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Pathophysiological roles of the cardic renin-angiotensin system after myocardial infarction-Chymase dependent angiotensin II-forming pathway and myocardial infarction-

Research Project

Project/Area Number 13670102
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field General pharmacology
Research InstitutionOsaka Medical College

Principal Investigator

JIN Denan  Osaka Medical College Faculty of Medicine Assistant Professor, 医学部, 講師 (90319533)

Co-Investigator(Kenkyū-buntansha) TAKAI Shinji  Osaka Medical College Faculty of Medicine Associate Professor, 医学部, 助教授 (80288703)
Project Period (FY) 2001 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 2002: ¥1,600,000 (Direct Cost: ¥1,600,000)
Keywordschymase inhibitor / myocardial infarction / ischemia-reperfusion / liverbility / arrhythmia / cardiac function / humster / dog
Research Abstract

1. Changes of cardiac chymase and the variances of angiotensin converting enzyme (ACE) inhibitor and angiotensin (A) II receptor antagonist on cardiac function and survival after myocardial infarction (MI)
After MI in hamsters, which possess both ACE- and chymase-dependent AII-generating pathways like in humans, we recently found that the activation of cardiac chymase was more permanent than that of ACE and that AT1 receptor antagonist treatment rather than ACE inhibitor treatment alone provided significant beneficial effects on cardiac function and survival in this model. These finding indicated that the excessive production of AII via activated cardiac chymase may play an important role in determination of prognosis after MI (Jpn J Pharmacol. 86:203-214 (2001)).
2. Effects of chymase inhibitor after MI
In hamster MI model, in connection with suppression of the activated-cardiac chymase, cardiac function and survival rate were significantly improved by treatment with chymase specific inh … More ibitor and degree of the prognostic beneficial effects were similar to the finding observed by AT1 receptor blockade in same model. These finding demonstrated that the excessive production of AII via activated cardiac chymase plays an important role in determination of prognosis after MI (Life Sci. 14:437-446 (2002)).
3. An antiarrythmic effect of chymase inhibitor after MI
Chymase inhibitors and AT1 receptor antagonists treatments did not affect infarct sizes significantly after MI, therefore these prognostic beneficial effects may closely relate to the suppression of lethal arrythmias during acute phase of MI. Therefore, we examined the antiarrythmic effects of chymase inhibitor and AT1 receptor antagonist in dog MI model induced by permanent left coronary ligation. The cardiac total AII-forming activity and plasma AII concentration were decreased significantly by the treatment with chymase inhibitor after MI. The rate of ventricular was also suppressed significantly. Similar results were also observed by treatment with AT1 antagonist treatment. These finding indicated that the excessive AII production via activated cardiac chymase by stimulating AT1 receptors may participate directly in the appearance of arrythmias in dog MI model and the antiarrythmic effect of chymase inhibitor may mainly responsible for the survival benefit after MI.
4. Roles of cardiac chymase in the pathogenesis of cardiac remodeling after coronary ischemia-reperfusion in hamsters
The cardiac remodeling remote from infarction seems to be important in the development of chronic heart failure after MI. Therefore, we are now examining changes of cardiac chymase and the effects of ACE inhibitor, chymase inhibitor AT1 receptor antagonist and ACE inhibitor combined with chymase inhibitor during chronic phase of MI (6 months) in the coronary ischemia-reperfusion model of hamsters. After MI in this model, we found that activation of cardiac chymase was associated with increases of cardiac mRNA levels of collagen I, III and TGF-β 4 weeks after MI and the examination about the effects of these agents during chronic phase of MI are ongoing. Less

Report

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

    (47 results)

All Other

All Publications (47 results)

  • [Publications] Takai S: "Oral administration of a specific chymase inhibitor, NK3201, inhibits vascular proliferation in grafted vein"Life Sci. 31・69. 1725-1732 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nishimoto M: "Significance of chymase-dependent angiotensin II-forming pathway in the development of vascular proliferation"Circulation. 11・104. 1274-1279 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Jin D: "Possible roles of cardiac chymase after myocardial infarction in hamster hearts"Jpn J Pharmacol. 86・2. 203-214 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Takai S: "An orally active chymase inhibitor, BCEAB, suppresses heart chymase activity in the hamster"Jpn J Pharmacol. 86・1. 124-126 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Sakaguchi M: "Inhibitory mechanism of daphnodorins for human chymase"Biochem Biophys Res Commun. 18・283. 831-836 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Takai S: "Different angiotensin II-forming pathways in human and rat vascular tissues"Clin Chim Acta. 305(1-2). 191-195 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] S.Takai: "12-Hydroxyeicosatetraenoic acid potentiates angiotensin II-induced pressor response in rats"Eur J Pharmacol. 418. R1-R2 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] 西本昌義: "Vein Graft Diseaseにおけるキマーゼ依存性アンジオテンシンIIの病態生理学的役割"脈管学. 41. 521-527 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] K.Okumura: "Beneficial effects of angiotensin-converting enzyme inhibition in adriamycin-induced cardiomyopathy in hamsters"Jpn J Pharmacol. 88. 183-188 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] D.Jin: "Beneficial effects of cardiac chymase inhibition during the acute phase of myocardial infarction"Life Sci. 71. 437-446 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] M.Nishimoto: "Increased local angiotensin II formation in aneurysmal aorta"Life Sci. 71. 2195-2205 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] K.Tsunemi: "Lengthy suppression of vascular proliferation by a chymase inhibitor in dog grafted veins"J Thorac Cardiovasc Surg. 124. 621-625 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] S.Takai: "12-Hydroxyeicosatetraenoic acid potentiates angiotensin II-induced pressor response in rats"Eur J Pharmacol. 418. R1-R2 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] 西本昌義: "Vein Graft Diseaseにおけるキマーゼ依存性アンジオテンシンIIの病態生理学的役割"脈管学. 41. 521-527 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Y.Iwamoto: "Multiple pathways of angiotensin I conversion and their functional role in the cnine penile corpus cavernosum"J Pharmacol Exp Ther. 298. 43-48 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] D.Jin: "Beneficial effects of cardiac chymase inhibition during the acute phase of myocardial infarction"Life Sci. 71. 437-446 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] M.Nishimoto: "Increased local angiotensin II formation in aneurysmal aorta"Life Sci. 71. 2195-2205 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] K.Tsunemi: "Lengthy suppression of vascular proliferation by a chymase inhibitor in dog grafted veins"J Thorac Cardiovasc Surg. 124. 621-625 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] K.Okumura: "Beneficial effects of angiotensin-converting enzyme inhibition in adriamycin-induced cardiomyopathy in hamsters"Jpn J Pharmacol. 88. 183-188 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Takai S: "A novel chymase inhibitor, 2-(5-formylamin-6-oxo-2-phenyl-1,6-dihydropyrimidine-1-yl)-N-[{3,4-dioxo-1-phenyl-7-(2-pyridyloxy)}-2-heptyl]acetamide (NK3201), suppressed intimal hyperplasia after balloon injury"J Pharmacol Exp Ther. 304. 841-844 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Takai S: "A novel chymase inhibitor, BCEAB 4-[1-{[bls-(4-methyl-phenyl)-methyl]-carbamoyl}-3-(2-ethoxy-benzyl)-4-oxo-azetidine-2-yloxy]-benzoic acid, suppressed cardiac fibrosis in cardiomyopathic hamsters"J Pharmacol Exp Ther. 305. 17-23 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] S. Takai: "A novel chymase inhibitor, BCEAB (4-[1-{[bis-(4-methyl)-methyl]-carbamoyl}-3-(2-ethoxy-benzyl)-4-oxo-azetidine-2-yloxy]-benzoic benzoic acid) suppressed cardiac fibrosis in cardiomyopathic hamsters"J Pharmacol Exp Ther. 305. 17-23 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] S. Takai: "A novel chymase inhibitor, 2-(5-formylamin-6-oxo-2-phenyl-1,6-dihydropyrimidine-1-yl)-N-[{3,4-dioxo-1-phenyl-7-(2-pyridyloxy)}-2-heptyl] acetamide (NK3201), suppresses intimal hyperplasia after balloon injury"J Pharmacol Exp Ther. 304. 841-844 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] K. Okumura: "Beneficial effects of angiotensin-converting enzyme inhibition in adriamycin-induced cardiomyopathy in hamsters"Jpn J Pharmacol. 88. 183-188 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] D. Jin: "Beneficial effects of cardiac chymase inhibition during the acute phase of myocardial infarction"Life Sci. 71. 437-446 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] M. Nishimoto: "Increased local angiotensin II formation in aneurysmal aorta"Life Sci. 71. 2195-2205 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] K. Tsunemi: "Lengthy suppression of vascular proliferation by a chymase inhibitor in dog grafted veins"J Thorac Cardiovasc Surg. 124. 621-625 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] S. Takai: "12-Hydroxyeicosatetraenoic acid potentiates angiotensin II-induced pressor response in rats"Eur J Pharmacol. 418. R1-R2 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] S. Takai: "Oral administration of a specific chymase inhibitor, NK3201, inhibits vascular proliferation in grafted vein"Life Sci. 31. 1725-1732 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nishimoto M: "Significance of chymase-dependent angiotensin II-forming pathway in the development of vascular proliferation"Circulation. 11. 1274-1279 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Jin D: "Possible roles of cardiac chymase after myocardial infarction in hamster hearts"Jpn J Pharmacol. 86. 203-214 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Takai S: "An orally active chymase inhibitor, BCEAB, suppresses heart chymase activity in the hamster"Jpn J Pharmacol. 86. 124-126 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Sakaguchi M: "Inhibitory mechanism of daphnodorins for human chymase"Biochem Biophys Res Commun. 18. 831-836 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Takai S: "Different angiotensin II-forming pathways in human and rat vascular tissues"Clin Chim Acta. 305(1-2). 191-195 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Iwamoto Y: "Multiple pathways of angiotensin I conversion and their functional role in the canine penile corpus cavernosum"J Pharmacol Exp Ther. 298. 43-48 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] S.Takai: "12-Hydroxyeicosatetraenoic acid potentiates angiotensin II-induced pressor response in rats"Eur J Pharmacol. 418. R1-R2 (2001)

    • Related Report
      2002 Annual Research Report
  • [Publications] 西本昌義: "Vein Graft Diseaseにおけるキマーゼ依存性アンジオテンシンIIの病態生理学的役割"脈管学. 41. 521-527 (2001)

    • Related Report
      2002 Annual Research Report
  • [Publications] K.Okumura: "Beneficial effects of angiotensin-converting enzyme inhibition in adriamycin-induced cardiomyopathy in hamsters"Jpn J Pharmacol. 88. 183-188 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] D.Jin: "Beneficial effects of cardiac chymase inhibition during the acute phase of myocardial infarction"Life Sci. 71. 437-446 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] M.Nishimoto: "Increased local angiotensin II formation in aneurysmal aorta"Life Sci. 71. 2195-2205 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] K.Tsunemi: "Lengthy suppression of vascular proliferation by a chymase inhibitor in dog grafted veins"J Thorac Cardiovasc Surg. 124. 621-625 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Takai S: "Oral administration of a specific chymase inhibitor, NK3201, inhibits vascular proliferation in grafted vein."Life Sci. 31・69. 1725-1732 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Nishimoto M: "Significance of chymase-dependent angiotensin Il-forming pathway in the development of vascular proliferation"Circulation. 11・104. 1274-1279 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Jin D: "Possible roles of cardiac chymase after myocardial infarction in hamster hearts"Jpn J Pharmacol. 86・2. 203-214 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Takai S: "An orally active chymase inhibitor, BCEAB, suppresses heart chymase activity in the hamster"Jpn J Pharmacol. 86・1. 124-216 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Sakaguchi M: "Inhibitory mechanism of daphnodorins for human chymase"Biochem Biophys Res Commun. 18・283. 831-836 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Takai S: "Different angiotensin II-forming pathways in human and rat vascular tissues"Clin Chim Acta. 305(1-2). 191-195 (2001)

    • Related Report
      2001 Annual Research Report

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

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