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¹ Department of Anaesthesia, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA² Department of Biology, State University of New York at Albany, Albany, NY, USA

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 ß1 subunit. The 50% inhibitory concentrations (IC₅₀) for the inactivated-state block and the resting-state block of wild-type Na⁺ channels by mexiletine were measured as 67.8 ± 7.0 µM and 431.2 ± 9.4 µM, respectively (n= 5). In contrast, the IC₅₀ for the block of open inactivation-deficient mutant channels at +30 mV by mexiletine was 3.3 ± 0.1 µM (n= 5), which was within the therapeutic plasma concentration range (2.8–11 µM). Estimated on- and off-rates for the open-state block by mexiletine at +30 mV were 10.4 µM^-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 IC₅₀ values for the block of persistent late hNav1.4 currents in chloramine-T-pretreated cells by mexiletine was 7.5 ± 0.8 µM (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.

(Received 15 September 2003; accepted after revision 7 November 2003; first published online 7 November 2003)
Corresponding author G. K. Wang: Department of Anaesthesia, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA. Email: wang{at}zeus.bwh.harvard.edu

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