title: Clinical concentrations of chemically diverse general anesthetics minimally affect lipid bilayer properties.
abstract: General anesthetics have revolutionized medicine by facilitating invasive procedures, and have thus become essential drugs. However, detailed understanding of their molecular mechanisms remains elusive. A mechanism proposed over a century ago involving unspecified interactions with the lipid bilayer known as the unitary lipid-based hypothesis of anesthetic action, has been challenged by evidence for direct anesthetic interactions with a range of proteins, including transmembrane ion channels. Anesthetic concentrations in the membrane are high (10-100 mM), however, and there is no experimental evidence ruling out a role for the lipid bilayer in their ion channel effects. A recent hypothesis proposes that anesthetic-induced changes in ion channel function result from changes in bilayer lateral pressure that arise from partitioning of anesthetics into the bilayer. We examined the effects of a broad range of chemically diverse general anesthetics and related nonanesthetics on lipid bilayer properties using an established fluorescence assay that senses drug-induced changes in lipid bilayer properties. None of the compounds tested altered bilayer properties sufficiently to produce meaningful changes in ion channel function at clinically relevant concentrations. Even supra-anesthetic concentrations caused minimal bilayer effects, although much higher (toxic) concentrations of certain anesthetic agents did alter lipid bilayer properties. We conclude that general anesthetics have minimal effects on bilayer properties at clinically relevant concentrations, indicating that anesthetic effects on ion channel function are not bilayer-mediated but rather involve direct protein interactions.
authors.affiliation: Department of Anesthesiology, Weill Cornell Medicine, New York, NY 10065.
authors.forename: Karl F
authors.initials: KF
authors.lastname: Herold
authors.affiliation: Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY 10065.
authors.forename: R Lea
authors.initials: RL
authors.lastname: Sanford
authors.affiliation: Department of Anesthesiology, Weill Cornell Medicine, New York, NY 10065.
authors.forename: William
authors.initials: W
authors.lastname: Lee
authors.affiliation: Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY 10065; hchemmi@med.cornell.edu sparre@med.cornell.edu.
authors.forename: Olaf S
authors.initials: OS
authors.lastname: Andersen
authors.affiliation: Department of Anesthesiology, Weill Cornell Medicine, New York, NY 10065; hchemmi@med.cornell.edu sparre@med.cornell.edu.|Department of Pharmacology, Weill Cornell Medicine, New York, NY 10065.
authors.forename: Hugh C
authors.initials: HC
authors.lastname: Hemmings
mesh_terms: D018681:Anesthetics, General / Q000737:chemistry* / Q000494:pharmacology*; D006096:Gramicidin / Q000737:chemistry; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D015640:Ion Channel Gating / Q000187:drug effects; D007473:Ion Channels / Q000378:metabolism; D008051:Lipid Bilayers / Q000737:chemistry*; D008564:Membrane Potentials / Q000187:drug effects; D015394:Molecular Structure
chemical_list: D018681:Anesthetics, General; D007473:Ion Channels; D008051:Lipid Bilayers; D006096:Gramicidin
keywords: amphiphiles; anesthetic mechanisms; bilayer modification; gramicidin channel; isoflurane