title: Targeting atrioventricular differences in ion channel properties for terminating acute atrial fibrillation in pigs.
abstract: OBJECTIVE
  The goal was to terminate atrial fibrillation (AF) by targeting atrioventricular differences in ionic properties.
  
  
  RESULTS
  Optical mapping was used to record electrical activity during carbachol (0.25-0.5 μM)-induced AF in pig hearts. The atrial-specific current, I(Kur), was blocked with 100 μM 4-aminopyridine (4-AP) or with 0.5 μM DPO-1. Hearts in AF and ventricular fibrillation (VF) were also subjected to increasing levels of extracellular K(+) ([K(+)](o): 6-12 mM), compared with controls (4 mM). We hypothesized that due to the more negative steady-state half inactivation voltage for the atrial Na(+) current, I(Na), compared with the ventricle, AF would terminate before VF in hyperkalaemia. Mathematical models were used to interpret experimental findings. The I(Kur) block did not terminate AF in a majority of experiments (6/9 with 4-AP and 3/4 with DPO-1). AF terminated in mild hyperkalaemia ([K(+)](o) ≤ 10.0 mM; N = 8). In contrast, only two of five VF episodes terminated at the maximum ([K(+)](o): 12 mM [K(+)](o)). The I(Kur) block did not terminate a simulated rotor in cholinergic AF because its contribution to repolarization was dwarfed by the large magnitude of the acetylcholine-activated K(+) current (I(K,ACh)). Simulations showed that the lower availability of the atrial Na(+) current at depolarized potentials, and a smaller atrial tissue size compared with the ventricle, could partly explain the earlier termination of AF compared with VF during hyperkalaemia.
  
  
  CONCLUSIONS
  I(Kur) is an ineffective anti-arrhythmic drug target in cholinergic AF. Manipulating Na(+) current 'availability' might represent a viable anti-arrhythmic strategy in AF.
authors.affiliation: Center for Arrhythmia Research, University of Michigan, Ann Arbor, MI, USA. sanpandi@med.umich.edu
authors.forename: Sandeep V
authors.initials: SV
authors.lastname: Pandit
authors.forename: Sharon
authors.initials: S
authors.lastname: Zlochiver
authors.forename: David
authors.initials: D
authors.lastname: Filgueiras-Rama
authors.forename: Sergey
authors.initials: S
authors.lastname: Mironov
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Yamazaki
authors.forename: Steven R
authors.initials: SR
authors.lastname: Ennis
authors.forename: Sami F
authors.initials: SF
authors.lastname: Noujaim
authors.forename: Antony J
authors.initials: AJ
authors.lastname: Workman
authors.forename: Omer
authors.initials: O
authors.lastname: Berenfeld
authors.forename: Jerome
authors.initials: J
authors.lastname: Kalifa
authors.forename: José
authors.initials: J
authors.lastname: Jalife
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001281:Atrial Fibrillation / Q000188:drug therapy*; D003198:Computer Simulation; D006947:Hyperkalemia / Q000503:physiopathology; D008297:Male; D010720:Phosphines / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000627:therapeutic use*; D013552:Swine
chemical_list: C507236:(2-isopropyl-5-methylcyclohexyl) diphenylphosphine oxide; D010720:Phosphines; D026902:Potassium Channel Blockers; D015761:4-Aminopyridine; D011188:Potassium