title: Distinct pharmacologic properties of neuromuscular blocking agents on human neuronal nicotinic acetylcholine receptors: a possible explanation for the train-of-four fade.
abstract: BACKGROUND
  Nondepolarizing neuromuscular blocking agents (NMBAs) are extensively used in the practice of anesthesia and intensive care medicine. Their primary site of action is at the postsynaptic nicotinic acetylcholine receptor (nAChR) in the neuromuscular junction, but their action on neuronal nAChRs have not been fully evaluated. Furthermore, observed adverse effects of nondepolarizing NMBAs might originate from an interaction with neuronal nAChRs. The aim of this study was to examine the effect of clinically used nondepolarizing NMBAs on muscle and neuronal nAChR subtypes.
  
  
  METHODS
  Xenopus laevis oocytes were injected with messenger RNA encoding for the subunits included in the human alpha1beta1epsilondelta, alpha3beta2, alpha3beta4, alpha4beta2, and alpha7 nAChR subtypes. The interactions between each of these nAChR subtypes and atracurium, cisatracurium, d-tubocurarine, mivacurium, pancuronium, rocuronium, and vecuronium were studied using an eight-channel two-electrode voltage clamp setup. Responses were measured as peak current and net charge.
  
  
  RESULTS
  All nondepolarizing NMBAs inhibited both muscle and neuronal nAChRs. The neuronal nAChRs were reversibly and concentration-dependently inhibited in the low micromolar range. The mechanism (i.e., competitive vs. noncompetitive) of the block at the neuronal nAChRs was dependent both on subtype and the NMBA tested. The authors did not observe activation of the nAChR subtypes by any of the NMBAs tested.
  
  
  CONCLUSIONS
  The authors conclude that nondepolarizing NMBAs concentration-dependently inhibit human neuronal nAChRs. The inhibition of the presynaptic alpha3beta2 nAChR subtype expressed at the motor nerve ending provides a possible molecular explanation for the tetanic and train-of-four fade seen during a nondepolarizing neuromuscular block.
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Karolinska University Hospital and Karolinska Institutet, Sweden. malin.jonsson@karolinska.se
authors.forename: Malin
authors.initials: M
authors.lastname: Jonsson
authors.forename: David
authors.initials: D
authors.lastname: Gurley
authors.forename: Michael
authors.initials: M
authors.lastname: Dabrowski
authors.forename: Olof
authors.initials: O
authors.lastname: Larsson
authors.forename: Edwin C
authors.initials: EC
authors.lastname: Johnson
authors.forename: Lars I
authors.initials: LI
authors.lastname: Eriksson
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D006801:Humans; D003473:Neuromuscular Nondepolarizing Agents / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects*; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000145:classification / Q000187:drug effects*; D014982:Xenopus laevis
chemical_list: D003473:Neuromuscular Nondepolarizing Agents; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D000109:Acetylcholine