Dantrolene Restores Altered RyR2-Mediated Ca Signaling in Heart Failure

Abstract

In heart failure (HF) arrhythmogenic Ca release and chronic [Ca]SR depletion arise due to altered function of ryanodine receptors. Dantrolene, a therapeautic agent used to treat malignant hyperthermia associated with mutations of the type 1 ryanodine receptor (RyR1), is purported to be without effects on the cardiac type 2 ryanodine receptor (RyR2). However, recent investigations suggest that dantrolene may correct abnormal RyR2-mediated calcium release associated with HF. In this investigation, we tested if dantrolene exerts anti-arrhythmic effects on heart failure ventricular myocytes by examining the intra-SR Ca threshold for arrhythmogenic Ca waves. Using the low-affinity calcium indicator fluo-5N entrapped in the SR, direct measurement of [Ca]SR showed that in normal rabbit myocytes dantrolene (1 microM) had no effect on SR Ca content, the amplitude of action potential induced intra-SR Ca depletions, or on the threshold for spontaneous Ca wave initiation (i.e., the SR Ca content at which spontaneous waves initiate). Furthermore, in field stimulated (0.5 Hz and 1.0 Hz) normal cardiomyocytes loaded with indo-1, dantrolene treatment had no effect on Ca transient amplitude, SR Ca load, or post-rest decay of SR Ca content. In cardiomyocytes from failing rabbit hearts, SR Ca content and the wave initiation threshold were decreased compared to normal myocytes. Interestingly, treatment of HF cardiomyocytes with dantrolene restored the SR Ca content and increased the wave initiation threshold. Together, these data suggest that dantrolene may exert anti-arrhythmic effects in heart failure cardiomyocytes by increasing the intra-SR Ca threshold at which spontaneous Ca waves occur.