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Cited by 1,238Nitric Oxide and Endothelin EffectsRedox biology and oxidative stressHemoglobin structure and function

Nitric oxide circulates in mammalian plasma primarily as an S-nitroso adduct of serum albumin.

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Stamler, J S, Jaraki, O, Osborne, J, Simon, D I, Keaney, J, Vita, J, Singel, D, Valeri, C R +1 more·1992·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.89.16.7674PMC PMC49773
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Abstract

We have recently shown that nitric oxide or authentic endothelium-derived relaxing factor generated in a biologic system reacts in the presence of specific protein thiols to form S-nitrosoprotein derivatives that have endothelium-derived relaxing factor-like properties. The single free cysteine of serum albumin, Cys-34, is particularly reactive toward nitrogen oxides (most likely nitrosonium ion) under physiologic conditions, primarily because of its anomalously low pK; given its abundance in plasma, where it accounts for approximately 0.5 mM thiol, we hypothesized that this plasma protein serves as a reservoir for nitric oxide produced by the endothelial cell. To test this hypothesis, we developed a methodology, which involves UV photolytic cleavage of the S--NO bond before reaction with ozone for chemiluminescence detection, with which to measure free nitric oxide, S-nitrosothiols, and S-nitrosoproteins in biologic systems. We found that human plasma contains approximately 7 microM S-nitrosothiols, of which 96% are S-nitrosoproteins, 82% of which is accounted for by S-nitroso-serum albumin. By contrast, plasma levels of free nitric oxide are only in the 3-nM range. In rabbits, plasma S-nitrosothiols are present at approximately 1 microM; 60 min after administration of NG-monomethyl-L-arginine at 50 mg/ml, a selective and potent inhibitor of nitric oxide synthetases, S-nitrosothiols decreased by approximately 40% (greater than 95% of which were accounted for by S-nitrosoproteins, and approximately 80% of which was S-nitroso-serum albumin); this decrease was accompanied by a concomitant increase in mean arterial blood pressure of 22%. These data suggest that naturally produced nitric oxide circulates in plasma primarily complexed in S-nitrosothiol species, principal among which is S-nitroso-serum albumin. This abundant, relatively long-lived adduct likely serves as a reservoir with which plasma levels of highly reactive, short-lived free nitric oxide can be regulated for the maintenance of vascular tone.

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  • Accumulating studies demonstrate production of bioavailable NO from incubation of erythrocytes with nitrite.

    “Although theoretical calculations suggest that this type of NO escape should be limited, accumulating studies by many research groups now demonstrate the production of bioavailable NO generated from the incubation of erythrocytes with nitrite (185, 196, 883, 975).”

    From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [883]

  • RSNOs are an endogenous class of NO donors and natural transporters of NO in tissues and blood.

    “S-Nitrosothiols (RSNO) represent an endogenous class of NO donors and natural transporters of NO within tissues and blood.120,158”

    From Recent advances in thromboresistant and antimicrobial polymers for biomedical applications: just say yes to nitric oxide (NO) (2016) · cites this paper as [158]

  • NO bioactivity in blood and tissue is preserved in the form of nitrite, nitrate, S-nitrosothiols, N-nitrosamines, nitrosylhemoglobin, and S-nitrosohemoglobin.

    “However studies conducted in this area over the last few years have unraveled mechanisms by which NO bioactivity in blood and in tissue have been preserved in the form of nitrite, nitrate, S-nitrosothiols (RSNO), N-nitrosamines (RNNO), nitrosylhemoglobin (NOHb), and S-nitrosohemoglobin (SNOHb) [16–21].”

    From Inorganic nitrite therapy: historical perspective and future directions (2011) · cites this paper as [16]

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Authors
Stamler, J. S., Jaraki, O., Osborne, J., Simon, D. I., Keaney, J., Vita, J., Singel, D., Valeri, C. R., & Loscalzo, J.
Affiliations
Harvard University (US)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
1992-08-15
Volume
89
Issue
16
Pages
7674-7677
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.89.16.7674
PMC
PMC49773
OpenAlex
W2002192155
Cited by
1,238
References
18
Citations by year
2026: 9 · 2025: 14 · 2024: 12 · 2023: 16 · 2022: 15 · 2021: 23 · 2020: 15 · 2019: 23 · 2018: 18 · 2017: 26 · 2016: 23 · 2015: 24 · 2014: 24 · 2013: 46 · 2012: 40
FWCI
23.81
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (1k08hl002582-01, 5r01hl040411-02, 5r01hl043344-04)
  • National Heart, Lung, and Blood Institute (HL43344, HL-40411, K08HL02582)
Topics
  • Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
Keywords
nitric oxide, S-nitrosothiols, plasma nitric oxide, endothelium-derived relaxing factor, L-NMMA, nitric oxide synthase inhibition, blood pressure, vascular tone, UV photolysis, chemiluminescence detection
MeSH terms
Animals, Arginine, Blood Pressure, Luminescent Measurements, Nitric Oxide, Nitroso Compounds, Photolysis, Protein Binding, Rabbits, Serum Albumin, omega-N-Methylarginine

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