Blockade and Activation of the Human Neuronal Nicotinic Acetylcholine Receptors by Atracurium and Laudanosine

Chiodini, Florence; Charpantier, Eric; Michelet, Dominique; Tassonyi, E.; Fuchs‐Buder, Thomas; Bertrand, Daniel

doi:10.1097/00000542-200104000-00019

Cited by 50 publications

(22 citation statements)

References 31 publications

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“…This is very informative because it can result only from a presynaptic blocking effect. Interestingly, atracurium has been shown to be able to interact with a number of neuronal nicotinic receptors (Chiodini et al 2001). Thus, the presynaptic effect of atracurium observed in the present work could be due to the blockade of presynaptic neuronal nicotinic receptors which have been proposed to positively modulate the release of acetylcholine during the high frequency stimulation of the motor nerve terminal (Bowman et al 1990; Wessler 1992).…”

Section: Discussionmentioning

confidence: 99%

Cellular Mechanisms of Atracurium‐Induced Tetanic Fade in the Isolated Rat Muscle

Nascimento

Serra

Oliveira

2004

Basic Clin Pharma Tox

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Although atracurium is a widely used neuromuscular blocker, we still lack knowledge regarding some of its cellular mechanisms of action. Thus, similar to other clinically used blockers atracurium induces, both in vivo and in vitro, fade of the tetanic contraction. However, the cellular mechanisms underlying this tetanic fade have never been systematically studied. In the present work these mechanisms were investigated in vitro. A sciatic nerve extensor digitorum longus muscle preparation of the rat was used. A combination of myographical and electrophysiological techniques was employed. Indirect twitches were evoked at 0.1 Hz and tetanic contractions at 50 Hz. Trains of end-plate potentials were evoked at a frequency of 50 Hz. The electrophysiological variables used in the analysis of the trains of end-plate potentials were: peak amplitude of the first end-plate potential in the train, peak amplitude of plateau end-plate potentials in the train, tetanic run-down of the end-plate potentials' train, quantal content of first and plateau end-plate potentials in the train, quantal size. In the myographical study atracurium, at a concentration of 2.4 mM, induced a complete fade of the tetanic contraction while only slightly affected the twitch. In the electrophysiological study atracurium, at the same 2.4 mM concentration, significantly decreased the amplitude of both first end-plate potentials in the train (control: 14.4 mV; atracurium: 3.2 mV) and plateau end-plate potentials (control: 10.8 mV; atracurium: 2.4 mV) and reinforced the tetanic run-down of the train of end-plate potentials, evaluated as the percent loss in amplitude of plateau end-plate potentials compared to first end-plate potentials in the trains (control: 25.2%; atracurium: 33.2%). Atracurium also significantly decreased the quantal content of first end-plate potentials in the train (control: 231; atracurium: 68), the quantal content of plateau end-plate potentials (control: 159; atracurium: 42) and the quantal size (control: 0.119 mV; atracurium: 0.075 mV). In relative terms the decrease in quantal content was about twice as large as the decrease in quantal size. This indicates that the fade of the tetanic contraction induced by atracurium (2.4 mM) is due to both pre-and postsynaptic blocking effects, the presynaptic one being stronger.

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Section: Discussionmentioning

confidence: 99%

Cellular Mechanisms of Atracurium‐Induced Tetanic Fade in the Isolated Rat Muscle

Nascimento

Serra

Oliveira

2004

Basic Clin Pharma Tox

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“…In the neuromuscular junction, the neuronal α3β2 subtype is found at the presynaptic nerve ending [24] and α7 is found postsynaptically at the muscle membrane during development and denervation [25]. Expression of neuronal nAChRs in in vitro systems has confirmed that non‐depolarising NMBs and their metabolites can inhibit these neuronal nAChRs [26, 27]. Interestingly, non‐depolarising NMBs decrease hypoxic ventilatory response in partially paralysed humans [28], and the mechanism behind the depression might be related inhibition of neuronal nAChRs within the carotid body [2].…”

Section: Nicotinic Acetylcholine Receptors (Nachrs)mentioning

confidence: 99%

Basic principles of neuromuscular transmission

Martyn

Fagerlund²,

Eriksson

2009

Anaesthesia

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SummaryNeuromuscular transmission at the skeletal muscle occurs when a quantum of acetylcholine from the nerve ending is released and binds to the nicotinic acetylcholine receptors on the postjunctional muscle membrane. The nicotinic acetylcholine receptors on the endplate respond by opening channels for the influx of sodium ions and subsequent endplate depolarisation leads to muscle contraction. The acetylcholine immediately detaches from the receptor and is hydrolysed by acetylcholinesterase enzyme. Suxamethonium is a cholinergic agonist stimulating the muscle nicotinic acetylcholine receptors prior to causing neuromuscular block. Non-depolarising neuromuscular blocking drugs bind to the nicotinic acetylcholine receptors preventing the binding of acetylcholine. Non-depolarising neuromuscular blocking drugs also inhibit prejunctional a3b2 nicotinic acetylcholine autoreceptors, which can be seen in the clinical setting as train-of-four fade. In some pathological states such as denervation, burns, immobilisation, inflammation and sepsis, there is expression of other subtypes of nicotinic acetylcholine receptors with upregulation of these receptors throughout the muscle membrane. The responses of these receptors to suxamethonium and non-depolarising neuromuscular blocking drugs are different and explain some of the aberrant responses to neuromuscular blocking drugs.

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“…It is of interest to note that at low concentrations, atracurium is an agonist, while at higher concentration, it displays both competitive and non-competitive inhibition with the a7 and a4b2 nAChRs, and only non-competitive inhibition with the a3b4 nAChR. Laudanosine, a metabolite of atracurium, also displays agonist, competitive antagonist, and NCI properties, 49 but most probably binds in the central lumen of the nAChR. 49,50 C. The Quinacrine-Binding Site…”

Section: B the Ethidium-binding Sitementioning

confidence: 99%

“…Laudanosine, a metabolite of atracurium, also displays agonist, competitive antagonist, and NCI properties, 49 but most probably binds in the central lumen of the nAChR. 49,50 C. The Quinacrine-Binding Site…”

Section: B the Ethidium-binding Sitementioning

confidence: 99%

Allosteric modifiers of neuronal nicotinic acetylcholine receptors: New methods, new opportunities

Moaddel

Jóźwiak

Wainer

2007

Medicinal Research Reviews

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Allosteric, non-competitive inhibitors (NCIs) of neuronal nicotinic acetylcholine receptors (nAChRs) have been shown to produce a wide variety of clinically relevant responses. Many of the observed effects are desired as the nAChR is the therapeutic target, while others are undesired consequences due to off-target binding at the nAChR. Thus, the determination of whether or not a lead drug candidate is an NCI should play an important role in drug discovery programs. However, the current experimental techniques used to identify NCIs are challenging, expensive, and time consuming. This review focuses on an alternative approach to the investigation of interactions between test compounds and nAChRs based upon liquid chromatographic stationary phases containing cellular fragments from cell lines expressing nAChRs. The development and validation of these phases as well as their use in drug discovery and pharmacophore modeling are discussed.

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Blockade and Activation of the Human Neuronal Nicotinic Acetylcholine Receptors by Atracurium and Laudanosine

Abstract: Adverse effects observed during atracurium administration may be attributed, at least partly, to an interaction with neuronal nicotinic receptors.

Cited by 50 publications

References 31 publications

Cellular Mechanisms of Atracurium‐Induced Tetanic Fade in the Isolated Rat Muscle

Cellular Mechanisms of Atracurium‐Induced Tetanic Fade in the Isolated Rat Muscle

Basic principles of neuromuscular transmission

Allosteric modifiers of neuronal nicotinic acetylcholine receptors: New methods, new opportunities

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