Phenol derivatives accelerate inactivation kinetics in one inactivation-deficient mutant human skeletal muscle Na+ channel

Altered inactivation kinetics in skeletal muscle Na+ channels due to mutati ons in the encoding gene are causal for the alterations in muscle excitabil ity in nondystrophic myotonia. Na+ channel blockers like lidocaine and mexi letine, suggested for therapy of myotonia, do not reconstitute inactivation in channels with defective inactivation in vitro. We examined the effects of four methylated and/or halogenated phenol derivatives on one heterologou sly expressed inactivation-deficient Paramyotonia congenita-mutant (R1448H) muscle Na+ channel in vitro. All these compounds accelerated delayed inact ivation of R1448H-whole-cell currents during a depolarization and delayed a ccelerated recovery from inactivation. The potency of these effects paralle led the potency of the drugs to block the peak current amplitude. We conclu de that the investigated phenol derivatives affect inactivation-deficient N a+ channels more specifically than lidocaine and mexiletine. However, for a ll compounds, the effect on inactivation was accompanied by a substantial b lock of the peak current amplitude. (C) 2001 Elsevier Science B.V. All righ ts reserved.