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

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 (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 μ m and 431.2 ± 9.4 μ m , 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 μ m ( n = 5), which was within the therapeutic plasma concentration range (2.8–11 μ m ). Estimated on‐ and off‐rates for the open‐state block by mexiletine at +30 mV were 10.4 μ m −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 μ m ( 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.