MECHANISM OF FREQUENCY-DEPENDENT INHIBITION OF SODIUM CURRENTS IN FROG MYELINATED NERVE BY LIDOCAINE DERIVATIVE GEA 968

Abstract

A new lidocaine derivative, GEA 968, depresses excitability of myelinated frog (Rana pipiens) nerve in a manner which depends upon the rate of use of the nerve. This phenomenon was shown, under voltage clamp conditions to involve frequency or use-dependent inhibition of the transient inward Na currents at the node of Ranvier. With 0.6 mM GEA 968 in the solution bathing the node, the inward Na currents produced by 5-ms depolarizing pulses to -20mV 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 Na channels by depolarizing pulses enhances this inhibition, e.g., currents are eventually reduced to 10 to 20% of control with repetitive depolarization at 2 s-1. If the preparation is then allowed to rest, this use-dependent increment in inhibition gradually declines with a time constant of about 10 s. Repetitive opening of the Na channels by depolarizing pulses preceded by large hyperpolarizing prepulses reverses the inhibition caused by application of depolarizing pulses alone. The GEA 968 molecule probably binds to open Na channels and simultaneously blocks the channel and shifts the curve relating Na inactivation to membrane potential by 20-40 mV in the hyperpolarizing direction. Several kinds of evidence supporting this molecular hypothesis are presented. Lidocaine, procaine, procaine amide and a quaternary lidocaine derivative, N-(2,6-dimethylphenyl) carbamoylmethyltriethylammonium bromide (QX-314), also cause use-dependent depression of Na currents in this preparation. This common mode of action of tertiary and quaternary anesthetics implies that the cationic form of tertiary anesthetics is active.