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 β1 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
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