Isoform-selective Effects of Isoflurane on Voltage-gated Na+ Channels

Background: Voltage-gated Na+ channels modulate membrane excitability in excitable tissues. Inhibition of Na+ channels has been implicated in the effects of volatile anesthetics on both nervous and peripheral excitable tissues. The authors investigated isoform-selective effects of isoflurane on the major Na+ channel isoforms expressed in excitable tissues.

Methods: Rat Nav1.2, Nav1.4, or Nav1.5 [alpha] subunits heterologously expressed in Chinese hamster ovary cells were analyzed by whole cell voltage clamp recording. The effects of isoflurane on Na+ current activation, inactivation, and recovery from inactivation were analyzed.

Results: The cardiac isoform Nav1.5 activated at more negative potentials (peak INa at -30 mV) than the neuronal Nav1.2 (0 mV) or skeletal muscle Nav1.4 (-10 mV) isoforms. Isoflurane reversibly inhibited all three isoforms in a concentration- and voltage-dependent manner at clinical concentrations (IC50 = 0.70, 0.61, and 0.45 mm, respectively, for Nav1.2, Nav1.4, and Nav1.5 from a physiologic holding potential of -70 mV). Inhibition was greater from a holding potential of -70 mV than from -100 mV, especially for Nav1.4 and Nav1.5. Isoflurane enhanced inactivation of all three isoforms due to a hyperpolarizing shift in the voltage dependence of steady state fast inactivation. Inhibition of Nav1.4 and Nav1.5 by isoflurane was attributed primarily to enhanced inactivation, whereas inhibition of Nav1.2, which had a more positive V1/2 of inactivation, was due primarily to tonic block.