title: The in vitro and in vivo enantioselectivity of etomidate implicates the GABAA receptor in general anaesthesia.
abstract: General anaesthetics exhibiting enantioselectivity afford valuable tools to assess the fundamental mechanisms underlying anaesthesia. Here, we characterised the actions of the R-(+)- and S-(-)-enantiomers of etomidate. In mice and tadpoles, R-(+)-etomidate was more potent (approximately 10-fold) than S-(-)-etomidate in producing loss of the righting reflex. In electrophysiological and radioligand binding assays, the enantiomers of etomidate positively regulated GABAA receptor function at anaesthetic concentrations and with an enantioselectivity paralleling their in vivo activity. GABA-evoked currents mediated by human recombinant GABAA receptors were potentiated by either R-(+)- or S-(-)-etomidate in a manner dependent upon receptor subunit composition. A direct, GABA-mimetic, effect was similarly subunit dependent. Modulation of GABA receptor activity was selective; R-(+)-etomidate inhibited nicotinic acetylcholine, or 5-hydroxytryptamine3 receptor subtypes only at supra-clinical concentrations and ionotropic glutamate receptor isoforms were essentially unaffected. Acting upon reticulothalamic neurones in rat brain slices, R-(+)-etomidate prolonged the duration of miniature IPSCs and modestly enhanced their peak amplitude. S-(-)-etomidate exerted qualitatively similar, but weaker, actions. In a model of locomotor activity, fictive swimming in Xenopus laevis tadpoles, R-(+)- but not S-(-)-etomidate exerted a depressant influence via enhancement of GABAergic neurotransmission. Collectively, these observations strongly implicate the GABAA receptor as a molecular target relevant to the anaesthetic action of etomidate.
authors.affiliation: Department of Pharmacology and Neuroscience, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, Scotland, UK.
authors.forename: Delia
authors.initials: D
authors.lastname: Belelli
authors.forename: Anna-Lisa
authors.initials: AL
authors.lastname: Muntoni
authors.forename: Simon D
authors.initials: SD
authors.lastname: Merrywest
authors.forename: Luc J
authors.initials: LJ
authors.lastname: Gentet
authors.forename: Anna
authors.initials: A
authors.lastname: Casula
authors.forename: Helen
authors.initials: H
authors.lastname: Callachan
authors.forename: Paola
authors.initials: P
authors.lastname: Madau
authors.forename: David K
authors.initials: DK
authors.lastname: Gemmell
authors.forename: Niall M
authors.initials: NM
authors.lastname: Hamilton
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Lambert
authors.forename: Keith T
authors.initials: KT
authors.lastname: Sillar
authors.forename: John A
authors.initials: JA
authors.lastname: Peters
mesh_terms: D018686:Anesthetics, Intravenous / Q000494:pharmacology*; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002460:Cell Line; D005045:Etomidate / Q000494:pharmacology*; D005071:Evoked Potentials / Q000187:drug effects; D005260:Female; D006801:Humans; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D066298:In Vitro Techniques; D007814:Larva; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects / Q000502:physiology; D012018:Reflex / Q000187:drug effects*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D009435:Synaptic Transmission / Q000187:drug effects; D013788:Thalamus / Q000166:cytology / Q000502:physiology; D014982:Xenopus laevis
chemical_list: D018686:Anesthetics, Intravenous; D019086:Bridged Bicyclo Compounds, Heterocyclic; D006993:Hypnotics and Sedatives; D011963:Receptors, GABA-A; C037476:tert-butylbicyclophosphorothionate; D005045:Etomidate