Tonic and phasic block of neuronal sodium currents by 5-hydroxyhexano-2',6'-xylide, a neutral lidocaine homologue.

The effects of a neutral lidocaine homologue, 5-hydroxyhexano-2',6'-xylidide (5-HHX), on the kinetics and amplitude of sodium currents in voltage-clamped amphibian nerve fibers are described. 5-HHX produced two types of sodium current inhibition: (a) tonic block, in resting fibers (IC50 approximately 2 mM), and (b) phasic block, an additional, incremental inhibition, in repetitively depolarized fibers (frequency greater than 1 Hz). The kinetics of phasic block were characterized by a single-receptor, switched-affinity model, in which binding increases during a depolarizing pulse and decreases between pulses. In the presence of 4 mM 5-HHX, binding increased during pulses from -80 to 0 mV, with an apparent rate constant of 6.4 +/- 1.4 s-1. Binding decreased between pulses with an apparent rate constant of 1.1 +/- 0.3 s-1. There was little effect of extracellular pH on the kinetics of phasic block. These findings demonstrate that neither the presence of a terminal amine nor a net charge on a local anesthetic is required for phasic block of sodium channels.