Mechanism of frequency-dependent inhibition of sodium currents in frog myelinated nerve by the lidocaine derivative GEA.

A new lidocaine derivative (Astra, GEA 968) depresses excitability of myelinated frog nerve in a manner which depends upon the rate of use of the nerve. This phenomenon has been shown, under voltage clamp conditions, to involve "frequency-" or "use-dependent" inhibition of the transient inward sodium currents at the node of Ranvier. With 0.6 mM GEA 968 in the solution bathing the node, the inward sodium currents produced by 5-msec depolarizing pulses to -20 mV are reduced to 40% of control values if the node is rested for a few hundred seconds prior to the test pulse. Repetitive opening of the sodium channels by depolarizing pulses enhances this inhibition, for example, currents are eventually reduced to 10 to 20% of control with repetitive depolarization at 2 sec-1. If the preparation is then allowed to rest, this use-dependent increment in inhibition gradually declines with a time constant of about 10 seconds. Repetitive opening of the sodium channels by depolarizing pulses preceded by large hyperpolarizing prepulses reverses the inhibition caused by application of depolarizing pulses alone. It is hypothesized that the GEA 968 molecule binds to open sodium channels and, in doing so, simultaneously blocks the channel and shifts the curve relating sodium inactivation to membrane potential by 20 to 40 mV in the hyperpolarizing direction. Several kinds of evidence supporting this molecular hypothesis are presented. Lidocaine, procaine, procaine amide and a quaternary lidocaine derivative QX-314 also cause use-dependent depression of sodium currents in this preparation. This common mode of action of tertiary and quaternary anesthetics implies that the cationic form of tertiary anesthetics is active.