Increased hindrance on the chiral carbon atom of mexiletine enhances the block of rat skeletal muscle Na+ channels in a model of myotonia induced by ATX

The antiarrhythmic drug mexiletine (Mex) is also used against myotonia. Searching for a more efficient drug, a new compound (Me5) was synthesized substituting the methyl group on the chiral carbon atom of Mex by an isopropyl group. Effects of Me5 on Na+ channels were compared to those of Mex in rat skeletal muscle fibres using the cell-attached patch clamp method. Me5 (10 mu M) reduced the maximal sodium current (I-Na) by 29.7+/-4.4 % (n = 6) at a frequency of stimulation of 0.3 Hz and 65.7+/-4.4 % (n=6) at 1 Hz. At same concentration (10 mu M), Mex was incapable of producing any effect (n=3). Me5 also shifted the steady-state inactivation curves by -7.9+/-0.9 mV (n = 6) at 0.3 Hz and -12.2+/-1.0 mV (n = 6) at 1 Hz. In the presence of sea anemone toxin II (ATX; 5 mu M), I-Na decayed more slowly and no longer to zero, providing a model of sodium channel myotonia. The effects of Me5 on peak I-Na were similar whatever ATX was present or not. Interestingly, Me5 did not modify the I-Na decay time constant nor the steady-state I-Na to peak I-Na ratio. Analysis of ATX-induced late Na+ channel activity shows that Me5 did not affect mean open times and single-channel conductance, thus excluding open channel block property. These results indicate that increasing hindrance on the chiral atom of Mex increases drug potency on wild-type and ATX-induced noninactivating I-Na and that Me5 might improve the prophylaxis of myotonia.