β-adrenergic augmentation of flecainide-induced conduction slowing in canine purkinje fibers

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 (Vm) ([K+]o=5.4 μmol), 1 μmol flecainide decreased Vmax from 698±55 to 610±72 V/s (P=.003) and squared conduction velocity (θ2) 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 θ2 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 θ2. The addition of 1 μmol isoproterenol to flecainide-superfused fibers at physiological Vm increased...