F. Chiodini, E. Charpantier, D. Muller
Apr 1, 2001
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42
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Journal
Anesthesiology
Abstract
BackgroundCuraremimetic nondepolarizing muscle relaxants are widely used in clinical practice to prevent muscle contraction either during surgery or during intensive care. Although primarily acting at the neuromuscular junction, these compounds can cause adverse effects, including modification of cardiac rhythm, arterial blood pressure, and in the worst cases, triggering of seizures. In this study, we assessed the interaction of atracurium and its metabolite, laudanosine, with neuronal nicotinic receptors. MethodsThe human neuronal nicotinic receptors &agr;4&bgr;2, &agr;3&bgr;4, &agr;3&agr;5&bgr;4, and &agr;7 are heterologously expressed in Xenopus laevis oocytes, and the effect of atracurium and its degradation product, laudanosine, were studied on these receptors. ResultsAtracurium and laudanosine inhibited in the micromolar range the major brain &agr;4&bgr;2 receptor and the ganglionic &agr;3&bgr;4 or &agr;3&bgr;4&agr;5 and the homomeric &agr;7 receptors. For all four receptors, inhibition was rapid and readily reversible within less than 1 min. Atracurium blockade was competitive at &agr;4&bgr;2 and &agr;7 receptors but displayed a noncompetitive blockade at the &agr;3&bgr;4 receptors. Inhibition at this receptor subtype was not modified by &agr;5. Laudanosine was found to have a dual mode of action; first, it competes with acetylcholine and, second, it blocks the ionic pore by steric hindrance. At low concentrations, these two drugs are able to activate both the &agr;4&bgr;2 and the &agr;3&bgr;4 receptors. ConclusionAdverse effects observed during atracurium administration may be attributed, at least partly, to an interaction with neuronal nicotinic receptors.