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

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).