Current Atherosclerosis Reports

, Volume 13, Issue 6, pp 484–492 | Cite as

Dietary Nitrates, Nitrites, and Cardiovascular Disease

Nutrition (William S. Harris, Section Editor)


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.


Nitrate Nitrite Nitric oxide Nitrosothiols Nitroalkenes Enterosalivary circulation 


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    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.CrossRefGoogle Scholar
  2. 2.
    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.PubMedCrossRefGoogle Scholar
  3. 3.
    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.Google Scholar
  4. 4.
    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.PubMedCrossRefGoogle Scholar
  5. 5.
    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.PubMedCrossRefGoogle Scholar
  6. 6.
    Authority EFS. Nitrate in vegetables: scientific opinion of the panel on contaminants in the food chain. EFSA J. 2008;689:1–79.Google Scholar
  7. 7.
    Pennington J. Dietary exposure models for nitrates and nitrites. Food Contr. 1998;9:385–95.CrossRefGoogle Scholar
  8. 8.
    Weitzberg E, Hezel M, Lundberg JO. Nitrate-nitrite-nitric oxide pathway: implications for anesthesiology and intensive care. Anesthesiology. 2010;113(6):1460–75.PubMedCrossRefGoogle Scholar
  9. 9.
    •• 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. CrossRefGoogle Scholar
  10. 10.
    Zweier JL, Samouilov A, Kuppusamy P. Non-enzymatic nitric oxide synthesis in biological systems. Biochim Biophys Acta. 1999;1411(2–3):250–62.PubMedGoogle Scholar
  11. 11.
    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.PubMedCrossRefGoogle Scholar
  12. 12.
    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.PubMedCrossRefGoogle Scholar
  13. 13.
    Lundberg JO, Weitzberg E. NO-synthase independent NO generation in mammals. Biochem Biophys Res Commun. 2010;396(1):39–45.PubMedCrossRefGoogle Scholar
  14. 14.
    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.Google Scholar
  15. 15.
    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. 2008Google Scholar
  16. 16.
    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.PubMedCrossRefGoogle Scholar
  17. 17.
    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.PubMedCrossRefGoogle Scholar
  18. 18.
    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.PubMedCrossRefGoogle Scholar
  19. 19.
    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. 2008Google Scholar
  20. 20.
    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.Google Scholar
  21. 21.
    Bryan NS. Cardioprotective actions of nitrite therapy and dietary considerations. Front Biosci. 2009;14:4793–808.PubMedCrossRefGoogle Scholar
  22. 22.
    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.PubMedCrossRefGoogle Scholar
  23. 23.
    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.PubMedCrossRefGoogle Scholar
  24. 24.
    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.PubMedCrossRefGoogle Scholar
  25. 25.
    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.CrossRefGoogle Scholar
  26. 26.
    • 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. PubMedCrossRefGoogle Scholar
  27. 27.
    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.PubMedCrossRefGoogle Scholar
  28. 28.
    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.PubMedCrossRefGoogle Scholar
  29. 29.
    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.PubMedCrossRefGoogle Scholar
  30. 30.
    Butler AR, Feelisch M. Therapeutic uses of inorganic nitrite and nitrate: from the past to the future. Circulation. 2008;117(16):2151–9.PubMedCrossRefGoogle Scholar
  31. 31.
    Greer FR, Shannon M. Infant methemoglobinemia: the role of dietary nitrate in food and water. Pediatrics. 2005;116(3):784–6.PubMedCrossRefGoogle Scholar
  32. 32.
    Cornblath M, Hartmann AF. Methemoglobinemia in young infants. J Pediatr. 1948;33(4):421–5.PubMedCrossRefGoogle Scholar
  33. 33.
    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.Google Scholar
  34. 34.
    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.PubMedCrossRefGoogle Scholar
  35. 35.
    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.PubMedCrossRefGoogle Scholar
  36. 36.
    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.PubMedCrossRefGoogle Scholar
  37. 37.
    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.CrossRefGoogle Scholar
  38. 38.
    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.PubMedGoogle Scholar
  39. 39.
    Panesar NS. Downsides to the nitrate-nitrite-nitric oxide pathway in physiology and therapeutics? Nat Rev. 2008;7(8):710. author reply 710.Google Scholar
  40. 40.
    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.CrossRefGoogle Scholar
  41. 41.
    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.CrossRefGoogle Scholar
  42. 42.
    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.PubMedCrossRefGoogle Scholar
  43. 43.
    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.PubMedCrossRefGoogle Scholar
  44. 44.
    Lundberg JO, Weitzberg E, Gladwin MT. The nitrate-nitrite-nitric oxide pathway in physiology and therapeutics. Nat Rev. 2008;7(2):156–67.CrossRefGoogle Scholar
  45. 45.
    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.PubMedCrossRefGoogle Scholar
  46. 46.
    •• 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. PubMedCrossRefGoogle Scholar
  47. 47.
    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.PubMedCrossRefGoogle Scholar
  48. 48.
    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.PubMedCrossRefGoogle Scholar
  49. 49.
    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.PubMedCrossRefGoogle Scholar
  50. 50.
    • 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 15days if supplementation is continued.PubMedCrossRefGoogle Scholar
  51. 51.
    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. 2010Google Scholar
  52. 52.
    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.PubMedCrossRefGoogle Scholar
  53. 53.
    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. 2011Google Scholar
  54. 54.
    Santamaria P. Nitrate in vegetables: toxicity, content, intake and EC regulation. J Sci Food Agr. 2006;86:10–7.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of Food Science and Human NutritionMichigan State UniversityEast LansingUSA

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