title: The mechanism of flecainide action in CPVT does not involve a direct effect on RyR2.
abstract: BACKGROUND
  Flecainide, a class 1c antiarrhythmic, has emerged as an effective therapy in preventing arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) refractory to β-adrenergic receptor blockade. It has been proposed that the clinical efficacy of flecainide in CPVT is because of the combined actions of direct blockade of ryanodine receptors (RyR2) and Na(+) channel inhibition. However, there is presently no direct evidence to support the notion that flecainide blocks RyR2 Ca(2+) flux in the physiologically relevant (luminal-to-cytoplasmic) direction. The mechanism of flecainide action remains controversial.
  
  
  OBJECTIVE
  To examine, in detail, the effect of flecainide on the human RyR2 channel and to establish whether the direct blockade of physiologically relevant RyR2 ion flow by the drug contributes to its therapeutic efficacy in the clinical management of CPVT.
  
  
  RESULTS
  Using single-channel analysis, we show that, even at supraphysiological concentrations, flecainide did not inhibit the physiologically relevant, luminal-to-cytosolic flux of cations through the channel. Moreover, flecainide did not alter RyR2 channel gating and had negligible effect on the mechanisms responsible for the sarcoplasmic reticulum charge-compensating counter current. Using permeabilized cardiac myocytes to eliminate any contribution of plasmalemmal Na(+) channels to the observed actions of the drug at the cellular level, flecainide did not inhibit RyR2-dependent sarcoplasmic reticulum Ca(2+) release.
  
  
  CONCLUSIONS
  The principal action of flecainide in CPVT is not via a direct interaction with RyR2. Our data support a model of flecainide action in which Na(+)-dependent modulation of intracellular Ca(2+) handling attenuates RyR2 dysfunction in CPVT.
authors: From the Institute of Molecular and Experimental Medicine, Wales Heart Research Institute, Cardiff University School of Medicine, Cardiff, United Kingdom (M.L.B., N.L.T., S.M., C.M., C.H.G., A.J.W.); and Myocardial Function Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom (M.B.S., K.T.M.).
authors: Mark L
authors: ML
authors: Bannister
authors: From the Institute of Molecular and Experimental Medicine, Wales Heart Research Institute, Cardiff University School of Medicine, Cardiff, United Kingdom (M.L.B., N.L.T., S.M., C.M., C.H.G., A.J.W.); and Myocardial Function Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom (M.B.S., K.T.M.).
authors: N Lowri
authors: NL
authors: Thomas
authors: From the Institute of Molecular and Experimental Medicine, Wales Heart Research Institute, Cardiff University School of Medicine, Cardiff, United Kingdom (M.L.B., N.L.T., S.M., C.M., C.H.G., A.J.W.); and Myocardial Function Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom (M.B.S., K.T.M.).
authors: Markus B
authors: MB
authors: Sikkel
authors: From the Institute of Molecular and Experimental Medicine, Wales Heart Research Institute, Cardiff University School of Medicine, Cardiff, United Kingdom (M.L.B., N.L.T., S.M., C.M., C.H.G., A.J.W.); and Myocardial Function Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom (M.B.S., K.T.M.).
authors: Saptarshi
authors: S
authors: Mukherjee
authors: From the Institute of Molecular and Experimental Medicine, Wales Heart Research Institute, Cardiff University School of Medicine, Cardiff, United Kingdom (M.L.B., N.L.T., S.M., C.M., C.H.G., A.J.W.); and Myocardial Function Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom (M.B.S., K.T.M.).
authors: Chloe
authors: C
authors: Maxwell
authors: From the Institute of Molecular and Experimental Medicine, Wales Heart Research Institute, Cardiff University School of Medicine, Cardiff, United Kingdom (M.L.B., N.L.T., S.M., C.M., C.H.G., A.J.W.); and Myocardial Function Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom (M.B.S., K.T.M.).
authors: Kenneth T
authors: KT
authors: MacLeod
authors: From the Institute of Molecular and Experimental Medicine, Wales Heart Research Institute, Cardiff University School of Medicine, Cardiff, United Kingdom (M.L.B., N.L.T., S.M., C.M., C.H.G., A.J.W.); and Myocardial Function Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom (M.B.S., K.T.M.).
authors: Christopher H
authors: CH
authors: George
authors: From the Institute of Molecular and Experimental Medicine, Wales Heart Research Institute, Cardiff University School of Medicine, Cardiff, United Kingdom (M.L.B., N.L.T., S.M., C.M., C.H.G., A.J.W.); and Myocardial Function Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom (M.B.S., K.T.M.). WilliamsAJ9@cardiff.ac.uk.
authors: Alan J
authors: AJ
authors: Williams
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D020013:Calcium Signaling / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005424:Flecainide / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D008297:Male; D008564:Membrane Potentials; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D017180:Tachycardia, Ventricular / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D013997:Time Factors; D014162:Transfection; D061567:Voltage-Gated Sodium Channel Blockers / Q000494:pharmacology*; D000098850:Polymorphic Catecholaminergic Ventricular Tachycardia
chemical_list: D000889:Anti-Arrhythmia Agents; D015221:Potassium Channels; D019837:Ryanodine Receptor Calcium Release Channel; D061567:Voltage-Gated Sodium Channel Blockers; D005424:Flecainide
keywords: antiarrhythmic drugs; cardiac arrhythmias; flecainide; polymorphic catecholergic ventricular tachycardia; ryanodine receptor calcium release channel