Cited by 856Nitric Oxide and Endothelin EffectsHemoglobin structure and functionRedox biology and oxidative stress

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Oxidation of nitric oxide in aqueous solution to nitrite but not nitrate: comparison with enzymatically formed nitric oxide from L-arginine

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Ignarro, L J, Fukuto, J M, Griscavage, J M, Rogers, N E, Byrns, R E·1993·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.90.17.8103PMC PMC47296

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Abstract

Nitric oxide (NO) in oxygen-containing aqueous solution has a short half-life that is often attributed to a rapid oxidation to both NO2- and NO3-. The chemical fate of NO in aqueous solution is often assumed to be the same as that in air, where NO is oxidized to NO2 followed by dimerization to N2O4. Water then reacts with N2O4 to form both NO2- and NO3-. We report here that NO in aqueous solution containing oxygen is oxidized primarily to NO2- with little or no formation of NO3-. In the presence of oxyhemoglobin or oxymyoglobin, however, NO and NO2- were oxidized completely to NO3-. Methemoglobin was inactive in this regard. The unpurified cytosolic fraction from rat cerebellum, which contains constitutive NO synthase activity, catalyzed the conversion of L-arginine primarily to NO3- (NO2-/NO3- ratio = 0.25). After chromatography on DEAE-Sephacel or affinity chromatography using 2',5'-ADP-Sepharose 4B, active fractions containing NO synthase activity catalyzed the conversion of L-arginine primarily to NO2- (NO2-/NO3- ratio = 5.6) or only to NO2-, respectively. Unpurified cytosol from activated rat alveolar macrophages catalyzed the conversion of L-arginine to NO2- without formation of NO3-. Addition of 30 microM oxyhemoglobin to all enzyme reaction mixtures resulted in the formation primarily of NO3- (NO2-/NO3- ratio = 0.09 to 0.20). Cyanide ion, which displaces NO2- from its binding sites on oxyhemoglobin, inhibited the formation of NO3-, thereby allowing NO2- to accumulate. These observations indicate clearly that the primary decomposition product of NO in aerobic aqueous solution is NO2- and that further oxidation to NO3- requires the presence of additional oxidizing species such as oxyhemoproteins.

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Electromagnetic fields as first messenger in biological signaling: Application to calmodulin-dependent signaling in tissue repair
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“As a gaseous free radical with an in situ half-life of about 5 s [31], NO diffuses locally through membranes and organelles and acts on molecular targets at a distance up to about 200 μm [32].”
Cerebrospinal fluid studies in children with cerebral malaria: an excitotoxic mechanism?
Dobbie, M. S., Crawley, J., Waruiru, C., Marsh, K., & Surtees, R. A. H. (2000) · American Journal of Tropical Medicine and Hygiene · doi:10.4269/ajtmh.2000.62.284 · Cited by 88
N -acetylcysteine prevents development of the hyperdynamic circulation in the portal hypertensive rat
Fernando, B., Marley, R., Holt, S., Anand, R., Harry, D. S., Sanderson, P., Smith, R. E., Hamilton, G., & Moore, K. P. (1998) · Hepatology · doi:10.1002/hep.510280314 · Cited by 89
Antigen presentation by astrocytes primes rat T lymphocytes for apoptotic cell death
Gold, R., Schmied, M. C., Tontsch, U., Hartung, H., Wekerle, H., Toyka, K. V., & Lassmann, H. (1996) · Brain · doi:10.1093/brain/119.2.651 · Cited by 88
Traffic-related air pollutants (TRAP-PM) promote neuronal amyloidogenesis through oxidative damage to lipid rafts
Cacciottolo, M., Morgan, T. E., Saffari, A. A., Shirmohammadi, F., Forman, H. J., Sioutas, C., & Finch, C. E. (2019) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2019.12.023 · Cited by 88
“Media nitrite was assayed by the Griess reagent [30] with NaNO2 as a standard, and untreated media as a control.”
Method
Enhanced Nitric Oxide Concentrations and Expression of Nitric Oxide Synthase in Acupuncture Points/Meridians
Ma, S. (2003) · The Journal of Alternative and Complementary Medicine · doi:10.1089/10755530360623329 · Cited by 87
“A 100-mL aliquot of the supernatant was injected onto a chemiluminescence NO analyser (Dasibi, Glendale, CA) and the concentrations of NO2(2) and NO3(2) were determined by chemiluminescence as described (Ignarro et al., 1993; Ma et al., 1999).”
Release of nitric oxide from donors with known half-life: a mathematical model for calculating nitric oxide concentrations in aerobic solutions
Schmidt, K., Desch, W., Klatt, P., Kukovetz, W. R., & Mayer, B. (1997) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/pl00004969 · Cited by 87
“However, the prediction of the NO concentrations is rendered difficult by the complex autoxidation kinetics of NO. In aqueous, aerobic solutions, NO reacts with molecular oxygen to nitrite according to the following reaction sequence ( Ignarro et al. 1993; Lewis and Deen 1994; Goldstein and Czapski 1995):”
15-Lipoxygenase Catalytically Consumes Nitric Oxide and Impairs Activation of Guanylate Cyclase
O’Donnell, V. B., Taylor, K. B., Parthasarathy, S., Kühn, H., Koesling, D., Friebe, A., Bloodsworth, A., Darley-Usmar, V. M., & Freeman, B. Α. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.29.20083 · Cited by 87
Salinity Tolerance of Picochlorum atomus and the Use of Salinity for Contamination Control by the Freshwater Cyanobacterium Pseudanabaena limnetica
von Alvensleben, N., Katherine, S., Magnusson, M. E., & Heimann, K. (2013) · PLoS ONE · doi:10.1371/journal.pone.0063569 · Cited by 90
“This has implications for the remediation of nitric oxide (NO) flue gas, which can be converted 1:1 to nitrite in water [12] to be then used as a nitrogen source.”
Background
Inhibition of Lipopolysaccharide-Induced Cyclooxygenase-2 and Inducible Nitric Oxide Synthase Expression by 4-[(2′- O -acetyl-α- L -Rhamnosyloxy)Benzyl]Isothiocyanate from Moringa oleifera
Park, E., Cheenpracha, S., Chang, L. C., Kondratyuk, T. P., & Pezzuto, J. M. (2011) · Nutrition and Cancer · doi:10.1080/01635581.2011.589960 · Cited by 86
“Due to a short half-life of NO and subsequent oxidation to stable nitrite (27), nitrite levels were measured to estimate NO levels.”
Method
Isotope Dilution Mass Spectrometric Quantification of 3-Nitrotyrosine in Proteins and Tissues Is Facilitated by Reduction to 3-Aminotyrosine
Crowley, J. R., Yarasheski, K. E., Leeuwenburgh, C., TURK, J. W., & Heinecke, J. W. (1998) · Analytical Biochemistry · doi:10.1006/abio.1998.2635 · Cited by 86
Nitric oxide evokes pain at nociceptors of the paravascular tissue and veins in humans.
Holthusen, H., & Arndt, J. O. (1995) · The Journal of Physiology · doi:10.1113/jphysiol.1995.sp020876 · Cited by 86
S-Nitrosothiol Formation in Blood of Lipopolysaccharide-Treated Rats
Jourd’heuil, D., Gray, L. T., & Grisham, M. B. (2000) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.2000.2892 · Cited by 83
Physiological Concentrations of 17β-Estradiol Inhibit the Synthesis of Nitric Oxide Synthase in Macrophages Via a Receptor-Mediated System
Hayashi, T., Yamada, K., Esaki, T., Muto, E., Chaudhuri, G., & Iguchi, A. (1998) · Journal of Cardiovascular Pharmacology · doi:10.1097/00005344-199802000-00016 · Cited by 85
Corticosterone regulates expression of BDNF and trkB but not NT-3 and trkC mRNA in the rat hippocampus
Schaaf, M. J. M., Hoetelmans, R. W. M., de Kloet, E. R., & Vreugdenhil, E. (1997) · Journal of Neuroscience Research · doi:10.1002/(sici)1097-4547(19970515)48:4 · Cited by 131
Phosphorylation of Tyrosine 801 of Vascular Endothelial Growth Factor Receptor-2 Is Necessary for Akt-dependent Endothelial Nitric-oxide Synthase Activation and Nitric Oxide Release from Endothelial Cells
Blanes, M. G., Oubaha, M., Rautureau, Y., & Gratton, J. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m609048200 · Cited by 83
Interference of Carboxy-PTIO with Nitric Oxide- and Peroxynitrite-Mediated Reactions
Pfeiffer, S., Leopold, E., Hemmens, B., Schmidt, K., Werner, E. R., & Mayer, B. (1997) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(96)00407-8 · Cited by 85
Screening of edible Japanese plants for nitric oxide generation inhibitory activities in RAW 264.7 cells
Kim, O. K., Murakami, A., Nakamura, Y., & Ohigashi, H. (1998) · Cancer Letters · doi:10.1016/s0304-3835(97)00513-2 · Cited by 83
Interleukin-1β Stimulates Nitrite Production in the Rat Ovary: Evidence for Heterologous Cell-Cell Interaction and for Insulin-Mediated Regulation of the Inducible Isoform of Nitric Oxide Synthase1
Ben‐Shlomo, I., Kokia, E. S., Jackson, M. J., Adashi, E. Y., & Payne, D. W. (1994) · Biology of Reproduction · doi:10.1095/biolreprod51.2.310 · Cited by 82
Toxicity of urban air pollution particulate matter in developing and adult mouse brain: Comparison of total and filter-eluted nanoparticles
Haghani, A., Johnson, R. G., Safi, N., Zhang, H., Thorwald, M. A., Mousavi, A. J., Woodward, N. C., Shirmohammadi, F., Coussa, V., Wise, J. P., et al. (2020) · Environment International · doi:10.1016/j.envint.2020.105510 · Cited by 83
Amperometric Ultramicrosensors for Peroxynitrite Detection and Its Application toward Single Myocardial Cells
Xue, J., Ying, X., Chen, J., Xian, Y., Jin, L., & Jin, J. (2000) · Analytical Chemistry · doi:10.1021/ac000701e · Cited by 82
Nitrite uptake and metabolism and oxidant stress in human erythrocytes
May, J. M., Qu, Z., Li, X., & Cobb, C. E. (2000) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.2000.279.6.c1946 · Cited by 82
“Much of the NO released into the bloodstream should be scavenged by Hb in erythrocytes (16) or converted to nitrite in the presence of molecular oxygen (13, 29).”
Background
The Role of Nitric Oxide in Bacterial Meningitis in Children
Kornelisse, R. F., Hoekman, K., Visser, J. J., Hop, W. C. J., Huijmans, J. G. M., van der Straaten, P. J. C., van der Heijden, A. J., Sukhai, R. N., Neijens, H. J., & de Groot, R. (1996) · The Journal of Infectious Diseases · doi:10.1093/infdis/174.1.120 · Cited by 82
“CSF is comparable to an oxygen-containing aqueous solution, a condition in which NO is oxidized primarily to nitrite with little or no formation of nitrate [41].”
Background
Novel mechanism of nitrosative stress from dietary nitrate with relevance to gastro-oesophageal junction cancers
Iijima, K. (2003) · Carcinogenesis · doi:10.1093/carcin/bgg168 · Cited by 81
Leptin Induces Growth Hormone Secretion from Peripheral Blood Mononuclear Cells via a Protein Kinase C- and Nitric Oxide-Dependent Mechanism
Dixit, V. D., Mielenz, M., Taub, D. D., & Parvizi, N. (2003) · Endocrinology · doi:10.1210/en.2003-0600 · Cited by 79
Increased intrathecal nitric oxide formation in multiple sclerosis; cerebrospinal fluid nitrite as activity marker
Brundin, L., Morcos, E., Olsson, T. P., Wiklund, P. N., & Andersson, M. (1999) · European Journal of Neurology · doi:10.1046/j.1468-1331.1999.650585.x · Cited by 79
Antibody‐dependent cell‐mediated cytotoxicity to newly excysted juvenile Fasciola hepatica in vitro is mediated by reactive nitrogen intermediates
Piedrafita, D. M., Parsons, J. C., Sandeman, R. M., Wood, P. R., Estuningsih, S., Partoutomo, S., & Spithill, T. W. (2001) · Parasite Immunology · doi:10.1046/j.1365-3024.2001.00404.x · Cited by 79
“The levels of nitrite in culture supernatants of lavage cells of Merino and Indonesian Thin Tail sheep and rats, following stimulation with cytokines and/or LPS, were used as an indicator of nitric oxide production ( 27 ).”
Method
Role of thiols in the targeting of S-nitroso thiols to red blood cells
Pietraforte, D., Mallozzi, C., Scorza, G., & Minetti, M. (1995) · Biochemistry · doi:10.1021/bi00021a032 · Cited by 79
Ergocalciferol and Microcirculatory Function in Chronic Kidney Disease and Concomitant Vitamin D Deficiency: An Exploratory, Double Blind, Randomised Controlled Trial
Dreyer, G., Tucker, A. T., Harwood, S., Pearse, R. M., Raftery, M., & Yaqoob, M. M. (2014) · PLoS ONE · doi:10.1371/journal.pone.0099461 · Cited by 78
“Nitrite levels in cell supernatant, to evaluate the downstream effect of changes in eNOS expression in cells, were measured by a chemiluminescent technique [44] (see File S1 and figures S1-5 for full description of all techniques).”
Method
Nitric oxide mediates interleukin‐1 induced inhibition of glycosaminoglycan synthesis in rat articular cartilage
Järvinen, T. A. H., Moilanen, T. P. S., Järvinen, T. A. H., & Moilanen, E. (1995) · Mediators of Inflammation · doi:10.1155/s0962935195000184 · Cited by 78
A spectrophotometric assay for nitrate in an excess of nitrite
Beda, N. V., & Nedospasov, A. A. (2005) · Nitric Oxide · doi:10.1016/j.niox.2005.05.002 · Cited by 78
Acute L-Arginine supplementation does not increase nitric oxide production in healthy subjects
Alvares, T., Conte-Junior, C., Silva, J., & Paschoalin, V. M. (2012) · Nutrition & Metabolism · doi:10.1186/1743-7075-9-54 · Cited by 76
“The further oxidation to NO3 - requires the presence of additional oxidizing species such as oxyhemoproteins [20].”
Background
Evidences that maternal swimming exercise improves antioxidant defenses and induces mitochondrial biogenesis in the brain of young Wistar rats
Marcelino, T. B., Longoni, A., Kudo, K. Y., Stone, V., RECH, A., de Assis, A. M., Scherer, E. B. S., da Cunha, M. J., Wyse, Â. T. D. S., Pettenuzzo, L. F., et al. (2013) · Neuroscience · doi:10.1016/j.neuroscience.2013.04.043 · Cited by 79
“Nitrite is the stable endproduct of the autoxidation of NO in aqueous solution (Ignarro et al., 1993).”
Background
Nitric oxide release and contractile properties of skeletal muscles from mice deficient in type III NOS
Hirschfield, W., Moody, M. R., O’Brien, W. E., Gregg, A. R., Bryan, R. M., & Reid, M. B. (2000) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.2000.278.1.r95 · Cited by 76
“Nitrite represents ,20% of the oxidized NO products that accumulate from enzymatic synthesis (14); nitrite measurements therefore are expected to yield a lower absolute value than the present method.”
Result
Cardiac nitric oxide: Emerging role for nNOS in regulating physiological function
Danson, E., Choate, J., & Paterson, D. J. (2005) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2004.11.003 · Cited by 77

Authors: Ignarro, L. J., Fukuto, J. M., Griscavage, J. M., Rogers, N. E., & Byrns, R. E.
Affiliations: University of California, Los Angeles (US)
ORCID: Fukuto, J M
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 1993-09
Volume: 90
Issue: 17
Pages: 8103-8107
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.90.17.8103
PMC: PMC47296
OpenAlex: W2033379487
Cited by: 856
References: 28
Citations by year: 2026: 14 · 2025: 14 · 2024: 19 · 2023: 21 · 2022: 14 · 2021: 15 · 2020: 21 · 2019: 19 · 2018: 20 · 2017: 21 · 2016: 18 · 2015: 23 · 2014: 28 · 2013: 27 · 2012: 24
FWCI: 17.78
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health (5r01hl040922-11, 5r01hl046388-03, 5r01hl035014-12)
National Heart, Lung, and Blood Institute (HL 46388, HL-35014, HL 40922)
Topics: Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Hemoglobin structure and function
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
Keywords: NO oxidation, nitrite, nitrate, aqueous solutions, oxyhemoglobin, oxymyoglobin, methemoglobin, nitric oxide synthase, L-arginine, alveolar macrophages, cyanide, heme proteins
MeSH terms: Amino Acid Oxidoreductases, Animals, Arginine, Hemeproteins, Humans, Kinetics, Methemoglobin, Myoglobin, Nitrates, Nitric Oxide, Nitrites, Oxidation-Reduction, Oxyhemoglobins, Solutions, Nitric Oxide Synthase

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Oxidation of nitric oxide in aqueous solution to nitrite but not nitrate: comparison with enzymatically formed nitric oxide from L-arginine

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