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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“Content of nitrite, a stable end product of nitric oxide formation, was determined to quantify nitric oxide production because a very short half-life of nitric oxide precludes its direct measurement, especially in animal studies (Ignarro et al. 1993).”
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“Since NO has an extremely short half-life and is rapidly oxidized to nitrite (NO2 ) and nitrate (NO3 ) in the presence of oxygen (Ignarro et al. 1993).”
Background
The effect of substance P on nitric oxide release in a rheumatoid arthritis model
O'Shaughnessy, M. C., Vetsika, E., Inglis, J. J., Carleson, J., Haigh, R. C., Kidd, B. L., & Winyard, P. G. (2006) · Inflammation Research · doi:10.1007/s00011-006-0079-8 · Cited by 33
“The presence of oxyhaemoglobin or oxymyoglobin is normally required to oxidise nitric oxide and nitrite to nitrate [28].”
Background
Mechanisms of NOx entrapment into hydrated cement paste containing activated carbon — Influences of the temperature and carbonation
Krou, N. J., Batonneau‐Gener, I., Belin, T., Mignard, S., Horgnies, M., & Dubois-Brugger, I. (2013) · Cement and Concrete Research · doi:10.1016/j.cemconres.2013.06.006 · Cited by 33
Effects of Arginine Supplementation on Post-Exercise Metabolic Responses
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DIRECT NITRIC OXIDE IMAGING IN CULTURED HIPPOCAMPAL NEURONS WITH DIAMINOANTHRAQUINONE AND CONFOCAL MICROSCOPY
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Aprotinin but Not Tranexamic Acid Inhibits Cytokine-Induced Inducible Nitric Oxide Synthase Expression
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In vivo quantification of endotoxin‐induced nitric oxide production in pigs from Na15NO3‐infusion
Šantak, B., Radermacher, P., Iber, T., Adler, J., Wachter, U. A., Vassilev, D., Georgieff, M., & Vogt, J. A. (1997) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0701553 · Cited by 33
“However, it could be argued that at least in the pig the kinetic of NO3 7 formation is not sensitive enough to indicate NO production (Klemm et al., 1995) since NO2 7 is the predominant metabolite of NO (Ignarro et al., 1993; Klemm et al., 1995).”
Background
Anti-Inflammatory Activities of Extracts of Thai Spices and Herbs with Lipopolysaccharide-Activated RAW 264.7 Murine Macrophages
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“20 However, excess NO production due to chronic inﬂammation can damage the endothelium and induce tumorigenesis.”
Cell-based assays that predict in vivo neurotoxicity of urban ambient nano-sized particulate matter
Zhang, H., Haghani, A., Mousavi, A. H., Cacciottolo, M., D’Agostino, C., Safi, N., Sowlat, M. H., Sioutas, C., Morgan, T. E., Finch, C. E., et al. (2019) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2019.09.016 · Cited by 33
“NO and NO2-/NO3- in cell media were measured by Griess reagent [63], with NaNO2 as standards.”
Method
Effect of albumin on the transformation of dinitrosyl iron complexes with thiourea ligands
Pokidova, O. V., Luzhkov, V. B., Emel’yanova, N. S., Krapivin, V. B., Kotelnikov, A. I., Санина, Н. А., & Aldoshin, S. M. (2020) · Dalton Transactions · doi:10.1039/d0dt02452j · Cited by 33
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An improved method to measure nitrate/nitrite with an NO-selective electrochemical sensor
Boo, Y. C., Tressel, S. L., & Jo, H. (2006) · Nitric Oxide · doi:10.1016/j.niox.2006.09.004 · Cited by 32
“NO is very unstable with a half-life of 2–30 s and rapidly reacts with molecular oxygen to form nitrite [5].”
Background
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Dijkers, P. F., & O’Farrell, P. H. (2009) · Molecular Biology of the Cell · doi:10.1091/mbc.e09-05-0362 · Cited by 29
“In the presence of O2, NOS activity generates NO, which is unstable and is rapidly oxidized to nitrite (NO2 (Ignarro et al., 1993).”
Background
Nitrite is the driver, phytohormones are modulators while NO and H2O2act as promoters of NO2-induced cell death
Kasten, D., Mithöfer, A., Georgii, E., Lang, H., Durner, J., & Gaupels, F. (2016) · Journal of Experimental Botany · doi:10.1093/jxb/erw401 · Cited by 32
“NO2 disproportionates into equimolar amounts of nitrite and nitrate, whereas NO decays to nitrite (Ignarro et al., 1993).”
Background
Endogenous Nitric Oxide Production in Canine Osteoarthritis: Detection in Urine, Serum, and Synovial Fluid Specimens
Spreng, D., Sigrist, N. E., Schweighauser, A., Busato, A. R., & Schawalder, P. (2001) · Veterinary Surgery · doi:10.1053/jvet.2001.21397 · Cited by 32
Keeping Reactive Oxygen Species (ROS) In their Proper Place
Gilbert, D. L. (1994) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1994.tb21783.x · Cited by 32
In VivoImaging of Nitric Oxide by Magnetic Resonance Imaging Techniques
Sharma, R. D., Seo, J.-W., & Kwon, S. (2014) · Journal of Nanomaterials · doi:10.1155/2014/523646 · Cited by 32
“Nevertheless, the use of esterified DAN has shown promise in studies of NO bioimaging [93, 94].”
Background
Nitrite enhances neutrophil-induced DNA strand breakage in pulmonary epithelial cells by inhibition of myeloperoxidase
Knaapen, A. M., Schins, R. P. F., Borm, P. J. A., & van Schooten, F. (2005) · Carcinogenesis · doi:10.1093/carcin/bgi116 · Cited by 31
Reactive nitrogen species generated by heme proteins: Mechanism of formation and targets
Roncone, R., Barbieri, M., Monzani, E., & Casella, L. (2006) · Coordination Chemistry Reviews · doi:10.1016/j.ccr.2005.11.015 · Cited by 31
Ultrasensitive and bifunctional ZnO nanoplates for an oxidative electrochemical and chemical sensor of NO 2 : implications towards environmental monitoring of the nitrite reaction
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Issues Pertinent to the in Vivo in Situ Spin Trapping of Free Radicals
Pou, S., Halpern, H. J., Tsai, P., & Rosen, G. M. (1998) · Accounts of Chemical Research · doi:10.1021/ar970251l · Cited by 31
Toward the Optimization of Dinitrosyl Iron Complexes as Therapeutics for Smooth Muscle Cells
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“It has been reported that nitrite is the only stable end-product of the autooxidation of NO in aqueous solution([11]) and measurement of nitrite concentrations in the serum and tissue homogenates widely accepted as an index for NOS activity([7,12-14]).”
Background
Mutagenesis induced by the nitric oxide donor sodium nitroprusside in mouse cells
Lee, D.-H., & Pfeifer, G. P. (2006) · Mutagenesis · doi:10.1093/mutage/gel051 · Cited by 30
“NO2 is the product of oxidation of NO (23), so the increase of NO2 concentration can be regarded as an indicator of the production of NO (18,24).”
Background
Mutagenicity and cytotoxicity of reactive oxygen and nitrogen species in the MN-11 murine tumor cell line
Sandhu, J. K., & Birnboim, H. C. (1997) · Mutation research. Fundamental and molecular mechanisms of mutagenesis · doi:10.1016/s0027-5107(97)00140-1 · Cited by 30
Role of Sodium Nitroprusside in the Improvement of Rat Liver Preservation in University of Wisconsin Solution: A Study in the Isolated Perfused Liver Model
Rodriguez, J. V., Guibert, E. E., Quintana, A., Scandizzi, A. L., & Almada, L. L. (1999) · Journal of Surgical Research · doi:10.1006/jsre.1999.5750 · Cited by 30
NO and the Vasculature: Where Does It Come from and What Does It Do?
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“The biological actions of NO are thought to be terminated when circulating oxyhemoglobin (HbO) reacts with NO to form the complex nitrosylHbO, which is then oxidized to metHbO and NO−3 [43].”
Background
Understanding the formation of nitrate from nitrogen at the interface of gas–water microbubbles
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Influence of Nonthermal Atmospheric Plasma-Activated Water on the Structural, Optical, and Biological Properties of Aspergillus brasiliensis Spores
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Ameliorative effect of apelin-13 against renal complications in L-NAME-induced preeclampsia in rats
Hamza, R. Z., Diab, A. A. A., Zahra, M. H., Asalah, A. K., Attia, M. S., & Moursi, S. M. M. (2021) · PeerJ · doi:10.7717/peerj.11110 · Cited by 29
“Measurement of serum NO Serum NO was estimated as nitrite, a NO metabolite, by detecting NO3 reduction to NO2 by nitrate reductase (sigma), then NO2 levels (nitrite levels) were measured using the calorimetric Griess Reaction (Ignarro et al., 1993).”
Method
Quercetin-dependent scavenging of reactive nitrogen species derived from nitric oxide and nitrite in the human oral cavity: Interaction of quercetin with salivary redox components
Takahama, U., Hirota, S., & Oniki, T. (2006) · Archives of Oral Biology · doi:10.1016/j.archoralbio.2006.02.011 · Cited by 29
Micro Gas Analyzer Measurement of Nitric Oxide in Breath by Direct Wet Scrubbing and Fluorescence Detection
Toda, K., Koga, T., Kosuge, J., Kashiwagi, M., Oguchi, H., & Arimoto, T. (2009) · Analytical Chemistry · doi:10.1021/ac901131d · Cited by 29
Biodegradation of RDX and MNX with Rhodococcus sp. Strain DN22: New Insights into the Degradation Pathway
Halasz, A., Manno, D., Strand, S. E., Bruce, N. C., & Hawari, J. A.-A. (2010) · Environmental Science & Technology · doi:10.1021/es1023724 · Cited by 29
Nitrite transport into pig erythrocytes and its potential biological role
Jensen, F. B. (2005) · Acta Physiologica Scandinavica · doi:10.1111/j.1365-201x.2005.01448.x · Cited by 28

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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