The DOI matches its Crossref record; 47 of the 47 references it cites were found in a registry or an index.
Mechanisms Underlying Erythrocyte and Endothelial Nitrite Reduction to Nitric Oxide in Hypoxia: Role for Xanthine Oxidoreductase and Endothelial Nitric Oxide Synthase
Open accessAbstract
Reduction of nitrite (NO 2−) provides a major source of nitric oxide (NO) in the circulation, especially in hypoxemic conditions. Our previous studies suggest that xanthine oxidoreductase (XOR) is an important nitrite reductase in the heart and kidney. Herein, we have demonstrated that conversion of nitrite to NO by blood vessels and RBCs was enhanced in the presence of the XOR substrate xanthine (10 μmol/L) and attenuated by the XOR inhibitor allopurinol (100 μmol/L) in acidic and hypoxic conditions only. Whereas endothelial nitric oxide synthase (eNOS) inhibition had no effect on vascular nitrite reductase activity, in RBCs L-NAME, L-NMMA, and l-arginine inhibited nitrite-derived NO production by >50% (P<0.01) at pH 7.4 and 6.8 under hypoxic conditions. Western blot and immunohistochemical analysis of RBC membranes confirmed the presence of eNOS and abundant XOR on whole RBCs. Thus, XOR and eNOS are ideally situated on the membranes of RBCs and blood vessels to generate intravascular vasodilator NO from nitrite during ischemic episodes. In addition to the proposed role of deoxyhemoglobin, our findings suggest that the nitrite reductase activity within the circulation, under hypoxic conditions (at physiological pH), is mediated by eNOS; however, as acidosis develops, a substantial role for XOR becomes evident.
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In the citing paper
“Other medications, including xanthine oxidase (XOR) inhibitors (e.g., allopurinol) and drugs that affect salivary flow or gastrointestinal motility, may further modify nitrate bioactivation [17,272].”
From Dietary Nitrate-Rich Vegetables as Natural Modulators of Health: Mechanisms and Benefits in Ageing Populations (2026) · cites this paper as [272]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Furthermore, the process was demonstrated to be dependent on xanthine oxidoreductase (XOR)”
From Vascular effects of dietary nitrate (as found in green leafy vegetables and beetroot) via the nitrate-nitrite-nitric oxide pathway (2013) · cites this paper as [125]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“eNOS can also bioactivate nitrite under anoxic and/or acidic conditions.102,103”
From Nitrate-Nitrite-Nitric Oxide Pathway: Implications for Anesthesiology and Intensive Care (2010) · cites this paper as [102]
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In the citing paper
“A similar pathway exists in the pulmonary vasculature in which mitochondria-generated oxidants signal the conserved phenomenon of hypoxic vasoconstriction (995).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [995]
Experimental — accuracy not yet measuredIn the citing paper
“Other proposed nitrite reductases catalyzing NO formation from nitrite under hypoxic conditions are carbonic anhydrase (1), xanthine oxidase (68), or eNOS (189), which are all present in RBCs.”
From Red Blood Cell Function and Dysfunction: Redox Regulation, Nitric Oxide Metabolism, Anemia (2017) · cites this paper as [189]
In the citing paper
“The NO-like effects of dietary nitrate range from lowering of blood pressure 14,38 to a reduction in experimental myocardial infarct size, 33 inhibition of platelet aggregation, 34 increase in exercise tolerance in peripheral arterial disease, 35 and improvement in intrinsic mitochondrial efficiency.36”
From Dietary nitrate supplementation improves revascularization in chronic ischemia (2012) · cites this paper as [34]
In the citing paper
“Nitrite may form NO either via deoxyhemoglobin (deoxyHb, Fe II Hb) [80,81], deoxymyoglobin [82] or xanthine oxidoreductase (XOR)-mediated reduction [83], or via spontaneous [84] and carbonic anhydrase-facilitated disproportionation [85].”
From On the chemical biology of the nitrite/sulfide interaction (2015) · cites this paper as [83]
In the citing paper
“The extent to which RBC XOR can contribute to NO generation from nitrite will depend on the concentrations of XOR that accumulate from circulating levels [88].”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [88]
In the citing paper
“In addition to XOR mediated NO generation from nitrite occurring in heart, liver, and smooth muscle tissue, XOR has been proposed to be associated with endothelial cells and RBCs and reduce nitrite there [88].”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [88]
In the citing paper
“XOR was also demonstrated to be active on the erythrocytic membrane [25, 88].”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [88]
In the citing paper
“They also suggested that eNOS, both in the RBC and endothelial cells, played a role in vascular NO production from nitrite using a NOS blocker [88].”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [88]
In the citing paper
“Webb and colleagues showed that nitrite-mediated NO production from human left internal mammary artery was substantially (but not completely) reduced by allopurinol, an XOR inhibitor [88].”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [88]
In the citing paper
“Several studies have emphasized the importance of XOR in mediating nitrite-dependent increases in blood flow either due to XOR in the blood vessels [39, 88] or erythrocytic XOR [25, 88].”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [88]
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Citations
Cites
The L-Arginine-Nitric Oxide Pathway
Epstein, F. H., Moncada, S., & Higgs, A. (1993) · New England Journal of Medicine · doi:10.1056/nejm199312303292706 · Cited by 6,678
The preparation and chemical characteristics of hemoglobin-free ghosts of human erythrocytes
Dodge, J. T., Mitchell, C. D., & Hanahan, D. J. (1963) · Archives of Biochemistry and Biophysics · doi:10.1016/0003-9861(63)90042-0 · Cited by 4,419
Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation
Cosby, K., Partovi, K. S., Crawford, J. H., Patel, R. P., Reiter, C. D., Martyr, S., Yang, B. K., Waclawiw, M. A., Zalos, G., Xu, X., et al. (2003) · Nature Medicine · doi:10.1038/nm954 · Cited by 1,807
Webb, A. J., Patel, N., Loukogeorgakis, S., Okorie, M., Aboud, Z., Misra, S., Rashid, R., Miall, P., Deanfield, J., Benjamin, N., et al. (2008) · Hypertension · doi:10.1161/hypertensionaha.107.103523 · Cited by 1,078
Self-citationSimulation of the diffusion and reaction of endogenously produced nitric oxide.
Lancaster, J. R. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.17.8137 · Cited by 689
Cytoprotective effects of nitrite during in vivo ischemia-reperfusion of the heart and liver
Duranski, M. R., Greer, J. J. M., Dejam, A., Jaganmohan, S., Hogg, N., Langston, W., Patel, R. P., Yet, S.-F., Wang, X., Kevil, C. G., et al. (2005) · Journal of Clinical Investigation · doi:10.1172/jci22493 · Cited by 674
The emerging biology of the nitrite anion
Gladwin, M. T., Schechter, A. N., Kim-Shapiro, D. B., Patel, R. P., Hogg, N., Shiva, S., Cannon, R. O., Kelm, M., Wink, D. A., Espey, M. G., et al. (2005) · Nature Chemical Biology · doi:10.1038/nchembio1105-308 · Cited by 609
Webb, A., Bond, R., McLean, P., Uppal, R., Benjamin, N., & Ahluwalia, A. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0402927101 · Cited by 608
Self-citationShiva, S., Huang, Z., Grubina, R., Sun, J., Ringwood, L. A., MacArthur, P. H., Xu, X., Murphy, E., Darley-Usmar, V. M., & Gladwin, M. T. (2007) · Circulation Research · doi:10.1161/01.res.0000260171.52224.6b · Cited by 599
Red blood cells express a functional endothelial nitric oxide synthase
Kleinbongard, P. (2005) · Blood · doi:10.1182/blood-2005-10-3992 · Cited by 575
Hypoxia, red blood cells, and nitrite regulate NO-dependent hypoxic vasodilation
Crawford, J. H. (2006) · Blood · doi:10.1182/blood-2005-07-2668 · Cited by 497
Millar, T. M., Stevens, C. R., Benjamin, N., Eisenthal, R., Harrison, R., & Blake, D. R. (1998) · FEBS Letters · doi:10.1016/s0014-5793(98)00430-x · Cited by 491
Self-citationHendgen-Cotta, U. B., Merx, M. W., Shiva, S., Schmitz, J., Becher, S., Klare, J. P., Steinhoff, H.-J., Goedecke, A., Schrader, J., Gladwin, M. T., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0801336105 · Cited by 418
Reduction of nitrite to nitric oxide catalyzed by xanthine oxidoreductase
Godber, B. L. J., Doel, J. J., Sapkota, G. P., Blake, D. R., Stevens, C. R., Eisenthal, R., & Harrison, R. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.11.7757 · Cited by 411
Dietary nitrite supplementation protects against myocardial ischemia-reperfusion injury
Bryan, N. S., Calvert, J. W., Elrod, J. W., Gundewar, S., Ji, S. Y., & Lefer, D. J. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0706579104 · Cited by 347
Dejam, A., Hunter, C. J., Tremonti, C., Pluta, R. M., Hon, Y. Y., Grimes, G., Partovi, K., Pelletier, M. M., Oldfield, E. H., Cannon, R. O., et al. (2007) · Circulation · doi:10.1161/circulationaha.107.712133 · Cited by 334
Intravascular flow decreases erythrocyte consumption of nitric oxide
Liao, J. C., Hein, T. W., Vaughn, M. W., Huang, K., & Kuo, L. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.15.8757 · Cited by 301
The functional nitrite reductase activity of the heme-globins
Gladwin, M. T., & Kim-Shapiro, D. B. (2008) · Blood · doi:10.1182/blood-2008-01-115261 · Cited by 293
Rassaf, T., Flögel, U., Drexhage, C., Hendgen-Cotta, U., Kelm, M., & Schrader, J. (2007) · Circulation Research · doi:10.1161/circresaha.107.152488 · Cited by 284
Inhaled nebulized nitrite is a hypoxia-sensitive NO-dependent selective pulmonary vasodilator
Hunter, C. J., Dejam, A., Blood, A. B., Shields, H., Kim-Shapiro, D. B., Machado, R. F., Tarekegn, S., Mulla, N., Hopper, A. O., Schechter, A. N., et al. (2004) · Nature Medicine · doi:10.1038/nm1109 · Cited by 281
Characterization of the Magnitude and Kinetics of Xanthine Oxidase-catalyzed Nitrite Reduction
Li, H., Samouilov, A., Liu, X., & Zweier, J. L. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m011648200 · Cited by 280
Pluta, R. M. (2005) · JAMA · doi:10.1001/jama.293.12.1477 · Cited by 261
Zoroğlu, S. S., Armutçu, F., Özen, Ş., Gürel, A., Sivaslı, E., Yetkin, O., & Meram, İ. (2004) · European Archives of Psychiatry and Clinical Neuroscience · doi:10.1007/s00406-004-0456-7 · Cited by 235
An S -nitrosothiol (SNO) synthase function of hemoglobin that utilizes nitrite as a substrate
Angelo, M., Singel, D. J., & Stamler, J. S. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0600942103 · Cited by 233
A sensitive fluorometric assay for measuring xanthine dehydrogenase and oxidase in tissues
Beckman, J. S., Parks, D. A., Pearson, J. D., Marshall, P. A., & Freeman, B. Α. (1989) · Free Radical Biology and Medicine · doi:10.1016/0891-5849(89)90068-3 · Cited by 233
Tripatara, P., Patel, N. S. A., Webb, A., Rathod, K., Lecomte, F. M. J., Mazzon, E., Cuzzocrea, S., Yaqoob, M. M., Ahluwalia, A., & Thiemermann, C. (2007) · Journal of the American Society of Nephrology · doi:10.1681/asn.2006050450 · Cited by 226
Self-citationCatalytic generation of N2O3 by the concerted nitrite reductase and anhydrase activity of hemoglobin
Basu, S., Grubina, R., Huang, J., Conradie, J., Huang, Z., Jeffers, A., Jiang, A., He, X., Azarov, I., Seibert, R., et al. (2007) · Nature Chemical Biology · doi:10.1038/nchembio.2007.46 · Cited by 224
Hypoxic Modulation of Exogenous Nitrite-Induced Vasodilation in Humans
Maher, A. R., Milsom, A. B., Gunaruwan, P., Abozguia, K., Ahmed, I., Weaver, R. A., Thomas, P., Ashrafian, H., Born, G. V. R., James, P. E., et al. (2008) · Circulation · doi:10.1161/circulationaha.107.719591 · Cited by 210
Self-citationNitric oxide, cytochrome-c oxidase and myoglobin
Brunori, M. (2001) · Trends in Biochemical Sciences · doi:10.1016/s0968-0004(00)01698-4 · Cited by 197
Xanthine Oxidase-mediated Decomposition of S-Nitrosothiols
Trujillo, M., Álvarez, M. N., Peluffo, G., Freeman, B. Α., & Radí, R. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.14.7828 · Cited by 195
Giraldez, R. R., Panda, A., Xia, Y., Sanders, S. P., & Zweier, J. L. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.34.21420 · Cited by 180
Nitric oxide synthase reduces nitrite to NO under anoxia
Vanin, A. F., Bevers, L. M., Slama-Schwok, A., & van Faassen, E. E. (2007) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-006-6374-2 · Cited by 151
Kaynar, H., Meral, M., Turhan, H., Keleş, M., Çelik, G., & Akçay, F. (2005) · Cancer Letters · doi:10.1016/j.canlet.2004.12.005 · Cited by 149
Characterization of the effects of oxygen on xanthine oxidase-mediated nitric oxide formation
Li, H., Samouilov, A., Liu, X., & Zweier, J. L. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m314336200 · Cited by 146
Endothelial nitric oxide synthase reduces nitrite anions to NO under anoxia
Gautier, C., van Faassen, E., Mikula, I., Martasek, P., & Slama-Schwok, A. (2006) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2006.01.031 · Cited by 143
Chen, L., & Mehta, J. L. (1998) · Journal of Cardiovascular Pharmacology · doi:10.1097/00005344-199807000-00009 · Cited by 141
Phosphorylation of Xanthine Dehydrogenase/Oxidase in Hypoxia
Kayyali, U. S., Donaldson, C., Huang, H., Abdelnour, R., & Hassoun, P. M. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m010100200 · Cited by 136
Terada, L. S., Dormish, J. J., Shanley, P. F., Leff, J. A., Anderson, B. O., & Repine, J. E. (1992) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.1992.263.3.l394 · Cited by 130
Hemoglobin-Mediated, Hypoxia-Induced Vasodilation via Nitric Oxide
Robinson, J. M., & Lancaster, J. R. (2005) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.f292 · Cited by 104
Superoxide-mediated Decomposition of BiologicalS-Nitrosothiols
Aleryani, S., Milo, E., Rose, Y., & Kostka, P. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.11.6041 · Cited by 91
Rouquette, M., Page, S., Bryant, R., Benboubetra, M., Stevens, C. R., Blake, D. R., Whish, W. D., Harrison, R., & Tosh, D. (1998) · FEBS Letters · doi:10.1016/s0014-5793(98)00385-8 · Cited by 78
Li, H., Cui, H., Liu, X., & Zweier, J. L. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m411905200 · Cited by 64
MacAllister, R. J., Calver, A., Riezebos, J., Collier, J., & Vallance, P. J. (1995) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)09496-0 · Cited by 60
Durak, İ., Aytaç, B., Atmaca, Y., Devrím, E., Avcı, A., Erol, Ç., & Oral, D. (2004) · Life Sciences · doi:10.1016/j.lfs.2004.04.015 · Cited by 56
Aktan, B., Tayşi, S., Gümüştekin, K., Bakan, N., & Sütbeyaz, Y. (2003) · PubMed · Cited by 51
Estimation of Nitric Oxide Concentration in Blood for Different Rates of Generation
Liu, X., Yan, Q., Baskerville, K. L., & Zweier, J. L. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m611684200 · Cited by 47
Xanthine oxidoreductase is present in bile ducts of normal and cirrhotic liver
Martin, H. M., Moore, K. P., Bosmans, E., Davies, S. E., Burroughs, A. K., Dhillon, A. P., Tosh, D., & Harrison, R. (2004) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2004.06.045 · Cited by 26
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Inorganic Nitrate Supplementation Lowers Blood Pressure in Humans: Role for Nitrite-Derived NO
Kapil, V., Milsom, A. B., Okorie, M., Maleki-Toyserkani, S., Akram, F., Rehman, F., Arghandawi, S., Pearl, V., Benjamin, N., Loukogeorgakis, S., et al. (2010) · Hypertension · doi:10.1161/hypertensionaha.110.153536 · Cited by 621
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Lundberg, J. O., Gladwin, M. T., Ahluwalia, A., Benjamin, N., Bryan, N. S., Butler, A., Cabrales, P., Fago, A., Feelisch, M., Ford, P. C., et al. (2009) · Nature Chemical Biology · doi:10.1038/nchembio.260 · Cited by 617
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Tejero, J., Shiva, S., & Gladwin, M. T. (2019) · Physiological Reviews · doi:10.1152/physrev.00036.2017 · Cited by 541
Red Blood Cell Function and Dysfunction: Redox Regulation, Nitric Oxide Metabolism, Anemia
Kuhn, V., Diederich, L., Keller, T. C. S., Kramer, C. M., Lückstädt, W., Panknin, C., Suvorava, T., Isakson, B. E., Kelm, M., & Cortese-Krott, M. M. (2017) · Antioxidants & Redox Signaling · doi:10.1089/ars.2016.6954 · Cited by 469
Metadata
- Authors
- Webb, A. J., Milsom, A. B., Rathod, K. S., Chu, W. L., Qureshi, S., Lovell, M. J., Lecomte, F. M. J., Perrett, D., Raimondo, C., Khoshbin, E., Ahmed, Z., Uppal, R., Benjamin, N., Hobbs, A. J., & Ahluwalia, A.
- Affiliations
- St Bartholomew's Hospital (GB)
- ORCID
- Venue
- Circulation Research
- Published
- 2008-10-24
- Volume
- 103
- Issue
- 9
- Pages
- 957-964
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- PMC
- PMC2841343
- OpenAlex
- W2158124791
- Cited by
- 203
- References
- 47
- Citations by year
- 2026: 7 · 2025: 9 · 2024: 6 · 2023: 7 · 2022: 5 · 2021: 8 · 2020: 7 · 2019: 8 · 2018: 13 · 2017: 16 · 2016: 10 · 2015: 14 · 2014: 23 · 2013: 14 · 2012: 19
- FWCI
- 8.12
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Research Portal (King's College London) (submittedVersion)
- Funders
- Wellcome Trust (067422)
- British Heart Foundation
- 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
- nitrite reduction, nitric oxide, hypoxia, xanthine oxidoreductase, erythrocytes, endothelial nitric oxide synthase, allopurinol, acidosis, L-arginine, L-NMMA, L-NAME, vasodilation, ischemia, deoxyhemoglobin, blood vessels
- MeSH terms
- Allopurinol, Animals, Aorta, Arginine, Cells, Cultured, Enzyme Inhibitors, Erythrocytes, Fluorometry, Humans, Hydrogen-Ion Concentration, Male, Nitric Oxide, Nitrite Reductases, Nitrites, Oxidation-Reduction, Xanthine Dehydrogenase, Cell Hypoxia, Rats, Wistar, omega-N-Methylarginine, NG-Nitroarginine Methyl Ester, Xanthine, Endothelial Cells, Rats, Nitric Oxide Synthase Type II, Nitric Oxide Synthase Type III
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