Dantrolene, a Therapeutic Agent for Malignant Hyperthermia, Inhibits Catecholaminergic Polymorphic Ventricular Tachycardia in a RyR2R2474S/+ Knock-In Mouse Model
Dantrolene, a Therapeutic Agent for Malignant Hyperthermia, Inhibits Catecholaminergic Polymorphic Ventricular Tachycardia in a RyR2R2474S/+ Knock-In Mouse Model
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DOI：
10.1253/circj.cj-10-0680
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发表时间：
2010-12-01
影响因子：
3.3
通讯作者：
Matsuzaki, Masunori
中科院分区：
文献类型：
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作者：
Kobayashi, Shigeki;Yano, Masafumi;Matsuzaki, Masunori
背景资料：丹曲林是一种治疗恶性高热的特异性药物，它不仅能抑制骨骼肌兰尼碱受体（RyR 1）的Ca ~（2+）渗漏，而且能通过纠正RyR 2的N-末端（1-619个氨基酸）和中心（2，000 - 2，500个氨基酸）结构域之间的相互作用来抑制RyR 2的Ca ~（2+）渗漏。在这里，丹曲林在体内的抗心律失常作用的人儿茶酚胺能多态性室性心动过速（CPVT）相关的RyR 2（R2474 S/+）敲入（KI）小鼠models.Methods和结果：心电图监测KI小鼠（n=6）和野生型（WT）小鼠（n=6），之前和之后注射肾上腺素（1.0 mg/kg）或使用跑步机运动。在所有KI（但非WT）小鼠中，在注射肾上腺素或运动后诱导双向室性心动过速（VT）。丹曲林预处理（7-10天）可明显抑制诱导性室性心动过速（P
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 (1.0 mg/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