Published: 2001-04-01   Modified: 2016-04-21  

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