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 (V(m)) (K⁺](o)=5.4 μmol), 1 μmol flecainide decreased V(max) 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 V(m)=-70 mV, flecainide further reduced V(max) 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 V(m) increased Θ² by 8% to 1.84±0.6 (m/s)² (P<.01) without altering V(max). At -70 mV, the addition of isoproterenol magnified the flecainide-induced reduction of V(max) an additional 24% to 185 ±52 V/s (P<.01) and Θ² 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(max) and Θ², respectively. At physiological V(m), 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 V(m), isoproterenol amplified the flecainide-induced reduction of V(max) and Θ², suggesting a further adrenergic-mediated reduction of Na⁺ current. Consequently, the synergy between catecholamines and flecainide at depolarized V(m) and the shortened APD₉₅ could facilitate arrhythmogenesis in the presence of underlying ischemia.