Skip to main content Accessibility help
×
Home

The role of inorganic nitrate and nitrite in CVD

  • Jacklyn Jackson (a1), Amanda J. Patterson (a2), Lesley MacDonald-Wicks (a2) and Mark McEvoy (a3)

Abstract

CVD is the leading cause of death worldwide, a consequence of mostly poor lifestyle and dietary behaviours. Although whole fruit and vegetable consumption has been consistently shown to reduce CVD risk, the exact protective constituents of these foods are yet to be clearly identified. A recent and biologically plausible hypothesis supporting the cardioprotective effects of vegetables has been linked to their inorganic nitrate content. Approximately 60–80 % inorganic nitrate exposure in the human diet is contributed by vegetable consumption. Although inorganic nitrate is a relatively stable molecule, under specific conditions it can be metabolised in the body to produce NO via the newly discovered nitrate–nitrite–NO pathway. NO is a major signalling molecule in the human body, and has a key role in maintaining vascular tone, smooth muscle cell proliferation, platelet activity and inflammation. Currently, there is accumulating evidence demonstrating that inorganic nitrate can lead to lower blood pressure and improved vascular compliance in humans. The aim of this review is to present an informative, balanced and critical review of the current evidence investigating the role of inorganic nitrate and nitrite in the development, prevention and/or treatment of CVD. Although there is evidence supporting short-term inorganic nitrate intakes for reduced blood pressure, there is a severe lack of research examining the role of long-term nitrate intakes in the treatment and/or prevention of hard CVD outcomes, such as myocardial infarction and cardiovascular mortality. Epidemiological evidence is needed in this field to justify continued research efforts.

Copyright

Corresponding author

* Corresponding author: Mark McEvoy, email Mark.Mcevoy@newcastle.edu.au

References

Hide All
1. World Health Organization (2011) Global status report on noncommunicable diseases 2010. http://www.who.int/nmh/publications/ncd_report_full_en.pdf (accessed December 2015).
2. Buttar, HS, Li, T & Ravi, N (2005) Prevention of cardiovascular diseases: role of exercise, dietary interventions, obesity and smoking cessation. Exp Clin Cardiol 10, 229249.
3. Cordain, L, Eaton, SB, Sebastian, A, et al. (2005) Origins and evolution of the Western diet: health implications for the 21st century. Am J Clin Nutr 81, 341354.
4. Barengo, NC, Hu, G, Lakka, TA, et al. (2004) Low physical activity as a predictor for total and cardiovascular disease mortality in middle-aged men and women in Finland. Eur Heart J 25, 22042211.
5. Clair, C, Rigotti, NA, Porneala, B, et al. (2013) Association of smoking cessation and weight change with cardiovascular disease among adults with and without diabetes. JAMA 309, 10141021.
6. Isomaa, B, Almgren, P, Tuomi, T, et al. (2001) Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care 24, 683689.
7. Carpentier, Y & Komsa-Penkova, R (2011) Clinical Nutrition University. The place of nutrition in the prevention of cardiovascular diseases (CVDs). E Spen Eur E J Clin Nutr Metab 6, e272e282.
8. Harnack, L, Block, G & Lane, S (1997) Influence of selected environmental and personal factors on dietary behavior for chronic disease prevention: a review of the literature. J Nutr Educ 29, 306312.
9. Sofi, F, Cesari, F, Abbate, R, et al. (2008) Adherence to Mediterranean diet and health status: meta-analysis. BMJ 337, a1344.
10. Dauchet, L, Amouyel, P, Hercberg, S, et al. (2006) Fruit and vegetable consumption and risk of coronary heart disease: a meta-analysis of cohort studies. J Nutr 136, 25882593.
11. Verlangieri, A, Kapeghian, J, El-Dean, S, et al. (1985) Fruit and vegetable consumption and cardiovascular mortality. Med Hypotheses 16, 715.
12. He, FJ, Nowson, CA & MacGregor, GA (2006) Fruit and vegetable consumption and stroke: meta-analysis of cohort studies. Lancet 367, 320326.
13. Bazzano, LA, He, J, Ogden, LG, et al. (2002) Fruit and vegetable intake and risk of cardiovascular disease in US adults: the first National Health and Nutrition Examination Survey Epidemiologic Follow-up Study. Am J Clin Nutr 76, 9399.
14. Wang, X, Ouyang, Y, Liu, J, et al. (2014) Fruit and vegetable consumption and mortality from all causes, cardiovascular disease, and cancer: systematic review and dose–response meta-analysis of prospective cohort studies. BMJ 349, g4490.
15. Ness, AR, Powles, JW & Khaw, K-T (1996) Vitamin C and cardiovascular disease: a systematic review. J Cardiovasc Risk 3, 513521.
16. Chong, MF-F, Macdonald, R & Lovegrove, JA (2010) Fruit polyphenols and CVD risk: a review of human intervention studies. Br J Nutr 104, S28S39.
17. Threapleton, DE, Greenwood, DC, Evans, CE, et al. (2013) Dietary fibre intake and risk of cardiovascular disease: systematic review and meta-analysis. BMJ 347, f6879.
18. Vivekananthan, DP, Penn, MS, Sapp, SK, et al. (2003) Use of antioxidant vitamins for the prevention of cardiovascular disease: meta-analysis of randomised trials. Lancet 361, 20172023.
19. Hord, NG (2011) Dietary nitrates, nitrites, and cardiovascular disease. Curr Atheroscler Rep 13, 484492.
20. Bhupathiraju, SN, Wedick, NM, Pan, A, et al. (2012) Quantity and variety in fruit and vegetable intake and risk of coronary heart disease. Am J Clin Nutr 98, 15141523.
21. Joshipura, KJ, Ascherio, A, Manson, JE, et al. (1999) Fruit and vegetable intake in relation to risk of ischemic stroke. JAMA 282, 12331239.
22. Hord, NG, Tang, Y & Bryan, NS (2009) Food sources of nitrates and nitrites: the physiologic context for potential health benefits. Am J Clin Nutr 90, 110.
23. Sobko, T, Marcus, C, Govoni, M, et al. (2010) Dietary nitrate in Japanese traditional foods lowers diastolic blood pressure in healthy volunteers. Nitric Oxide 22, 136140.
24. L’Hirondel, J & L’Hirondel, J-L (2002) Nitrate and Man: Toxic, Harmless or Beneficial? Wallingford: CABI.
25. Lundberg, J & Weitzberg, E (2010) Chapter 16: Nitric oxide formation from inorganic nitrate and nitrite. In Nitric Oxide, 2nd ed., pp. 539553 [LJ Ignarro, editor]. Burlington, MA: Academic Press.
26. McKnight, G, Smith, L, Drummond, R, et al. (1997) Chemical synthesis of nitric oxide in the stomach from dietary nitrate in humans. Gut 40, 211214.
27. Kapil, V, Weitzberg, E, Lundberg, J, et al. (2014) Clinical evidence demonstrating the utility of inorganic nitrate in cardiovascular health. Nitric Oxide 38, 4557.
28. Hobbs, DA, Kaffa, N, George, TW, et al. (2012) Blood pressure-lowering effects of beetroot juice and novel beetroot-enriched bread products in normotensive male subjects. Br J Nutr 108, 20662074.
29. Kapil, V, Khambata, RS, Robertson, A, et al. (2015) Dietary nitrate provides sustained blood pressure lowering in hypertensive patients: a randomized, phase 2, double-blind, placebo-controlled study. Hypertension 65, 320327.
30. Bailey, SJ, Winyard, P, Vanhatalo, A, et al. (2009) Dietary nitrate supplementation reduces the O2 cost of low-intensity exercise and enhances tolerance to high-intensity exercise in humans. J Appl Physiol 107, 11441155.
31. Kelm, M (1999) Nitric oxide metabolism and breakdown. Biochim Biophys Acta 1411, 273289.
32. Hotchkiss, J (1988) Nitrate, nitrite balance, and de novo synthesis of nitrate. Am J Clin Nutr 47, 161162.
33. Webb, AJ, Patel, N, Loukogeorgakis, S, et al. (2008) Acute blood pressure lowering, vasoprotective, and antiplatelet properties of dietary nitrate via bioconversion to nitrite. Hypertension 51, 784790.
34. Li, H & Förstermann, U (2000) Nitric oxide in the pathogenesis of vascular disease. J Pathol 190, 244254.
35. Green, LC, De Luzuriaga, KR, Wagner, DA, et al. (1981) Nitrate biosynthesis in man. Proc Natl Acad Sci U S A 78, 77647768.
36. Palmer, R, Ashton, D & Moncada, S (1988) Vascular endothelial cells synthesize nitric oxide from l-arginine. Nature 333, 664666.
37. Guzik, TJ, Mussa, S, Gastaldi, D, et al. (2002) Mechanisms of increased vascular superoxide production in human diabetes mellitus: role of NAD(P)H oxidase and endothelial nitric oxide synthase. Circulation 105, 16561662.
38. Taddei, S, Virdis, A, Ghiadoni, L, et al. (2001) Age-related reduction of NO availability and oxidative stress in humans. Hypertension 38, 274279.
39. Feron, O, Dessy, C, Moniotte, S, et al. (1999) Hypercholesterolemia decreases nitric oxide production by promoting the interaction of caveolin and endothelial nitric oxide synthase. J Clin Invest 103, 897905.
40. Kharitonov, SA, Robbins, RA, Yates, D, et al. (1995) Acute and chronic effects of cigarette smoking on exhaled nitric oxide. Am J Respir Crit Care Med 152, 609612.
41. Böger, RH, Bode-Böger, SM, Szuba, A, et al. (1998) Asymmetric dimethylarginine (ADMA): a novel risk factor for endothelial dysfunction its role in hypercholesterolemia. Circulation 98, 18421847.
42. Ichiki, K, Ikeda, H, Haramaki, N, et al. (1996) Long-term smoking impairs platelet-derived nitric oxide release. Circulation 94, 31093114.
43. Bryan, NS & Loscalzo, J (2011) Nitrite and Nitrate in Human Health and Diesease. New York: Humana Press.
44. Sibal, L, Agarwal, SC, Home, PD, et al. (2010) The role of asymmetric dimethylarginine (ADMA) in endothelial dysfunction and cardiovascular disease. Curr Cardiol Rev 6, 8290.
45. Creager, MA, Gallagher, SJ, Girerd, XJ, et al. (1992) l-Arginine improves endothelium-dependent vasodilation in hypercholesterolemic humans. J Clin Invest 90, 12481253.
46. Bednarz, B, Jaxa-Chamiec, T, Maciejewski, P, et al. (2005) Efficacy and safety of oral l-arginine in acute myocardial infarction. Results of the multicenter, randomized, double-blind, placebo-controlled ARAMI pilot trial. Kardiol Pol 62, 421427.
47. Schulman, SP, Becker, LC, Kass, DA, et al. (2006) l-Arginine therapy in acute myocardial infarction: the Vascular Interaction With Age in Myocardial Infarction (VINTAGE MI) randomized clinical trial. JAMA 295, 5864.
48. The Natural Standard Research Collaboration (2013) Drugs and supplements: arginine. Mayo Foundation for Medical Education and Research. http://www.mayoclinic.org/drugs-supplements/arginine/safety/hrb-20058733 (accessed June 2016).
49. Nakaki, T & Hishikawa, K (2002) The arginine paradox. Nihon Yakurigaku Zasshi 199, 714.
50. Mirmiran, P, Bahadoran, Z, Ghasemi, A, et al. (2016) The association of dietary l-arginine intake and serum nitric oxide metabolites in adults: a population-based study. Nutrients 8, E311.
51. Weitzberg, E & Lundberg, J (1998) Nonenzymatic nitric oxide production in humans. Nitric Oxide 2, 17.
52. Zweier, JL, Samouilov, A & Kuppusamy, P (1999) Non-enzymatic nitric oxide synthesis in biological systems. Biochim Biophys Acta 1411, 250262.
53. Hobbs, DA, George, TW & Lovegrove, JA (2013) The effects of dietary nitrate on blood pressure and endothelial function: a review of human intervention studies. Nutr Res Rev 26, 210222.
54. van Velzen, AG, Sips, AJ, Schothorst, RC, et al. (2008) The oral bioavailability of nitrate from nitrate-rich vegetables in humans. Toxicol Lett 181, 177181.
55. Lundberg, JO & Govoni, M (2004) Inorganic nitrate is a possible source for systemic generation of nitric oxide. Free Radic Biol Med 37, 395400.
56. Pannala, AS, Mani, AR, Spencer, JP, et al. (2003) The effect of dietary nitrate on salivary, plasma, and urinary nitrate metabolism in humans. Free Radic Biol Med 34, 576584.
57. Bondonno, CP, Liu, AH, Croft, KD, et al. (2015) Absence of an effect of high nitrate intake from beetroot juice on blood pressure in treated hypertensive individuals: a randomized controlled trial. Am J Clin Nutr 102, 368375.
58. Tannenbaum, S, Weisman, M & Fett, D (1976) The effect of nitrate intake on nitrite formation in human saliva. Food Cosmet Toxoicol 14, 549552.
59. Benjamin, N, O’Driscoll, F, Dougall, H, et al. (1994) Stomach NO synthesis. Nature 368, 502.
60. Coggan, AR, Leibowitz, JL, Spearie, CA, et al. (2015) Acute dietary nitrate intake improves muscle contractile function in patients with heart failure a double-blind, placebo-controlled, randomized trial. Circ Heart Fail 8, 914920.
61. Lundberg, JO, Weitzberg, E & Gladwin, MT (2008) The nitrate–nitrite–nitric oxide pathway in physiology and therapeutics. Nat Rev Drug Discov 7, 156167.
62. Sobko, T, Reinders, C, Norin, E, et al. (2004) Gastrointestinal nitric oxide generation in germ-free and conventional rats. Am J Physiol Gastrointest Liver Physiol 287, G993G997.
63. Bondonno, CP, Liu, AH, Croft, KD, et al. (2015) Antibacterial mouthwash blunts oral nitrate reduction and increases blood pressure in treated hypertensive men and women. Am J Hypertens 28, 572575.
64. Govoni, M, Jansson, , Weitzberg, E, et al. (2008) The increase in plasma nitrite after a dietary nitrate load is markedly attenuated by an antibacterial mouthwash. Nitric Oxide 19, 333337.
65. Duncan, C, Dougall, H, Johnston, P, et al. (1995) Chemical generation of nitric oxide in the mouth from the enterosalivary circulation of dietary nitrate. Nat Med 1, 546551.
66. Zhang, Z, Naughton, D, Winyard, PG, et al. (1998) Generation of nitric oxide by a nitrite reductase activity of xanthine oxidase: a potential pathway for nitric oxide formation in the absence of nitric oxide synthase activity. Biochem Biophys Res Commun 249, 767772.
67. Millar, TM, Stevens, CR, Benjamin, N, et al. (1998) Xanthine oxidoreductase catalyses the reduction of nitrates and nitrite to nitric oxide under hypoxic conditions. FEBS Lett 427, 225228.
68. Webb, A, Bond, R, McLean, P, et al. (2004) Reduction of nitrite to nitric oxide during ischemia protects against myocardial ischemia–reperfusion damage. Proc Natl Acad Sci U S A 101, 1368313688.
69. Duranski, MR, Greer, JJ, Dejam, A, et al. (2005) Cytoprotective effects of nitrite during in vivo ischemia–reperfusion of the heart and liver. J Clin Invest 115, 12321240.
70. Gladwin, MT, Raat, NJ, Shiva, S, et al. (2006) Nitrite as a vascular endocrine nitric oxide reservoir that contributes to hypoxic signaling, cytoprotection, and vasodilation. Am J Physiol Heart Circ Physiol 60, H2026H2035.
71. Cosby, K, Partovi, KS, Crawford, JH, et al. (2003) Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation. Nat Med 9, 14981505.
72. Brooks, J (1937) The action of nitrite on haemoglobin in the absence of oxygen. Proc R Soc Lond B Biol Sci 123, 368382.
73. Doyle, MP, Pickering, RA, DeWeert, TM, et al. (1981) Kinetics and mechanism of the oxidation of human deoxyhemoglobin by nitrites. J Biol Chem 256, 1239312398.
74. Ashworth, A, Mitchell, K, Blackwell, JR, et al. (2015) High-nitrate vegetable diet increases plasma nitrate and nitrite concentrations and reduces blood pressure in healthy women. Public Health Nutr 18, 26692678.
75. Lundberg, J, Weitzberg, E, Lundberg, J, et al. (1994) Intragastric nitric oxide production in humans: measurements in expelled air. Gut 35, 15431546.
76. Mowat, C, Carswell, A, Wirz, A, et al. (1999) Omeprazole and dietary nitrate independently affect levels of vitamin C and nitrite in gastric juice. Gastroenterology 116, 813822.
77. Gago, B, Lundberg, JO, Barbosa, RM, et al. (2007) Red wine-dependent reduction of nitrite to nitric oxide in the stomach. Free Radic Biol Med 43, 12331242.
78. Crawford, NM (1995) Nitrate: nutrient and signal for plant growth. Plant Cell 7, 859868.
79. Ysart, G, Clifford, R & Harrison, N (1999) Monitoring for nitrate in UK-grown lettuce and spinach. Food Addit Contam 16, 301306.
80. Kaiser, WM & Brendle-Behnisch, E (1991) Rapid modulation of spinach leaf nitrate reductase activity by photosynthesis. I. Modulation in vivo by CO2 availability. Plant Physiol 96, 363367.
81. Muramoto, J (1999) Comparison of Nitrate Content in Leafy Vegetables from Organic and Conventional Farms in California. University of California, Santa Cruz, CA: Center for Agroecology and Sustainable Food Systems.
82. Ekart, K, Gorenjal, AH, Madorran, E, et al. (2013) Study on the influence of food processing on nitrate levels in vegetables. EFSA J 10, 514E.
83. Omar, SA, Artime, E & Webb, AJ (2012) A comparison of organic and inorganic nitrates/nitrites. Nitric Oxide 26, 229240.
84. Du, S-T, Zhang, Y-S & Lin, X-Y (2007) Accumulation of nitrate in vegetables and its possible implications to human health. Agric Sci China 6, 12461255.
85. Food Standards Australia New Zealand (2015) Survey of nitrates and nitrites in food and beverages in Australia. http://www.foodstandards.gov.au/consumer/additives/nitrate/Pages/default.aspx (accessed November 2015).
86. National Health and Medical Research Council & National Resource Management Ministerial Council (2011) Australian Drinking Water Guidelines Paper 6: National Water Quality Management Strategy. Canberra: National Health and Medical Research Council, National Resource Management Ministerial Council, Commonwealth of Australia.
87. United States Food and Drug Administration (2006) Food Additive Status List. Rockville, MD: United States Food and Drug Administration.
88. Ward, MH, DeKok, TM, Levallois, P, et al. (2005) Workgroup report: drinking-water nitrate and health – recent findings and research needs. Environ Health Perspect 113, 16071614.
89. Shuval, HI & Gruener, N (1972) Epidemiological and toxicological aspects of nitrates and nitrites in the environment. Am J Public Health 62, 10451052.
90. Jukes, D (2013) Food Additives in the European Union. Reading: The Department of Food Science and Technology, University of Reading. http://www.reading.ac.uk/foodlaw/additive.htm (accessed April 2017).
91. Food Standards Agency (2015) Food additives legislation guidance to compliance. http://www.food.gov.uk/sites/default/files/multimedia/pdfs/guidance/food-additives-legislation-guidance-to-compliance.pdf (accessed December 2016).
92. United States Department of Health and Human Services (2014) Food additives permitted for direct addition to food for human consumption. www.fda.gov/Food/ingredientsPackagingLabeling/FoodAdditivesUngredients.ucm091048.htm (accessed June 2016).
93. Weitzberg, E & Lundberg, JO (2013) Novel aspects of dietary nitrate and human health. Annu Rev Nutr 33, 129159.
94. Machha, A & Schechter, AN (2011) Dietary nitrite and nitrate: a review of potential mechanisms of cardiovascular benefits. Eur J Nutr 50, 293303.
95. Kelm, M & Schrader, J (1990) Control of coronary vascular tone by nitric oxide. Circ Res 66, 15611575.
96. Cornwell, TL, Arnold, E, Boerth, NJ, et al. (1994) Inhibition of smooth muscle cell growth by nitric oxide and activation of cAMP-dependent protein kinase by cGMP. Am J Physiol Cell Physiol 267, C1405C1413.
97. Radomski, M, Palmer, R & Moncada, S (1987) Endogenous nitric oxide inhibits human platelet adhesion to vascular endothelium. Lancet 330, 10571058.
98. Kubes, P, Suzuki, M & Granger, D (1991) Nitric oxide: an endogenous modulator of leukocyte adhesion. Proc Natl Acad Sci U S A 88, 46514655.
99. De Caterina, R, Libby, P, Peng, H-B, et al. (1995) Nitric oxide decreases cytokine-induced endothelial activation. Nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines. J Clin Invest 96, 6068.
100. Versari, D, Daghini, E, Virdis, A, et al. (2009) Endothelium‐dependent contractions and endothelial dysfunction in human hypertension. Br J Pharmacol 157, 527536.
101. Vanhoutte, P (1997) Endothelial dysfunction and atherosclerosis. Eur Heart J 18, Suppl. E, 1929.
102. Kleinbongard, P, Dejam, A, Lauer, T, et al. (2006) Plasma nitrite concentrations reflect the degree of endothelial dysfunction in humans. Free Radic Biol Med 40, 295302.
103. Landmesser, U & Drexler, H (2007) Endothelial function and hypertension. Curr Opin Cardiol 22, 316320.
104. Al Suwaidi, J, Hamasaki, S & Higano, ST (2000) Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction. Circulation 101, 948954.
105. Neunteufl, T, Katzenschlager, R, Hassan, A, et al. (1997) Systemic endothelial dysfunction is related to the extent and severity of coronary artery disease. Atherosclerosis 129, 111118.
106. Drexler, H, Hayoz, D, Münzel, T, et al. (1992) Endothelial function in chronic congestive heart failure. Am J Cardiol 69, 15961601.
107. Gokce, N, Keaney, JF, Hunter, LM, et al. (2003) Predictive value of noninvasively determined endothelial dysfunction for long-term cardiovascular events inpatients with peripheral vascular disease. J Am Coll Cardiol 41, 17691775.
108. Vita, JA & Keaney, JF (2002) Endothelial function a barometer for cardiovascular risk? Circulation 106, 640642.
109. Schächinger, V, Britten, MB & Zeiher, AM (2000) Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation 101, 18991906.
110. Katz, SD, Hryniewicz, K, Hriljac, I, et al. (2005) Vascular endothelial dysfunction and mortality risk in patients with chronic heart failure. Circulation 111, 310314.
111. Lidder, S & Webb, AJ (2013) Vascular effects of dietary nitrate (as found in green leafy vegetables and beetroot) via the nitrate–nitrite–nitric oxide pathway. Br J Clin Pharmacol 75, 677696.
112. Lundberg, JO, Gladwin, MT & Weitzberg, E (2015) Strategies to increase nitric oxide signalling in cardiovascular disease. Nat Rev Drug Discov 14, 623641.
113. Jeerooburkhan, N, Jones, LC, Bujac, S, et al. (2001) Genetic and environmental determinants of plasma nitrogen oxides and risk of ischemic heart disease. Hypertension 38, 10541061.
114. Panza, JA, Quyyumi, AA, Brush, JE Jr, et al. (1990) Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension. N Engl J Med 323, 2227.
115. Casino, PR, Kilcoyne, CM, Quyyumi, AA, et al. (1993) The role of nitric oxide in endothelium-dependent vasodilation of hypercholesterolemic patients. Circulation 88, 25412547.
116. Henry, RM, Ferreira, I, Kostense, PJ, et al. (2004) Type 2 diabetes is associated with impaired endothelium-dependent, flow-mediated dilation, but impaired glucose metabolism is not: The Hoorn Study. Atherosclerosis 174, 4956.
117. Tsuchiya, M, Asada, A, Kasahara, E, et al. (2002) Smoking a single cigarette rapidly reduces combined concentrations of nitrate and nitrite and concentrations of antioxidants in plasma. Circulation 105, 11551157.
118. Green, DJ, Maiorana, A, O’Driscoll, G, et al. (2004) Effect of exercise training on endothelium‐derived nitric oxide function in humans. J Physiol 561, 125.
119. Lopez-Garcia, E, Schulze, MB, Fung, TT, et al. (2004) Major dietary patterns are related to plasma concentrations of markers of inflammation and endothelial dysfunction. Am J Clin Nutr 80, 10291035.
120. Celermajer, DS, Sorensen, KE, Spiegelhalter, DJ, et al. (1994) Aging is associated with endothelial dysfunction in healthy men years before the age-related decline in women. J Am Coll Cardiol 24, 471476.
121. Celermajer, D, Sorensen, K, Georgakopoulos, D, et al. (1993) Cigarette smoking is associated with dose-related and potentially reversible impairment of endothelium-dependent dilation in healthy young adults. Circulation 88, 21492155.
122. Fuentes, F, Lopez-Miranda, J, Sanchez, E, et al. (2001) Mediterranean and low-fat diets improve endothelial function in hypercholesterolemic men. Ann Intern Med 134, 11151119.
123. O’Driscoll, G, Green, D & Taylor, RR (1997) Simvastatin, an HMG-coenzyme A reductase inhibitor, improves endothelial function within 1 month. Circulation 95, 11261131.
124. Hornig, B, Maier, V & Drexler, H (1996) Physical training improves endothelial function in patients with chronic heart failure. Circulation 93, 210214.
125. DeVan, A, Brooks, F, Evans, T, et al. (2014) Safety and efficacy of sodium nitrite supplementation for improving vascular endothelial dysfunction in middle-aged and older healthy adults. FASEB J 28, Suppl., 698.4.
126. Wilson, J & Hunt, T (2014) Molecular Biology of the Cell: The Problems Book. New York: Garland Science.
127. Channon, KM, Qian, H & George, SE (2000) Nitric oxide synthase in atherosclerosis and vascular injury: insights from experimental gene therapy. Arterioscler Thromb Vasc Biol 20, 18731881.
128. Hobbs, DA, Goulding, MG, Nguyen, A, et al. (2013) Acute ingestion of beetroot bread increases endothelium-independent vasodilation and lowers diastolic blood pressure in healthy men: a randomized controlled trial. J Nutr 143, 13991405.
129. Simon, DI, Stamler, JS, Jaraki, O, et al. (1993) Antiplatelet properties of protein S-nitrosothiols derived from nitric oxide and endothelium-derived relaxing factor. Arterioscler Thromb Vasc Biol 13, 791799.
130. Clapp, BR, Hingorani, AD, Kharbanda, RK, et al. (2004) Inflammation-induced endothelial dysfunction involves reduced nitric oxide bioavailability and increased oxidant stress. Cardiovasc Res 64, 172178.
131. Vallance, PJ & Webb, DJ (2003) Vascular Endothelium in Human Physiology and Pathophysiology, vol. 7. Boca Raton, FL: CRC Press.
132. Gago, B, Nyström, T, Cavaleiro, C, et al. (2008) The potent vasodilator ethyl nitrite is formed upon reaction of nitrite and ethanol under gastric conditions. Free Radic Biol Med 45, 404412.
133. Klemenska, E & Beresewicz, A (2009) Bioactivation of organic nitrates and the mechanism of nitrate tolerance. Cardiol J 16, 1119.
134. Bassenge, E, Fink, N, Skatchkov, M, et al. (1998) Dietary supplement with vitamin C prevents nitrate tolerance. J Clin Invest 102, 6771.
135. Gori, T, Burstein, JM, Ahmed, S, et al. (2001) Folic acid prevents nitroglycerin-induced nitric oxide synthase dysfunction and nitrate tolerance. Circulation 104, 11191123.
136. Fontaine, D, Otto, A, Fontaine, J, et al. (2003) Prevention of nitrate tolerance by long-term treatment with statins. Cardiovasc Drugs Ther 17, 123128.
137. Greer, FR & Shannon, M (2005) Infant methemoglobinemia: the role of dietary nitrate in food and water. Pediatrics 116, 784786.
138. Martinez, A, Sanchez-Valverde, F, Gil, F, et al. (2013) Methemoglobinemia induced by vegetable intake in infants in northern Spain. J Peadiatr Gastroenterol Nutr 56, 573577.
139. Milkowski, A, Garg, HK, Coughlin, JR, et al. (2010) Nutritional epidemiology in the context of nitric oxide biology: a risk–benefit evaluation for dietary nitrite and nitrate. Nitric Oxide 22, 110119.
140. Avery, AA (1999) Infantile methemoglobinemia: reexamining the role of drinking water nitrates. Environ Health Perspect 107, 583586.
141. Bouvard, V, Loomis, D, Guyton, KZ, et al. (2015) Carcinogenicity of consumption of red and processed meat. Lancet Oncol 16, 15991600.
142. Bingham, SA (1999) High-meat diets and cancer risk. Proc Nutr Soc 58, 243248.
143. Gilchrist, M, Winyard, PG & Benjamin, N (2010) Dietary nitrate – good or bad? Nitric Oxide 22, 104109.
144. Magee, PN & Barnes, J (1956) The production of malignant primary hepatic tumours in the rat by feeding dimethylnitrosamine. Br J Cancer 10, 114122.
145. Assembly of Life Sciences (1981) The Health Effects of Nitrate, Nitrite, and N-Nitroso Compounds: Part 1 of a 2-Part Study. Washington, DC: National Academies Press.
146. Kapil, V, Milsom, AB, Okorie, M, et al. (2010) Inorganic nitrate supplementation lowers blood pressure in humans. Hypertension 56, 274281.
147. Asgary, S, Afshani, M, Sahebkar, A, et al. (2016) Improvement of hypertension, endothelial function and systemic inflammation following short-term supplementation with red beet (Beta vulgaris L.) juice: a randomized crossover pilot study. J Hum Hypertens 30, 627632.
148. Richardson, G, Hicks, S, O’Byrne, S, et al. (2002) The ingestion of inorganic nitrate increases gastric S-nitrosothiol levels and inhibits platelet function in humans. Nitric Oxide 7, 2429.
149. Baker, JE, Su, J, Fu, X, et al. (2007) Nitrite confers protection against myocardial infarction: role of xanthine oxidoreductase, NADPH oxidase and K ATP channels. J Mol Cell Cardiol 43, 437444.
150. Lansley, KE, Winyard, PG, Bailey, SJ, et al. (2011) Acute dietary nitrate supplementation improves cycling time trial performance. Med Sci Sports Exerc 43, 11251131.
151. Dykhuizen, R, Frazer, R, Duncan, C, et al. (1996) Antimicrobial effect of acidified nitrite on gut pathogens: importance of dietary nitrate in host defense. Antimicrob Agents Chemother 40, 14221425.
152. Carlström, M, Persson, AEG, Larsson, E, et al. (2011) Dietary nitrate attenuates oxidative stress, prevents cardiac and renal injuries, and reduces blood pressure in salt-induced hypertension. Cardiovasc Res 89, 574585.
153. Petersson, J, Carlström, M, Schreiber, O, et al. (2009) Gastroprotective and blood pressure lowering effects of dietary nitrate are abolished by an antiseptic mouthwash. Free Radic Biol Med 46, 10681075.
154. Kanematsu, Y, Yamaguchi, K, Ohnishi, H, et al. (2008) Dietary doses of nitrite restore circulating nitric oxide level and improve renal injury in l-NAME-induced hypertensive rats. Am J Physiol Renal Physiol 295, F1457F1462.
155. Ferguson, SK, Hirai, DM, Copp, SW, et al. (2013) Impact of dietary nitrate supplementation via beetroot juice on exercising muscle vascular control in rats. J Physiol 591, 547557.
156. Bryan, NS, Calvert, JW, Elrod, JW, et al. (2007) Dietary nitrite supplementation protects against myocardial ischemia–reperfusion injury. Proc Natl Acad Sci U S A 104, 1914419149.
157. Shiva, S, Sack, MN, Greer, JJ, et al. (2007) Nitrite augments tolerance to ischemia/reperfusion injury via the modulation of mitochondrial electron transfer. J Exp Med 204, 20892102.
158. Minicucci, MF, Azevedo, PS, Polegato, BF, et al. (2011) Heart failure after myocardial infarction: clinical implications and treatment. Clin Cardiol 34, 410414.
159. Nieswandt, B, Pleines, I & Bender, M (2011) Platelet adhesion and activation mechanisms in arterial thrombosis and ischaemic stroke. J Thromb Haemost 9, 92104.
160. Raskob, GE, Angchaisuksiri, P, Blanco, AN, et al. (2014) Thrombosis: a major contributor to global disease burden. Semi Throm Hemost 40, 724735.
161. Park, JW, Piknova, B, Huang, PL, et al. (2013) Effect of blood nitrite and nitrate levels on murine platelet function. PLOS ONE 8, e55699.
162. Apostoli, G, Solomon, A, Smallwood, M, et al. (2014) Role of inorganic nitrate and nitrite in driving nitric oxide–cGMP‐mediated inhibition of platelet aggregation in vitro and in vivo . J Thromb Haemost 12, 18801889.
163. Moraes, DL, Colucci, WS & Givertz, MM (2000) Secondary pulmonary hypertension in chronic heart failure. Circulation 102, 17181723.
164. Hunter, CJ, Dejam, A, Blood, AB, et al. (2004) Inhaled nebulized nitrite is a hypoxia-sensitive NO-dependent selective pulmonary vasodilator. Nat Med 10, 11221127.
165. Zuckerbraun, BS, Shiva, S, Ifedigbo, E, et al. (2010) Nitrite potently inhibits hypoxic and inflammatory pulmonary arterial hypertension and smooth muscle proliferation via xanthine oxidoreductase–dependent nitric oxide generation. Circulation 121, 98109.
166. Casey, DB, Badejo, AM, Dhaliwal, JS, et al. (2009) Pulmonary vasodilator responses to sodium nitrite are mediated by an allopurinol-sensitive mechanism in the rat. Am J Physiol Heart Circ Physiol 296, H524H533.
167. Hendgen-Cotta, UB, Luedike, P, Totzeck, M, et al. (2012) Dietary nitrate supplementation improves revascularization in chronic ischemia. Circulation 126, 19831992.
168. Heiss, C, Meyer, C, Totzeck, M, et al. (2012) Dietary inorganic nitrate mobilizes circulating angiogenic cells. Free Radic Biol Med 52, 17671772.
169. Sindler, AL, Fleenor, BS, Calvert, JW, et al. (2011) Nitrite supplementation reverses vascular endothelial dysfunction and large elastic artery stiffness with aging. Aging Cell 10, 429437.
170. Cai, H & Harrison, DG (2000) Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. Circ Res 87, 840844.
171. Stokes, KY, Dugas, TR, Tang, Y, et al. (2009) Dietary nitrite prevents hypercholesterolemic microvascular inflammation and reverses endothelial dysfunction. Am J Physiol Heart Circ Physiol 296, H1281H1288.
172. Carlström, M, Larsen, FJ, Nyström, T, et al. (2010) Dietary inorganic nitrate reverses features of metabolic syndrome in endothelial nitric oxide synthase-deficient mice. Proc Natl Acad Sci U S A 107, 1771617720.
173. Larsen, FJ, Ekblom, B, Sahlin, K, et al. (2006) Effects of dietary nitrate on blood pressure in healthy volunteers. N Engl J Med 355, 27922793.
174. Siervo, M, Lara, J, Ogbonmwan, I, et al. (2013) Inorganic nitrate and beetroot juice supplementation reduces blood pressure in adults: a systematic review and meta-analysis. J Nutr 143, 818826.
175. Bondonno, CP, Liu, AH, Croft, KD, et al. (2014) Short-term effects of nitrate-rich green leafy vegetables on blood pressure and arterial stiffness in individuals with high-normal blood pressure. Free Radic Biol Med 77, 353362.
176. Gilchrist, M, Winyard, PG, Aizawa, K, et al. (2013) Effect of dietary nitrate on blood pressure, endothelial function, and insulin sensitivity in type 2 diabetes. Free Radic Biol Med 60, 8997.
177. Golzarand, M, Bahadoran, Z, Mirmiran, P, et al. (2016) Consumption of nitrate-containing vegetables is inversely associated with hypertension in adults: a prospective investigation from the Tehran Lipid and Glucose Study. J Nephrol 29, 377384.
178. Raitakari, OT & Celermajer, DS (2000) Testing for endothelial dysfunction. Ann Med 32, 293304.
179. Hadi, HA, Carr, CS & Suwaidi, J (2005) Endothelial dysfunction: cardiovascular risk factors, therapy, and outcome. Vasc Health Risk Manag 1, 183198.
180. Bondonno, CP, Yang, X, Croft, KD, et al. (2012) Flavonoid-rich apples and nitrate-rich spinach augment nitric oxide status and improve endothelial function in healthy men and women: a randomized controlled trial. Free Radic Biol Med 52, 95102.
181. Rodriguez-Mateos, A, Hezel, M, Aydin, H, et al. (2015) Interactions between cocoa flavanols and inorganic nitrate: additive effects on endothelial function at achievable dietary amounts. Free Radic Biol Med 80, 121128.
182. Joris, PJ & Mensink, RP (2013) Beetroot juice improves in overweight and slightly obese men postprandial endothelial function after consumption of a mixed meal. Atherosclerosis 231, 7883.
183. Ingram, TE, Fraser, AG, Bleasdale, RA, et al. (2013) Low-dose sodium nitrite attenuates myocardial ischemia and vascular ischemia–reperfusion injury in human models. J Am Coll Cardiol 61, 25342541.
184. Heiss, C, Jahn, S, Taylor, M, et al. (2010) Improvement of endothelial function with dietary flavanols is associated with mobilization of circulating angiogenic cells in patients with coronary artery disease. J Am Coll Cardiol 56, 218224.
185. The Reference Values for Arterial Stiffness’ Collaboration (2010) Determinants of pulse wave velocity in healthy people and in the presence of cardiovascular risk factors: ‘establishing normal and reference values’. Eur Heart J 31, 23382350.
186. Chirinos, JA, Zambrano, JP, Chakko, S, et al. (2005) Aortic pressure augmentation predicts adverse cardiovascular events in patients with established coronary artery disease. Hypertension 45, 980985.
187. Zamani, P, Rawat, D, Shiva-Kumar, P, et al. (2014) The effect of inorganic nitrate on exercise capacity in heart failure with preserved ejection fraction. Circulation 114, 371380.
188. Rammos, C, Hendgen-Cotta, UB, Sobierajski, J, et al. (2014) Dietary nitrate reverses vascular dysfunction in older adults with moderately increased cardiovascular risk. J Am Coll Cardiol 63, 15841585.
189. Liu, AH, Bondonno, CP, Croft, KD, et al. (2013) Effects of a nitrate-rich meal on arterial stiffness and blood pressure in healthy volunteers. Nitric Oxide 35, 123130.
190. Jones, DA, Pellaton, C, Velmurugan, S, et al. (2014) Randomized phase 2 trial of intra-coronary nitrite during acute myocardial infarction. Circ Res 114, 437447.
191. Alexander, J, Benford, D, Cockburn, A, et al. (2008) Nitrate in vegetables: Scientific Opinion of the Panel on Contaminants in the Food chain. EFSA J 689, 179.
192. Siciliano, J, Krulick, S, Heisler, EG, et al. (1975) Nitrate and nitrite content of some fresh and processed market vegetables. J Agric Food Chem 23, 461464.
193. Jackson, WA, Steel, JS & Boswell, VR (1967) Nitrates in edible vegetables and vegetable products. Proc Amer Soc Hort Sci 90, 349352.
194. Corré, WJ (1979) Nitrate and Nitrite in Vegetables. Wageningen, the Netherlands: Wageningen University and Research Centre.
195. Richardson, W (1907) The occurrence of nitrates in vegetable foods, in cured meats and elsewhere. J Am Chem Soc 29, 17571767.
196. Wilson, J (1949) Nitrate in foods and its relation to health. Agron J 41, 2022.
197. Lee, DH (1970) Nitrates, nitrites, and methemoglobinemia. Environ Res 3, 484511.
198. White, JW (1975) Relative significance of dietary sources of nitrate and nitrite. J Agric Food Chem 23, 886891.
199. Santamaria, P, Elia, A, Serio, F, et al. (1999) A survey of nitrate and oxalate content in fresh vegetables. J Sci Food Agric 79, 18821888.
200. Öztekin, N, Nutku, MS & Erim, FB (2002) Simultaneous determination of nitrite and nitrate in meat products and vegetables by capillary electrophoresis. Food Chem 76, 103106.
201. Tamme, T, Reinik, M, Roasto, M, et al. (2006) Nitrates and nitrites in vegetables and vegetable-based products and their intakes by the Estonian population. Food Addit Contam 23, 355361.
202. Hsu, J, Arcot, J & Lee, NA (2009) Nitrate and nitrite quantification from cured meat and vegetables and their estimated dietary intake in Australians. Food Chem 115, 334339.
203. Thomson, B, Nokes, C & Cressey, P (2007) Intake and risk assessment of nitrate and nitrite from New Zealand foods and drinking water. Food Addit Contam 24, 113121.
204. Walker, R (1990) Nitrates, nitrites and N‐nitrosocompounds: a review of the occurrence in food and diet and the toxicological implications. Food Addit Contam 7, 717768.
205. Wang, Z, Wei, Y & Li, S (2000) Nitrate accumulation and its regulation by nutrient management in vegetables. In Balanceable Fertilization and High Quality Vegetables Continual Production. Beijing: China Agricultural University.
206. Petersen, A & Stoltze, S (1999) Nitrate and nitrite in vegetables on the Danish market: content and intake. Food Addit Contam 16, 291299.
207. Ysart, G, Miller, P, Barrett, G, et al. (1999) Dietary exposures to nitrate in the UK. Food Addit Contam 16, 521532.
208. Sušin, J, Kmecl, V & Gregorčič, A (2006) A survey of nitrate and nitrite content of fruit and vegetables grown in Slovenia during 1996–2002. Food Addit Contam 23, 385390.
209. Pickston, L, Smith, J & Todd, M (1980) Nitrate and nitrite levels in fruit and vegetables in New Zealand and the effect of storage and pressure cooking on these levels. Food Technol New Zeal 15, 1117.
210. Zhong, W, Hu, C & Wang, M (2002) Nitrate and nitrite in vegetables from north China: content and intake. Food Addit Contam 19, 11251129.
211. Panalaks, T, Iyengar, J & Sen, N (1973) Nitrate, nitrite, and dimethylnitrosamine in cured meat products. J Ass Offic Anal Chem 56, 621625.
212. Sen, NP & Baddoo, PA (1997) Trends in the levels of residual nitrite in Canadian cured meat products over the past 25 years. J Agric Food Chem 45, 47144718.
213. Sen, NP, Baddoo, PA & Seaman, SW (1994) Rapid and sensitive determination of nitrite in foods and biological materials by flow injection or high-performance liquid chromatography with chemiluminescence detection. J Chromatogr A 673, 7784.
214. Panalaks, T, Iyengar, JR, Donaldson, BA, et al. (1974) Further survey of cured meat products for volatile N-nitrosamines. J Assoc Off Anal Chem 57, 806812.
215. Meah, M, Harrison, N & Davies, A (1994) Nitrate and nitrite in foods and the diet. Food Addit Contam 11, 519532.
216. Buege, D, Lee, M & Cassens, R (1978) Residual Nitrite Levels in Meat Products Manufactured by Wisconsin Meat Processors. Madison, WI: University of Wisconsin.
217. Reinik, M, Tamme, T, Roasto, M, et al. (2005) Nitrites, nitrates and N-nitrosoamines in Estonian cured meat products: intake by Estonian children and adolescents. Food Addit Contam 22, 10981105.
218. Cassens, RG (1997) Composition and safety of cured meats in the USA. Food Chem 59, 561566.
219. Kerr, R, Marsh, C, Schroeder, W, et al. (1926) The use of sodium nitrite in the curing of meat. J Agric Res 33, 541551.
220. Coppola, ED, Wickroski, AF & Hanna, JG (1976) Nitrite in meat products determined by fluorescence quenching of p-aminobenzoate ion. J Assoc Off Anal Chem 59, 783786.
221. Siu, DC & Henshall, A (1998) Ion chromatographic determination of nitrate and nitrite in meat products. J Chromatogr A 804, 157160.
222. Greenberg, R (1977) Nitrosopyrrolidine in United States cured meat products. In Proceedings of the International Symposium on Nitrite in Meat Products, 1976, Zeist, the Netherlands, pp. 203–210 [BJ Tinbergen and B Krol, editors]. Wageningen, the Netherlands: Centre for Agricultural Publishing and Documentation.
223. Sen, N, Donaldson, B & Charbonneau, C (1975) Formation of nitrosodimethylamine from the interaction of certain pesticides and nitrite. In N-Nitroso Compounds in the Environment, IARC Scientific Publications , no. 9, pp. 7579 [P Bogovski and EA Walker, editors]. Lyon, France: IARC.
224. Sen, N, Donaldson, B, Seaman, S, et al. (1977) Recent nitrosamine analyses in cooked bacon. J Can Inst Food Sci Technol 10, A13A15.

Keywords

The role of inorganic nitrate and nitrite in CVD

  • Jacklyn Jackson (a1), Amanda J. Patterson (a2), Lesley MacDonald-Wicks (a2) and Mark McEvoy (a3)

Metrics

Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed