S-nitrosothiols signal the ventilatory response to hypoxia.
Increased ventilation in response to hypoxia has been appreciated for over a century, but the biochemistry underlying this response remains poorly understood. Here we define a pathway in which increased minute ventilation (&Vdot;E ) is signalled by deoxyhaemoglobin-derived S-nitrosothiols (SNOs). Specifically, we demonstrate that S-nitrosocysteinyl glycine (CGSNO) and S-nitroso-l-cysteine (l-CSNO)-but not S-nitroso-d-cysteine (d-CSNO)-reproduce the ventilatory effects of hypoxia at the level of the nucleus tractus solitarius (NTS). We show that plasma from deoxygenated, but not from oxygenated, blood produces the ventilatory effect of both SNOs and hypoxia. Further, this activity is mediated by S-nitrosoglutathione (GSNO), and GSNO activation by gamma-glutamyl transpeptidase (gamma-GT) is required. The normal response to hypoxia is impaired in a knockout mouse lacking gamma-GT. These observations suggest that S-nitrosothiol biochemistry is of central importance to the regulation of breathing.
Lipton
A J
AJ
Kosair Children's Hospital Research Institute, Departments of Pediatrics, Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky 40202, USA.
Johnson
M A
MA
Macdonald
T
T
Lieberman
M W
MW
Gozal
D
D
Gaston
B
B
D000818:Animals; D015687:Cell Hypoxia; D003545:Cysteine / Q000031:analogs & derivatives / Q000378:metabolism*; D005978:Glutathione / Q000031:analogs & derivatives / Q000378:metabolism*; D007555:Isoxazoles / Q000494:pharmacology; D051379:Mice; D009603:Nitroso Compounds / Q000378:metabolism*; D010100:Oxygen / Q000097:blood; D051381:Rats; D012143:Respiratory Physiological Phenomena; D026422:S-Nitrosoglutathione; D026403:S-Nitrosothiols; D017552:Solitary Nucleus / Q000378:metabolism*; D013438:Sulfhydryl Compounds / Q000378:metabolism*; D005723:gamma-Glutamyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism*
D007555:Isoxazoles; D009603:Nitroso Compounds; D026403:S-Nitrosothiols; C417091:S-nitrosocysteinylglycine; D013438:Sulfhydryl Compounds; D026422:S-Nitrosoglutathione; C021315:S-nitrosocysteine; D005723:gamma-Glutamyltransferase; D005978:Glutathione; D003545:Cysteine; C006303:acivicin; D010100:Oxygen