Comparative effects of halogenated inhaled anesthetics on voltage-gated Na+ channel function

Abstract

BACKGROUND: Inhibition of voltage-gated Na channels (Nav) is implicated in the synaptic actions of volatile anesthetics. We studied the effects of the major halogenated inhaled anesthetics (halothane, isoflurane, sevoflurane, enflurane, and desflurane) on Nav1.4, a well-characterized pharmacological model for Nav effects. METHODS: Na currents (INa) from rat Nav1.4 α-subunits heterologously expressed in Chinese hamster ovary cells were analyzed by whole cell voltage-clamp electrophysiological recording. RESULTS: Halogenated inhaled anesthetics reversibly inhibited Nav1.4 in a concentration-and voltage-dependent manner at clinical concentrations. At equianesthetic concentrations, peak INa was inhibited with a rank order of desflurane > halothane enflurane > isoflurane sevoflurane from a physiologic holding potential (-80 mV). This suggests that the contribution of Na channel block to anesthesia might vary in an agent-specific manner. From a hyperpolarized holding potential that minimizes inactivation (-120 mV), peak INa was inhibited with a rank order of potency for tonic inhibition of peak INa of halothane > isoflurane sevoflurane > enflurane > desflurane. Desflurane produced the largest negative shift in voltage-dependence of fast inactivation consistent with its more prominent voltage-dependent effects. A comparison between isoflurane and halothane showed that halothane produced greater facilitation of current decay, slowing of recovery from fast inactivation, and use-dependent block than isoflurane. CONCLUSIONS: Five halogenated inhaled anesthetics all inhibit a voltage-gated Na channel by voltage-and use-dependent mechanisms. Agent-specific differences in efficacy for Na channel inhibition due to differential state-dependent mechanisms creates pharmacologic diversity that could underlie subtle differences in anesthetic and nonanesthetic actions.