Innovation of treatment for malignant hyperthermia and arrhythmia by inhibition of abnormal intracellular Ca2+ release through the ryanodine receptor

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Dantrolene, a specific drug 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) amd central (2000-2500 amino acid) domains of RyRs. Here, we examined 1)the effect of dantrolene on the Ca2+ release and cardiomyocyte function in chronic rapid pacing-induced heart failure dog model 2) the anti-arrhythmic effect of dantrolene in human CPVT-associated RyR2^<R2474S /+> knock-in (KI) mouse model. In heart failure model, dantrolene corrects defective inter-domain interactions within RyR2 in failing hearts, inhibits spontaneous Ca^<2+> leak, in turn improves cardiomyocyte function in failing hearts. In human CPVT-associated RyR2^<R2474S /+> knock-in (KI) mouse model, dantrolene prevents CPVT, presumably by correction of catecholamine-induced defective inter-domain interaction within RyR2inhibiting and inhibition of Ca^<2+> leak through RyR2. Thus, dantrolene may have a potential to treat heart failure and lethal arrhythmia, specifically targeting RyR2.