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.
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Haldane, J. & Smith, J. L. The physiological effects of air vitiated by respiration. J. Pathol. Bacteriol. 1, 168–186 (1892).
Bisgard, G. E. & Neubauer, J. A. in Regulation of Breathing 2nd edn (eds Dempsey, J. A. & Pack, A. I.) (Marcel Dekker, New York, 1995).
Lin, L. H., Emson, P. C. & Talman, W. T. Apposition of neuronal elements containing nitric oxide synthase and glutamate in the nucleus tractus solitarii of rat: a confocal microscopic analysis. Neuroscience 96, 341–350 (2000).
Gozal, D. et al. Nitric oxide modulates ventilatory responses to hypoxia in conscious developing rats. Am. J. Respir. Crit. Care Med. 155, 1755–1762 (1997).
Kluge, I., Gutteck-Amsler, U., Zollinger, M. & Do, K. Q. S-Nitrosoglutathione in rat cerebellum: identification and quantification by liquid chromatography-mass spectrometry. J. Neurochem. 69, 2599–2607 (1997).
Schmidt, H. et al. No NO from NO synthase. Proc. Natl Acad. Sci. USA 93, 14492–14497 (1996).
Jia, L., Bonaventura, C., Bonaventura, J. & Stamler, J. S. S-Nitrosohaemoglobin: a dynamic activity of blood involved in vascular control. Nature 380, 221–226 (1996).
Pawloski, J. R., Hess, D. T. & Stamler, J. S. Export by red blood cells of nitric oxide bioactivity. Nature 409, 622–626 (2001).
Palmer, L. A., Gaston, B. & Johns, R. A. Normoxic stabilization of hypoxia inducible factor 1 expression and activity by nitrosonium donors. Mol. Pharmacol. 58, 1197–1203 (2000).
Anwar, M., Kissen, I. & Weiss, H. R. Effect of chemodenervation on the cerebral vascular response and microvascular response to hypoxia. Circ. Res. 67, 1365–1373 (1990).
Gaston, B. et al. Umbilical arterial S-nitrosothiols in stressed newborns: role in perinatal circulatory transition. Biochem. Biophys. Res. Commun. 253, 899–901 (1998).
Chiueh, C. C. & Rauhala, P. The redox pathway of S-nitrosoglutathione, glutathione and nitric oxide in cell to neuron communications. Free Rad. Res. 31, 641–650 (1999).
Ohta, H., Bates, J., Lewis, S. & Talman, W. Actions of S-Nitrosocysteine in the nucleus tractus solitarii are unrelated to release of nitric oxide. Brain Res. 746, 98–104 (1997).
Davisson, R. L., Travis, M. D., Bates, J. N., Johnson A. K. & Lewis, S. J. Stereoselective actions of S-Nitrosocysteine in central nervous system of conscious rats. Am. J. Physiol. 272, H2361–H2368 (1997).
Lipton, S. A. et al. A redox-based mechanism for the neuroprotective and neurodestructive effects of nitric oxide and related nitroso-compounds. Nature 364, 626–632 (1993).
Menendez, A. A., Nuckton, T. J., Torres, J. E. & Gozal, D. Short-term potentiation of ventilation after different levels of hypoxia. J. Appl. Physiol. 86, 1478–1482 (1999).
Askew, S. C., Butler, A. R., Flitney, F. W., Kemp, G. D. & Megson, I. L. Chemical mechanisms underlying the vasodilator and platelet anti-aggregating properties of S-nitroso-N-acetyl-dl-penicillamine and S-nitrosoglutathione. Biorgan. Med. Chem. 3, 1–9 (1995).
Choi, Y. et al. Molecular basis of NMDA receptor-coupled ion channel modulation by S-nitrosylation. Nature Neurosci. 3, 15–21 (2000).
Smith, T. K., Ikeda, Y., Fujii, J., Taniguchi, N. & Meister, A. Different sites of acivicin binding and inactivation of γ-glutamyl-transpeptidases. Proc. Natl Acad. Sci. USA 92, 2360–2364 (1995).
Torres, J. E., Kreisman, N. R. & Gozal, D. Nitric oxide modulates in vitro intrinsic optical signal and neural activity in the nucleus tractus solitarius of the rat. Neurosci. Lett. 232, 175–178 1997).
Gozal, D., Torres, J. E., Gozal, Y. M. & Littwin, S. M. Effect of nitric oxide synthase inhibition on cardiorespiratory responses in the conscious rat. J. Appl. Physiol. 81, 2068–2077 (1996).
Kline, D., Yang, T., Premkumar, D., Thomas, A. & Prabhakar, N. Blunted respiratory responses to hypoxia in mutant mice deficient in nitric oxide synthase-3. J. Appl. Physiol. 88, 1496–1508 (2000).
Paxinos, G. & Watson, C. The Rat Brain in Stereotaxic Coordinates (Academic, New York, 1986).
Stamler, J. S. & Feelisch, M. in Methods in Nitric Oxide Research (eds Stamler, J. S. & Feelisch, M.) 521–539 (Wiley, Chichester, 1996).
Fang, K., Ragsdale, N. V., Carey, R. M., Macdonald, T. & Gaston, B. Reductive assays for S-nitrosothiols: implications for measurements in biological systems. Biochem. Biophys. Res. Commun. 252, 535–540 (1998).
Lieberman, M. W. et al. Growth retardation and cysteine deficiency in γ-glutamyl transpeptidase-deficient mice. Proc. Natl Acad. Sci. USA 93, 7923–7926.
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This work was supported by the NIH/NHLBI and the Commonwealth of Kentucky Research Challenge Trust Fund.
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Lipton, A., Johnson, M., Macdonald, T. et al. S-Nitrosothiols signal the ventilatory response to hypoxia. Nature 413, 171–174 (2001). https://doi.org/10.1038/35093117
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DOI: https://doi.org/10.1038/35093117
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