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2004 Fiscal Year Final Research Report Summary

Study for detection of intracellular sodium transients and their pathophysiological roles in myocytes

Research Project

Project/Area Number 15590733
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  Hamamatsu University School of Medicine, Department of Medicine, Research Associate, 医学部附属病院, 助手 (30293632)

Co-Investigator(Kenkyū-buntansha) KATOH Hideki  Hamamatsu University School of Medicine, Department of Medicine, Research Associate, 医学部, 助手 (80314029)
TERADA Hajime  Hamamatsu University School of Medicine, Department of Medicine, Research Associate, 医学部附属病院, 講師 (50252177)
URUSHIDA Tsuyoshi  Hamamatsu University School of Medicine, Department of Medicine, Research Associate, 医学部附属病院, 助手 (20334980)
WATANABE Yasuhide  Hamamatsu University School of Medicine, Department of Nursing, Professor, 医学部, 教授 (50305380)
HAYASHI Hideharu  Hamamatsu University School of Medicine, Department of Medicine, Professor, 医学部, 教授 (50135258)
Project Period (FY) 2003 – 2004
KeywordsSodium ion / Calcium ion / Myocytes / Na^+ / Ca^<2+> exchange / Excitation-contraction coupling
Research Abstract

In cardiac myocytes the Ca^<2+>-induced Ca^<2+> release (CICR) from the sarcoplasmicr reticulum (SR) plays pivotal roles in Ca transients. However, the changes in intracellular Na^+ concentration ([Na^+]_i) also contribute significantly to CICR via Na^+/Ca^<2+> exchange. The negative inotropic effect of Na^+ channel blockers (NCB) is mediated by disturbance of intracellular Ca^<2+> regulation. The Na^+ channel gating could induce intracellular Na^+ accumulation, thereby increasing Ca^<2+> influx via the reverse-mode Na^+/Ca^<2+> exchange (rNCX). The primary aim of this study was to investigate whether the reduction of cellular Na^+ accumulation by NCB actually contributes to the negative inotropic effects through the elimination of Ca^<2+> influx via rNCX. To elucidate the involvement of rNCX in the negative inotropic effects of Na^+ channel blockers, we examined the effects of a pure Na^+ channel blocker, pilsicainide, on the frequency-dependent increases in twitch cell shortenings (C … More S) and Ca^<2+> transients (CaT) in Indo-1 or fluo-3 loaded guinea pig ventricular myocytes. The changes in [Na^+]_i was also evaluated with Sodium-Green and laser scanning confocal microscopy. Na^+/Ca^<2+> exchange current (I_<NCX>) was measured by the whole cell patch clamp method. (1) Pilsicainide (>5 μM) significantly reduced CaT at all stimulation rates, and the reduction was more prominent use-dependently (p<0.05 vs. control, n=7). (2) An inhibitor of rNCX, 1 μM KB-R7943 decreased CS and CaT only at 2 Hz (peak indo-1 ratio ; from 1.02±0.13 to 0.98±0.11 at 0.5 Hz, n.s., 1.96±0.11 to 1.45±0.11 at 2 Hz, p<0.05, n=7). (3) On diminishing CS and CaT by 30 μM plisicainide at 2 Hz, the following addition of 1 μM KB-R7943 had no further effects. (4) 100 μM Pilsicainide did not affect to I_<NCX>. (5) The significant cytosolic Na^+ accumulation was observed only at 2 Hz in control, and Pilsicainide suppressed the accumulation in [Na^+]_i dose-dependently at 2 Hz. (p<0.05 vs. control, n=5). The negative inotropic effects of NCB could involve the reduction of Ca^<2+> influx via rNCX by preventing cytosolic (not only subsarcolemmal) Na^+ accumulation. The mechanism would have a more important implication in failed heart with tachyarrhythmia. Less

  • Research Products

    (14 results)

All 2005 2004 2003 Other

All Journal Article (14 results)

  • [Journal Article] Mitochondrial membrane motential modulates regulation of mitochondrial Ca^<2+> in skinned rat ventricular myocytes.2005

    • Author(s)
      Masao Saotome.
    • Journal Title

      Am J Physiol Heart Circ Physiol 288

      Pages: H1820-H1828

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Difference in the cardioprotective mechanisms between ischemic preconditioning and pharmacological preconditioning by diazoxide in rat hearts.2004

    • Author(s)
      Nobuyuki Wakahara
    • Journal Title

      Circulation Journal 68

      Pages: 156-162

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Difference in the cardioprotective mechanisms between ischemic preconditioning and pharmacological preconditioning by diazoxide in rat hearts.2004

    • Author(s)
      Nobuyuki Wakahara.
    • Journal Title

      Circ J 68

      Pages: 156-162

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Usefulness of stress myocardial perfusion imaging to evaluate asymptomatic patients after coronary scent implantation.2004

    • Author(s)
      Toshihiko Sugi.
    • Journal Title

      Circ J 68

      Pages: 462-466

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Involvement of Na^+/Ca^<2+> exchange in normal cardiac excitation-contraction coupling and in Ca^<2+> overload during ischemia and reperfusion.2003

    • Author(s)
      Hiroshi Satoh.
    • Journal Title

      Myocardial Ischemia and Preconditioning

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Importance of Ca^<2+> influx by Na^+/Ca^<2+> exchange under normal and sodium-loaded conditions in mammalian ventricles.2003

    • Author(s)
      Hiroshi Satoh.
    • Journal Title

      Mol Cell Biochem 242

      Pages: 11-17

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Effects of cytochrome P450 inhibitors on agonist-induced Ca^<2+> responses and production of NO and PGI_2 in vascular endothelial cells.2003

    • Author(s)
      Kazuhiro Takeuchi.
    • Journal Title

      Mol Cell Biochem 248

      Pages: 129-134

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Protective effects of hydrogen peroxide against ischemia/repeifusion injury in perfused rat hearts.2003

    • Author(s)
      Yasuhiro Yaguchi.
    • Journal Title

      Circ J 67

      Pages: 253-258

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Modulation of SR Ca^<2+> release by FK506 induces defective excitation-contaction coupling only when SR Ca^<2+> recycling is disturbed.

    • Author(s)
      Shu Yoshihara
    • Journal Title

      Canadian Journal of Physiology and Pharmacology (In press)

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Mitochondrial membrane potential modulates regulation of mitochondrial Ca^<2+> in skinned rat ventricular myocytes.

    • Author(s)
      Masao Saotome
    • Journal Title

      American Journal of Physiology (In press)

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Resumption of intracellular Ca^<2+> cycling as a therapeutic strategy for heart failure

    • Author(s)
      Hiroshi Satoh
    • Journal Title

      Research Trends, Current Topics in Pharmacology (In press)

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Post-challenge hyperinsulinemia rather than hyperglycemia is associated with the severity of coronary artery disease in patients without previous diagnosis of diabetes mellitus.

    • Author(s)
      Hiroshi Satoh.
    • Journal Title

      Heart (in press)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Modulation of SR Ca^<2+> release by FK506 induces defective excitation-contraction coupling only when SR Ca^<2+> recycling is disturbed.

    • Author(s)
      Shu Yoshihara.
    • Journal Title

      Can J Physiol Pharmacol (in press)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Resumption of intracellular Ca^<2+> cycling as a therapeutic strategy for heart failure.

    • Author(s)
      Hiroshi Satoh.
    • Journal Title

      Current Topics in Pharmacology (in press)

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

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Published: 2006-07-11  

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