Skip to main content

Advertisement

SpringerLink
Log in

Enzyme-independent formation of nitric oxide in biological tissues

  • Article
  • Published:

From Nature Medicine

View current issue Submit your manuscript

Abstract

The gaseous free radical nitric oxide (NO˙) is an important regulator of a variety of biological functions and also has a role in the pathogenesis of cellular injury. It has been generally accepted that NO˙ is solely generated in biological tissues by specific nitric oxide synthases, NOSs, which metabolize arginine to citrulline with the formation of NO˙. We report that NO˙ can also be generated in the ischaemic heart by direct reduction of nitrite to NO˙ under the acidotic and highly reduced conditions that occur. This NO˙ formation is not blocked by NOS inhibitors, and with long periods of ischaemia progressing to necrosis, this mechanism of NO˙ formation predominates. We observe that enzyme-independent NO˙ generation results in myocardial injury with a loss of contractile function. The existence of this enzyme independent mechanism of NO˙ formation has important implications in our understanding of the pathogenesis and treatment of tissue injury.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Moncada, S., Palmer, R.M. Jr & Higgs, E.A. Nitric oxide: Physiology, pathophysiology and pharmacology. Pharmac. Rev. 43, 109–142. 1991.

    CAS  Google Scholar 

  2. Furchgott, R.F. & Zawadzki, J.V. The obligatory role of endothelial cells on the relaxation of arterial muscle by acetylcholine. Nature 288, 373–376. 1980.

    Article  CAS  Google Scholar 

  3. Palmer, R.M. Jr, Ferridge, A.G. & Moncada, S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 327, 524–526. 1987.

    Article  CAS  Google Scholar 

  4. Ignarro, L.J., Byrns, R.E., Buga, G.M. & Wood, K.S. Endothelium-derived relaxing factor from pulmonary artery and vein possesses pharmacologic and chemical properties. Circ. Res. 61, 866–879. 1987.

    Article  CAS  Google Scholar 

  5. Furchgott, R.F. & Vanhoutte, P.M. Endothelium-derived relaxing and contracting factors. FASEB J. 3, 2007–2018. 1989.

    Article  CAS  Google Scholar 

  6. Marletta, M.A., Yoon, P.S., Iyengar, R., Leaf, C.D. & Wishnok, J.S. Macrophage oxidation of L-arginine to nitrite and nitrate: Nitric oxide is an intermediate. Biochemistry 27, 8706–8711. 1988.

    Article  CAS  Google Scholar 

  7. Bredt, D.S. et al. Cloned and expressed nitric oxide synthase structurally resembles cytochrome P-450 reductase. Nature 351, 714–718. 1991.

    Article  CAS  Google Scholar 

  8. Bredt, D.S. & Synder, S.H. Nitric oxide: A novel neuronal messenger. Neuron 8, 3–11. 1992.

    Article  CAS  Google Scholar 

  9. Moncada, S., Palmer, R.M. Jr & Higgs, E.A. Biosynthesis of nitric oxide from L-arginine: A pathway for the regulation of cell function and communication. Biochem. Pharmac. 38, 1709–1715. 1989.

    Article  CAS  Google Scholar 

  10. Garthwaite, J. Glutamate, nitric oxide and cell-cell signalling in the nervous system. Trends Neurosci. 14, 60–67. 1991.

    Article  CAS  Google Scholar 

  11. Langrehr, J.M., Hoffman, R.A., Lancaster, J.R. Jr & Simmons, R.L. Nitric oxide, a new endogenous immunomodulator. Transplantation 55, 1205–1212. 1993.

    Article  CAS  Google Scholar 

  12. Beckman, J.S., Beckman, T.W., Chen, J., Marshall, P.A. & Freeman, B.A. Apparent hydroxyl radical production by peroxynitrite: Implications for endothelial injury from nitric oxide and superoxide. Proc. natn. Acad. Sci. U.S.A. 87, 1620–1624. 1990.

    Article  CAS  Google Scholar 

  13. Zweier, J.L., Wang, P. & Kuppusamy, P. Direct measurement of nitric oxide generation in the ischemic heart using electron paramagnetic resonance spectroscopy. J. biol. Chem. 270, 304–307. 1995.

    Article  CAS  Google Scholar 

  14. Lancaster, J.R. Jr et al. Detection of nitric oxide by electron paramagnetic resonance spectroscopy during rejection of rat heart allograft. J. biol. Chem. 267, 10994–10998. 1992.

    CAS  PubMed  Google Scholar 

  15. Lai, C.S. & Komarov, A.M. Spin trapping of nitric oxide produced in vivo in septic-shock mice. FEBS Lett. 345, 120–124. 1994.

    Article  CAS  Google Scholar 

  16. Shinobu, L.A., Jones, S.G. & Jones, M.M. Sodium N-methyl-D-glucamine dithiocarbamate and cadmium intoxication. Acta Pharmacol. Toxicol. 54, 189–194. 1984.

    Article  CAS  Google Scholar 

  17. Zweier, J.L. Measurement of superoxide-derived free radicals in the reperfused heart: Evidence for a free radical mechanism of reperfusion injury. J. biol. Chem. 263, 1353–1357. 1988.

    CAS  PubMed  Google Scholar 

  18. Zweier, J.L. et al. Measurement and characterization of postischemic free radical generation in the isolated perfused heart. J. biol. Chem. 264, 18890–18895. 1989.

    CAS  PubMed  Google Scholar 

  19. Furfine, E.S., Harmon, M.F., Paith, J.E. & Garvey, E.P. Selective inhibition of constitutive nitric oxide synthase by L-NG-nitroarginine. Biochemistry 32, 8512–8517. 1993.

    Article  CAS  Google Scholar 

  20. Zweier, J.L. & Jacobus, W.E. Substrate-induced alterations of high energy phosphate metabolism and contractile function in the perfused heart. J. biol. Chem. 262, 8015–8021. 1987.

    CAS  PubMed  Google Scholar 

  21. Garside, C. A chemiluminescent technique for the determination of nanomolar concentrations of nitrate and nitrite in seawater. Marine Chem. 11, 159–167. 1982.

    Article  CAS  Google Scholar 

  22. Chzhan, M., Shteynbuk, M., Kuppusamy, P. & Zweier, J.L. An optimized L-band ceramic resonator for EPR imaging of biological samples. J. Magnet. Reson. A105, 49–53. 1993.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Molecular and Cellular Biophysics Laboratories, Department of Medicine, Division of Cardiology,

    Jay L. Zweier, Penghai Wang, Alexandre Samouilov & Periannan Kuppusamy

  2. the Electron Paramagnetic Resonance Center, The Johns Hopkins Medical Institutions, Johns Hopkins Bayview Medical Center, 5501 Hopkins Bayview Circle, Baltimore, Maryland, 21224, USA

    Jay L. Zweier, Penghai Wang, Alexandre Samouilov & Periannan Kuppusamy

Authors
  1. Jay L. Zweier
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Penghai Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alexandre Samouilov
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Periannan Kuppusamy
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zweier, J., Wang, P., Samouilov, A. et al. Enzyme-independent formation of nitric oxide in biological tissues. Nat Med 1, 804–809 (1995). https://doi.org/10.1038/nm0895-804

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm0895-804

  • Springer Nature America, Inc.

This article is cited by

Search

Navigation