Mexiletine block of wild-type and inactivation-deficient human skeletal muscle hNav1.4 Na+ channels

J Physiol. 2004 Feb 1;554(Pt 3):621-33. doi: 10.1113/jphysiol.2003.054973. Epub 2003 Nov 7.


Mexiletine is a class 1b antiarrhythmic drug used for ventricular arrhythmias but is also found to be effective for paramyotonia congenita, potassium-aggravated myotonia, long QT-3 syndrome, and neuropathic pain. This drug elicits tonic block of Na(+) channels when cells are stimulated infrequently and produces additional use-dependent block during repetitive pulses. We examined the state-dependent block by mexiletine in human skeletal muscle hNav1.4 wild-type and inactivation-deficient mutant Na(+) channels (hNav1.4-L443C/A444W) expressed in HEK293t cells with a beta1 subunit. The 50% inhibitory concentrations (IC(50)) for the inactivated-state block and the resting-state block of wild-type Na(+) channels by mexiletine were measured as 67.8 +/- 7.0 microm and 431.2 +/- 9.4 microm, respectively (n= 5). In contrast, the IC(50) for the block of open inactivation-deficient mutant channels at +30 mV by mexiletine was 3.3 +/- 0.1 microm (n= 5), which was within the therapeutic plasma concentration range (2.8-11 microm). Estimated on- and off-rates for the open-state block by mexiletine at +30 mV were 10.4 microm(-1) s(-1) and 54.4 s(-1), respectively. Use-dependent block by mexiletine was greater in inactivation-deficient mutant channels than in wild-type channels during repetitive pulses. Furthermore, the IC(50) values for the block of persistent late hNav1.4 currents in chloramine-T-pretreated cells by mexiletine was 7.5 +/- 0.8 microm (n= 5) at +30 mV. Our results together support the hypothesis that the in vivo efficacy of mexiletine is primarily due to the open-channel block of persistent late Na(+) currents, which may arise during various pathological conditions.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Anti-Arrhythmia Agents / metabolism
  • Anti-Arrhythmia Agents / pharmacology
  • Binding, Competitive
  • Cell Line
  • Chloramines / pharmacology
  • Electric Conductivity
  • Homeostasis
  • Humans
  • Mexiletine / metabolism
  • Mexiletine / pharmacology*
  • Muscle Proteins / antagonists & inhibitors*
  • Muscle Proteins / genetics
  • Muscle, Skeletal / metabolism*
  • Mutation
  • Myocardium / metabolism
  • NAV1.4 Voltage-Gated Sodium Channel
  • Patch-Clamp Techniques
  • Receptors, Cell Surface / metabolism
  • Sodium Channel Blockers / pharmacology*
  • Sodium Channels / drug effects
  • Sodium Channels / genetics
  • Sodium Channels / physiology
  • Tosyl Compounds / pharmacology


  • Anti-Arrhythmia Agents
  • Chloramines
  • Muscle Proteins
  • NAV1.4 Voltage-Gated Sodium Channel
  • Receptors, Cell Surface
  • SCN4A protein, human
  • Sodium Channel Blockers
  • Sodium Channels
  • Tosyl Compounds
  • chloramine-T
  • Mexiletine