Ketamine and its preservative, benzethonium chloride, both inhibit human recombinant α7 and α4β2 neuronal nicotinic acetylcholine receptors in Xenopus oocytes

被引:97
作者
Coates, KM [1 ]
Flood, P [1 ]
机构
[1] Columbia Univ, Dept Anesthesiol, New York, NY 10032 USA
关键词
neuronal nicotinic acetylcholine receptors; benzethonium chloride; ketamine; anaesthetic mechanism;
D O I
10.1038/sj.bjp.0704315
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
1 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 alpha7 subunit or alpha4 and beta2 subunits expressed in Xenopus laevis oocytes. 2 Ketamine inhibited responses to 1 mm acetylcholine (ACh) in both the human alpha7 and alpha4 beta2 nAChRs, with IC50 values of 20 and 50,um respectively. Inhibition of the alpha7 nAChRs occurred within a clinically relevant concentration range, while inhibition of the alpha4 beta2 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 alpha7 (IC50 value of 122 nM) and alpha4 beta2 (IC50 value of 49 nM) nACh (R) under bars at concentrations present in the clinical formulation of Ketalar. 3 Ketamine is a noncompetitive inhibitor at both the alpha7 and alpha4 beta2 nAChR. In contrast, BCl causes a parallel shift in the ACh dose-response curve at the alpha7 nAChR suggesting competitive inhibition. Ketamine causes both voltage-dependent and use-dependent inhibition, only in the alpha4 beta2 nAChR. 4 Since alpha7 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.
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收藏
页码:871 / 879
页数:9
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