title: Antiarrhythmic effects of dantrolene in human diseased cardiomyocytes.
abstract: Cardiac type 2 ryanodine receptors (RyR2s) play a pivotal role in cellular electrophysiology and contractility. Increased RyR2-mediated diastolic sarcoplasmic reticulum (SR) Ca2+release is linked to heart failure (HF) and arrhythmias. Dantrolene, a drug used for the treatment of malignant hyperthermia, is known to stabilize RyRs in skeletal muscle.
  
  
  
  The purpose of this study was to investigate the effects of dantrolene on arrhythmogenic triggers and contractile function in human atrial fibrillation (AF) and HF cardiomyocytes (CM).
  
  
  
  Human CM were isolated from either patients with HF (ventricular) or patients with AF (atrial), and Ca2+imaging, patch-clamp, or muscle strip experiments were performed.
  
  
  
  After exposure to dantrolene, human atrial AF and left ventricular HF CM showed significant reductions in proarrhythmic SR Ca2+spark frequency and diastolic SR Ca2+leak. Moreover, dantrolene decreased the frequency of Ca2+waves and spontaneous Ca2+transients in HF CM. Patch-clamp experiments revealed that dantrolene significantly suppressed delayed afterdepolarizations in HF and AF CM. Importantly, dantrolene had no effect on action potential duration in AF or in HF CM. In addition, dantrolene had neutral effects on contractile force of human isometrically twitching ventricular HF trabeculae.
  
  
  
  Our study showed that dantrolene beneficially influenced disrupted SR Ca2+homeostasis in human HF and AF CM. Cellular arrhythmogenic triggers were potently suppressed by dantrolene, whereas action potential duration and contractility were not affected. As a clinically approved drug for the treatment of malignant hyperthermia, dantrolene may be a potential antiarrhythmic drug for patients with rhythm disorders and merits further clinical investigation.
authors.affiliation: Department of Cardiology and Pneumology, Georg-August-University Göttingen, Göttingen, Germany.
authors.forename: Nico
authors.initials: N
authors.lastname: Hartmann
authors.affiliation: Department of Cardiology and Pneumology, Georg-August-University Göttingen, Göttingen, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Pabel
authors.affiliation: Department of Cardiology and Pneumology, Georg-August-University Göttingen, Göttingen, Germany.
authors.forename: Jonas
authors.initials: J
authors.lastname: Herting
authors.affiliation: Department of Cardiology and Pneumology, Georg-August-University Göttingen, Göttingen, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Schatter
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, Heart and Diabetes Center NRW, Ruhr University Bochum, Bad Oeynhausen, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Renner
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, Heart and Diabetes Center NRW, Ruhr University Bochum, Bad Oeynhausen, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Gummert
authors.affiliation: Department of Anesthesiology, Emergency and Intensive Care Medicine, Georg-August-University Göttingen, Göttingen, Germany.
authors.forename: Hanna
authors.initials: H
authors.lastname: Schotola
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, Georg-August-University Göttingen, Göttingen, Germany.
authors.forename: Bernhard C
authors.initials: BC
authors.lastname: Danner
authors.affiliation: Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany.
authors.forename: Lars S
authors.initials: LS
authors.lastname: Maier
authors.affiliation: Department of Internal Medicine III: Cardiology and Angiology, University of Kiel, Kiel, Germany; DZHK (German Center for Cardiovascular Research), partner site Göttingen, Göttingen, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Frey
authors.affiliation: Department of Cardiology and Pneumology, Georg-August-University Göttingen, Göttingen, Germany; DZHK (German Center for Cardiovascular Research), partner site Göttingen, Göttingen, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Hasenfuss
authors.affiliation: Department of Cardiology and Pneumology, Georg-August-University Göttingen, Göttingen, Germany.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Fischer
authors.affiliation: Department of Cardiology and Pneumology, Georg-August-University Göttingen, Göttingen, Germany; Department of Internal Medicine III: Cardiology and Angiology, University of Kiel, Kiel, Germany; DZHK (German Center for Cardiovascular Research), partner site Göttingen, Göttingen, Germany. Electronic address: ssossalla@med.uni-goettingen.de.
authors.forename: Samuel
authors.initials: S
authors.lastname: Sossalla
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001281:Atrial Fibrillation / Q000378:metabolism / Q000503:physiopathology; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003620:Dantrolene / Q000494:pharmacology*; D006333:Heart Failure / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D009200:Myocardial Contraction / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism
chemical_list: D000889:Anti-Arrhythmia Agents; D019837:Ryanodine Receptor Calcium Release Channel; D003620:Dantrolene
keywords: Antiarrhythmic agent; Arrhythmia; Atrial fibrillation; Dantrolene; Electrophysiology; Heart failure; Ryanodine receptor; Sarcoplasmic reticulum Ca(2+) leak