Abstract
Propofol is a widely used general anaesthetic with muscle relaxant properties. Similarly as propofol, the new general anaesthetic AZD3043 targets the GABAA receptor for its anaesthetic effects, but the interaction with nicotinic acetylcholine receptors (nAChRs) has not been investigated. Notably, there is a gap of knowledge about the interaction between propofol and the nAChRs found in the adult neuromuscular junction. The objective was to evaluate whether propofol or AZD3043 interact with the α1β1δε, α3β2, or α7 nAChR subtypes that can be found in the neuromuscular junction and if there are any differences in affinity for those subtypes between propofol and AZD3043. Human nAChR subtypes α1β1δε, α3β2, and α7 were expressed into Xenopus oocytes and studied with an automated voltage-clamp. Propofol and AZD3043 inhibited ACh-induced currents in all of the nAChRs studied with inhibitory concentrations higher than those needed for general anaesthesia. AZD3043 was a more potent inhibitor at the adult muscle nAChR subtype compared to propofol. Propofol and AZD3043 inhibit nAChR subtypes that can be found in the adult NMJ in concentrations higher than needed for general anaesthesia. This finding needs to be evaluated in an in vitro nerve-muscle preparation and suggests one possible explanation for the muscle relaxant effect of propofol seen during higher doses.
Highlights
Propofol (2,6-diisopropylphenol) is a widely used intravenous anesthetic for both general anesthesia and conscious sedation
The aim of this study was, to evaluate whether propofol or AZD3043 interact with the α1β1δε, α3β2, or α7 nicotinic acetylcholine receptors (nAChRs) subtypes that can be found in the adult neuromuscular junction and if there are any differences in affinity for those subtypes between propofol and AZD3043
All oocytes injected with the adult muscle or neuronal nAChR subtypes produced a concentration-dependent inward current in response to acetylcholine when voltage-clamped
Summary
Propofol (2,6-diisopropylphenol) is a widely used intravenous anesthetic for both general anesthesia and conscious sedation. The GABAA receptor belongs to the cys-loop family of the ligand-gated ion-channels composed by five transmembrane protein subunits assembled around a central pore. Most GABAA receptor subtypes are composed of α, β, and γ or δ subunits, with the stoichiometry 2:2:1 (α:β:γ/δ) [2]. Many of the general anesthetics targeting GABAA receptors have affinity to other receptors of the cys-loop family such as the nicotinic acetylcholine receptors (nAChRs), glycine and 5-HT3-receptors [3]. Propofol inhibit fetal muscle (α1β1δγ) and the neuronal α4β2 nAChR subtype in concentrations higher than required for sedation and anesthesia [4,5]. Intact transmission in the neuromuscular junction (NMJ) is dependent on both pre- and postsynaptic nAChRs; the presynaptic receptor being the α3β2 and the postsynaptic receptor present at the muscle membrane in adults is the α1β1δε, that in fetus is the α1β1δγ subtype or during denervation/inflammation the α7 nAChR subtype [7,8]
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