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(Circulation. 1997;96:2701-2708.)
© 1997 American Heart Association, Inc.

Articles

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

Kevin T. Cragun, MD; Susan B. Johnson, BS; ; Douglas L. Packer, MD

From the Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic and Mayo Foundation, Rochester, Minn.

Correspondence to Kevin T. Cragun, MD, Mayo Foundation/St Marys Hospital, 1216 2nd St SW, Room 4-416 Alfred Bldg, Rochester, MN 55902. E-mail packer{at}mayo.edu

Background This study was undertaken to test the hypothesis that ß-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 ß-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 _max from 698±55 to 610±72 V/s (P=.003) and squared conduction velocity (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 _max from 306±101 to 245±65 V/s and 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 ². The addition of 1 µmol isoproterenol to flecainide-superfused fibers at physiological V_m increased ² by 8% to 1.84±0.6 (m/s)² (P<.01) without altering _max. At -70 mV, the addition of isoproterenol magnified the flecainide-induced reduction of _max an additional 24% to 185±52 V/s (P<.01) and 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 _max and ², 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 _max and ², 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.

Key Words: flecainide • isoproterenol • receptors, adrenergic, beta • sodium