Dantrolene, a Therapeutic Agent for Malignant Hyperthermia, Inhibits Catecholaminergic Polymorphic Ventricular Tachycardia in a RyR2^<R2474S/+> Knock-In Mouse Model

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Author(s)

    • KOBAYASHI Shigeki
    • Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine
    • YANO Masafumi
    • Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine
    • UCHINOUMI Hitoshi
    • Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine
    • SUETOMI Takeshi
    • Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine
    • SUSA Takehisa
    • Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine
    • ONO Makoto
    • Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine
    • XU Xiaojuan
    • Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine
    • TATEISHI Hiroki
    • Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine
    • ODA Tetsuro
    • Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine
    • OKUDA Shinichi
    • Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine
    • DOI Masahiro
    • Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine
    • YAMAMOTO Takeshi
    • Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine
    • MATSUZAKI Masunori
    • Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine

Abstract

<b><i>Background:</i></b> Dantrolene, a specific agent for the treatment of malignant hyperthermia, was found to inhibit Ca<sup>2+</sup> leak through not only the skeletal ryanodine receptor (RyR1), but also the cardiac ryanodine receptor (RyR2) by correcting the defective inter-domain interaction between N-terminal (1-619 amino acid) and central (2,000-2,500 amino acid) domains of RyRs. Here, the in vivo anti-arrhythmic effect of dantrolene in a human catecholaminergic polymorphic ventricular tachycardia (CPVT)-associated RyR2<sup>R2474S/+</sup> knock-in (KI) mouse model was investigated. <b><i>Methods and Results:</i></b> ECG was monitored in KI mice (n=6) and wild-type (WT) mice (n=6), before and after an injection of epinephrine (1.0mg/kg) or on exercise using a treadmill. In all KI (but not WT) mice, bi-directional ventricular tachycardia (VT) was induced after an injection of epinephrine or on exercise. Pre-treatment with dantrolene (for 7-10 days) significantly inhibited the inducible VT (P<0.01). In KI cardiomyocytes, Ca<sup>2+</sup> spark frequency (SpF; s<sup>-1</sup>·100μm<sup>-1</sup>: 5.8±0.3, P<0.01) was much more increased after the addition of isoproterenol than in WT cardiomyocytes (SpF: 3.6±0.2). The increase in SpF seen in KI cardiomyocytes was attenuated by 1.0μmol/L dantrolene (SpF: 3.6±0.5, P<0.01). <b><i>Conclusions:</i></b> Dantrolene prevents CPVT, presumably by inhibiting Ca<sup>2+</sup> leak through the RyR2. (<i>Circ J</i> 2010; <b>74:</b> 2579 . 2584).<br>

Journal

  • Circulation Journal

    Circulation Journal 74(12), 2579-2584, 2010-11-25

    The Japanese Circulation Society

References:  22

Cited by:  4

Codes

  • NII Article ID (NAID)
    10027424202
  • NII NACSIS-CAT ID (NCID)
    AA11591968
  • Text Lang
    ENG
  • Article Type
    Journal Article
  • ISSN
    13469843
  • Data Source
    CJP  CJPref  J-STAGE 
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