Dietary nitrate (NO3), nitrite (NO2), and arginine can serve as sources for production of NOx (a diverse group of metabolites including nitric oxide, nitrosothiols, and nitroalkenes) via ultraviolet light exposure to skin, mammalian nitrate/nitrite reductases in tissues, and nitric oxide synthase enzymes, respectively. NOx are responsible for the hypotensive, antiplatelet, and cytoprotective effects of dietary nitrates and nitrites. Current regulatory limits on nitrate intakes, based on concerns regarding potential risk of carcinogenicity and methemoglobinemia, are exceeded by normal daily intakes of single foods, such as soya milk and spinach, as well as by some recommended dietary patterns such as the Dietary Approaches to Stop Hypertension diet. This review includes a call for regulatory bodies to consider all available data on the beneficial physiologic roles of nitrate and nitrite in order to derive rational bases for dietary recommendations.
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Couto E, Boffetta P, Lagiou P, Ferrari P, Buckland G, Overvad K, et al. Mediterranean dietary pattern and cancer risk in the EPIC cohort. Br J Canc. 2011;104(9):1493–9.
Trichopoulou A, Bamia C, Trichopoulos D. Mediterranean diet and survival among patients with coronary heart disease in Greece. Arch Intern Med. 2005;165(8):929–35.
Joshipura KJ, Hu FB, Manson JE, Stampfer MJ, Rimm EB, Speizer FE, et al. The effect of fruit and vegetable intake on risk for coronary heart disease. Arch Intern Med. 2001;134(12):1106–14.
Appel LJ, Brands MW, Daniels SR, Karanja N, Elmer PJ, Sacks FM. Dietary approaches to prevent and treat hypertension: a scientific statement from the American Heart Association. Hypertension. 2006;47(2):296–308.
Hord NG, Tang Y, Bryan NS. Food sources of nitrates and nitrites: the physiologic context for potential health benefits. Am J Clin Nutr. 2009;90(1):1–10.
Authority EFS. Nitrate in vegetables: scientific opinion of the panel on contaminants in the food chain. EFSA J. 2008;689:1–79.
Pennington J. Dietary exposure models for nitrates and nitrites. Food Contr. 1998;9:385–95.
Weitzberg E, Hezel M, Lundberg JO. Nitrate-nitrite-nitric oxide pathway: implications for anesthesiology and intensive care. Anesthesiology. 2010;113(6):1460–75.
•• Larsen FJ, Schiffer TA, Borniquel S, Sahlin K, Ekblom B, Lundberg JO, Weitzberg E. Dietary inorganic nitrate improves mitochondrial efficiency in humans. Cell Metabol. 2011;13(2):149–59. This article provides evidence of the mechanistic basis for dietary nitrate’s ability to enhance physical endurance. The article demonstrates that improved mitochondrial P/O ratio is correlated to the reduction in oxygen cost during exercise. Nitrate was shown to decrease the expression of ATP/ADP translocase, a protein involved in proton conductance.
Zweier JL, Samouilov A, Kuppusamy P. Non-enzymatic nitric oxide synthesis in biological systems. Biochim Biophys Acta. 1999;1411(2–3):250–62.
Lundberg JO, Gladwin MT, Ahluwalia A, Benjamin N, Bryan NS, Butler A, et al. Nitrate and nitrite in biology, nutrition and therapeutics. Nat Chem Biol. 2009;5(12):865–9.
van Faassen EE, Bahrami S, Feelisch M, Hogg N, Kelm M, Kim-Shapiro DB, et al. Nitrite as regulator of hypoxic signaling in mammalian physiology. Med Res Rev. 2009;29(5):683–741.
Lundberg JO, Weitzberg E. NO-synthase independent NO generation in mammals. Biochem Biophys Res Commun. 2010;396(1):39–45.
Ambs S, Merriam WG, Bennett WP, Felley-Bosco E, Ogunfusika MO, Oser SM, et al. Frequent nitric oxide synthase-2 expression in human colon adenomas: implication for tumor angiogenesis and colon cancer progression. Canc Res. 1998;58(2):334–41.
Bryan NS, Calvert JW, Gundewar S, Lefer DJ. Dietary nitrite restores NO homeostasis and is cardioprotective in endothelial nitric oxide synthase-deficient mice. Free Radic Biol Med. 2008
Spiegelhalder B, Eisenbrand G, Preussmann R. Influence of dietary nitrate on nitrite content of human saliva: possible relevance to in vivo formation of N-nitroso compounds. Food Cosmet Toxicol. 1976;14(6):545–8.
Jansson EA, Huang L, Malkey R, Govoni M, Nihlen C, Olsson A, et al. A mammalian functional nitrate reductase that regulates nitrite and nitric oxide homeostasis. Nat Chem Biol. 2008;4(7):411–7.
Duncan C, Dougall H, Johnston P, Green S, Brogan R, Leifert C, et al. Chemical generation of nitric oxide in the mouth from the enterosalivary circulation of dietary nitrate. Nat Med. 1995;1(6):546–51.
Govoni M, Jansson EA, Weitzberg E, Lundberg JO. The increase in plasma nitrite after a dietary nitrate load is markedly attenuated by an antibacterial mouthwash. Nitric Oxide. 2008
Petersson J, Phillipson M, Jansson EA, Patzak A, Lundberg JO, Holm L. Dietary nitrate increases gastric mucosal blood flow and mucosal defense. Am J Physiol. 2007;292(3):G718–24.
Bryan NS. Cardioprotective actions of nitrite therapy and dietary considerations. Front Biosci. 2009;14:4793–808.
Sobko T, Huang L, Midtvedt T, Norin E, Gustafsson LE, Norman M, et al. Generation of NO by probiotic bacteria in the gastrointestinal tract. Free Radic Biol Med. 2006;41(6):985–91.
Oplander C, Volkmar CM, Paunel-Gorgulu A, van Faassen EE, Heiss C, Kelm M, et al. Whole body UVA irradiation lowers systemic blood pressure by release of nitric oxide from intracutaneous photolabile nitric oxide derivates. Circ Res. 2009;105(10):1031–40.
Carlstrom M, Persson AE, Larsson E, Hezel M, Scheffer PG, Teerlink T, et al. Dietary nitrate attenuates oxidative stress, prevents cardiac and renal injuries, and reduces blood pressure in salt-induced hypertension. Cardiovasc Res. 2011;89(3):574–85.
Feelisch M, Kolb-Bachofen V, Liu D, Lundberg JO, Revelo LP, Suschek CV, et al. Is sunlight good for our heart? Eur Hear J. 2010;31(9):1041–5.
• Mowbray M, McLintock S, Weerakoon R, Lomatschinsky N, Jones S, Rossi AG, Weller RB. Enzyme-independent NO stores in human skin: quantification and influence of UV radiation. J Investig Dermatol. 2009;129(4):834–42. This fascinating article demonstrates that dermal stores of nitrate can be liberated by UV radiation and result in lowering of blood pressure. These results provide another example of the context-dependent (and enzyme independent) production of nitric oxide from nitrate.
Bryan NS, Rassaf T, Maloney RE, Rodriguez CM, Saijo F, Rodriguez JR, et al. Cellular targets and mechanisms of nitros(yl)ation: an insight into their nature and kinetics in vivo. Proc Natl Acad Sci U S A. 2004;101(12):4308–13.
Lundberg JO, Feelisch M, Bjorne H, Jansson EA, Weitzberg E. Cardioprotective effects of vegetables: is nitrate the answer? Nitric Oxide. 2006;15(4):359–62.
Borniquel S, Jansson EA, Cole MP, Freeman BA, Lundberg JO. Nitrated oleic acid up-regulates PPARgamma and attenuates experimental inflammatory bowel disease. Free Radic Biol Med. 2010;48(4):499–505.
Butler AR, Feelisch M. Therapeutic uses of inorganic nitrite and nitrate: from the past to the future. Circulation. 2008;117(16):2151–9.
Greer FR, Shannon M. Infant methemoglobinemia: the role of dietary nitrate in food and water. Pediatrics. 2005;116(3):784–6.
Cornblath M, Hartmann AF. Methemoglobinemia in young infants. J Pediatr. 1948;33(4):421–5.
Kortboyer JM, Olling M, Zeilmaker MJ. The oral bioavailability of sodium nitrite investigated in healthy adult volunteers. Bilthoven: National Institute of Public Health and the Environment; 1997.
Dejam A, Hunter CJ, Tremonti C, Pluta RM, Hon YY, Grimes G, et al. Nitrite infusion in humans and nonhuman primates: endocrine effects, pharmacokinetics, and tolerance formation. Circulation. 2007;116(16):1821–31.
Powlson DS, Addiscott TM, Benjamin N, Cassman KG, de Kok TM, van Grinsven H, et al. When does nitrate become a risk for humans? J Environ Qual. 2008;37(2):291–5.
Camargo JA, Alonso A. Ecological and toxicological effects of inorganic nitrogen pollution in aquatic ecosystems: a global assessment. Environ Int. 2006;32(6):831–49.
Ward MH, Kilfoy BA, Weyer PJ, Anderson KE, Folsom AR, Cerhan JR. Nitrate intake and the risk of thyroid cancer and thyroid disease. Epidemiol (Cambridge, Mass). 2010;21(3):389–95.
Jiang R, Camargo Jr CA, Varraso R, Paik DC, Willett WC, Barr RG. Consumption of cured meats and prospective risk of chronic obstructive pulmonary disease in women. Am J Clin Nutr. 2008;87(4):1002–8.
Panesar NS. Downsides to the nitrate-nitrite-nitric oxide pathway in physiology and therapeutics? Nat Rev. 2008;7(8):710. author reply 710.
Norat T, Bingham S, Ferrari P, Slimani N, Jenab M, Mazuir M, et al. Meat, fish, and colorectal cancer risk: the European Prospective Investigation into cancer and nutrition. J Natl Canc Inst. 2005;97(12):906–16.
Alexander DD, Miller AJ, Cushing CA, Lowe KA. Processed meat and colorectal cancer: a quantitative review of prospective epidemiologic studies. Eur J Canc Prev. 2010;19(5):328–41.
Rao GS, Osborn JC, Adatia MR. Drug-nitrite interactions in human saliva: effects of food constituents on carcinogenic N-nitrosamine formation. J Dent Res. 1982;61(6):768–71.
Lundberg JO, Carlstrom M, Larsen FJ, Weitzberg E. Roles of dietary inorganic nitrate in cardiovascular health and disease. Cardiovasc Res. 2011;89(3):525–32.
Lundberg JO, Weitzberg E, Gladwin MT. The nitrate-nitrite-nitric oxide pathway in physiology and therapeutics. Nat Rev. 2008;7(2):156–67.
Casey DP, Beck DT, Braith RW. Systemic plasma levels of nitrite/nitrate (NOx) reflect brachial flow-mediated dilation responses in young men and women. Clin Exp Pharmacol Physiol. 2007;34(12):1291–3.
•• Sobko T, Marcus C, Govoni M, Kamiya S. Dietary nitrate in Japanese traditional foods lowers diastolic blood pressure in healthy volunteers. Nitric Oxide. 2010;22(2):136–40. Although potassium nitrate and beetroot juice predictably lower blood pressure in humans, this study used traditional Japanese foods high in nitrate to demonstrate this effect. Diastolic blood pressure was lowered an average of 4.5 mm Hg in normotensive subjects, an observation consistent with other studies using ordinary food sources of nitrates.
Kapil V, Milsom AB, Okorie M, Maleki-Toyserkani S, Akram F, Rehman F, et al. Inorganic nitrate supplementation lowers blood pressure in humans: role for nitrite-derived NO. Hypertension. 2010;56(2):274–81.
Lauer T, Heiss C, Balzer J, Kehmeier E, Mangold S, Leyendecker T, et al. Age-dependent endothelial dysfunction is associated with failure to increase plasma nitrite in response to exercise. Basic Res Cardiol. 2008;103(3):291–7.
Larsen FJ, Weitzberg E, Lundberg JO, Ekblom B. Dietary nitrate reduces maximal oxygen consumption while maintaining work performance in maximal exercise. Free Radic Biol Med. 2010;48(2):342–7.
• Vanhatalo A, Bailey SJ, Blackwell JR, DiMenna FJ, Pavey TG, Wilkerson DP, Benjamin N, Winyard PG, Jones AM. Acute and chronic effects of dietary nitrate supplementation on blood pressure and the physiological responses to moderate-intensity and incremental exercise. Am J Physiol Regul Integr Comp Physiol. 2010;299(4):R1121–31. Dietary nitrate supplementation with beetroot juice over 4 to 6 days has been shown to reduce the oxygen cost of submaximal exercise and to improve exercise tolerance. This study demonstrates that dietary nitrate supplementation acutely reduces blood pressure and the oxygen cost of submaximal exercise and that these effects are maintained for at least 15 days if supplementation is continued.
Hord NG, Ghannam JS, Garg HK, Berens PD, Bryan NS. Nitrate and nitrite content of human, formula, bovine, and soy milks: implications for dietary nitrite and nitrate recommendations. Breastfeed Med. 2010
Dezfulian C, Shiva S, Alekseyenko A, Pendyal A, Beiser DG, Munasinghe JP, et al. 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. Circulation. 2009;120(10):897–905.
Rocha BS, Gago B, Pereira C, Barbosa RM, Bartesaghi S, Lundberg JO, Radi R, Laranjinha J. Dietary nitrite in nitric oxide biology: a redox interplay with implications for pathophysiology and therapeutics. Curr Drug Targets. 2011
Santamaria P. Nitrate in vegetables: toxicity, content, intake and EC regulation. J Sci Food Agr. 2006;86:10–7.
N. Hord is board member of Neogenis Labs.
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Hord, N.G. Dietary Nitrates, Nitrites, and Cardiovascular Disease. Curr Atheroscler Rep 13, 484–492 (2011). https://doi.org/10.1007/s11883-011-0209-9
- Nitric oxide
- Enterosalivary circulation