title: Effects of Dantrolene Treatment on Ventricular Electrophysiology and Arrhythmogenesis in Rats With Chronic β-Adrenergic Receptor Activation.
abstract: Dantrolene, which is primarily used to treat malignant hyperthermia, has recently been suggested for the prevention of arrhythmogenesis in various animal models. In this study, the effects of dantrolene treatment on electrophysiological properties and ventricular arrhythmias (VAs) in rats with chronic β-adrenergic receptor (β-AR) activation were investigated. Rats were randomized to treatment with saline (control group), isoproterenol (ISO; ISO group), or ISO + dantrolene (ID group) for 2 weeks. An electrophysiological study was performed to assess action potential duration restitution (APDR) and induce action potential duration (APD) alternans or VA in vitro. The protein levels of Cav1.2, sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2a), and ryanodine receptor 2 (RyR2) were detected by Western blot. Compared with the control group, chronic administration of ISO significantly increased APD, the maximum slope (Smax) of APDR curve, and the spatial dispersions of Smax and APD (all P < .01), and all effects were attenuated by dantrolene treatment (all P < .05). Additionally, chronic ISO administration significantly reduced the protein levels of SERCA2 and RyR2, but increased the Cav1.2 protein expression (all P < .05). However, compared with the ISO group, dantrolene treatment preserved SERCA2a and RyR2 protein levels and decreased Cav1.2 protein levels in the ID group (all P < .05). The intracellular Ca(2+) ([Ca(2+)]i) levels measured by incubating isolated cardiomyocytes with Fluo-3/alveolar macrophages were significantly increased in the ISO group compared with the control group (P < .01). Dantrolene treatment markedly reduced the rise of [Ca(2+)]i levels caused by chronic administration of ISO (P < .05). Dantrolene treatment also prevented the reductions in the APD alternans and VA thresholds induced by chronic ISO stimulation (all P < .05). These data suggest that dantrolene stabilizes ventricular electrophysiological characteristics and increases the expression of key sarcoplasmic reticulum calcium cycling proteins to reduce vulnerability to VA in rats with chronic β-AR activation.
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China Cardiovascular Research Institute, Wuhan University, Wuhan, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Liu
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China Cardiovascular Research Institute, Wuhan University, Wuhan, China.
authors.forename: Shao-bo
authors.initials: SB
authors.lastname: Shi
authors.affiliation: Department of Cardiology, The First Clinical Medical College of Three Gorges University, Yichang, China.
authors.forename: Mu
authors.initials: M
authors.lastname: Qin
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China Cardiovascular Research Institute, Wuhan University, Wuhan, China huangcongxing1951@126.com.
authors.forename: Cong-xin
authors.initials: CX
authors.lastname: Huang
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000188:drug therapy*; D002118:Calcium / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003620:Dantrolene / Q000494:pharmacology*; D004195:Disease Models, Animal; D055724:Electrophysiological Phenomena / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism
chemical_list: D002316:Cardiotonic Agents; D011943:Receptors, Adrenergic, beta; D019837:Ryanodine Receptor Calcium Release Channel; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D003620:Dantrolene; D007545:Isoproterenol; D002118:Calcium
keywords: dantrolene; electrophysiology; isoproterenol; ventricular arrhythmia