β-Adrenergic Augmentation of Flecainide-Induced Conduction Slowing in Canine Purkinje Fibers

Abstract

Background This study was undertaken to test the hypothesis that β-adrenergic stimulation in the setting of membrane depolarization will potentiate flecainide-induced conduction slowing. Methods and Results To elucidate the potential mechanism for the flecainide proarrhythmia observed in CAST, the voltage dependence of β-adrenergic modulation of impulse propagation in eight flecainide-superfused canine Purkinje fibers was examined with a dual-microelectrode technique. At physiological membrane potentials (V m ) ([K + ] o =5.4 μmol), 1 μmol flecainide decreased V̇ max from 698±55 to 610±72 V/s ( P =.003) and squared conduction velocity (θ 2 ) from 2.11±1.1 to 1.72±0.9 (m/s) 2 ( P =.001). With K + depolarization to V m =−70 mV, flecainide further reduced V̇ max from 306±101 to 245±65 V/s and θ 2 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 θ 2 . The addition of 1 μmol isoproterenol to flecainide-superfused fibers at physiological V m increased θ 2 by 8% to 1.84±0.6 (m/s) 2 ( P <.01) without altering V̇ max . At −70 mV, the addition of isoproterenol magnified the flecainide-induced reduction of V̇ max an additional 24% to 185±52 V/s ( P <.01) and θ 2 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 V̇ max and θ 2 , respectively. At physiological V m , the action potential duration (APD 95 ) 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 + , APD 95 decreased from 198±23 to 182±17 ms ( P =.005) with flecainide and to 164±10 ms ( P =.004) with isoproterenol. Conclusions At depolarized V m , isoproterenol amplified the flecainide-induced reduction of V̇ max and θ 2 , suggesting a further adrenergic-mediated reduction of Na + current. Consequently, the synergy between catecholamines and flecainide at depolarized V m and the shortened APD 95 could facilitate arrhythmogenesis in the presence of underlying ischemia.