title: Multiple targets for flecainide action: implications for cardiac arrhythmogenesis.
abstract: Flecainide suppresses cardiac tachyarrhythmias including paroxysmal atrial fibrillation, supraventricular tachycardia and arrhythmic long QT syndromes (LQTS), as well as the Ca2+-mediated, catecholaminergic polymorphic ventricular tachycardia (CPVT). However, flecainide can also exert pro-arrhythmic effects most notably following myocardial infarction and when used to diagnose Brugada syndrome (BrS). These divergent actions result from its physiological and pharmacological actions at multiple, interacting levels of cellular organization. These were studied in murine genetic models with modified Navchannel or intracellular ryanodine receptor (RyR2)-Ca2+channel function. Flecainide accesses its transmembrane Nav1.5 channel binding site during activated, open, states producing a use-dependent antagonism. Closing either activation or inactivation gates traps flecainide within the pore. An early peak INarelated to activation of Navchannels followed by rapid de-activation, drives action potential (AP) upstrokes and their propagation. This is diminished in pro-arrhythmic conditions reflecting loss of function of Nav1.5 channels, such as BrS, accordingly exacerbated by flecainide challenge. Contrastingly, pro-arrhythmic effects attributed to prolonged AP recovery by abnormal late INaLfollowing gain-of-function modifications of Nav1.5 channels in LQTS3 are reduced by flecainide. Anti-arrhythmic effects of flecainide that reduce triggering in CPVT models mediated by sarcoplasmic reticular Ca2+release could arise from its primary actions on Navchannels indirectly decreasing [Ca2+]ithrough a reduced [Na+]iand/or direct open-state RyR2-Ca2+channel antagonism. The consequent [Ca2+]ialterations could also modify AP propagation velocity and therefore arrhythmic substrate through its actions on Nav1.5 channel function. This is consistent with the paradoxical differences between flecainide actions upon Na+currents, AP conduction and arrhythmogenesis under circumstances of normal and increased RyR2 function.
  
  
  
  This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc.
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge, UK.|Physiological Laboratory, University of Cambridge, Cambridge, UK.
authors.forename: Samantha C
authors.identifier: 0000-0002-5793-2349
authors.initials: SC
authors.lastname: Salvage
authors.affiliation: Physiological Laboratory, University of Cambridge, Cambridge, UK.
authors.forename: Karthik H
authors.identifier: 0000-0003-4486-6191
authors.initials: KH
authors.lastname: Chandrasekharan
authors.affiliation: Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK.|School of Medicine, Perdana University - Royal College of Surgeons Ireland, Serdang, Selangor Darul Ehsan, Malaysia.
authors.forename: Kamalan
authors.identifier: 0000-0002-6232-388X
authors.initials: K
authors.lastname: Jeevaratnam
authors.affiliation: Muscle Research Group, Eccles Institute of Neuroscience, John Curtin School of Medical Research, Australian National University, Acton, Australia.
authors.forename: Angela F
authors.identifier: 0000-0001-9493-4944
authors.initials: AF
authors.lastname: Dulhunty
authors.affiliation: Department of Pharmacology, University of Cambridge, Cambridge, UK.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Thompson
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge, UK.
authors.forename: Antony P
authors.identifier: 0000-0002-2895-7387
authors.initials: AP
authors.lastname: Jackson
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge, UK.|Physiological Laboratory, University of Cambridge, Cambridge, UK.
authors.forename: Christopher L-H
authors.identifier: 0000-0001-9553-6112
authors.initials: CL
authors.lastname: Huang
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001145:Arrhythmias, Cardiac / Q000188:drug therapy / Q000503:physiopathology*; D002118:Calcium / Q000502:physiology; D005424:Flecainide / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D026902:Potassium Channel Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D015221:Potassium Channels / Q000502:physiology; D019837:Ryanodine Receptor Calcium Release Channel / Q000502:physiology
chemical_list: D000889:Anti-Arrhythmia Agents; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D019837:Ryanodine Receptor Calcium Release Channel; D005424:Flecainide; D002118:Calcium