Dantrolene, a Therapeutic Agent for Malignant Hyperthermia, Inhibits Catecholaminergic Polymorphic Ventricular Tachycardia in a RyR2R2474S/+ Knock-In Mouse Model
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- Kobayashi Shigeki
- Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine
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- Yano Masafumi
- Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine
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- Uchinoumi Hitoshi
- Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine
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- Suetomi Takeshi
- Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine
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- Susa Takehisa
- Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine
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- Ono Makoto
- Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine
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- Xu Xiaojuan
- Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine
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- Tateishi Hiroki
- Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine
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- Oda Tetsuro
- Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine
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- Okuda Shinichi
- Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine
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- Doi Masahiro
- Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine
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- Yamamoto Takeshi
- Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine
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- Matsuzaki Masunori
- Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine
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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 RyR2R2474S/+ 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).<br>
Journal
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- Circulation Journal
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Circulation Journal 74 (12), 2579-2584, 2010
The Japanese Circulation Society
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Details 詳細情報について
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- CRID
- 1390282680081527936
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- NII Article ID
- 10027424202
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- NII Book ID
- AA11591968
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- ISSN
- 13474820
- 13469843
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- Text Lang
- en
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- Data Source
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- JaLC
- Crossref
- CiNii Articles
- KAKEN
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- Abstract License Flag
- Disallowed