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S-Nitrosothiols signal the ventilatory response to hypoxia

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 (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 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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Figure 1: Glutathione reacts with deoxygenated but not oxygenated blood to form GSNO.
Figure 2: Ventilatory effects of SNOs.
Figure 3: The low-mass fraction from deoxygenated blood signals an increase in E at the level of the NTS.
Figure 4: Effect of γ-GT inhibition or deficiency on the ventilatory effects of SNOs.

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References

  1. Haldane, J. & Smith, J. L. The physiological effects of air vitiated by respiration. J. Pathol. Bacteriol. 1, 168–186 (1892).

    Article  Google Scholar 

  2. Bisgard, G. E. & Neubauer, J. A. in Regulation of Breathing 2nd edn (eds Dempsey, J. A. & Pack, A. I.) (Marcel Dekker, New York, 1995).

    Google Scholar 

  3. 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).

    Article  CAS  Google Scholar 

  4. 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).

    Article  CAS  Google Scholar 

  5. 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).

    Article  CAS  Google Scholar 

  6. Schmidt, H. et al. No NO from NO synthase. Proc. Natl Acad. Sci. USA 93, 14492–14497 (1996).

    Article  ADS  CAS  Google Scholar 

  7. 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).

    Article  ADS  CAS  Google Scholar 

  8. Pawloski, J. R., Hess, D. T. & Stamler, J. S. Export by red blood cells of nitric oxide bioactivity. Nature 409, 622–626 (2001).

    Article  ADS  CAS  Google Scholar 

  9. 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).

    Article  CAS  Google Scholar 

  10. 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).

    Article  CAS  Google Scholar 

  11. Gaston, B. et al. Umbilical arterial S-nitrosothiols in stressed newborns: role in perinatal circulatory transition. Biochem. Biophys. Res. Commun. 253, 899–901 (1998).

    Article  CAS  Google Scholar 

  12. 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).

    Article  CAS  Google Scholar 

  13. 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).

    Article  CAS  Google Scholar 

  14. 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).

    CAS  PubMed  Google Scholar 

  15. 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).

    Article  ADS  CAS  Google Scholar 

  16. 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).

    Article  CAS  Google Scholar 

  17. 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).

    Article  CAS  Google Scholar 

  18. Choi, Y. et al. Molecular basis of NMDA receptor-coupled ion channel modulation by S-nitrosylation. Nature Neurosci. 3, 15–21 (2000).

    Article  ADS  CAS  Google Scholar 

  19. 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).

    Article  ADS  CAS  Google Scholar 

  20. 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).

    Article  CAS  Google Scholar 

  21. 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).

    Article  CAS  Google Scholar 

  22. 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).

    Article  CAS  Google Scholar 

  23. Paxinos, G. & Watson, C. The Rat Brain in Stereotaxic Coordinates (Academic, New York, 1986).

    Google Scholar 

  24. Stamler, J. S. & Feelisch, M. in Methods in Nitric Oxide Research (eds Stamler, J. S. & Feelisch, M.) 521–539 (Wiley, Chichester, 1996).

    Google Scholar 

  25. 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).

    Article  CAS  Google Scholar 

  26. 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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Acknowledgements

This work was supported by the NIH/NHLBI and the Commonwealth of Kentucky Research Challenge Trust Fund.

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Correspondence to Benjamin Gaston.

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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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