Commentary: A Revised View of Local Anesthetic Action: What Channel State Is Really Stabilized?

A relatively large group of compounds, which includes local anesthetics, antiarrhythmics, and anticonvulsants induce voltage-and/or frequency-dependent block of sodium and other ion channels. Current block increases as the stimulus voltage and frequency of depo-larization is increased. These voltage-and frequency-dependent blocking properties have been recognized for over 40 yr (Weidmann, 1955), and the voltage-and use-dependent properties of a wide range of molecules have been described in detail. A characteristic set of features describes local anesthetic block, but the prevalence (or presence) of any one of these characteristics varies with drug structure and physical properties (Butterworth and Strichartz, 1990; Hille, 1992), which in turn affects the qualitative characteristics of current block. In quiescent cells with a very negative resting potential, even relatively high local anesthetic concentrations have little effect on electrical activity. However, when depolarizing pulses arrive at high frequency, the peak sodium current elicited by each subsequent depolarization becomes smaller until the current reaches a new steady level. The degree of this use dependent or phasic block will increase with increasing depolarization frequency. Local anesthetics also respond to steady depolarizations. When the membrane is depolarized before the test de-polarization that elicits the sodium current, this will increase the fraction of the current that is blocked by a local anesthetic. When this effect of earlier depolariza-tion on local anesthetic block is measured as a function of voltage using a voltage-clamp protocol designed to measure the voltage dependence of channel inactiva-tion or availability, local anesthetics shift the voltage dependence of channel availability to more hyperpo-larized potentials. At any particular potential, a smaller fraction of the channels is available for activation by depolarization. Finally, when local anesthetic block is increased by depolarization, the recovery from block upon repolarization is slow and may not be complete before the next depolarization. Local anesthetics that cause slow recovery from block after depolarization produce use-dependent block. When recovery from block on repolarization occurs rapidly, use dependence is not observed. Whether or not a given local anesthetic produces use-dependent block thus will vary with the binding kinetics of the local anesthetic and the stimulus frequency. Although much of this basic phenomenology was established over time, it was during the 1970's that many of the key features of block by local anesthetics were outlined and their mechanisms of action explored intensively. Studies of tertiary amine and quaternary local anesthetics led Hille (1977) and Hondeghem and Kat-zung (1977) to propose a …