The sea anemone toxin ATX II impairs skeletal muscle sodium channel inactivation, mimicking the persistent inward current observed in patients suffering from sodium channel myotonia. Mexiletine has beneficial effects on myotonia. To verify the efficiency of the drug on persistent inward current, we investigated the effect of 50 microM R(-)-mexiletine on sodium channels in cell-attached patches of rat skeletal muscle fibres, in the absence or presence of 2 microM ATX II. With the toxin, a proportion of channels displayed remarkable abnormal activity lasting the entire depolarisation, which resulted in a persistent inward current that represented up to 2.0% of the peak current. Mexiletine reduced by 75% the peak current elicited by depolarisation from -100 to -20 mV. This was due to the reduction by 60% of the maximal available peak current Imax and to the negative shift by -7 mV of steady-state inactivation. Mexiletine also greatly decreased the late current, but the effect was limited to 60% of reduction, comparable to that on Imax. Therefore mexiletine was able to block the ATX II-modified sodium channels, inhibiting the myotonia-producing persistent inward current.