Dantrolene prevents arrhythmogenic Ca2+ release in heart failure

Maxwell JT, Domeier TL, Blatter LA. Dantrolene prevents arrhythmogenic Ca2+ 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 Ca2+ release and chronic Ca2+ depletion of the sarcoplasmic reticulum (SR) arise due to altered function of the ryanodine receptor (RyR) SR Ca2+ -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 Ca2+ handling. In normal rabbit myocytes, dantrolene (1 mu M) had no effect on SR Ca2+ load, postrest decay of SR Ca2+ content, the threshold for spontaneous Ca2+ wave initiation (i.e., the SR Ca2+ content at which spontaneous waves initiate) and Ca2+ spark frequency. In cardiomyocytes from failing rabbit hearts, SR Ca2+ load and the wave initiation threshold were decreased compared with normal myocytes, Ca2+ spark frequency was increased, and the postrest decay was potentiated. Using a novel approach of measuring cytosolic and intra-SR Ca2+ concentration (using the low-affinity Ca2+ 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 Ca2+ spark frequency while increasing the SR Ca2+ content in HF myocytes. These data suggest that dantrolene exerts antiarrhythmic effects and preserves inotropy in HF cardiomyocytes by decreasing the incidence of diastolic Ca2+ sparks, increasing the intra-SR Ca2+ threshold at which spontaneous Ca2+ waves occur, and decreasing the loss of Ca2+ 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.