title: Rapacuronium augments acetylcholine-induced bronchoconstriction via positive allosteric interactions at the M3 muscarinic receptor.
abstract: BACKGROUND
  Neuromuscular blocking agents' detrimental airway effects may occur as a result of interactions with muscarinic receptors, allergic reactions, or histamine release. Rapacuronium, a nondepolarizing muscle relaxant, was withdrawn from clinical use because of its association with fatal bronchospasm. Despite its withdrawal from clinical use, it is imperative that the mechanism by which bronchospasm occurred is understood so that new muscle relaxants introduced to clinical practice do not share these same detrimental airway effects.
  
  
  METHODS
  Airway smooth muscle force was measured in guinea pig tracheal rings in organ baths exposed to muscle relaxants with or without subthreshold concentrations of acetylcholine. Antagonism of muscarinic, histamine, neurokinin, leukotriene receptors, or blockade of L-type calcium channels or depletion of nonadrenergic, noncholinergic neurotransmitters was performed. Muscle relaxants' potentiation of acetylcholine-stimulated inositol phosphate synthesis and allosteric interactions on the kinetics of atropine-induced [3H]N-methylscopolamine dissociation were measured in cells expressing recombinant human M3 muscarinic receptors.
  
  
  RESULTS
  Rapacuronium, within clinically achieved concentrations, contracted tracheal rings in the presence but not in the absence of subthreshold concentrations of acetylcholine. This effect was prevented or reversed only by atropine. The allosteric action of rapacuronium was demonstrated by the slowing of atropine-induced dissociation of [3H]N-methylscopolamine, and positive cooperativity was demonstrated by potentiation of acetylcholine-induced inositol phosphate synthesis.
  
  
  CONCLUSIONS
  Many muscle relaxants have allosteric properties at muscarinic receptors; however, positive cooperativity at the M3 muscarinic receptor within clinically relevant concentrations is unique to rapacuronium. These findings establish novel parameters that should be considered in the evaluation of airway safety of any newly synthesized neuromuscular blocking agents considered for clinical practice.
authors.affiliation: Department of Anesthesiology, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, NY 10032, USA.
authors.forename: Edmund H
authors.initials: EH
authors.lastname: Jooste
authors.forename: Amit
authors.initials: A
authors.lastname: Sharma
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Charles W
authors.initials: CW
authors.lastname: Emala
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology*; D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects*; D004357:Drug Synergism; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000378:metabolism; D007700:Kinetics; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D019832:N-Methylscopolamine / Q000494:pharmacology; D003473:Neuromuscular Nondepolarizing Agents / Q000494:pharmacology*; D010276:Parasympatholytics / Q000494:pharmacology; D011869:Radioligand Assay; D043587:Receptor, Muscarinic M3 / Q000187:drug effects*; D013237:Stereoisomerism; D014132:Trachea / Q000187:drug effects; D014673:Vecuronium Bromide / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D007295:Inositol Phosphates; D003473:Neuromuscular Nondepolarizing Agents; D010276:Parasympatholytics; D043587:Receptor, Muscarinic M3; D014673:Vecuronium Bromide; C082938:rapacuronium; D000109:Acetylcholine; D019832:N-Methylscopolamine