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• W2017183797 abstract "Abstract 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 α 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. Conclusions: Two principal mechanisms contribute to Na+ channel inhibition by isoflurane: enhanced inactivation due to a hyperpolarizing shift in the voltage dependence of steady state fast inactivation (Nav1.5 ≈ Nav1.4 &gt; Nav1.2) and tonic block (Nav1.2 &gt; Nav1.4 ≈ Nav1.5). These novel mechanistic differences observed between isoforms suggest a potential pharmacologic basis for discrimination between Na+ channel isoforms to enhance anesthetic specificity." @default.
• W2017183797 created "2016-06-24" @default.
• W2017183797 creator A5009933627 @default.
• W2017183797 creator A5056426328 @default.
• W2017183797 date "2007-07-01" @default.
• W2017183797 modified "2023-09-23" @default.
• W2017183797 title "Isoform-selective Effects of Isoflurane on Voltage-gated Na+ Channels" @default.
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• W2017183797 doi "https://doi.org/10.1097/01.anes.0000268390.28362.4a" @default.
• W2017183797 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/17585220" @default.
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