Propofol and AZD3043 Inhibit Adult Muscle and Neuronal Nicotinic Acetylcholine Receptors Expressed in Xenopus Oocytes

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.

Influence of propofol on isolated neonatal rat carotid body glomus cell response to hypoxia and hypercapnia

“…This was fully inhibited by propofol (Fig. 5) adding further support to the hypothesis that propofol is able to inhibit some nicotinic receptors, as is already well established (Jonsson Fagerlund et al, 2016. Notably however, the cholinergic antagonists vecuronium and MLA inhibited only the nicotine-induced, but not the hypoxia-induced rise in [Ca 2+ ] i (Fig.…”

Effect of Compound Muscle Action Potential After Peripheral Nerve Stimulation Normalization on Anesthetic Fade of Intraoperative Transcranial Motor-Evoked Potential

“…The accumulation of propofol has been reported to suppress the excitability of a-motor neurons, 17 to exert presynaptic inhibition before spinal anterior horn cells, [18][19][20] and to inhibit synaptic transmission at the neuromuscular junction. 21,22 Although propofol is not considered to have a muscle relaxant effect, the accumulation of propofol may suppress synaptic transmission at the neuromuscular junction. 21,22 However, normalization by CMAP after peripheral nerve stimulation compensated for a decrease in the excitation of a-motor neurons and synaptic transmission at the neuromuscular junction.…”

“…21,22 Although propofol is not considered to have a muscle relaxant effect, the accumulation of propofol may suppress synaptic transmission at the neuromuscular junction. 21,22 However, normalization by CMAP after peripheral nerve stimulation compensated for a decrease in the excitation of a-motor neurons and synaptic transmission at the neuromuscular junction. Because anesthetic fade was normalized by CMAP after peripheral nerve stimulation, anesthetic fade is caused by a decrease in the excitability of a-motor neurons and a suppression of synaptic transmission at the neuromuscular junction.…”

Cholinergic Chemotransmission and Anesthetic Drug Effects at the Carotid Bodies

“…Similar to what was found for muscle relaxants, in vitro experiments demonstrate that propofol is able to block various muscle and neuronal subtype nAChr. This effect was noted in concentrations below that needed for general anesthesia [ 34 ]. Evidence that cholinergic inhibition by propofol underlies its chemodepressant effects comes from various animal and human observations.…”