Dantrolene, a Therapeutic Agent for Malignant Hyperthermia, Inhibits Catecholaminergic Polymorphic Ventricular Tachycardia in a RyR2R2474S/+ Knock-In Mouse Model

Shigeki Kobayashi; Masafumi Yano; Hitoshi Uchinoumi; Takeshi Suetomi; Takehisa Susa; Makoto Ono; Xiaojuan Xu; Hiroki Tateishi; Tetsuro Oda; Shinichi Okuda; Masahiro Doi; Takeshi Yamamoto; Masunori Matsuzaki

doi:10.1253/circj.CJ-10-0680

Arrhythmia/Electrophysiology

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

Shigeki Kobayashi, Masafumi Yano, Hitoshi Uchinoumi, Takeshi Suetomi, Takehisa Susa, Makoto Ono, Xiaojuan Xu, Hiroki Tateishi, Tetsuro Oda, Shinichi Okuda, Masahiro Doi, Takeshi Yamamoto, Masunori Matsuzaki

Author information

Shigeki Kobayashi
Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine
Masafumi Yano
Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine
Hitoshi Uchinoumi
Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine
Takeshi Suetomi
Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine
Takehisa Susa
Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine
Makoto Ono
Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine
Xiaojuan Xu
Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine
Hiroki Tateishi
Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine
Tetsuro Oda
Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine
Shinichi Okuda
Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine
Masahiro Doi
Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine
Takeshi Yamamoto
Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine
Masunori Matsuzaki
Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine

Keywords: Calcium, Excitation-contraction (E-C) coupling, Ventricular tachycardia

JOURNAL FREE ACCESS

2010 Volume 74 Issue 12 Pages 2579-2584

DOI https://doi.org/10.1253/circj.CJ-10-0680

View "Advance Publication" version (October 7, 2010).

Details

Abstract

Background: Dantrolene, a specific agent for the treatment of malignant hyperthermia, was found to inhibit Ca²⁺ 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^R2474S/+ knock-in (KI) mouse model was investigated. Methods and Results: 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, Ca²⁺ spark frequency (SpF; s^-1·100μm^-1: 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). Conclusions: Dantrolene prevents CPVT, presumably by inhibiting Ca²⁺ leak through the RyR2. (Circ J 2010; 74: 2579 . 2584).

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