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Study for the Abnormality of Intracellular Calcium Regulation in Myocardial Ischemia

Research Project

Project/Area Number 11670670
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Circulatory organs internal medicine
Research InstitutionHamamatsu University School of Medicine

Principal Investigator

SATOH Hiroshi  Department of Medicine, Hamamatsu University School of Medicine, Research Associate, 医学部, 助手 (30293632)

Co-Investigator(Kenkyū-buntansha) HAYASHI Hideharu  Department of Medicine, Hamamatsu University School of Medicine, Professor, 医学部, 教授 (50135258)
TERADA Hajime  Department of Medicine, Hamamatsu University School of Medicine, Research Associate, 医学部, 助手 (50252177)
Project Period (FY) 1999 – 2000
Project Status Completed (Fiscal Year 2000)
Budget Amount *help
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2000: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 1999: ¥3,000,000 (Direct Cost: ¥3,000,000)
Keywordsmyocardial contraction / ischemia / reperfusion injury / calcium ion / sarcoplasmic reticulum / acidosis / digitalis toxicity / arrhythmia / ミトコンドリア
Research Abstract

1999 : The role of Ca influx via sarcolemmal Na/Ca exchange (NCX) in digitalis- and ischemia/reperfusion-induced injuries.
Na/Ca exchange (NCX) is a major Ca extrusion system in cardiac myocytes, but can also mediate Ca influx and can trigger SR Ca release. Under conditions such as digitalis toxicity or ischemia/reperfusion, increased [Na] i may lead to a rise in [Ca] i through NCX, causing Ca overload and triggered arrhythmias. We used an agent reported to selectively block Ca influx by NCX, KB-R7943 (KBR) and assessed twitch contractions and Ca transients in rat ventricular myocytes loaded with indo-1, and in guinea pig (GP) papillary muscles. In rat, KBR (5μM) did not decrease control steady-state twitch contractions or Ca transients. When cells were Na-loaded by perfusion of strophanthidin, the addition of KBR reduced diastolic [Ca] i and abolished spontaneous Ca oscillations which occured. In GP exposed to substrate-free hypoxic medium for 60 min, KBR reduced reoxygenation-induced … More arrhythmias both in incidence and in duration. KBR also enhanced the recovery of developed tension after reoxygenation. We conclude that Ca influx via NCX may be critical in causing myocardial Ca overload and triggered activity induced by cardiac glycoside or by reoxygenation.
2000 : Effects of intracellular acidosis on twitch contraction and Ca transients
Acidosis disturbs contractile performance by decreasing myofibrillar Ca response, but the contraction recovers at prolonged acidosis. We examined the mechanism of the contractile recovery during acidosis in isolated rat ventricular myocytes. Stable acidosis was obtained by increasing the percentage of CO2 in a bicarbonate buffer. During initial min of acidosis, the twitch cell shortening decreased, but these cells appeared subsequent contractile recovery. During the initial decline, both the diastolic [Ca] i and amplitude of Ca transient (CaT) increased, and decline of CaT prolonged. The following recovery was accompanied by a further increase in amplitude and an acceleration of decline of CaT.A blockade of SR function or selective inhibition of Ca-calmodulin kinase II (CaMKII) completely abolished the reacceleration in the decline of CaT and almost eliminated the contractile recovery. We concluded that during prolonged acidosis, the CaMKII-dependent reactivation of SR Ca uptake can increase SR Ca content and CaT amplitude. This recovery can compensate for the decreased myofibrillar Ca response, but may also cause Ca overload after returning to physiological pH.
In future projects, we plan to build a setup for simulated ischemia/reperfusion with inhibition of mitochondrial oxidative phosphorylation, then to study the effects on Ca currents, Ca transients and SR Ca contents, and also to estimate the activity of SR Ca release channel with Ca sparks which can be visualized using laser confocal microscopy. In addtion, we would like to examine the possibility of KBR and drugs protective for mitochondria (e.g. diazoxide) against ischemic/reperfused injuries. Less

Report

(3 results)
  • 2000 Annual Research Report   Final Research Report Summary
  • 1999 Annual Research Report
  • Research Products

    (21 results)

All Other

All Publications (21 results)

  • [Publications] Hiroshi Watanabe: "Increased cytosolic Ca2+ concentration in endothelial cells by calmodulin antagonists."Biochem.Biophys.Res.Commun.. 265. 697-702 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Takurou Nakamura: "A single cell model of myocardial reperfusion injury:changes in intracellular Na+ and Ca2+ concentrations in guinea pig ventricular myocytes."Mol.Cell.Biochem.. 194. 147-157 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Hiroshi Satoh: "KB-R7943 block of Ca2+ influx via Na+/Ca2+ exchange does not alter twitches or glycoside inotropy,but prevents Ca2+ overload in rat ventricular myocytes."Circulation. 101. 1441-1446 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Masaaki Mukai: "Effects of a selective inhibitor of Na+/Ca2+ exchange,KB-R7943,on reoxygenation-induced injuries in guinea pig papillary muscles."J.Cardiovasc.Pharmacol.. 35. 121-128 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Shiho Sugiyama: "The importance of glycolytically-derived ATP for the Na+/H+ exchange activity in guinea pig ventricular myocytes."Mol.Cell.Biochem.. 217. 153-161 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] 佐藤洋: "心筋細胞の興奮収縮連関におけるNa+/Ca2+交換機構を介するCa2+流入の関与-選択的阻害薬KB-R7943を用いた検討-"心筋の構造と代謝. 22. 223-229 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Hiroshi Watanabe.: "Increased cytosolic Ca2+ concentration in endothelial cells by calmodulin antagonists."Biochem. Biophys. Res. Commun.. 265. 697-702 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Takurou Nakamura.: "A single cell model of myocardial reperfusion injury : changes in intracellular Na+ and Ca2+ concentrations in guinea pig ventricular myocytes."Mol. Cell. Biochem.. 194. 147-157 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Hiroshi Satoh.: "KB-R7943 block of Ca2+ influx via Na+/Ca2+ exchange does not alter twitches or glycoside inotropy, but prevents Ca2+ overload in rat ventricular myocytes."Circulation.. 101. 1441-1446 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Masaaki Mukai.: "Effects of a selective inhibitor of Na+/Ca2+ exchange, KB-R7943, on reoxygenation -induced injuries in guinea pig papillary muscles."J.Cardiovasc. Pharmacol.. 35. 121-128 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Shiho Sugiyama.: "The importance of glycolytically-derived ATP for the Na+/H+ exchange activity in guinea pig ventricular myocytes."Mol. Cell. Biochem.. 217. 153-161 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Hiroshi Watanabe: "Increased cytosolic Ca2+ concentration in endothelial cells by camodulin antagonists."Biochem.Biophys.Res.Commun.. 265. 697-702 (1999)

    • Related Report
      2000 Annual Research Report
  • [Publications] Takurou Nakamura: "A single cell model of myocardial reperfusion injury : changes in intracellular Na+ and Ca2+ concentrations in guinea pig ventricular myocytes."Mol.Cell.Biochem.. 194. 147-157 (1999)

    • Related Report
      2000 Annual Research Report
  • [Publications] Hiroshi Satoh: "KB-R7943 block of Ca2+ influx via Na+/Ca2+ exchange does not alter twitches or glycoside inotropy, but prevents Ca2+ overload in rat ventricular myocytes."Circulation. 101. 1441-1446 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Masaaki Mukai: "Effects of a selective inhibitor of Na+/Ca2+ exchange, KB-R7943, on reoxygenation -induced injuries in guinea pig papillary muscles."J.Cardiovasc. Pharmacol.. 35. 121-128 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Shibo Sugiyama: "The importance of glycolytically-derived ATP for the Na+/H+ exchange activity in guinea pig ventricular myocytes."Mol.Cell.Biochem.. 217. 153-161 (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] 佐藤洋: "心筋細胞の興奮収縮連関におけるNa+/Ca2+交換機構を介するCa2+流入の関与-選択的阻害薬KB-R7943を用いた検討-"心筋の構造と代謝. 22. 223-229 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Hiroshi Satoh: "KB-R7943 block of Ca^<2+> influx via Na^+/Ca^<2+> exchange does not alter twiwches or glycoside inotropy but prevent Ca^<2+> overload in rat ventricular myocytes"Circulation. (in press). (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] 佐藤洋: "心筋細胞の興奮収縮連関におけるNa^+/Ca^<2+>交換機構を介するCa^<2+>流入の関与"心筋の構造と代謝. (in press). (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Masaki Mukai: "Effect of a selective inhibitor of Na^+/Ca^<2+>exchange,KB-R7943,on reoxygenation-induced injury in guinea pig papillary muscle"Journal of Cardiovascular Pharmacology. (in press). (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Takuro Nakamura: "A single model of myocardial reperfusion injury : chauges in intracellalar Na^+ a-d Ca^<2+> concentrations in guinea pig ventricular myocytes"Molecular and Cellular Biochemistry. 194. 147-157 (1999)

    • Related Report
      1999 Annual Research Report

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Published: 1999-04-01   Modified: 2016-04-21  

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