title: N-acetylcysteine administration and loaded breathing.
abstract: Recent work has shown that loaded breathing produces alterations in diaphragmatic glutathione metabolism. Moreover, it has been suggested that alterations in glutathione levels may be related to the development of respiratory muscle fatigue and respiratory failure during loading. The purpose of this study was to determine whether it was possible to augment diaphragmatic stores of reduced glutathione (GSH) and thereby delay the development of respiratory failure during loaded breathing by administering N-acetylcysteine (NAC), a glutathione precursor. We compared the effects of massive inspiratory loading on saline- and NAC-treated groups of decerebrate unanesthetized rats with loading continuing until respiratory arrest occurred. As controls, we also studied unloaded saline- and NAC-treated animals. After arrest, diaphragms were excised, measurement was made of diaphragmatic GSH and oxidized glutathione (GSSG) concentrations, and assessment was made of in vitro diaphragmatic contractility (i.e., the force-frequency relationship and in vitro fatigability). We found that loading of saline-treated animals produced reductions in the diaphragmatic force-frequency curve, reductions in GSH, and increases in GSSG levels. NAC administration blunted loading-induced decreases in diaphragmatic GSH levels and reduced the in vitro fatigability of excised diaphragm muscle strips. NAC did not significantly alter the time to respiratory arrest, however, and also failed to alter the effect of loaded breathing on the diaphragmatic force-frequency relationship. These findings suggest that free radical-mediated GSH depletion is not the limiting factor determining the development of respiratory failure in this model of loaded breathing.
authors.affiliation: Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: G S
authors.initials: GS
authors.lastname: Supinski
authors.forename: D
authors.initials: D
authors.lastname: Stofan
authors.forename: R
authors.initials: R
authors.lastname: Ciufo
authors.forename: A
authors.initials: A
authors.lastname: DiMarco
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D003655:Decerebrate State; D003964:Diaphragm / Q000187:drug effects* / Q000502:physiology*; D005978:Glutathione / Q000031:analogs & derivatives / Q000378:metabolism; D019803:Glutathione Disulfide; D008297:Male; D009119:Muscle Contraction; D018763:Muscle Fatigue / Q000187:drug effects*; D009994:Osmolar Concentration; D051381:Rats; D012119:Respiration; D012131:Respiratory Insufficiency / Q000517:prevention & control*; D014939:Work of Breathing
chemical_list: D005978:Glutathione; D019803:Glutathione Disulfide; D000111:Acetylcysteine