Dantrolene pre-treatment significantly inhibited inducible bi-directional ventricular tachycardia and improved exercise tolerance in a CPVT-associated RyR2R2474S/+ knock-in mouse model.
Does dantrolene prevent inducible ventricular tachycardia in a RyR2(R2474S/+) knock-in mouse model of CPVT?
Dantrolene prevents catecholaminergic polymorphic ventricular tachycardia in a RyR2 knock-in mouse model, suggesting a potential therapeutic role by inhibiting Ca2+ leak.
p-value: p=<0.01
BACKGROUND: Dantrolene, a specific agent for the treatment of malignant hyperthermia, was found to inhibit Ca(2+) 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, Ca(2+) 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 Ca(2+) leak through the RyR2.
Kobayashi et al. (Fri,) conducted a other in Catecholaminergic polymorphic ventricular tachycardia (CPVT) (n=24). Dantrolene vs. Untreated KI mice / WT mice was evaluated on Inducible bi-directional ventricular tachycardia (VT) after epinephrine injection or exercise (p=<0.01). Dantrolene pre-treatment significantly inhibited inducible bi-directional ventricular tachycardia and improved exercise tolerance in a CPVT-associated RyR2R2474S/+ knock-in mouse model.