title: Nitric oxide is not a mediator of inflammation-induced resistance to atracurium.
abstract: Resistance to atracurium as a result of increased drug binding to alpha1-acid glycoprotein is associated with increased inducible nitric oxide synthase activity and increased nitric oxide levels in plasma. We investigated if the inhibition of inducible nitric oxide synthase and suppression of nitric oxide can reverse the resistance to atracurium. As a model of alpha1-acid glycoprotein and nitric oxide increase, 84 male Sprague-Dawley rats received an IV injection of either 60 mg/kg Corynebacterium parvum (CP) or saline (control). The 2 groups (CP/Control) were further divided into subgroups, receiving the selective inducible nitric oxide synthase inhibitor, N-Iminolysine, via drinking water at different concentrations. On day 4 post-CP injection, the pharmacodynamics of atracurium were determined. Plasma concentrations of nitric oxide, atracurium, and alpha1-acid glycoprotein were measured and acetylcholine receptor numbers were quantified. In the CP groups, N-Iminolysine suppressed nitric oxide levels in a dose-dependent manner. Resistance to atracurium persisted. alpha1-acid glycoprotein serum levels remained increased in all CP groups with no differences in acetylcholine receptor expression. Our results suggest that the mechanism leading to increased expression of alpha1-acid glycoprotein and consecutive increased protein binding of atracurium is not mediated by inducible nitric oxide synthase induction and nitric oxide expression.
authors.affiliation: *Klinik für Anaesthesiologie der Technischen Universität München and #Institut für Klinische Chemie und Pathobiochemie der Technischen Universität München, Klinikum rechts der Isar, Munich, Germany; and §Department of Anesthesiology and Critical Care, Harvard Medical School and Anesthesia Services, Massachusetts General Hospital, and Shriners Hospital for Children, Boston, MA.
authors.forename: Heidrun
authors.initials: H
authors.lastname: Fink
authors.forename: Ralph
authors.initials: R
authors.lastname: Bogdanski
authors.forename: Peter
authors.initials: P
authors.lastname: Luppa
authors.forename: J A Jeevendra
authors.initials: JAJ
authors.lastname: Martyn
authors.forename: Manfred
authors.initials: M
authors.lastname: Blobner
mesh_terms: D000818:Animals; D001279:Atracurium / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D007249:Inflammation / Q000378:metabolism*; D008297:Male; D003473:Neuromuscular Nondepolarizing Agents / Q000494:pharmacology*; D009569:Nitric Oxide / Q000502:physiology*; D009961:Orosomucoid / Q000378:metabolism; D011425:Propionibacterium acnes; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D003473:Neuromuscular Nondepolarizing Agents; D009961:Orosomucoid; D001279:Atracurium; D009569:Nitric Oxide