EFFECTS OF LOCAL-ANESTHETICS ON NA+ CHANNELS CONTAINING THE EQUINE HYPERKALEMIC PERIODIC PARALYSIS MUTATION

We examined the ability of local anesthetics to correct altered inacti vation properties of rat skeletal muscle Na+ channels containing the e quine hyperkalemic periodic paralysis (eqHPP) mutation when expressed in Xenopus oocytes. Increased time constants of current decay in eqHPP channels compared with wild-type channels were restored by 1 mM benzo caine but were not altered by lidocaine or mexiletine. Inactivation cu rves, which were determined by measuring the dependence of the relativ e peak current amplitude after depolarization to -10 mV on conditionin g prepulse voltages, could be shifted in eqHPP channels back toward th at observed for wild-type (WT) channels using selected concentrations of benzocaine, lidocaine, and mexiletine. Recovery from inactivation a t -80 mV (50-ms conditioning pulse) in eqHPP channels followed a monoe xponential time course and was markedly accelerated compared with wild -type channels (tau(WT) = 10.8 +/- 0.9 ms; tau(eqHPP) = 2.9 +/- 0.4 ms ). Benzocaine slowed the time course of recovery (tau(eqHpp,ben) = 9.6 +/- 0.4 ms at 1 mM) in a concentration-dependent manner. In contrast, the recovery from inactivation with lidocaine and mexiletine had a fa st component (tau(fast,lid) = 3.2 +/- 0.2 ms; tau(fast,mex) = 3.1 +/- 0.2 ms), which was identical to the recovery in eqHPP channels without drug, and a slow component (tau(slow,lid) = 1,688 +/- 180 ms; tau(slo w,mex) = 2,323 +/- 328 ms). The time constant of the slow component of the recovery from inactivation was independent of the drug concentrat ion, whereas the fraction of current recovering slowly depended on dru g concentrations and conditioning pulse durations. Our results show th at local anesthetics are generally incapable of fully restoring normal WT behavior in inactivation-deficient eqHPP channels.