title: Beta-adrenergic augmentation of flecainide-induced conduction slowing in canine Purkinje fibers.
abstract: BACKGROUND
  This study was undertaken to test the hypothesis that beta-adrenergic stimulation in the setting of membrane depolarization will potentiate flecainide-induced conduction slowing.
  
  
  RESULTS
  To elucidate the potential mechanism for the flecainide proarrhythmia observed in CAST, the voltage dependence of beta-adrenergic modulation of impulse propagation in eight flecainide-superfused canine Purkinje fibers was examined with a dual-microelectrode technique. At physiological membrane potentials (Vm) ([K+]o=5.4 micromol), 1 micromol flecainide decreased Vmax from 698+/-55 to 610+/-72 V/s (P=.003) and squared conduction velocity (theta2) from 2.11+/-1.1 to 1.72+/-0.9 (m/s)2 (P=.001). With K+ depolarization to Vm=-70 mV, flecainide further reduced Vmax from 306+/-101 to 245+/-65 V/s and theta2 from 1.12+/-0.4 to 0.99+/-0.6 (m/s)2, producing a 2.0-mV hyperpolarizing shift of apparent Na+ channel availability curves derived from theta2. The addition of 1 micromol isoproterenol to flecainide-superfused fibers at physiological Vm increased theta2 by 8% to 1.84+/-0.6 (m/s)2 (P<.01) without altering Vmax. At -70 mV, the addition of isoproterenol magnified the flecainide-induced reduction of Vmax an additional 24% to 185+/-52 V/s (P<.01) and theta2 by 17% to 0.82+/-0.5 (m/s)2 (P=.04), producing an additional 1.8-mV (P=.002) and 1.9-mV (P=.002) hyperpolarizing shift in the apparent Na+ channel inactivation curves generated from Vmax and theta2, respectively. At physiological Vm, the action potential duration (APD95) was reduced from 307+/-35 to 269+/-27 ms (P<.001) by flecainide and subsequently to 217+/-4 ms (P<.001) with isoproterenol addition. With 12 mmol/L K+, APD95 decreased from 198+/-23 to 182+/-17 ms (P=.005) with flecainide and to 164+/-10 ms (P=.004) with isoproterenol.
  
  
  CONCLUSIONS
  At depolarized Vm, isoproterenol amplified the flecainide-induced reduction of Vmax and theta2, suggesting a further adrenergic-mediated reduction of Na+ current. Consequently, the synergy between catecholamines and flecainide at depolarized Vm and the shortened APD95 could facilitate arrhythmogenesis in the presence of underlying ischemia.
authors.affiliation: Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic and Mayo Foundation, Rochester, Minn 55902, USA.
authors.forename: K T
authors.initials: KT
authors.lastname: Cragun
authors.forename: S B
authors.initials: SB
authors.lastname: Johnson
authors.forename: D L
authors.initials: DL
authors.lastname: Packer
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D004285:Dogs; D005260:Female; D005424:Flecainide / Q000494:pharmacology*; D007545:Isoproterenol / Q000494:pharmacology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009431:Neural Conduction / Q000187:drug effects*; D011188:Potassium / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D011690:Purkinje Fibers / Q000187:drug effects*; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000502:physiology; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism
chemical_list: D000318:Adrenergic beta-Agonists; D000889:Anti-Arrhythmia Agents; D011943:Receptors, Adrenergic, beta; D015222:Sodium Channels; D011493:Protein Kinase C; D005424:Flecainide; D007545:Isoproterenol; D011188:Potassium