beta-adrenergic augmentation of flecainide-induced conduction slowing in canine Purkinje fibers

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. Methods and 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 (V-m) ([K+](o) = 5.4 mu mol), 1 mu mol flecainide decreased (V) over dot(max) from 698+/-55 to 610+/-72 V/s (P=.003) and squared conduction velocity (theta(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 (V) over dot(max) from 306+/-101 to 245+/-65 V/s and theta(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 theta(2). The addition of 1 mu mol isoproterenol to flecainide-superfused fibers at physiological V-m increased theta(2) by 8% to 1.84+/-0.6 (m/s)(2) (P<.01) without altering (V) over dot(max). At -70 mV, the addition of isoproterenol magnified the flecainide-induced reduction of (V) over dot(max) an additional 24% to 185+/-52 V/s (P<.01) and theta(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 (V) over dot(max) and theta(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 (V) over dot(max) and theta(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.