Dantrolene prevents arrhythmogenic Ca2+release in heart failure

Abstract

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 μM) 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.