LOCAL-ANESTHETICS BLOCK TRANSIENT OUTWARD POTASSIUM CURRENTS IN RAT NEOCORTICAL NEURONS

1. Whole-cell patch clamp techniques were used to record transient out ward potassium currents in embryonic rat neocortical neurons maintaine d in culture. The effect of lidocaine and its quarternary derivative Q X222 on this transient outward current (TOC) was examined. 2. Extracel lular application of lidocaine produced a progressive decrease in peak TOC amplitude with no change in the overall current waveform. Peak am plitude was reduced to 74 +/- 6% (mean +/- SE) of control by 0.5 mM an d to 48 +/- 2% by 2 mM lidocaine. The effect of lidocaine was fully re versible. Intracellular application of QX222 also resulted in a concen tration-dependent reduction of the TOC with 0.5 mM reducing the peak a mplitude to 73 +/- 8% of control and 1 mM reducing it to 41 +/- 4%. 3. Lidocaine reduced TOCs when applied intracellularly but the rate of b lock was considerably slower than with extracellular application. QX22 2 had no effect on the TOC when applied extracellularly. 4. Lidocaine (1 mM) induced a 4-5 mV hyperpolarizing shift in the voltage-dependenc e of activation and steady-state inactivation with no change in the sl ope factor. This small hyperpolarizing shift could not account for the > 30% reduction in peak amplitude produced by 1 mM lidocaine. Hyperpo larizing shifts were not seen with 0.5 mM intracellular QX222. The lac k of effect on the slope of the activation and steady-state inactivati on curves indicates that local anesthetic (LA) actions were not voltag e-dependent. 5. Lidocaine or QX222 did not produce a significant chang e in the TOC decay time-constant. The lack of any significant change i n the voltage-dependence of steady-state inactivation or time course o f recovery from inactivation indicates that LAs were not altering inac tivation mechanisms. 6. Application of lidocaine or QX222 during a 60- s period, when the TOC channels were kept in the resting state, reduce d the peak amplitude of the first evoked TOC. The reduction was not as large as when TOCs were evoked at regular 0.1-Hz intervals during dru g application. This indicates that the amount of tonic block induced b y the LA is dependent on channel activation. Increasing the activation frequency to 1 Hz after a steady-state had been obtained with lidocai ne or QX222 did not result in additional reductions in the TOC. 7. It is proposed that lidocaine and QX222 tonically block TOCs by binding t o a site within the channel protein complex, rendering the channel non -conductive. The apparent activation-dependence of the tonic block cou ld be due to an increase in accessibility of the binding site as a res ult of channel activation. The binding site is accessible to both char ged and uncharged LAs via different pathways.