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2001 Fiscal Year Final Research Report Summary

Exploration of the novel therapeutic methods for the treatment of chronic circulatory diseases

Research Project

Project/Area Number 11357019
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section展開研究
Research Field 応用薬理学・医療系薬学
Research InstitutionUniversity of Tsukuba

Principal Investigator

GOTO Katsutoshi  University of Tsukuba, Institute of Basic Medical Sciences, Professor, 基礎医学系, 教授 (30012660)

Co-Investigator(Kenkyū-buntansha) MIYAUCHI Takashi  University of Tsukuba, Institute of Basic Medical Sciences, Professor, 臨床医学系, 講師 (60222329)
MIWA Yoshihiro  University of Tsukuba, Institute of Basic Medical Sciences, Assistant Professor, 基礎医学系, 講師 (70263845)
SAKURAI Takeshi  University of Tsukuba, Institute of Basic Medical Sciences, Associate Professor, 基礎医学系, 助教授 (60251055)
MURATA Sakae  Insti. Drug Develop., Tanabe Pharmaceut. Comp. Chief, 循環薬理部, 部長
KASUYA Yoshitoshi  Grad.Sch. Med. Chiba Univ. Associate Professor, 大学院・医学研究科・高次機能系分子生体機構学, 助教授 (70221877)
Project Period (FY) 1999 – 2001
Keywordsendothelin / chronic circulatory disease / myocardial infarction / chronic heart failure / cardiac remodeling / cardiomyopathic hamster / ET receptor antagonist / HIF-1α
Research Abstract

The aim of this research project is to develop new therapeutic drugs for the treatment of chronic circulatory diseases e.g. chronic heart failure, pulmonary hypertension, etc., by paying special attention on the role of endothelin (ET) as an endogenous factor in the development, maintenance and aggravation of the diseases. For this purpose, various animal models of chronic circulatory diseases were utilized. In cardiac tissues of rats with chronic heart Mure due to coronary artery occlusion, the expression of ET-1 mRNA and the content of ET-1 peptide were significantly increased, and the expression of ET_A receptors was also elevated, indicating that the ET system was markedly enhanced in the failing heart. ETA receptor antagonist decreased the left ventricular +dp/dt/pmax in rats with myocardial infarction soon after coronary occlusion, suggesting that endogenous ET-1 is playing an important role for maintaining cardiac function at the acute phase. However, if the stimulation by ET-1 continues for a long period, the heart would gradually bear overload, thereby resulting in chronic heart, failure with marked hypertrophy 'and flbrosis, I.e. so-called cardiac remodeling. An identical phenomenon was also observed in hamster with cardiomyopathy, an animal model of non-ischemic heart failure. Impairment of cardiac metabolism by the inhibition of mitochondrial Respiratory pathway in cultured cardiomyocytes, an in vitro model of heart failure, ET-1 production was markedly enhanced via expression of HIF-1 α.

  • Research Products

    (17 results)

All Other

All Publications (17 results)

  • [Publications] Kobayashi T: "Expression of endothlin-1, ETA and ETB receptors, and ECE and distribution of endothelin-1 in falling rat heart"Am J Physiol.. 276. H1197-H1206 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Yamauchi-Kono R.: "Role or endothelin in deterioration of heart failure due to cardiomyopathy in hamsters : increase in endothelin-1 production in the heart and beneficial effect of endothelin A receptor antagonist on survival and cardiac function"Circulation. 99. 2171-2176 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Abe Y.: "Subtype-specific trafficking of endothelin receptors"J Biol Chem.. 275. 8664-8671 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kakinuma Y.: "Novel molecular mechanisms of increased myocardial endothelin-1 expression in the falling heart involving the transcriptional factor hypoxia-inducible factor-1 alpha induced for impaired myocardial energy metabolism"Circulation. 103. 2387-2394 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Yuki K: "Endothelin-1 production is enhanced by rotenone, a mitochondrial complex I inhibitor, in cultured rat myocytes"J Cardiovasc Pharmacol.. 38. 850-858 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Goto K.: "Basic and therapeutic relevance of endothelin-mediated regulation"Biol Pharm Bull. 24. 1219-1230 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Goto K.: "History of endothelin. in "Pulmonary Actions of Endothelins""Binkhauser Verlag, Basel/Switzerland. 1-20 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kobayashi T, Miyauchi T, Sakai S, Kobayashi M, Yamaguchi I, Goto K, Sugishita Y: "Expression of endothelin-1, ETA and ETB receptors, and ECE and distribution of endothelin-1 in failing rat heart"Am J Physiol.. 276. H1197-H1206 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Ueno M, Miyauchi T, Sakai S, Kobayashi T, Goto K, Yamaguchi I: "Effects of physiological or pathophysiological pressure load in vivo on myocardial expression of ET-1 and receptors"Am J Physiol.. 277. R1321-R1330 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kakinuma K, Miyauchi T, Kobayashi T, Yuki K, Maeda S, Sakai S, Goto K, Yamaguchi I: "Myocardial expression of endothelin-2 is altered reciprocally to that of endothelin-1 during ischemia of cardiomyocytes in vitro and during heart failure in vivo"Life Sci.. 65. 1671-1683 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Yamauchi-Kono R, Miyauci T, Hoshina T, Kobayashi T, Aihara H, Sakai S, Yabana H, Goto K, Sugishita Y,Murata S: "Role of endothelin in deterioration of heart failure due to cardiomyopathy in hamsters : increase in endothelin-1 production in the heart and beneficial effect of endothelin A receptor antagonist on survival and cardiac function"Circulation. 99. 2171-2176 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Abe Y, Nakayama K, Yamanaka A, Sakurai T, Goto K: "Super-specific trafficking of endothelin receptors"J Biol Chem.. 275. 8664-8671 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kakinuma Y, Miyauchi T, Yuki K, Murakosho N, Goto K, Yamaguchi I: "Novel molecular mechanisms of increased myocardial endothelin-1 expression in the failing heart involving the transcriptional factor hypoxia-inducible factor-1 alpha induced for impaired myocardial energy metabolism"Circulation. 103. 2387-2394 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Yuki K, Miyauchi T, Kakimuma Y, Murakoshi N, Maeda S, Goto K, Yamaguchi I: "Endothelin-1 production is enhanced by rotenone, a mitochondrial complex I inhibitor, in cultured rat cardiomyocytes"J Cardiovasc Pharmacol.. 38. 850-858 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Goto K: "History of endothelin"in "Pulmonary Actions of Endothelins" ed by Goldie RG & Hay DW, Birkhauser Verlag, Basel/Switzerland. 1-20 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Miyauchi T, Goto K: "Heart failure and endothelin receptor antagoftists"Trends Pharmacol Sci. 20. 210-217 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Goto K: "Basic and therapeutic relevance of endothelin-mediated regulation"Biol Pharm Bull. 24. 1219-1230 (2001)

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2003-09-17  

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