Blockade and activation of the human neuronal nicotinic acetylcholine receptors by atracurium and laudanosine

Abstract

Background: Curaremimetic 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. Methods: The human neuronal nicotinic receptors α4β2, α3β4, α3α5β4, and α7 are heterologously expressed in Xenopus laevis oocytes, and the effect of atracurium and its degradation product, laudanosine, were studied on these receptors. Results: Atracurium and laudanosine inhibited in the micromolar range the major brain α4β2 receptor and the ganglionic α3β4 or α3β4α5 and the homomeric α7 receptors. For all four receptors, inhibition was rapid and readily reversible within less than 1 min. Atracurium blockade was competitive at α4β2 and α7 receptors but displayed a noncompetitive blockade at the α3β4 receptors. Inhibition at this receptor subtype was not modified by α5. 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 α4β2 and the α3β4 receptors. Conclusion: Adverse effects observed during atracurium administration may be attributed, at least partly, to an interaction with neuronal nicotinic receptors.