Measurement of in vivo nitric oxide synthesis in humans using stable isotopic methods: a systematic review.
Open accessAbstract
Stable isotopic methods are considered the "gold standard" for the measurement of rates of in vivo NO production. However, values reported for healthy human individuals differ by more than 1 order of magnitude. The reason for the apparent variability in NO production is unclear. The primary aim of this review was to evaluate and compare the rates of in vivo NO production in health and disease using stable isotope methods. Articles were retrieved using the PubMed electronic database. Information on concentrations, isotopic enrichments of fluxes, and conversion rates of molecules involved in the NO metabolic pathway was extracted from selected articles; 35 articles were included in the final analysis. Three protocols were identified, including the arginine-citrulline, the arginine-nitrate, and the oxygen-nitrate protocols. The arginine-citrulline protocol showed a wider variability compared to the arginine-nitrate and oxygen-nitrate protocols. The direction of the association between disease state and rate of NO production was essentially determined by the etiopathogenesis of the disorder (inflammatory, metabolic, vascular). Considerable variation in methodologies used to assess whole-body NO synthesis in humans exists. The precision of several aspects of the techniques and the validity of some assumptions made remain unknown, and there is a paucity of information about physiological rates of NO production from childhood over adolescence to old age.
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Inorganic nitrate may lower blood pressure through greater nitric oxide production.
“The BP-lowering effects of inorganic nitrate may derive from increased generation of nitric oxide (NO) (13,14), a pleiotropic molecule involved in the vasodilation of large arteries and resistance vessels (13,14).”
From Inorganic Nitrate and Beetroot Juice Supplementation Reduces Blood Pressure in Adults: A Systematic Review and Meta-Analysis (2013) · cites this paper as [13]
Cyclic GMP is the second messenger of the nitric oxide pathway and a biomarker of nitric oxide bioactivity.
“Cyclic GMP (cGMP) is the second messenger of the NO pathway and it represents a biomarker of NO bioactivity (13).”
From Inorganic Nitrate and Beetroot Juice Supplementation Reduces Blood Pressure in Adults: A Systematic Review and Meta-Analysis (2013) · cites this paper as [13]
Plasma nitrite concentration is a biomarker of nitric oxide bioavailability.
“Plasma nitrite concentrations are a biomarker of NO bioavailability (13).”
From Inorganic Nitrate and Beetroot Juice Supplementation Reduces Blood Pressure in Adults: A Systematic Review and Meta-Analysis (2013) · cites this paper as [13]
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Griendling, K. K., Touyz, R. M., Zweier, J. L., Dikalov, S., Chilian, W. M., Chen, Y., Harrison, D. G., & Bhatnagar, A. (2016) · Circulation Research · doi:10.1161/res.0000000000000110 · Cited by 452 · see citing works
Siervo, M., Lara, J., Ogbonmwan, I., & Mathers, J. C. (2013) · The Journal of Nutrition · doi:10.3945/jn.112.170233 · Cited by 375 · see citing works
Self-citationCortese-Krott, M. M., Koning, A. M., Kuhnle, G., Nagy, P., Bianco, C. L., Pasch, A., Wink, D. A., Fukuto, J. M., Jackson, A. A., van Goor, H., et al. (2017) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7083 · Cited by 363 · see citing works
Self-citationRole of L-Arginine in Nitric Oxide Synthesis and Health in Humans
Wu, G., Meininger, C. J., McNeal, C. J., Bazer, F. W., & Rhoads, J. M. (2021) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-74180-8_10 · Cited by 311 · see citing works
Connecting the Chemical and Biological Properties of Nitric Oxide
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Medinets, S., Skiba, U., Rennenberg, H., & Butterbach‐Bahl, K. (2014) · Soil Biology and Biochemistry · doi:10.1016/j.soilbio.2014.09.025 · Cited by 219 · see citing works
Ashor, A. W., Lara, J., Mathers, J. C., & Siervo, M. (2014) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2014.04.004 · Cited by 185 · see citing works
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Arginine and Ornithine Are the Main Precursors for Citrulline Synthesis in Mice3
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Ashmore, T., Fernandez, B. O., Branco‐Price, C., West, J. A., Cowburn, A. S., Heather, L. C., Griffin, J. L., Johnson, R. S., Feelisch, M., & Murray, A. J. (2014) · The Journal of Physiology · doi:10.1113/jphysiol.2014.275263 · Cited by 58 · see citing works
Self-citationWang, Y., Nikodem, M. P., Zhang, E., Cikach, F. S., Barnes, J. W., COMHAIR, S. A. A., Dweik, R. A., Kao, C. C., & Wysocki, G. (2015) · Scientific Reports · doi:10.1038/srep09096 · Cited by 55 · see citing works
Ashmore, T., Roberts, L. D., Morash, A. J., Kotwica, A. O., Finnerty, J., West, J. A., Murfitt, S. A., Fernandez, B. O., Branco, C. M., Cowburn, A. S., et al. (2015) · BMC Biology · doi:10.1186/s12915-015-0221-6 · Cited by 51 · see citing works
Self-citationHussin, A. M., Ashor, A. W., Schoenmakers, I., Hill, T. R., Mathers, J. C., & Siervo, M. (2016) · European Journal of Nutrition · doi:10.1007/s00394-016-1159-3 · Cited by 52 · see citing works
Self-citationDecreased serum L-arginine and L-citrulline levels in major depression
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Lara, J., Ogbonmwan, I., Oggioni, C., Zheng, D., Qadir, O., Ashor, A. W., Brandt, K., Mathers, J. C., & Siervo, M. (2015) · Maturitas · doi:10.1016/j.maturitas.2015.07.028 · Cited by 43 · see citing works
Self-citationLobysheva, I. I., Biller, P., Gallez, B., Beauloye, C., & Balligand, J. (2013) · PLoS ONE · doi:10.1371/journal.pone.0076457 · Cited by 33 · see citing works
Ishaq, A., Tchkonia, T., Kirkland, J. L., Siervo, M., & Saretzki, G. C. (2022) · Experimental Gerontology · doi:10.1016/j.exger.2022.111798 · Cited by 32 · see citing works
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Quantitative aspects of nitric oxide production from nitrate and nitrite
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Kuo, H.-C., Hsu, C., Huang, C.-F., Lo, M., Chien, S., & Tain, Y. (2012) · Journal of the American Society of Hypertension · doi:10.1016/j.jash.2012.09.003 · Cited by 26 · see citing works
Nanotechnology Allied to Nitric Oxide Release Materials for Dermatological Applications
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Zotti, F. D., Lobysheva, I. I., & Balligand, J. (2018) · PLoS ONE · doi:10.1371/journal.pone.0200352 · Cited by 23 · see citing works
Lin, Y.-J., Hsu, C., Lo, M., Huang, C.-F., Chien, S., & Tain, Y. (2012) · Circulation Journal · doi:10.1253/circj.cj-12-0602 · Cited by 23 · see citing works
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Metabolic effects of L ‐citrulline in type 2 diabetes
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Suppression of erythropoiesis by dietary nitrate
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Self-citationCumpstey, A. F., & Feelisch, M. (2017) · Wiley-VCH eBooks · doi:10.1002/9783527692156.ch27 · Cited by 22 · see citing works
Self-citationPPARα-independent effects of nitrate supplementation on skeletal muscle metabolism in hypoxia
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Quantitative aspects of nitric oxide production in the heart
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Deveaux, A., Fouillet, H., Petzke, K. J., Hermier, D., André, E., Bunouf, P., Lantoine, F., Benamouzig, R., Mathé, V., Huneau, J., et al. (2016) · Journal of Nutrition · doi:10.3945/jn.116.231910 · Cited by 14 · see citing works
Marealle, A. I., Siervo, M., Wassell, S., Bluck, L. J. C., Prentice, A. M., Minzi, O., Sasi, P. G., Kamuhabwa, A. A. R., Soka, D., Makani, J., et al. (2018) · Nitric Oxide · doi:10.1016/j.niox.2017.12.009 · Cited by 13 · see citing works
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The reactive species interactome
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Self-citationTracer‐based metabolomics for profiling nitric oxide metabolites in a 3D microvessels‐on‐chip model
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Glutamine and citrulline concentrations reflect nitric oxide synthesis in the human nervous system
Pérez‐Neri, I., Ramírez‐Bermúdez, J., Ojeda-López, C., Montes, S., Soto‐Hernández, J. L., & Rı́os, C. (2019) · Neurología (English Edition) · doi:10.1016/j.nrleng.2017.07.005 · Cited by 7 · see citing works
Adams, K. J., Wilson, J. G., Millington, D. S., Moseley, M. A., Colton, C. A., Thompson, J. W., & Gottschalk, W. K. (2021) · Journal of the American Society for Mass Spectrometry · doi:10.1021/jasms.1c00055 · Cited by 7 · see citing works
Siervo, M., Tomatis, V., Stephan, B. C. M., Feelisch, M., & Bluck, L. J. C. (2012) · European Journal of Clinical Investigation · doi:10.1111/j.1365-2362.2012.02684.x · Cited by 6 · see citing works
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Kardol, L. R., Gray, A., Rhaman, A., Larcombe, A. N., Jeffries‐Stokes, C., Stokes, A., Bourke, S. A., Shinde, S., Croft, K. D., & Wyrwoll, C. S. (2026) · Regulatory Toxicology and Pharmacology · doi:10.1016/j.yrtph.2026.106030 · Cited by 1 · see citing works
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Exploring Redox Biology in physiology and disease
Koning, A. M. (2017) · University of Groningen research database (University of Groningen / Centre for Information Technology) · Cited by 1 · see citing works
Associação da ventilação mecânica e seu desmame com o estresse oxidativo
de Sousa, G. B. (2012)
Lin, I.-C., Hsu, C., Lo, M., Chien, S., & Tain, Y. (2016)
Gallardo, E. J., Zoughaib, W. S., Singhal, A., Hoffman, R. L., & Coggan, A. R. (2024) · medRxiv · doi:10.1101/2024.05.21.24307698
Gallardo, E. J., Zoughaib, W. S., Singhal, A., Hoffman, R. L., & Coggan, A. R. (2025) · PLoS ONE · doi:10.1371/journal.pone.0312961
Loftus, T., Benjamim, C. J. R., Vaccarezza, M., Stephan, B. C. M., Nguyen, V. H., Ashor, A. W., & Siervo, M. (2026) · Nitric Oxide · doi:10.1016/j.niox.2026.01.001 · Cited by 1 · see citing works
Self-citation
- Authors
- Siervo, M., Stephan, B. C. M., Feelisch, M., & Bluck, L. J. C.
- Affiliations
- MRC Elsie Widdowson Laboratory (GB)
- University of Cambridge (GB)
- University of Warwick (GB)
- Corresponding author
- Siervo, M.
- Venue
- Free Radical Biology and Medicine
- Publisher
- Elsevier BV
- Published
- 2011-08
- Volume
- 51
- Issue
- 4
- Pages
- 795-804
- ISSN
- 0891-5849 (ISSN-L)
- OpenAlex
- W1989312455
- Cited by
- 52
- References
- 89
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 2 · 2023: 5 · 2022: 3 · 2021: 2 · 2019: 3 · 2018: 5 · 2017: 6 · 2016: 4 · 2015: 4 · 2014: 5 · 2013: 3 · 2012: 7
- FWCI
- 0.51
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Free Radical Biology and Medicine (publishedVersion)
- PubMed (publishedVersion)
- ePrints Soton (University of Southampton) (submittedVersion)
- Newcastle University ePrints (Newcastle Univesity)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- nitric oxide production, nitric oxide metabolism, interindividual variability, healthy volunteers
- MeSH terms
- Age Factors, Arginine, Arteries, Cardiovascular Diseases, Citrulline, Humans, Nitrates, Nitric Oxide, Oxygen, Radioisotopes, Vasodilation, Reproducibility of Results, Clinical Laboratory Techniques
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