S-Nitrosothiols signal the ventilatory response to hypoxia

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Abstract
Increased ventilation in response to hypoxia has been appreciated for over a century1, but the biochemistry underlying this response remains poorly understood. Here we define a pathway in which increased minute ventilation (V̇E ) 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 γ-glutamyl transpeptidase (γ-GT) is required. The normal response to hypoxia is impaired in a knockout mouse lacking γ-GT. These observations suggest that S-nitrosothiol biochemistry is of central importance to the regulation of breathing.