title: Synergistic antiarrhythmic effect of combining inhibition of Ca²⁺-activated K⁺ (SK) channels and voltage-gated Na⁺ channels in an isolated heart model of atrial fibrillation.
abstract: BACKGROUND
  Application of antiarrhythmic compounds is limited by both proarrhythmic and extracardiac toxicities, as well as incomplete antiarrhythmic efficacy. An improved antiarrhythmic potential may be obtained by combining antiarrhythmic drugs with different modes of action, and a reduction of the adverse effect profile could be an additional advantage if compound concentrations could be reduced.
  
  
  OBJECTIVE
  The purpose of this study was to test the hypothesis that combined inhibition of Ca(2+)-activated K(+) channels (SK channels) and voltage-gated Na(+) channels, in concentrations that would be subefficacious as monotherapy, may prevent atrial fibrillation (AF) and have reduced proarrhythmic potential in the ventricles.
  
  
  METHODS
  Subefficacious concentrations of ranolazine, flecainide, and lidocaine were tested alone or in combination with the SK channel blocker N-(pyridin-2-yl)-4-(pyridin-2-yl)thiazol-2-amine (ICA) in a Langendorff-perfused guinea pig heart model in which AF was induced after acetylcholine application and burst pacing.
  
  
  RESULTS
  AF duration was reduced when both flecainide and ranolazine were combined with ICA in doses that did not reduce AF as monotherapy. At higher concentrations, both flecainide and ranolazine revealed proarrhythmic properties.
  
  
  CONCLUSIONS
  A synergistic effect in AF treatment was obtained by combining low concentrations of SK and Na(+) channel blockers.
authors.affiliation: The Danish National Research Foundation, Centre for Cardiac Arrhythmia, Department of Biomedical Sciences, University of Copenhagen, Denmark; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
authors.forename: Jeppe Egedal
authors.initials: JE
authors.lastname: Kirchhoff
authors.affiliation: The Danish National Research Foundation, Centre for Cardiac Arrhythmia, Department of Biomedical Sciences, University of Copenhagen, Denmark; Acesion Pharma, Copenhagen, Denmark.
authors.forename: Jonas Goldin
authors.initials: JG
authors.lastname: Diness
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
authors.forename: Majid
authors.initials: M
authors.lastname: Sheykhzade
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark; Acesion Pharma, Copenhagen, Denmark; Lundbeck A/S, Copenhagen, Denmark.
authors.forename: Morten
authors.initials: M
authors.lastname: Grunnet
authors.affiliation: The Danish National Research Foundation, Centre for Cardiac Arrhythmia, Department of Biomedical Sciences, University of Copenhagen, Denmark. Electronic address: thojes@sund.ku.dk.
authors.forename: Thomas
authors.initials: T
authors.lastname: Jespersen
mesh_terms: D000083:Acetanilides / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001281:Atrial Fibrillation / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004562:Electrocardiography / Q000187:drug effects*; D005260:Female; D005424:Flecainide / Q000494:pharmacology; D006168:Guinea Pigs; D010879:Piperazines / Q000494:pharmacology; D000069458:Ranolazine; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D061567:Voltage-Gated Sodium Channel Blockers / Q000494:pharmacology*; D061566:Voltage-Gated Sodium Channels / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000083:Acetanilides; D000889:Anti-Arrhythmia Agents; D010879:Piperazines; D051640:Small-Conductance Calcium-Activated Potassium Channels; D061567:Voltage-Gated Sodium Channel Blockers; D061566:Voltage-Gated Sodium Channels; D000069458:Ranolazine; D005424:Flecainide
keywords: Calcium-activated potassium channel; Combination therapy; Flecainide; Lidocaine; Ranolazine