Dantrolene prevents arrhythmogenic Ca release in heart failure

Maxwell JT, Domeier TL, Blatter LA. Dantrolene prevents arrhythmogenic Ca release in heart failure. Am J Physiol Heart Circ Physiol 302: H953–H963, 2012. First published December 16, 2011; doi:10.1152/ajpheart.00936.2011.—In heart failure (HF), arrhythmogenic Ca release and chronic Ca depletion of the sarcoplasmic reticulum (SR) arise due to altered function of the ryanodine receptor (RyR) SR Ca -release channel. Dantrolene, a therapeutic agent used to treat malignant hyperthermia associated with mutations of the skeletal muscle type 1 RyR (RyR1), has recently been suggested to have effects on the cardiac type 2 RyR (RyR2). In this investigation, we tested the hypothesis that dantrolene exerts antiarrhythmic and inotropic effects on HF ventricular myocytes by examining multiple aspects of intracellular Ca handling. In normal rabbit myocytes, dantrolene (1 M) had no effect on SR Ca load, postrest decay of SR Ca content, the threshold for spontaneous Ca wave initiation (i.e., the SR Ca content at which spontaneous waves initiate) and Ca spark frequency. In cardiomyocytes from failing rabbit hearts, SR Ca load and the wave initiation threshold were decreased compared with normal myocytes, Ca spark frequency was increased, and the postrest decay was potentiated. Using a novel approach of measuring cytosolic and intra-SR Ca concentration (using the low-affinity Ca indicator fluo-5N entrapped within the SR), we showed that treatment of HF cardiomyocytes with dantrolene rescued postrest decay and increased the wave initiation threshold. Additionally, dantrolene decreased Ca spark frequency while increasing the SR Ca content in HF myocytes. These data suggest that dantrolene exerts antiarrhythmic effects and preserves inotropy in HF cardiomyocytes by decreasing the incidence of diastolic Ca sparks, increasing the intra-SR Ca threshold at which spontaneous Ca waves occur, and decreasing the loss of Ca from the SR. Furthermore, the observation that dantrolene reduces arrhythmogenicity while at the same time preserves inotropy suggests that dantrolene is a potentially useful drug in the treatment of arrhythmia associated with HF.