| Abstract: | We examined theability of local anesthetics to correct altered inactivation propertiesof rat skeletal muscle Na+channels containing the equine hyperkalemic periodic paralysis (eqHPP)mutation when expressed in Xenopusoocytes. Increased time constants of current decay in eqHPP channelscompared with wild-type channels were restored by 1 mM benzocaine butwere not altered by lidocaine or mexiletine. Inactivation curves, which were determined by measuring the dependence of the relative peak current amplitude after depolarization to  10 mV on conditioning prepulse voltages, could be shifted in eqHPP channels back toward thatobserved for wild-type (WT) channels using selected concentrations ofbenzocaine, lidocaine, and mexiletine. Recovery from inactivation at80 mV (50-ms conditioning pulse) in eqHPP channels followed amonoexponential time course and was markedly accelerated compared withwild-type channels ( WT = 10.8 ± 0.9 ms; eqHPP = 2.9 ± 0.4 ms). Benzocaine slowed the time course of recovery(eqHPP,ben = 9.6 ± 0.4 msat 1 mM) in a concentration-dependent manner. In contrast, the recoveryfrom inactivation with lidocaine and mexiletine had a fast component(fast,lid = 3.2 ± 0.2 ms;fast,mex = 3.1 ± 0.2 ms),which was identical to the recovery in eqHPP channels without drug, anda slow component (slow,lid = 1,688 ± 180 ms; slow,mex = 2,323 ± 328 ms). The time constant of the slow component of therecovery from inactivation was independent of the drug concentration,whereas the fraction of current recovering slowly depended on drugconcentrations and conditioning pulse durations. Our results show thatlocal anesthetics are generally incapable of fully restoring normal WTbehavior in inactivation-deficient eqHPP channels. |
