S-nitrosoglutathione breakdown prevents airway smooth muscle relaxation in the guinea pig.
Airway levels of the endogenous bronchodilator S-nitrosoglutathione (GSNO) are low in children with near-fatal asthma. We hypothesized that GSNO could be broken down in the lung and that this catabolism could inhibit airway smooth muscle relaxation. In our experiments, GSNO was broken down by guinea pig lung homogenates, particularly after ovalbumin sensitization (OS). Two lung protein fractions had catabolic activity. One was NADPH dependent and was more active after OS. The other was NADPH independent and was partially inhibited by aurothioglucose. Guinea pig lung tissue protein fractions with GSNO catabolic activity inhibited GSNO-mediated guinea pig tracheal ring relaxation. The relaxant effect of GSNO was partially restored by aurothioglucose. These observations suggest that catabolism of GSNO in the guinea pig 1) is mediated by lung proteins, 2) is partially upregulated after OS, and 3) may contribute to increased airway smooth muscle tone. We speculate that enzymatic breakdown of GSNO in the lung could contribute to asthma pathophysiology by inhibiting the beneficial effects of GSNO, including its effect on airway smooth muscle tone.
Fang
K
K
Department of Pediatric Respiratory Medicine, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA.
Johns
R
R
Macdonald
T
T
Kinter
M
M
Gaston
B
B
D000818:Animals; D005978:Glutathione / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D005979:Glutathione Peroxidase / Q000378:metabolism; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007700:Kinetics; D008168:Lung / Q000502:physiology*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology*; D009126:Muscle Relaxation / Q000187:drug effects / Q000502:physiology; D009130:Muscle, Smooth / Q000502:physiology*; D009249:NADP / Q000378:metabolism; D009603:Nitroso Compounds / Q000378:metabolism* / Q000494:pharmacology*; D010047:Ovalbumin / Q000276:immunology; D026422:S-Nitrosoglutathione; D014132:Trachea / Q000502:physiology*; D014969:Xanthine Oxidase / Q000378:metabolism
D009603:Nitroso Compounds; D009249:NADP; D026422:S-Nitrosoglutathione; D010047:Ovalbumin; D005979:Glutathione Peroxidase; D014969:Xanthine Oxidase; D005978:Glutathione