title: Antiarrhythmic effect of vernakalant in electrically remodeled goat atria is caused by slowing of conduction and prolongation of postrepolarization refractoriness.
abstract: BACKGROUND
  Vernakalant inhibits several potassium currents and causes a rate- and voltage-dependent inhibition of the sodium current.
  
  
  OBJECTIVE
  The aim of this study was to evaluate the antiarrhythmic mechanism of vernakalant in normal and electrically remodeled atria.
  
  
  METHODS
  Fourteen goats were instrumented with electrodes on both atria. Drug effects on refractory period (ERP), conduction velocity (CV), and atrial fibrillation cycle length (AFCL) were determined in normal goats (control) and after 2 (2dAF) or 11 (11dAF) days of pacing-induced atrial fibrillation (AF) in awake goats. To evaluate the contribution of changes in conduction and ERP, the same experiments were performed with flecainide and AVE0118. In a subset of goats, monophasic action potentials were recorded during anesthesia.
  
  
  RESULTS
  Vernakalant dose-dependently prolonged ERP and decreased CV in CTL experiments. Both effects were maintained after 2dAF and 11dAF. After 11dAF, conduction slowed down by 8.2 ± 1.5 cm/s and AFCL increased by 55 ± 3 ms, leading to AF termination in 5 out of 9 goats. Monophasic action potential measurements revealed that ERP prolongation was due to enhanced postrepolarization refractoriness. During pacing, vernakalant had comparable effects on CV as flecainide, while effect on ERP was comparable to AVE0118. During AF, all compounds had comparable effects on median AFCL and ERP despite differences in their effects on CV during pacing.
  
  
  CONCLUSIONS
  The antiarrhythmic effect of vernakalant in the goat, at clinically relevant plasma concentrations, is based on both conduction slowing and ERP prolongation due to postrepolarization refractoriness. These electrophysiological effects were not affected by long-term electrical remodeling of the atria.
authors.affiliation: Department of Physiology, Faculty of Medicine, Maastricht University, Maastricht, The Netherlands.
authors.forename: Arne
authors.initials: A
authors.lastname: van Hunnik
authors.affiliation: Department of Physiology, Faculty of Medicine, Maastricht University, Maastricht, The Netherlands.
authors.forename: Dennis H
authors.initials: DH
authors.lastname: Lau
authors.affiliation: Department of Physiology, Faculty of Medicine, Maastricht University, Maastricht, The Netherlands.
authors.forename: Stef
authors.initials: S
authors.lastname: Zeemering
authors.affiliation: Department of Physiology, Faculty of Medicine, Maastricht University, Maastricht, The Netherlands.
authors.forename: Marion
authors.initials: M
authors.lastname: Kuiper
authors.affiliation: Department of Physiology, Faculty of Medicine, Maastricht University, Maastricht, The Netherlands.
authors.forename: Sander
authors.initials: S
authors.lastname: Verheule
authors.affiliation: Department of Physiology, Faculty of Medicine, Maastricht University, Maastricht, The Netherlands. Electronic address: schotten@maastrichtuniversity.nl.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schotten
mesh_terms: D000200:Action Potentials; D000818:Animals; D000840:Anisoles / Q000627:therapeutic use*; D001281:Atrial Fibrillation / Q000188:drug therapy* / Q000503:physiopathology; D064752:Atrial Remodeling / Q000187:drug effects / Q000502:physiology*; D004195:Disease Models, Animal; D006041:Goats; D006325:Heart Atria / Q000187:drug effects / Q000503:physiopathology*; D011759:Pyrrolidines / Q000627:therapeutic use*; D012032:Refractory Period, Electrophysiological / Q000502:physiology*
chemical_list: D000840:Anisoles; D011759:Pyrrolidines; C524581:vernakalant
keywords: AVE0118; Antiarrhythmic drugs; Atrial fibrillation; Flecainide; In vivo model; Remodeling; Vernakalant