Different effects of mexiletine on two mutant sodium channels causing paramyotonia congenita and hyperkalemic periodic paralysis

Effects of the antiarrhythmic and antimyotonic drug mexiletine were studied on two sodium channel mutants causing paramyotonia congenita (R1448H) and an overlap paramyotonic and hyperkalemic paralytic syndrome (M1360V). Chann els were expressed in human embryonic kidney cells and studied electrophysi ologically, using the whole-cell patch-clamp technique. Compared to the wil d-type, channel, both mutants showed alterations of inactivation, i.e. slow er inactivation, left shift of steady-state inactivation and faster recover y from inactivation. Mexiletine caused a significantly larger use-dependent block of the R1448H mutant when compared to M1360V and wild-type channels. This can be explained by a prolonged recovery from mexiletine block as obs erved for R1448H channels, since the affinity of mexiletine for the inactiv ated state was similar for all three clones. The use-dependent block of sod ium channels by mexiletine reduces repetitive series of action potentials a nd therefore improves muscle stiffness in myotonic patients. The enhanced u se-dependent block as seen with R1448H may explain the extraordinary therap eutic efficacy of mexiletine in most patients with paramyotonia congenita. (C) 2000 Elsevier Science B.V. All rights reserved.