title: Mexiletine block of wild-type and inactivation-deficient human skeletal muscle hNav1.4 Na+ channels.
abstract: 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.
authors: Department of Anaesthesia, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA. wang@zeus.bwh.harvard.edu
authors: Ging Kuo
authors: GK
authors: Wang
authors: Corinna
authors: C
authors: Russell
authors: Sho-Ya
authors: SY
authors: Wang
mesh_terms: D000889:Anti-Arrhythmia Agents / Q000378:metabolism / Q000494:pharmacology; D001667:Binding, Competitive; D002460:Cell Line; D002700:Chloramines / Q000494:pharmacology; D004553:Electric Conductivity; D006706:Homeostasis; D006801:Humans; D008801:Mexiletine / Q000378:metabolism / Q000494:pharmacology*; D009124:Muscle Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D018482:Muscle, Skeletal / Q000378:metabolism*; D009154:Mutation; D009206:Myocardium / Q000378:metabolism; D062553:NAV1.4 Voltage-Gated Sodium Channel; D018408:Patch-Clamp Techniques; D011956:Receptors, Cell Surface / Q000378:metabolism; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D015222:Sodium Channels / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D014105:Tosyl Compounds / Q000494:pharmacology
chemical_list: D000889:Anti-Arrhythmia Agents; D002700:Chloramines; D009124:Muscle Proteins; D062553:NAV1.4 Voltage-Gated Sodium Channel; D011956:Receptors, Cell Surface; C106251:SCN4A protein, human; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D014105:Tosyl Compounds; C016300:chloramine-T; D008801:Mexiletine