S-Nitrosothiols signal the ventilatory response to hypoxia

Abstract

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.

Reassessing the risk of hemodilutional anemia: Some new pieces to an old puzzle

“…81 In addition, NOS-derived NO may have a profound effect through S-nitrosylation of a number of important regulatory proteins, including hemoglobin. 91 …”

A nitric oxide processing defect of red blood cells created by hypoxia: Deficiency of S-nitrosohemoglobin in pulmonary hypertension

“…Transnitrosylation of AE1 by SNO-Hb involves a direct protein-protein interaction. The steps by which the NO group is subsequently transferred to the vessel wall are not yet established, although recent studies suggest that membrane SNO becomes accessible to plasma reactants, including glutathione (10,20).Hb is continuously cycling in vivo between oxygenated and deoxygenated states that influence the propensity for binding vs. release of NO groups (5,16,18,21). In support of this proposition, SNO-Hb levels have been found by several independent groups and methods (3) to be higher in oxygenated blood than in deoxygenated blood of adults (6, 8, 10) and newborns (22) and to vary as a function of tissue oxygen saturations (6,8,10,23).…”

Assessment of nitric oxide signals by triiodide chemiluminescence

“…Additionally, NO can be transported in endocrine or paracrine fashion by reacting with heme iron and cysteine thiols in proteins [hemoglobin (Hb) and albumin] and peptides (glutathione and cysteinlyglycine) to form NO adducts with longer biological lifetimes (3)(4)(5); release of NO bioactivity from stable adducts is effected by allosteric and redox-based mechanisms that alter FeNO or S-nitrosothiol (SNO) reactivity (5,6). An updated discussion of the factors influencing reactivity of S-nitrosohemoglobin, S-nitrosoalbumin, and low-molecular-weight SNO in the context of vasoregulation (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15) can be found in supporting information (SI) Text.…”