title: Dantrolene prevents arrhythmogenic Ca2+ release in heart failure.
abstract: In heart failure (HF), arrhythmogenic Ca(2+) release and chronic Ca(2+) depletion of the sarcoplasmic reticulum (SR) arise due to altered function of the ryanodine receptor (RyR) SR Ca(2+)-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(2+) handling. In normal rabbit myocytes, dantrolene (1 μM) had no effect on SR Ca(2+) load, postrest decay of SR Ca(2+) content, the threshold for spontaneous Ca(2+) wave initiation (i.e., the SR Ca(2+) content at which spontaneous waves initiate) and Ca(2+) spark frequency. In cardiomyocytes from failing rabbit hearts, SR Ca(2+) load and the wave initiation threshold were decreased compared with normal myocytes, Ca(2+) spark frequency was increased, and the postrest decay was potentiated. Using a novel approach of measuring cytosolic and intra-SR Ca(2+) concentration (using the low-affinity Ca(2+) 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(2+) spark frequency while increasing the SR Ca(2+) 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(2+) sparks, increasing the intra-SR Ca(2+) threshold at which spontaneous Ca(2+) waves occur, and decreasing the loss of Ca(2+) 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.
authors.affiliation: Department of Molecular Biophysics and Physiology, Rush University Medical Center, Chicago, IL 60612, USA.
authors.forename: Joshua T
authors.initials: JT
authors.lastname: Maxwell
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Domeier
authors.forename: Lothar A
authors.initials: LA
authors.lastname: Blatter
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000378:metabolism* / Q000473:pathology; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D003620:Dantrolene / Q000494:pharmacology*; D004195:Disease Models, Animal; D006333:Heart Failure / Q000378:metabolism* / Q000473:pathology; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009125:Muscle Relaxants, Central / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011817:Rabbits; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism
chemical_list: D009125:Muscle Relaxants, Central; D003620:Dantrolene; D002118:Calcium