Novel Aspects of Dietary Nitrate and Human Health

Weitzberg, Eddie; Lundberg, Jon O.

doi:10.1146/annurev-nutr-071812-161159

Cited by 324Nitric Oxide and Endothelin EffectsNutritional Studies and DietPhytochemicals and Antioxidant Activities

Novel Aspects of Dietary Nitrate and Human Health

Weitzberg, Eddie, Lundberg, Jon O.·2013·Annual Review of Nutrition

DOI 10.1146/annurev-nutr-071812-161159

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Abstract

The circulation of nitrogen in nature is a prerequisite for life on earth. In the nitrogen cycle atmospheric nitrogen is fixated by bacteria into forms that can be utilized by plants and mammals. Nitrate and nitrite are obligate intermediates in this cycle, and for more than half a century these anions have interested nutritional scientists, mostly in relation to cancer, because of their ability to form nitrosamines. However, after the discovery of mammalian endogenous nitric oxide (NO) generation and later that its oxidation products nitrate and nitrite can be recycled back to bioactive NO, a novel field of research has emerged that explores a potentially beneficial role of these anions in physiology, nutrition, and therapeutics. In our diet, vegetables are the major source of nitrate that can fuel a nitrate-nitrite-NO pathway. Herein we discuss the nutritional aspects of this pathway and what is presently known about the implications for human health.

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NOX1 expression is activated by several factors including angiotensin II, PDGF, and thrombin.
“NOX1 expression is activated by several factors including angiotensin II, PDGF, and thrombin (382, 492, 630, 695, 999).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [999]
Nitrate and nitrite derived from vegetables and fruits are reduced to NO, followed by formation of S-nitrosothiols, rather than formation of nitrosamines, especially in the presence of reducing agents such as vitamin C and E in the stomach.
“Although it may be difficult to isolate the specific effects of these dietary nutrients, as discussed above, the nitrate and nitrite derived from vegetables and fruits are reduced to NO, which is followed by the formation of S-nitrosothiols [123], rather than the formation of nitrosamines especially in the presence of reducing agents such as vitamin C and E in the stomach [28,124].”
From NO-Rich Diet for Lifestyle-Related Diseases (2015) · cites this paper as [123]
Nitrate-rich diets increase plasma and tissue levels of nitrite, but this cannot be accounted solely by nitrate reduction from oral bacteria.
“Recent and past data have demonstrated that nitrate-rich diets increase plasma and tissue levels of nitrite [9,10], but this cannot be accounted solely by nitrate reduction from oral bacteria and other mechanisms have been implicated and are under investigation [11].”
From Nitrate reduction to nitrite, nitric oxide and ammonia by gut bacteria under physiological conditions (2015) · cites this paper as [11]

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Acute effect of a high nitrate diet on brain perfusion in older adults
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Nitrite in Human Saliva. Its Possible Relationship to Nitrosamine Formation23
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Gastroprotective and blood pressure lowering effects of dietary nitrate are abolished by an antiseptic mouthwash
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Dietary nitrate reduces muscle metabolic perturbation and improves exercise tolerance in hypoxia
Vanhatalo, A., Fulford, J., Bailey, S. J., Blackwell, J. R., Winyard, P. G., & Jones, A. M. (2011) · The Journal of Physiology · doi:10.1113/jphysiol.2011.216341 · Cited by 233 · see citing works
Effects of short-term dietary nitrate supplementation on blood pressure, O2uptake kinetics, and muscle and cognitive function in older adults
Kelly, J., Fulford, J., Vanhatalo, A., Blackwell, J. R., French, O., Bailey, S. J., Gilchrist, M., Winyard, P. G., & Jones, A. M. (2013) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00406.2012 · Cited by 232 · see citing works
Nitrite supplementation reverses vascular endothelial dysfunction and large elastic artery stiffness with aging: Sodium nitrite and vascular dysfunction with aging
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Sialin ( SLC17A5 ) functions as a nitrate transporter in the plasma membrane
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Nitrite reductase activity of cytochrome c
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Generation of nitric oxide from nitrite by carbonic anhydrase: a possible link between metabolic activity and vasodilation
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Nitric oxide and quality and safety of muscle based foods
Skibsted, L. H. (2011) · Nitric Oxide · doi:10.1016/j.niox.2011.03.307 · Cited by 201 · see citing works
Biology of nitrogen oxides in the gastrointestinal tract
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Mediterranean food pattern and the primary prevention of chronic disease: recent developments
Martinez-Gonzalez, M. A., Bes-Rastrollo, M., Serra-Majem, L., Lairon, D., Estruch, R., & Trichopoulou, A. (2009) · Nutrition Reviews · doi:10.1111/j.1753-4887.2009.00172.x · Cited by 200 · see citing works
Blood pressure-lowering effects of beetroot juice and novel beetroot-enriched bread products in normotensive male subjects
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Concomitant presence of N-nitroso and S-nitroso proteins in human plasma
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Dietary nitrate generates potentially mutagenic concentrations of nitric oxide at the gastroesophageal junction
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Helicobacter pylori stimulates inducible nitric oxide synthase expression and activity in a murine macrophage cell line
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Effects of pH, Nitrite, and Ascorbic Acid on Nonenzymatic Nitric Oxide Generation and Bacterial Growth in Urine
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Nitrate in vegetables Scientific Opinion of the Panel on Contaminants in the Food chain 1
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Chronic sodium nitrite therapy augments ischemia-induced angiogenesis and arteriogenesis
Kumar, D., Branch, B. G., Pattillo, C. B., Hood, J., Thoma, S., Simpson, S., Illum, S., Arora, N., Chidlow, J. H., Langston, W., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0711480105 · Cited by 187 · see citing works
Red wine-dependent reduction of nitrite to nitric oxide in the stomach
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Dietary nitrate in Japanese traditional foods lowers diastolic blood pressure in healthy volunteers
Sobko, T., Marcus, C., Govoni, M., & Kamiya, S. (2010) · Nitric Oxide · doi:10.1016/j.niox.2009.10.007 · Cited by 185 · see citing works
Cardioprotective effects of vegetables: is nitrate the answer?
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Nitrite therapy after cardiac arrest reduces reactive oxygen species generation, improves cardiac and neurological function, and enhances survival via reversible inhibition of mitochondrial complex I
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GASTRIC-JUICE NITRITE
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Fatty Acid Transduction of Nitric Oxide Signaling
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Dietary nitrite prevents hypercholesterolemic microvascular inflammation and reverses endothelial dysfunction
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Inhibition of peroxynitrite dependent DNA base modification and tyrosine nitration by the extra virgin olive oil-derived antioxidant hydroxytyrosol
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Effect of beetroot juice on lowering blood pressure in free-living, disease-free adults: a randomized, placebo-controlled trial
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Base Modification and Strand Breakage in Isolated Calf Thymus DNA and in DNA from Human Skin Epidermal Keratinocytes Exposed to Peroxynitrite or 3-Morpholinosydnonimine
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Conjugated linoleic acid is a preferential substrate for fatty acid nitration
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Reactions of ferrous neuroglobin and cytoglobin with nitrite under anaerobic conditions
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Mechanisms of nitrite reduction to nitric oxide in the heart and vessel wall
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Characterization of the Mechanism and Magnitude of Cytoglobin-mediated Nitrite Reduction and Nitric Oxide Generation under Anaerobic Conditions
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Helicobacter pylori is killed by nitrite under acidic conditions
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Inhaled ethyl nitrite gas for persistent pulmonary hypertension of the newborn
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Dietary nitrate supplementation improves revascularization in chronic ischemia
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Dietary Nitrate Ameliorates Pulmonary Hypertension: Cytoprotective Role for Endothelial Nitric Oxide Synthase and Xanthine Oxidoreductase
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Protection from nonsteroidal anti-inflammatory drug (NSAID)-induced gastric ulcers by dietary nitrate
Jansson, E. Å., Petersson, J., Reinders, C., Sobko, T., Björne, H., Phillipson, M., Weitzberg, E., Holm, L., & Lundberg, J. O. (2007) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2006.11.018 · Cited by 106 · see citing works
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N‐nitroso compounds: Their chemical andin vivoformation and possible importance as environmental carcinogens
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Glutathione, protein sulfhydryls and cysteine proteases in gastric mucosal injury and protection
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Nitrate-reducing bacteria on rat tongues
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The ingestion of inorganic nitrate increases gastric S-nitrosothiol levels and inhibits platelet function in humans
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Increase in gastric pH reduces hypotensive effect of oral sodium nitrite in rats
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Tumors face NO problems?
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Bacterially catalysed N-nitrosation reactions and their relative importance in the human stomach
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Dietary nitrate and nitrite modulate blood and organ nitrite and the cellular ischemic stress response
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Decreased leukocyte recruitment by inorganic nitrate and nitrite in microvascular inflammation and NSAID-induced intestinal injury
Jädert, C., Petersson, J., Massena, S., Ahl, D., Grapensparr, L., Holm, L., Lundberg, J. O., & Phillipson, M. (2012) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2011.11.018 · Cited by 97 · see citing works
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Dietary Nitrate Supplementation Protects Against Doxorubicin-Induced Cardiomyopathy by Improving Mitochondrial Function
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Nitrate and gastric cancer risks
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Human xanthine oxidase converts nitrite ions into nitric oxide (NO)
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Nitric oxide and cancer: an introduction
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Novel mechanism of nitrosative stress from dietary nitrate with relevance to gastro-oesophageal junction cancers
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Nitrite Promotes Lymphoma Incidence in Rats
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Dietary inorganic nitrate mobilizes circulating angiogenic cells
Heiß, C., Meyer, C. G., Totzeck, M., Hendgen-Cotta, U. B., Heinen, Y., Luedike, P., Keymel, S., Ayoub, N., Lundberg, J. O., Weitzberg, E., et al. (2012) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2012.02.051 · Cited by 78 · see citing works
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N-NITROSO COMPOUNDS: A PERSPECTIVE ON HUMAN EXPOSURE
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Gastrointestinal nitric oxide generation in germ-free and conventional rats
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NF-κB, inducible nitric oxide synthase and apoptosis by Helicobacter pylori infection
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Dietary nitrate inhibits stress-induced gastric mucosal injury in the rat
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Nitrotyrosine formation and its role in various pathological conditions
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Effect of sodium nitrate loading on electrolyte transport by the renal tubule
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Various intracellular compartments cooperate in the release of nitric oxide from glycerol trinitrate in liver
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Endothelial Function, Nitric Oxide, and Cocoa Flavanols
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ANTAGONISM BETWEEN PERCHLORATE, IODIDE, THIOCYANATE, AND NITRATE FOR SECRETION IN HUMAN SALIVA ANALOGY WITH THE IODIDE TRAP OF THE THYROID
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Role for endothelial nitric oxide synthase in nitrite-induced protection against renal ischemia–reperfusion injury in mice
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Nitrite directly vasodilates hypoxic vasculature via nitric oxide‐dependent and ‐independent pathways
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Intragastric generation of antimicrobial nitrogen oxides from saliva—Physiological and therapeutic considerations
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Dietary Nitrite in Nitric Oxide Biology: A Redox Interplay with Implications for Pathophysiology and Therapeutics
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Effect of nitrogen fertiliser on the nitrate contents of field vegetables grown in Britain
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Intragastric nitric oxide is abolished in intubated patients and restored by nitrite*
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Nitrate transport in salivary glands with implications for NO homeostasis
Lundberg, J. O. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1210412109 · Cited by 49 · see citing works
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The potent vasodilator ethyl nitrite is formed upon reaction of nitrite and ethanol under gastric conditions
Gago, B., Nyström, T., Cavaleiro, C., Rocha, B. S., Barbosa, R. M., Laranjinha, J., & Lundberg, J. O. (2008) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2008.04.027 · Cited by 48 · see citing works
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DNA damage by nitrite and peroxynitrite: Protection by dietary phenols
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Dietary doses of nitrite restore circulating nitric oxide level and improve renal injury in<scp>l</scp>-NAME-induced hypertensive rats
Kanematsu, Y., Yamaguchi, K., Ohnishi, H., Motobayashi, Y., Ishizawa, K., Izawa, Y., Kawazoe, K., Kondo, S., Kagami, S., Tomita, S., et al. (2008) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00621.2007 · Cited by 44 · see citing works
Protective effect of dietary nitrate on experimental gastritis in rats
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Nitrate and glasshouse vegetables
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Acute dietary nitrate supplementation improves dry static apnea performance
Engan, H. K., JONES, A. M., Ehrenberg, F., & Schagatay, E. K. A. (2012) · Respiratory Physiology & Neurobiology · doi:10.1016/j.resp.2012.05.007 · Cited by 41 · see citing works
Excretion of nitrates and nitrites in saliva and bile in the dog
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Endogenous formation of N-nitroso compounds: a current perspective.
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Pepsin is nitrated in the rat stomach, acquiring antiulcerogenic activity: A novel interaction between dietary nitrate and gut proteins
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Orally administered nitrite attenuates cardiac allograft rejection in rats
Zhan, J., Nakao, A., Sugimoto, R., Dhupar, R., Wang, Y., Wang, Z., Billiar, T. R., & McCurry, K. R. (2009) · Surgery · doi:10.1016/j.surg.2009.05.002 · Cited by 19 · see citing works
Preserving vessel function during ischemic disease: new possibilities of inorganic nitrite therapy
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Effects of dietary inorganic nitrate on static and dynamic breath-holding in humans
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Self-citation
Effect of Cooking on the Nitrate Levels in Vegetables
Fletcher, J. R., Law, S. J., & Walters, A. H. (1987) · Nutrition and Health · doi:10.1177/026010608700500209 · Cited by 10 · see citing works

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Nitric oxide signaling in health and disease
Lundberg, J. O., & Weitzberg, E. (2022) · Cell · doi:10.1016/j.cell.2022.06.010 · Cited by 850 · see citing works
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Strategies to increase nitric oxide signalling in cardiovascular disease
Lundberg, J. O., Gladwin, M. T., & Weitzberg, E. (2015) · Nature Reviews Drug Discovery · doi:10.1038/nrd4623 · Cited by 576 · see citing works
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Overweight decreases the chance of achieving good response and low disease activity in early rheumatoid arthritis
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Integrated Soil and Crop Management in Organic Agriculture: A Logical Framework to Ensure Food Quality and Human Health?
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Nitrite Anion Therapy Protects Against Chronic Ischemic Tissue Injury in db/db Diabetic Mice in a NO/VEGF-Dependent Manner
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Long-term effect of linseed plus nitrate fed to dairy cows on enteric methane emission and nitrate and nitrite residuals in milk
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Use of multiple isotopic and chemical tracers to identify sources of nitrate in shallow groundwaters along the northern slope of the Qinling Mountains, China
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Effects of antiseptic mouthwash on resting metabolic rate: a randomized, double-blind, crossover study
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Physicochemical, nutritional, and sensory analyses of a nitrate-enriched beetroot gel and its effects on plasmatic nitric oxide and blood pressure
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Protective effects of sodium nitrate against testicular apoptosis and spermatogenesis impairments in streptozotocin-induced diabetic male rats
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Adaptation of Vibrio cholerae to Hypoxic Environments
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Authors: Weitzberg, E., & Lundberg, J. O.
Affiliations: Department of Physiology and Pharmacology, 1Section for Anesthesiology and Intensive Care,
Karolinska Institutet (SE)
ORCID: Weitzberg, Eddie
Lundberg, Jon O.
Venue: Annual Review of Nutrition
Publisher: Annual Reviews
Published: 2013-07-17
Volume: 33
Issue: 1
Pages: 129-159
ISSN: 0199-9885 (ISSN-L)
1545-4312
DOI: 10.1146/annurev-nutr-071812-161159
OpenAlex: W2158062208
Semantic Scholar: 43620fb624544326341074f9123e88b713aa29ac
Cited by: 324
References: 159
Citations by year: 2026: 15 · 2025: 23 · 2024: 30 · 2023: 26 · 2022: 22 · 2021: 22 · 2020: 19 · 2019: 36 · 2018: 33 · 2017: 27 · 2016: 23 · 2015: 25 · 2014: 18 · 2013: 5
FWCI: 2.61
Type: journal article
Language: en
Open access: closed
Locations: Annual Review of Nutrition (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Nutritional Studies and Diet
Health Sciences › Medicine › Biochemistry › Phytochemicals and Antioxidant Activities
Keywords: dietary nitrate, nitrite, nitric oxide, nitrate-nitrite-NO pathway, endogenous nitric oxide, nitrogen cycling, nitrosamines, cancer, vegetables, human health
MeSH terms: Animals, Carcinogens, Diet, Health Status, Humans, Nitrates, Nitric Oxide, Nitrites, Nitrosamines, Signal Transduction

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Novel Aspects of Dietary Nitrate and Human Health

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