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¹ Department of Anesthesia, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115
² Department of Biology, State University of New York at Albany, Albany, NY 12222

Address correspondence to Dr. Ging Kuo Wang, Department of Anesthesia, Brigham and Women's Hospital, 75 Francis St., Boston, MA 02115. Fax: (617) 730-2801; email: wang{at}zeus.bwh.harvard.edu

The antiarrhythmic agent flecainide appears beneficial for painful congenital myotonia and LQT-3/KPQ syndrome. Both diseases manifest small but persistent late Na⁺ currents in skeletal or cardiac myocytes. Flecainide may therefore block late Na⁺ currents for its efficacy. To investigate this possibility, we characterized state-dependent block of flecainide in wild-type and inactivation-deficient rNav1.4 muscle Na⁺ channels (L435W/L437C/A438W) expressed with ß1 subunits in Hek293t cells. The flecainide-resting block at -140 mV was weak for wild-type Na⁺ channels, with an estimated 50% inhibitory concentration (IC₅₀) of 365 µM when the cell was not stimulated for 1,000 s. At 100 µM flecainide, brief monitoring pulses of +30 mV applied at frequencies as low as 1 per 60 s, however, produced an 70% use-dependent block of peak Na⁺ currents. Recovery from this use-dependent block followed an exponential function, with a time constant over 225 s at -140 mV. Inactivated wild-type Na⁺ channels interacted with flecainide also slowly at -50 mV, with a time constant of 7.9 s. In contrast, flecainide blocked the open state of inactivation-deficient Na⁺ channels potently as revealed by its rapid time-dependent block of late Na⁺ currents. The IC₅₀ for flecainide open-channel block at +30 mV was 0.61 µM, right within the therapeutic plasma concentration range; on-rate and off-rate constants were 14.9 µM^-1s^-1 and 12.2 s^-1, respectively. Upon repolarization to -140 mV, flecainide block of inactivation-deficient Na⁺ channels recovered, with a time constant of 11.2 s, which was 20-fold faster than that of wild-type counterparts. We conclude that flecainide directly blocks persistent late Na⁺ currents with a high affinity. The fast-inactivation gate, probably via its S6 docking site, may further stabilize the flecainide-receptor complex in wild-type Na⁺ channels.

Key Words: sodium channel • flecainide • persistent sodium currents • state-dependent block • fast inactivation gate

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