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State-dependent block of wild-type and inactivation-deficient Na+ channels by flecainide.

Abstract
The antiarrhythmic agent flecainide appears beneficial for painful congenital myotonia and LQT-3/DeltaKPQ 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 beta1 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 micro M when the cell was not stimulated for 1,000 s. At 100 micro M flecainide, brief monitoring pulses of +30 mV applied at frequencies as low as 1 per 60 s, however, produced an approximately 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 micro M, right within the therapeutic plasma concentration range; on-rate and off-rate constants were 14.9 micro M-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 approximately 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.
AuthorsGing Kuo Wang, Corinna Russell, Sho-Ya Wang
JournalThe Journal of general physiology (J Gen Physiol) Vol. 122 Issue 3 Pg. 365-74 (Sep 2003) ISSN: 0022-1295 [Print] United States
PMID12913091 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Anti-Arrhythmia Agents
  • Muscle Proteins
  • Scn4a protein, rat
  • Sodium Channel Blockers
  • Sodium Channels
  • Flecainide
Topics
  • Anti-Arrhythmia Agents (administration & dosage, pharmacology)
  • Cell Line
  • Dose-Response Relationship, Drug
  • Electric Stimulation
  • Electrophysiology
  • Flecainide (administration & dosage, pharmacology)
  • Humans
  • Ion Channel Gating
  • Muscle Proteins (drug effects, physiology)
  • Mutation
  • Sodium Channel Blockers (administration & dosage, pharmacology)
  • Sodium Channels (drug effects, genetics, metabolism, physiology)

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