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Mechanism of Oxygen Free Radical-Induced Cellular Damage in Myocardium

Research Project

Project/Area Number 63571102
Research Category

Grant-in-Aid for General Scientific Research (C)

Allocation TypeSingle-year Grants
Research Field 応用薬理学・医療系薬学
Research InstitutionKanagawa Dental College

Principal Investigator

OKABE Eiichiro  Kanagawa Dental College, Department of Pharmacology, Associate Professor, 歯学部, 助教授 (50097276)

Co-Investigator(Kenkyū-buntansha) TOMOKAWA Shigeji  Kanagawa Dental College, Department of Pharmacology, Instructor, 歯学部, 助手 (40197918)
TODOKI Kazuo  Kanagawa Dental College, Department of Pharmacology, Assistant Professor, 歯学部, 講師 (90139577)
Project Period (FY) 1988 – 1989
Project Status Completed (Fiscal Year 1989)
Budget Amount *help
¥2,200,000 (Direct Cost: ¥2,200,000)
Fiscal Year 1989: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 1988: ¥1,700,000 (Direct Cost: ¥1,700,000)
KeywordsFree Radical / Sarcoplasmic Reticulum / Calcium / Ischemia / Coronary Vessel / Calmodulin / 心筋虚血 / 内皮細胞 / フリーラジカル / 興奮-収縮連関 / 筋鞘
Research Abstract

We tested the hypothesis that oxygen free radical-induced breakdown in the function of sarcoplasmic reticulum (SR) and sarcolemma may serve as the source of intracellular calcium overload analogous to that seen in the ischemic myocardium, and extrapolated the in vitro results to the ischemic myocardium. The following results were obtained:
1) Oxygen free radicals can produce a dininished level of accumulated calcium of SR, which is reflected by the decreased calcium load and an increase in calcium permeability, and the decreased calcium accumulation in the presence of oxygen free radical generating system may not be mainly due to an inhibited calcium pump. 2) Calmodulin-dependent component of calcium fluxes in SR vesicles is modified directly by oxygen free radicals, and oxygen free radicals can reduce steady-state calcium accumulation due to increased calcium release through a calcium efflux pathway which is inhibited by calmodulin. 3) Oxygen free radicals have no effect on myofibrilla … More r pCa-ATPase curve. 4) Oxygen free radicals reduce sarcolemmal Na^+, K^+ -ATPase activity and stimulate Na^+-Ca^<2+> exchange activity. 5) Oxygen free radicals produce endothelium-dependent and SOD inhibitable contraction of isolated left circumflex coronary arteries. 6) All these effects described above seem to be responsible for ^.O^-_ and/or closely related species of oxygen free radical, possibly ^.OH.
The lack of an effect of oxygen free radicals may suggest that no structural alterations of contractile proteins have occurred. Thus, we would hypothesize that a major target organelles attacked by oxygen free radicals generated during the ischemic process is the portion of the excitation-contraction coupling system that regulates calcium delivery (the SR and sarcolemmal membrane) to the contractile proteins and not the contractile proteins per se. The SR calcium efflux pathways and sarcolemmal Na^+,K^+-ATPase involving Na^+-Ca^<2+> exchange activity may be altered by oxygen free radicals in ischemic myocardium where the occurrence of intracellular calcium overload plays an important role in cardiac dysfunction. Furthermore, it is postulated that oxygen free radicals participate in spasmogenesis in coronary vessels. Less

Report

(3 results)
  • 1989 Annual Research Report   Final Research Report Summary
  • 1988 Annual Research Report
  • Research Products

    (54 results)

All Other

All Publications (54 results)

  • [Publications] 岡部栄逸朗: "心虚血:虚血ー再灌流のメディエ-タ-としてのフリ-ラジカル." 日本臨床. 46. 2190-2195 (1988)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] 岡部栄逸朗: "細胞内カルシウムと虚血心筋障害:フリ-ラジカルによる細胞内カルシウム過剰蓄積" トキシコロジ-フォ-ラム. 11. 595-609 (1988)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] 岡部栄逸朗: "フリ-ラジカルによる心筋細胞内Ca^<2+>過剰蓄積の機構:虚血心筋とフリ-ラジカル" メディカルトリビュ-ン. 4-5 (1988)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Kukreja RC.: "Oxygen radical-mediated lipid peroxidation and inhibition of Ca^<2+>-ATPase activity of cardiac sarcoplasmic reticulum." Arch.Biohem.Biophys.261. 447-457 (1988)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Okabe E.: "Proposed role of free radicals in the pathogenesis of myocardial ischemia." Microcirc.an update.1. 673-674 (1988)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Okabe E.: "The effect of oxygen free radicals on calcium permeability and calcium loading at steady state in cardiac sarcoplasmic reticulum." Mol.Pharmacol.34. 388-394 (1988)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] 岡部栄逸朗: "フリ-ラジカルと心筋障害." 循環. 10. 17-22 (1989)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Okabe E.: "Calmodulin and free oxygen radicals interaction with steady-state calcium accumulation and passive calcium permeability of cardiac sarcoplasmic reticulum." J.Pharmacol.Exp.Ther.250. 286-292 (1989)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Okabe E.: "Possible mechanism responsible for mechanical dysfunction of ischemic myocardium:A role of oxygen free radicals." Jpn.Circ.J.53. 1132-1137 (1989)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Okabe E.: "A permissive role for calcium efflux pathway,possibly a channel,in decreased calcium accumulation of cardiac sarcoplasmic reticulum induced by free radicals." Microcirc.ann.4. 37-38 (1989)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Todoki K.: "Endothelium-dependent response of contracted canine coronary artery by potassium to oxygen free radicals." Microcirc.ann.4. 143-144 (1989)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] 岡部栄逸朗: "心筋再灌流と活性酸素ラジカル." クリニカ. 17. 73-81 (1990)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] 岡部栄逸朗: "フリ-ラジカルと循環器疾患:フリ-ラジカルは虚血ー再灌流障害とStunned Myocardiumのメディエ-タ-か?" Pharma Medica. (1990)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Okabe E.: "The effect of hypochlorous acid and hydrogen peroxide on coronary flow and arrhythmogenesis in the globally ischemic and reperfused rat heart." J.Mol.Cell.Cardiol.(1990)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Okabe E.: "Effect of oxygen free radicals on myocardial subcellular function." Am.J.Physiol.(1990)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Okabe E.: "Effect of oxygen free radicals on ryanodine-sensitive calcium uptake of cardiac sarcoplasmic reticulum." J.Pharmacol.Exp.Ther.(1990)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Hess ML.: "Free Radical in the Pathophysiology of Heart Disease" Kluwer Acad.Pub.,Boston, 11 (1988)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Okabe E.: "Medical,Biochemical and Chemical Aspect of Free Radicals" Elsevier Science Pub.,Amsterdam, 6 (1989)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Okabe E and Ito H: "Review/Myocardial ischemia:Oxygen free radicals as a mediator of ischemia-reperfusion." Jpn. J. Clin. Med. 46:2190-2195, 1988.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Okabe E: "Review/Cellular calcium and myocardial injury during ischemia: Oxygen free radical-induced intracellular calcium overload." Toxicol. Forum 11:595-609, 1988.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Okabe E: "Mechanisms of oxygen free radical-induced myocardial calcium overload." Ischemic Myocardium (Medical Tribune, Osaka), pp.4-5, 1988.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Hess ML, Greenfield TD, Manson NH, Okabe E: "The role of oxygen free radicals during the course of myocardial ischemia/reperfusion injury: An analysis and critique." In: Free Radical in the Pathophysiology of Heart Disease (Kluwer Acad. Pub., Boston), pp.111-122, 1988.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Kukreja RC, Okabe E, Schrier GM, Hess ML: "Oxygen radical-mediated lipid peroxidation and inhibition of Ca^<2+>-ATPase activity of cardiac sarcoplasmic reticulum." Arch. Biochem. Biophys. 261:447-457, 1988.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Okabe E, Ito H: "Proposed role of free radicals in the pathogenesis of myocardial ischemia." Microcirc. an update. 1:673-674, 1988.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Okabe E, Odajima C, Taga R, Kukreja RC, Hess ML, Ito H: "The effect of oxygen free radicals on calcium permeability and calcium loading at steady state in cardiac sarcoplasmic reticulum." Mol. Pharmacol. 34:388-394, 1988.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Okabe E, Ito H: "Evidence that oxygen free radicals mimic the effect of ischemia on myocardial excitation-contraction coupling system: Extrapolation of the in vitro results to ischemic myocardial dysfunction." In: Medical, Biochemical and Chemical Aspect of Free Radicals (Elsevier Science Pub., Amsterdam), pp.1169-1172, 1989.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Okabe E, Sugihara M, Tanaka K, Sasaki H, Ito H: "Calmodulin and free oxygen radicals interaction with steady-state calcium accumulation and passive calcium permeability of cardiac sarcoplasmic reticulum." J. Pharmacol. Exp. Ther. 250:286-292, 1989.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Okabe E, Fujimaki R, Murayama M, Ito H: "Possible mechanism responsible for mechanical dysfunction of ischemic myocardium: A role of oxygen free radicals." Jpn. Circ. J. 53:1132-1137, 1989.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Okabe E, Ito H: "A permissive role for calcium efflux pathway, possibly a channel, in decreased calcium accumulation of cardiac sarcoplasmic reticulum induced by free radicals." Microcirc. ann. 4:37-38, 1989.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Todoki K, Okabe E, Ito H: "Endothelium-dependent response of contracted canine coronary artery by potassium to oxygen free radicals." Microcirc. ann. 4:143-144, 1989.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Okabe E: "Review/Oxygen free radicals and myocardial injury." Circulation 10:17-22, 1989.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Okabe E: "Review/Ischemia-reperfusion injury and oxygen free radicals." Klinika 17:73-81, 1989.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Okabe E, Fujimaki R, Takahashi S: "Review/Free oxygen radicals and ischemic cardiovascular disease: Are free oxygen radicals mediators for reperfusion injury and stunned myocardium." Pharma Medica 1990.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Okabe E, Manson NH, Hess ML: "The effect of hypochlorous acid and hydrogen peroxide on coronary flow and arrhythmogenesis in the globally ischemic and reperfused rat heart." J. Mol. Cell. Cardiol., 1990.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Okabe E, Ito H: "Effect of oxygen free radicals on myocardial subcellular function." Am. J. Physiol.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Okabe E, Ito H: "Effect of oxygen free radicals on ryanodine-sensitive calcium uptake of cardiac sarcoplasmic reticulum." J. Pharmacol. Exp. Ther.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] 岡部栄逸朗: "フリ-ラジカルと心筋障害" 循環. 10. 17-22 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] Okabe E.: "Calmodulin and free oxygen radicals interaction with steady-state calcium accumulation and passive calcium permeability of cardiac sarcoplasmic reticulum." J.Pharmacol.Exp.Ther.250. 286-292 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] Okabe E.: "Possible mechanism responsible for mechanical dysfunction of ischemic myocardium:A role of oxygen free radicals." Jpn.Circ.J.53. 1132-1137 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] Okabe E.: "A permissive role for calcium efflux pathway,possibly a channel,in decreased calcium accumulation of cardiac sarcoplasmic reticulum induced by free radicals." Microcirc.ann.4. 37-38 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] Todoki K.: "Endothelium-dependent response of contracted canine coronary artery by potassium to oxygen free radicals." Microcirc.ann.4. 143-144 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] 岡部栄逸朗: "心筋再潅流と活性酸素ラジカル" クリニカ. 17. 73-81 (1990)

    • Related Report
      1989 Annual Research Report
  • [Publications] 岡部栄逸朗: "フリ-ラジカルと循環器疾患:フリ-ラジカルは虚血-再潅流障害とStunned Myocardiumのメディエ-タ-か?" Pharma Medica. (1990)

    • Related Report
      1989 Annual Research Report
  • [Publications] Okabe E.: "The effect of hypochlorous acid and hydrogen peroxide on coronary flow and arrhythmogenesis in the globally ischemic and reperfused rat heart." J.Mol.Cell.Cardiol.,. (1990)

    • Related Report
      1989 Annual Research Report
  • [Publications] Okabe E.: "Effect of oxygen free radicals on myocardial subcellular function." Am.J.Physiol.(1990)

    • Related Report
      1989 Annual Research Report
  • [Publications] Okabe E.: "Effect of oxygen free radicals on ryanodine-sensitive calcium uptake of cardiac sarcoplasmic reticulum." J.Pharmacol.Exp.Ther.(1990)

    • Related Report
      1989 Annual Research Report
  • [Publications] Okabe E.: "Medical,Biochemical and Chemical Aspect of Free Radicals" Elsevier Science Pub.,Amsterdam, 6 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] 岡部栄逸郎、伊藤春生: 日本臨床. 46. 2190-2195 (1988)

    • Related Report
      1988 Annual Research Report
  • [Publications] 岡部栄逸郎: トキシコロジーフォーラム. 11. 595-609 (1988)

    • Related Report
      1988 Annual Research Report
  • [Publications] Kukreja RC;Okabe E;Schrire GM.Hess ML.: Archives of Biochemistry and Biophysics. 261. 447-457 (1988)

    • Related Report
      1988 Annual Research Report
  • [Publications] Okade E,;Odajima C,;Taga R,;Kukreja RC,;Hess ML,;Ito H.: Moleculae Pharmacology. 34. 388-394 (1988)

    • Related Report
      1988 Annual Research Report
  • [Publications] Okabe E;Ito H.: Microcirculation an update. 1. 673-674 (1988)

    • Related Report
      1988 Annual Research Report
  • [Publications] Okabe E,;Sugihara,m,;tanaka K,Sasaki H,;Ito H.: Jounal of Pharmacology and Experimental Therapeutics.

    • Related Report
      1988 Annual Research Report
  • [Publications] Hess ML,Greenfield TD,;Manson NH,;Okabe E.: "Free Radical in the Pathophysiology of Heart Disease The role of oxygen free radicals during the course of myocardial ischemia/reperfusion injury:An analysis and critique" Kluwer Academic Publishers, 111-122 (1988)

    • Related Report
      1988 Annual Research Report

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Published: 1988-04-01   Modified: 2016-04-21  

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