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Elucidation of roles of Na^+-driven cation transporter in blood pressure control and arterial lesions

Research Project

Project/Area Number 14570097
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field General pharmacology
Research InstitutionFukuoka University (2003)
National Cardiovascular Center Research Institute (2002)

Principal Investigator

IWAMOTO Takahiro  Fukuoka University, School of Medicine, Lecturer, 医学部, 講師 (20300973)

Project Period (FY) 2002 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 2003: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2002: ¥2,000,000 (Direct Cost: ¥2,000,000)
KeywordsNa^+ / Ca^<2+> exchanger / Hypertension / Calcium ion / Salt-sensitivity / Vasodilation / トランスジェニックマウス / 食塩感受性高血圧 / 心肥大 / 血管肥厚 / 腎臓障害 / 血管拡張
Research Abstract

Excessive salt intake is a major risk factor for hypertension Here we identify the role of Na^+/Ca^<2+> exchanger type 1 (NCX1) in salt-sensitive hypertension using SEA0400, a specific inhibitor for Ca^<2+> entry via NCX1, and genetically engineered mice. SEA0400 lowers arterial blood pressure in salt-dependent hypertensive rat models, but not in normotensive rats or other types of hypertensive rats. Infusion of SEA0400 into the femoral artery in salt-dependent hypertensive rats increases arterial blood flow indicating peripheral vasodilation. SEA0400 reverses ouabain-induced cytosolic Ca^<2+> elevation and vasoconstriction in arteries. Furthermore, heterozygous NCX1-deflcient mice have low salt-sensitivity, whereas transgenic mice that specifically express NCX1.3 in smooth muscle are hypersensitive to salt SEA0400 significantly lowers the blood pressure in salt-dependent hypertensive mice expressing NCX1.3, but not in SEA0400-insensitive NCX1.3 mutants. These findings indicate that salt-sensitive hypertension is triggered by Ca^<2+> entry via NCX1 in arterial smooth muscle and suggest that NCX1 inhibitors might be useful therapeutically.

Report

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

    (37 results)

All Other

All Publications (37 results)

  • [Publications] Matsumura, Y.: "Pathophysiological roles of Ca^<2+> overload via the Na^+/Ca^<2+> exchanger and eddotheline-1 overproduction in ischemia/reperfusion-induced acute renal failure"Clin.Sci.. 103・Suppl48. 389S-392S (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Shigekawa, M.: "Probing ion binding sites in Na^+/Ca^<2+> exchanger"Ann.N.Y.Aced.Sci.. 976. 19-30 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 岩本隆宏: "遺伝子改変マウスを用いたNa^+/Ca^<2+>交換輸送体の機能解析と創薬"日薬理誌. 120・Suppl1. 91P-93P (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Yamashita, J.: "Attenuation of ischemia/reperfusion-induced renal injury in mice deficient in Na^+/Ca^<2+> exchanger"J.Pharmacol.Exp.Ther.. 304・1. 284-293 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Wakimoto, K.: "Na^+/Ca^<2+> exchanger-deficient mice have disorganized myofibrls and swollen mitochondria in cardiomyocytes."Comp.Biochem.Physiol.B.Biochem.Mol.Biol.. 135・1. 9-15 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Ogata, M.: "A novel and selective Na^+/Ca^<2+> exchange inhibitor, SEA0400, improves ischemia/reperfusion-induced renal injury."Eur.J.Pharmacol.. 478・2-3. 187-198 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 岩本隆宏: "Na^+/Ca^<2+>交換体と虚血再灌流障害"Heart View. 7・12. 126-131 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Iwamoto, T.: "Molecular determinants of Na^+/Ca^<2+> exchanger (NCX1) inhibition by SEA0400."J.Biol.Chem.. 279・9. 187-198 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 岩本隆宏: "Na^+/Ca^<2+>交換体を標的とした虚血治療の新展開"医学のあゆみ. 208・5. 382-387 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Iwamoto, T.: "Development and application of Na^+/Ca^<2+> exchange inhibitors"Mol.Cell.Biochem.. 259・1-2. 157-161 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Iwamoto, T.: "The exchanger inhibitory peptide region-dependent inhibition of Na^+/Ca^<2+> exchange by SN-6[2-[4-(4-nitrobenzyloxy)benzyl]thiazolidine-4-carboxylic acid ethyl esterl, a novel benzyloxyphenyl derivative."Mol.Pharmacol.. in press.

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Iwamoto, T.: "Endothelin-1 aggravates hypoxia/reoxygenation-induced injury in renal epithelial cells through the activation of Na^+/Ca^<2+> exchanger."J.Cardiovasc.Pharmacol.. in press.

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kita, S.: "Endothelin-1 enhances the activity of Na^+/Ca^<2+> exchanger type 1 (NCX1) in renal epithelial cells."J.Cardiovasc.Pharmacol.. in press.

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Matsumura, Y: "Pathophysiological roles of Ca^<2+> overload via the Na^+/Ca^<2+> exchanger and endotheline-1 overproduction in ischemia/reperfusion-induced acute renal failure."Clin.Sci.. 103-Suppl48. 389S-392S (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Shigekawa, M: "Probing ion binding sites in Na^+/Ca^<2+> exchanger."Ann.N.Y.Acad.Sci.. 976. 19-30 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Iwamoto, T.: "Functional analysis of Na^+/Ca^<2+> exchanger using novel drugs and genetically engineered mice."Folia Pharmacol.Jpn.. 120-Suppl1. 91-93 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Yamashita, J.: "Attenuation of ischemia/reperfusion induced renal injury in mice deficient in Na^+/Ca^<2+> exchanger."J.Pharmacol.Exp.Ther.. 304-1. 284-293 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Wakimoto, K.: "Na^+/Ca^<2+> exchanger-deficient mice have disorganized myofibrils and swollen mitochondria in cardiomyocytes."Comp.Biochem.Physiol.B.Biochem.Mol.Biol.. 135-1. 9-15 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Ogata, M.: "A novel and selective Na^+/Ca^<2+> exchanger inhibitor, SEA0400, improves ischemia/reperfusion-induced renal injury."Eur.J.Pharmacol. 478-(2-3). 187-198 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Iwamoto, T.: "Na^+/Ca^<2+> exchanger and ischemia/reperfusion injury."Heart View. 7-12. 126-131 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Iwamoto, T.: "Molecular determinants of Na^+/Ca^<2+> exchanger (NCX1) inhibition by SEA0400."J.Biol.Chem.. 279-9. 187-198 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Iwamoto, T.: "New perspective on Na^+/Ca^<2+> exchanger-targeted therapeutics for ischemia."J.Clin.Exper.Med.. 208-5. 382-387 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Iwamoto, T.: "Development and application of Na^+/Ca^<2+> exchanger inhibitors"Mol.Cell.Biochem.. 259-(1-2). 157-161 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Iwamoto, T.: "The exchanger inhibitory peptide region-dependent inhibition of Na^+/Ca^<2+> exchanger by SN-6 [2-[4-(4-nitrobenzyloxy)benzyl]thiazolidine-4-carboxylic acid ethyl ester], a novel benzyloxyphenyl derivative."Mol.Pharmacol.. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Iwamoto, T.: "Endothelin-1 aggravates hypoxia/reoxygenation-induced injury in renal epithelial cells through the activation of Na^+/Ca^<2+> exchanger."J.Cardiovasc.Pharmacol.. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kita, S.: "Endothelin-1 enhances the activity of Na^+/Ca^<2+> exchanger type 1 (NCX1) in renal epithelial cells."J.Cardiovasc.Pharmacol.. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Wakimoto, K.: "Na^+/Ca^<2+> exchanger-deficient mice have disorganized myofibrils and swollen mitochondria in cardiomyocytes."Comp.Biochem.Physiol.B.Biochem.Mol.Biol.. 135・1. 9-15 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Ogata, M.: "A novel and selective Na^+/Ca^<2+> exchange inhibitor, SEA0400, improves ischemia/reperfusion-induced renal injury."Eur.J.Pharmacol.. 478・2-3. 187-198 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Iwamoto, T.: "Molecular determinants of Na^+/Ca^<2+> exchange (NCX1) inhibition by SEA0400."J.Biol.Chem. 279・9. 7544-7553 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Iwamoto, T.: "The XIP region-dependent inhibition of Na^+/Ca^<2+> exchange (NCX1) by SN-6, a novel benzyloxyphenyl derivative."Mol.Pharmacol.. (in press).

    • Related Report
      2003 Annual Research Report
  • [Publications] Iwamoto, T.: "Endothelin-1 Aggravates Hypoxia/Reoxygenation-Induced Injury in Renal Epithelial Cells through the Activation of Na^+/Ca^<2+> Exchanger."J.Cardiovasc.Pharmacol.. (in press).

    • Related Report
      2003 Annual Research Report
  • [Publications] Kita, S.: "Endothelin-1 enhances the activity of Na^+/Ca^<2+> exchanger type 1 (NCX1) in renal epithelial cells."J.Cardiovasc.Pharmacol.. (in press).

    • Related Report
      2003 Annual Research Report
  • [Publications] 岩本 隆宏: "分子標的薬「Na^+/Ca^<2+>交換体を標的とした虚血治療の新展開」"医歯薬出版株式会社. 6 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Matsumura, Y.: "Pathophysiological roles of Ca^<2+> overload via the Na^+/Ca^<2+> exchanger and endothelin1 overproduction in ischaemia/reperfusion induced acute renal failure"Clin.Sci.. 103・Supple48. 389S-392S (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Shigekawa, M.: "Probing ion binding sites in Na^+/Ca^<2+> exchanger"Ann.N.Y.Acad.Sci.. 976. 19-30 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 岩本 隆宏: "遺伝子改変マウスを用いたNa^+/Ca^<2+>交換輸送体の機能解析と創薬"日薬理誌. 120・Suppl1. 91-93 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yamashita, J.: "Attenuation of Ischemia/Reperfusion Induced Renal Injury in Mice Deficient in Na^+/Ca^<2+> exchanger"J.Pharmacol.Exp.Ther.. 304・1. 284-293 (2003)

    • Related Report
      2002 Annual Research Report

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Published: 2002-04-01   Modified: 2016-04-21  

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