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Ketamine and its preservative, benzethonium chloride, both inhibit human recombinant α7 and α4β2 neuronal nicotinic acetylcholine receptors in Xenopus oocytes
Author(s) -
Coates Kristen M,
Flood Pamela
Publication year - 2001
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0704315
Subject(s) - ketamine , nicotinic agonist , acetylcholine receptor , pharmacology , chemistry , acetylcholine , xenopus , nmda receptor , nicotinic acetylcholine receptor , inhibitory postsynaptic potential , receptor , biochemistry , endocrinology , anesthesia , biology , medicine , gene
Ketamine is a dissociative anaesthetic that is formulated as Ketalar, which contains the preservative benzethonium chloride (BCl). We have studied the effects of pure racemic ketamine, the preservative BCl and the Ketalar mixture on human neuronal nicotinic acetylcholine receptors (nAChRs) composed of the α7 subunit or α4 and β2 subunits expressed in Xenopus laevis oocytes. Ketamine inhibited responses to 1 m M acetylcholine (ACh) in both the human α7 and α4β2 nAChRs, with IC 50 values of 20 and 50 μ M respectively. Inhibition of the α7 nAChRs occurred within a clinically relevant concentration range, while inhibition of the α4β2 nAChR was observed only at higher concentrations. The Ketalar formulation inhibited nAChR function more effectively than was expected given its ketamine concentration. The surprising increased inhibitory potency of Ketalar compared with pure ketamine appeared to be due to the activity of BCl, which inhibited both α7 (IC 50 value of 122 n M ) and α4β2 (IC 50 value of 49 n M ) nAChRs at concentrations present in the clinical formulation of Ketalar. Ketamine is a noncompetitive inhibitor at both the α7 and α4β2 nAChR. In contrast, BCl causes a parallel shift in the ACh dose‐response curve at the α7 nAChR suggesting competitive inhibition. Ketamine causes both voltage‐dependent and use‐dependent inhibition, only in the α4β2 nAChR. Since α7 nAChRs are likely to be inhibited during clinical use of Ketalar, the actions of ketamine and BCl on this receptor subtype may play a role in the profound analgesia, amnesia, immobility and/or autonomic modulation produced by this anaesthetic.British Journal of Pharmacology (2001) 134 , 871–879; doi: 10.1038/sj.bjp.0704315