Isoflurane inhibits the tetrodotoxin-resistant voltage-gated sodium channel Nav1.8

Karl F. Herold, Carla Nau, Wei Ouyang, Hugh C. Hemmings

38 Citations (Scopus)


Background: Voltage-gated sodium channels (Nav) mediate neuronal action potentials. Tetrodotoxin inhibits all Nav isoforms, but Nav1.8 and Nav1.9 are relatively tetrodotoxin-resistant (TTX-r) compared to other isoforms. Nav1.8 is highly expressed in dorsal root ganglion neurons and is functionally linked to nociception, but the sensitivity of TTX-r isoforms to inhaled anesthetics is unclear. Methods: The sensitivities of heterologously expressed rat TTX-r Nav1.8 and endogenous tetrodotoxin-sensitive (TTX-s) Nav to the prototypic inhaled anesthetic isoflurane were tested in mammalian ND7/23 cells using patch-clamp electrophysiology. Results: From a holding potential of -70 mV, isoflurane (0.53 ± 0.06 mm, 1.8 minimum alveolar concentration at 24°C) reduced normalized peak Na+ current (INa) of Nav1.8 to 0.55 ± 0.03 and of endogenous TTX-s Nav to 0.56 ± 0.06. Isoflurane minimally inhibited INa from a holding potential of -140 mV. Isoflurane did not affect voltage-dependence of activation, but it significantly shifted voltage-dependence of steady-state inactivation by -6 mV for Nav1.8 and by -7 mV for TTX-s Na v IC50 values for inhibition of peak INa were 0.67 ± 0.06 mm for Nav1.8 and 0.66 ± 0.09 mm for TTX-s Nav; significant inhibition occurred at clinically relevant concentrations as low as 0.58 minimum alveolar concentration. Isoflurane produced use-dependent block of Nav1.8; at a stimulation frequency of 10 Hz, 0.56 ± 0.08 mm isoflurane reduced INa to 0.64 ± 0.01 versus 0.78 ± 0.01 for control. Conclusion Isoflurane inhibited the tetrodotoxin-resistant isoform Nav1.8 with potency comparable to that for endogenous tetrodotoxin-sensitive Nav isoforms, indicating that sensitivity to inhaled anesthetics is conserved across diverse Na v family members. Block of Nav1.8 in dorsal root ganglion neurons could contribute to the effects of inhaled anesthetics on peripheral nociceptive mechanisms.

Original languageEnglish
Issue number3
Pages (from-to)591-599
Number of pages9
Publication statusPublished - 09.2009


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