Nitrate ingestion: A review of the health and physical performance effects

Nutrients

Volumn 6, Issue 11, 2014, Pages 5224-5264

  Clements, William T ^a   Lee, Sang Rok ^a   Bloomer, Richard J ^a  

^a UNIVERSITY OF MEMPHIS   (United States)

Author keywords

Beetroot; Blood flow; Blood pressure; Exercise; Nitrate; Nitric oxide

Indexed keywords

ADENOSINE DIPHOSPHATE; MYOGLOBIN; NITRATE; NITRIC OXIDE SYNTHASE; NITRIC ACID DERIVATIVE; NITRIC OXIDE;

AEROBIC EXERCISE; ANTIMICROBIAL ACTIVITY; ASTHMA; ATHLETE; BEETROOT; BLOOD PRESSURE MEASUREMENT; ENDOTHELIAL DYSFUNCTION; FUSOBACTERIUM; HEART INFARCTION; HOST RESISTANCE; HUMAN; HYPOXIA; INGESTION; ISCHEMIA; MINERAL SUPPLEMENTATION; PERIPHERAL OCCLUSIVE ARTERY DISEASE; PHYSICAL PERFORMANCE; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; SPLANCHNIC BLOOD FLOW; ATHLETIC PERFORMANCE; BEET; BLOOD PRESSURE; CARDIOVASCULAR SYSTEM; CHEMISTRY; DIET SUPPLEMENTATION; DRUG EFFECTS; MOTOR ACTIVITY; PLANT ROOT; VEGETABLE;

ATHLETES; ATHLETIC PERFORMANCE; BETA VULGARIS; BLOOD PRESSURE; CARDIOVASCULAR SYSTEM; DIETARY SUPPLEMENTS; HUMANS; MOTOR ACTIVITY; NITRATES; NITRIC OXIDE; PLANT ROOTS; RANDOMIZED CONTROLLED TRIALS AS TOPIC; VEGETABLES;

EID: 84938865075     PISSN: None     EISSN: 20726643     Source Type: Journal    
DOI: 10.3390/nu6115224     Document Type: Review

References (106)

1. Consumer Trends That Matter: Personalization. Available online: https://circleup.com/blog/2013/06/24/consumer-trends-matter-personalization/ (accessed on 24 June 2013).
2. Hord, N.G.; Tang, Y.; Bryan, N.S. Food sources of nitrates and nitrites: The physiological context for potential health benefits. Am. J. Clin. Nutr.2009, 90, 1–10.
3. Detopoulou, P.; Panagiotakos, D.B.; Antonopoulou, S.; Pitsavos, C.; Stefanadis, C. Dietary choline and betaine intakes in relation to concentrations of inflammatory markers in healthy adults: The ATTICA study. Am. J. Clin. Nutr.2008, 87, 424–430.
4. Lundberg, J.O.; Weitzberg, E.; Gladwin, M.T. The nitrate-nitrite-nitric oxide pathway in physiology and therapeutics. Nat. Rev. Drug Discov.2008, 7, 156–167.
5. Doel, J.J.; Benjamin, N.; Hector, M.P.; Rogers, M.; Allaker, R.P. Evaluation of bacterial nitrate reduction in the human oral cavity. Eur. J. Oral Sci.2005, 113, 14–19.
6. Hyde, E.R.; Andrade, F.; Vaksman, Z.; Parthasarathy, K.; Jiang, H.; Parthasarathy, D.K.; Torregrossa, A.C.; Tribble, G.; Kaplan, H.B.; Petrosino, J.F. et al. Metagenomic analysis of nitrate-reducing bacteria in the oral cavity: Implications for nitric oxide homeostasis. PLoS One2014, 9, e88645.
7. Gladwin, M.T.; Schechter, A.N.; Kim-Shapiro, D.B.; Patel, R.P.; Hogg, N.; Shiva, S.; Cannon, R.O., III; Kelm, M.; Wink, D.A.; Espey, M.G. et al. The emerging biology of the nitrite anion. Nat. Chem. Biol.2005, 1, 308–314.
8. Lundberg, J.O.; Gladwin, M.T.; Ahluwalia, A.; Benjamin, N.; Bryan, N.S.; Butler, A.; Cabrales, P.; Fago, A.; Feelisch, M.; Ford, P.C. et al. Nitrate and nitrite in biology, nutrition and therapeutics. Nat. Chem. Biol.2009, 5, 865–869.
9. Hoon, M.W.; Johnson, N.A.; Chapman, P.G.; Burke, L.M. The effect of nitrate supplementation on exercise performance in healthy individuals: A systematic review and meta-analysis. Int. J. Sport Nutr. Exerc. Metab.2013, 23, 522–532.
10. Jones, A.M. Dietary nitrate supplementation and exercise performance. Sports Med. 2014, 44(Suppl. 1), S35–S45.
11. Bailey, S.J.; Fulford, J.; Vanhatalo, A.; Winyard, P.G.; Blackwell, J.R.; DiMenna, F.J.; Wilkerson, D.P.; Benjamin, N.; Jones, A.M. Dietary nitrate supplementation enhances muscle contractile efficiency during knee-extensor exercise in humans. J. Appl. Physiol.2010, 109, 135–148.
12. Lansley, K.E.; Winyard, P.G.; Bailey, S.J.; Vanhatalo, A.; Wilkerson, D.P.; Blackwell, J.R.; Gilchrist, M.; Benjamin, N.; Jones, A.M. Acute dietary nitrate supplementation improves cycling time trial performance. Med. Sci. Sports Exerc.2011, 43, 1125–1131.
13. Lansley, K.E.; Winyard, P.G.; Fulford, J.; Vanhatalo, A.; Bailey, S.J.; Blackwell, J.R.; DiMenna, F.J.; Gilchrist, M.; Benjamin, N.; Jones, A.M. Dietary nitrate supplementation reduces the O2 cost of walking and running: A placebo-controlled study. J. Appl. Physiol.2011, 110, 591–600.
14. Larsen, F.J.; Schiffer, T.A.; Borniquel, S.; Sahlin, K.; Ekblom, B.; Lundberg, J.O.; Weitzberg, E. Dietary inorganic nitrate improves mitochondrial efficiency in humans. Cell Metab. 2011, 13, 149–159.
15. Larsen, F.J.; Weitzberg, E.; Lundberg, J.O.; Ekblom, B. Dietary nitrate reduces maximal oxygen consumption while maintaining work performance in maximal exercise. Free Radic. Biol. Med.2010, 48, 342–347.
16. Nitrite and Nitrate in Human Health and Disease. Available online: http://link.springer.com/book/10.1007%2F978-1-60761-616-0 (accessed on 4 April 2013).
17. Dejam, A.; Hunter, C.J.; Gladwin, M.T. Effects of dietary nitrate on blood pressure. N. Engl. J. Med.2007, 356, 1590.
18. Kapil, V.; Milsom, A.B.; Okorie, M.; Maleki-Toyserkani, S.; Akram, F.; Rehman, F.; Arghandawi, S.; Pearl, V.; Benjamin, N.; Loukogeorgakis, S. et al. Inorganic nitrate supplementation lowers blood pressure in humans: Role for nitrite-derived NO. Hypertension2010, 56, 274–281.
19. Kelly, J.; Fulford, J.; Vanhatalo, A.; Blackwell, J.R.; French, O.; Bailey, S.J.; Gilchrist, M.; Winyard, P.G.; Jones, A.M. Effects of short-term dietary nitrate supplementation on blood pressure, O2 uptake kinetics, and muscle and cognitive function in older adults. Am. J. Physiol. Regul. Integr. Comp. Physiol.2013, 304, R73–R83.
20. Larsen, F.J.; Ekblom, B.; Sahlin, K.; Lundberg, J.O.; Weitzberg, E. Effects of dietary nitrate on blood pressure in healthy volunteers. N. Engl. J. Med.2006, 355, 2792–2793.
21. Petersson, J.; Carlstrom, M.; Schreiber, O.; Phillipson, M.; Christoffersson, G.; Jagare, A.; Roos, S.; Jansson, E.A.; Persson, A.E.; Lundberg, J.O. et al. Gastroprotective and blood pressure lowering effects of dietary nitrate are abolished by an antiseptic mouthwash. Free Radic. Biol. Med.2009, 46, 1068–1075.
22. Vanhatalo, A.; Bailey, S.J.; Blackwell, J.R.; DiMenna, F.J.; Pavey, T.G.; Wilkerson, D.P.; Benjamin, N.; Winyard, P.G.; Jones, A.M. 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, R1121–R1131.
23. Webb, A.J.; Patel, N.; Loukogeorgakis, S.; Okorie, M.; Aboud, Z.; Misra, S.; Rashid, R.; Miall, P.; Deanfield, J.; Benjamin, N. et al. Acute blood pressure lowering, vasoprotective, and antiplatelet properties of dietary nitrate via bioconversion to nitrite. Hypertension2008, 51, 784–790.
24. Cosby, K.; Partovi, K.S.; Crawford, J.H.; Patel, R.P.; Reiter, C.D.; Martyr, S.; Yang, B.K.; Waclawiw, M.A.; Zalos, G.; Xu, X. et al. Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation. Nat. Med.2003, 9, 1498–1505.
25. Dejam, A.; Hunter, C.J.; Schechter, A.N.; Gladwin, M.T. Emerging role of nitrite in human biology. Blood Cells Mol. Dis2004, 32, 423–429.
26. Hendgen-Cotta, U.B.; Luedike, P.; Totzeck, M.; Kropp, M.; Schicho, A.; Stock, P.; Rammos, C.; Niessen, M.; Heiss, C.; Lundberg, J.O. et al. Dietary nitrate supplementation improves revascularization in chronic ischemia. Circulation2012, 126, 1983–1992.
27. Hickner, R.C.; Fisher, J.S.; Ehsani, A.A.; Kohrt, W.M. Role of nitric oxide in skeletal muscle blood flow at rest and during dynamic exercise in humans. Am. J. Physiol.1997, 273, H405–H410.
28. Bailey, S.J.; Winyard, P.; Vanhatalo, A.; Blackwell, J.R.; Dimenna, F.J.; Wilkerson, D.P.; Tarr, J.; Benjamin, N.; Jones, A.M. Dietary nitrate supplementation reduces the O2 cost of low-intensity exercise and enhances tolerance to high-intensity exercise in humans. J. Appl. Physiol.2009, 107, 1144–1155.
29. Bond, H.; Morton, L.; Braakhuis, A.J. Dietary nitrate supplementation improves rowing performance in well-trained rowers. Int. J. Sport Nutr. Exerc. Metab.2012, 22, 251–256.
30. Breese, B.C.; McNarry, M.A.; Marwood, S.; Blackwell, J.R.; Bailey, S.J.; Jones, A.M. Beetroot juice supplementation speeds O2 uptake kinetics and improves exercise tolerance during severe-intensity exercise initiated from an elevated metabolic rate. Am. J. Physiol. Regul. Integr. Comp. Physiol.2013, 305, R1441–R1450.
31. Cermak, N.M.; Gibala, M.J.; van Loon, L.J. Nitrate supplementation’s improvement of 10-km time-trial performance in trained cyclists. Int. J. Sport Nutr. Exerc. Metab.2012, 22, 64–71.
32. Cermak, N.M.; Res, P.; Stinkens, R.; Lundberg, J.O.; Gibala, M.J.; van Loon, L.J.C. No improvement in endurance performance after a single dose of beetroot juice. Int. J. Sport Nutr. Exerc. Metab.2012, 22, 470–478.
33. Christensen, P.M.; Nyberg, M.; Bangsbo, J. Influence of nitrate supplementation on VO2 kinetics and endurance of elite cyclists. Scand. J. Med. Sci. Sports2013, 23, e21–e31.
34. Engan, H.K.; Jones, A.M.; Ehrenberg, F.; Schagatay, E. Acute dietary nitrate supplementation improves dry static apnea performance. Respir. Physiol. Neurobiol.2012, 182, 53–59.
35. Fulford, J.; Winyard, P.G.; Vanhatalo, A.; Bailey, S.J.; Blackwell, J.R.; Jones, A.M. Influence of dietary nitrate supplementation on human skeletal muscle metabolism and force production during maximum voluntary contractions. Pflug. Arch.2013, 465, 517–528.
36. Kelly, J.; Vanhatalo, A.; Wilkerson, D.P.; Wylie, L.J.; Jones, A.M. Effects of nitrate on the power-duration relationship for severe-intensity exercise. Med. Sci. Sports Exerc.2013, 45, 1798–1806.
37. Kenjale, A.A.; Ham, K.L.; Stabler, T.; Robbins, J.L.; Johnson, J.L.; Vanbruggen, M.; Privette, G.; Yim, E.; Kraus, W.E.; Allen, J.D. Dietary nitrate supplementation enhances exercise performance in peripheral arterial disease. J. Appl. Physiol.2011, 110, 1582–1591.
38. Muggeridge, D.J.; Howe, C.C.F.; Spendiff, O.; Pedlar, C.; James, P.E.; Easton, C. The effects of a single dose of concentrated beetroot juice on performance in trained flatwater kayakers. Int. J. Sport Nutr. Exerc. Metab.2013, 23, 498–506.
39. Bescos, R.; Ferrer-Roca, V.; Galilea, P.A.; Roig, A.; Drobnic, F.; Sureda, A.; Martorell, M.; Cordova, A.; Tur, J.A.; Pons, A. Sodium nitrate supplementation does not enhance performance of endurance athletes. Med. Sci. Sports Exerc.2012, 44, 2400–2409.
40. Bescos, R.; Rodriguez, F.A.; Iglesias, X.; Ferrer, M.D.; Iborra, E.; Pons, A. Acute administration of inorganic nitrate reduces VO(2peak) in endurance athletes. Med. Sci. Sports Exerc.2011, 43, 1979–1986.
41. Larsen, F.J.; Weitzberg, E.; Lundberg, J.O.; Ekblom, B. Effects of dietary nitrate on oxygen cost during exercise. Acta Physiol. 2007, 191, 59–66.
42. Benjamin, N.; O’Driscoll, F.; Dougall, H.; Duncan, C.; Smith, L.; Golden, M.; McKenzie, H. Stomach NO synthesis. Nature1994, 368, 502.
43. Lundberg, J.O.; Weitzberg, E.; Lundberg, J.M.; Alving, K. Intragastric nitric oxide production in humans: Measurements in expelled air. Gut1994, 35, 1543–1546.
44. Zweier, J.L.; Samouilov, A.; Kuppusamy, P. Non-enzymatic nitric oxide synthesis in biological systems. Biochim. Biophys. Acta.1999, 1411, 250–262.
45. Zweier, J.L.; Wang, P.; Samouilov, A.; Kuppusamy, P. Enzyme-independent formation of nitric oxide in biological tissues. Nat. Med.1995, 1, 804–809.
46. Modin, A.; Bjorne, H.; Herulf, M.; Alving, K.; Weitzberg, E.; Lundberg, J.O. Nitrite-derived nitric oxide: A possible mediator of “acidic-metabolic” vasodilation. Acta Physiol. Scand.2001, 171, 9–16.
47. Vanhatalo, A.; Fulford, J.; Bailey, S.J.; Blackwell, J.R.; Winyard, P.G.; Jones, A.M. Dietary nitrate reduces muscle metabolic perturbation and improves exercise tolerance in hypoxia. J. Physiol.2011, 589, 5517–5528.
48. Roy, C.S.; Brown, J.G. The blood-pressure and its variations in the arterioles, capillaries, and smaller veins. J. Physiol.1879, 2, 323–359.
49. Tune, J.; Gorman, M.; Feigl, E. Matching coronary blood flow to myocardial oxygen consumption. J. Appl. Physiol.2004, 97, 404–415.
50. Furchgott, R.F.; Bhadrakom, S. Reactions of strips of rabbit aorta to epinephrine, isopropylarterenol, sodium nitrite and other drugs. J. Pharmacol. Exp. Ther.1953, 108, 129–143.
51. Ignarro, L.J.; Gruetter, C.A. Requirement of thiols for activation of coronary arterial guanylate cyclase by glyceryl trinitrate and sodium nitrite: Possible involvement of S-nitrosothiols. Biochim. Biophys. Acta1980, 631, 221–231.
52. Ignarro, L.J.; Lippton, H.; Edwards, J.C.; Baricos, W.H.; Hyman, A.L.; Kadowitz, P.J.; Gruetter, C.A. Mechanism of vascular smooth muscle relaxation by organic nitrates, nitrites, nitroprusside and nitric oxide: Evidence for the involvement of S-nitrosothiols as active intermediates. J. Pharmacol. Exp. Ther.1981, 218, 739–749.
53. Mittal, C.K.; Arnold, W.P.; Murad, F. Characterization of protein inhibitors of guanylate cyclase activation from rat heart and bovine lung. J. Biol. Chem.1978, 253, 1266–1271.
54. Lauer, T.; Preik, M.; Rassaf, T.; Strauer, B.E.; Deussen, A.; Feelisch, M.; Kelm, M. Plasma nitrite rather than nitrate reflects regional endothelial nitric oxide synthase activity but lacks intrinsic vasodilator action. Proc. Natl. Acad. Sci. USA2001, 98, 12814–12819.
55. Allen, B.W.; Piantadosi, C.A. How do red blood cells cause hypoxic vasodilation? The SNO-hemoglobin paradigm. Am. J. Physiol. Heart Circ. Physiol.2006, 291, H1507–H1512.
56. McMahon, T.J. Hemoglobin and nitric oxide. N. Engl. J. Med.2003, 349, 402–405.
57. Ferguson, S.K.; Hirai, D.M.; Copp, S.W.; Holdsworth, C.T.; Allen, J.D.; Jones, A.M.; Musch, T.I.; Poole, D.C. Effects of nitrate supplementation via beetroot juice on contracting rat skeletal muscle microvascular oxygen pressure dynamics. Respir. Physiol. Neurobiol.2013, 187, 250–255.
58. Ferguson, S.K.; Hirai, D.M.; Copp, S.W.; Holdsworth, C.T.; Allen, J.D.; Jones, A.M.; Musch, T.I.; Poole, D.C. Impact of dietary nitrate supplementation via beetroot juice on exercising muscle vascular control in rats. J. Physiol.2013, 591, 547–557.
59. Gangolli, S.D.; van den Brandt, P.A.; Feron, V.J.; Janzowsky, C.; Koeman, J.H.; Speijers, G.J.; Spiegelhalder, B.; Walker, R.; Wisnok, J.S. Nitrate, nitrite and N-nitroso compounds. Eur. J. Pharmacol.1994, 292, 1–38.
60. Guadagnin, S.G.; Rath, S.; Reyes, F.G. Evaluation of the nitrate content in leaf vegetables produced through different agricultural systems. Food Addit. Contam.2005, 22, 1203–1208.
61. Cassens, R. Use of sodium nitrite in cured meats today. Food Technol. 1995, 49, 72–81.
62. White, J.W., Jr. Relative significance of dietary sources of nitrate and nitrite. J. Agric. Food Chem.1975, 23, 886–891.
63. Allaker, R.P.; Silva Mendez, L.S.; Hardie, J.M.; Benjamin, N. Antimicrobial effect of acidified nitrite on periodontal bacteria. Oral. Microbiol. Immunol.2001, 16, 253–256.
64. Xu, Y.; He, Y.; Li, X.; Gao, C.; Zhou, L.; Sun, S.; Pang, G. Antifungal effect of ophthalmic preservatives phenylmercuric nitrate and benzalkonium chloride on ocular pathogenic filamentous fungi. Diagn. Microbiol. Infect. Dis.2013, 75, 64–67.
65. Bartholomew, B.; Hill, M.J. The pharmacology of dietary nitrate and the origin of urinary nitrate. Food Chem. Toxicol.1984, 22, 789–795.
66. 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, 545–548.
67. Tannenbaum, S.R.; Correa, P. Nitrate and gastric cancer risks. Nature1985, 317, 675–676.
68. Tannenbaum, S.R.; Sinskey, A.J.; Weisman, M.; Bishop, W. Nitrite in human saliva. Its possible relationship to nitrosamine formation. J. Natl. Cancer Inst.1974, 53, 79–84.
69. Kim-Shapiro, D.B.; Gladwin, M.T. Mechanisms of nitrite bioactivation. Nitric Oxide2014, 38, 58–68.
70. Hunault, C.C.; van Velzen, A.G.; Sips, A.J.; Schothorst, R.C.; Meulenbelt, J. Bioavailability of sodium nitrite from an aqueous solution in healthy adults. Toxicol. Lett.2009, 190, 48–53.
71. Stamler, J.; Mendelsohn, M.E.; Amarante, P.; Smick, D.; Andon, N.; Davies, P.F.; Cooke, J.P.; Loscalzo, J. N-acetylcysteine potentiates platelet inhibition by endothelium-derived relaxing factor. Circ. Res.1989, 65, 789–795.
72. Gilligan, D.M.; Panza, J.A.; Kilcoyne, C.M.; Waclawiw, M.A.; Casino, P.R.; Quyyumi, A.A. Contribution of endothelium-derived nitric oxide to exercise-induced vasodilation. Circulation1994, 90, 2853–2858.
73. Dykhuizen, R.S.; Frazer, R.; Duncan, C.; Smith, C.C.; Golden, M.; Benjamin, N.; Leifert, C. Antimicrobial effect of acidified nitrite on gut pathogens: Importance of dietary nitrate in host defense. Antimicrob. Agents Chemother.1996, 40, 1422–1425.
74. Candipan, R.C.; Wang, B.Y.; Buitrago, R.; Tsao, P.S.; Cooke, J.P. Regression or progression. Dependency on vascular nitric oxide. Arterioscler. Thromb. Vasc. Biol.1996, 16, 44–50.
75. Cooke, J.P.; Stamler, J.; Andon, N.; Davies, P.F.; McKinley, G.; Loscalzo, J. Flow stimulates endothelial cells to release a nitrovasodilator that is potentiated by reduced thiol. Am. J. Physiol.1990, 259, H804–H812.
76. Von der Leyen, H.E.; Gibbons, G.H.; Morishita, R.; Lewis, N.P.; Zhang, L.; Nakajima, M.; Kaneda, Y.; Cooke, J.P.; Dzau, V.J. Gene therapy inhibiting neointimal vascular lesion: In vivo transfer of endothelial cell nitric oxide synthase gene. Proc. Natl. Acad. Sci. USA1995, 92, 1137–1141.
77. Castello, P.R.; David, P.S.; McClure, T.; Crook, Z.; Poyton, R.O. Mitochondrial cytochrome oxidase produces nitric oxide under hypoxic conditions: Implications for oxygen sensing and hypoxic signaling in eukaryotes. Cell Metab. 2006, 3, 277–287.
78. Castello, P.R.; Woo, D.K.; Ball, K.; Wojcik, J.; Liu, L.; Poyton, R.O. Oxygen-regulated isoforms of cytochrome c oxidase have differential effects on its nitric oxide production and on hypoxic signaling. Proc. Natl. Acad. Sci. USA2008, 105, 8203–8208.
79. Mensinga, T.T.; Speijers, G.J.; Meulenbelt, J. Health implications of exposure to environmental nitrogenous compounds. Toxicol. Rev.2003, 22, 41–51.
80. Maruthur, N.M.; Wang, N.Y.; Appel, L.J. Lifestyle interventions reduce coronary heart disease risk: Results from the PREMIER trial. Circulation2009, 119, 2026–2031.
81. Magee, P.N.; Barnes, J.M. The production of malignant primary hepatic tumours in the rat by feeding dimethylnitrosamine. Br. J. Cancer1956, 10, 114–122.
82. Mirvish, S.S. Role of N-nitroso compounds (NOC) and N-nitrosation in etiology of gastric, esophageal, nasopharyngeal and bladder cancer and contribution to cancer of known exposures to NOC. Cancer Lett. 1995, 93, 17–48.
83. Mirvish, S.S. N-nitroso compounds: Their chemical and in vivo formation and possible importance as environmental carcinogens. J. Toxicol. Environ. Health1977, 2, 1267–1277.
84. Xia, D.S.; Liu, Y.; Zhang, C.M.; Yang, S.H.; Wang, S.L. Antimicrobial effect of acidified nitrate and nitrite on six common oral pathogens in vitro. Chin. Med. J.2006, 119, 1904–1909.
85. Grosse, Y.; Baan, R.; Straif, K.; Secretan, B.; El Ghissassi, F.; Cogliano, V.; WHO International Agency for Research on Cancer Monograph Working Group. Carcinogenicity of nitrate, nitrite, and cyanobacterial peptide toxins. Lancet Oncol. 2006, 7, 628–629.
86. Kanner, J.; Harel, S.; Granit, R. Betalains--a new class of dietary cationized antioxidants. J. Agric. Food Chem.2001, 49, 5178–5185.
87. Jansson, E.A.; Petersson, J.; Reinders, C.; Sobko, T.; Bjorne, H.; Phillipson, M.; Weitzberg, E.; Holm, L.; Lundberg, J.O. Protection from nonsteroidal anti-inflammatory drug (NSAID)-induced gastric ulcers by dietary nitrate. Free Radic. Biol. Med.2007, 42, 510–518.
88. Murphy, M.; Eliot, K.; Heuertz, R.M.; Weiss, E. Whole beetroot consumption acutely improves running performance. J. Acad. Nutr. Diet.2012, 112, 548–552.
89. Ghosh, S.M.; Kapil, V.; Fuentes-Calvo, I.; Bubb, K.J.; Pearl, V.; Milsom, A.B.; Khambata, R.; Maleki-Toyserkani, S.; Yousuf, M.; Benjamin, N. et al. Enhanced vasodilator activity of nitrite in hypertension: Critical role for erythrocytic xanthine oxidoreductase and translational potential. Hypertension2013, 61, 1091–1102.
90. Wylie, L.J.; Mohr, M.; Krustrup, P.; Jackman, S.R.; Ermiotadis, G.; Kelly, J.; Black, M.I.; Bailey, S.J.; Vanhatalo, A.; Jones, A.M. Dietary nitrate supplementation improves team sport-specific intense intermittent exercise performance. Eur. J. Appl. Physiol.2013, 113, 1673–1684.
91. Celermajer, D.S.; Sorensen, K.E.; Spiegelhalter, D.J.; Georgakopoulos, D.; Robinson, J.; Deanfield, J.E. Aging is associated with endothelial dysfunction in healthy men years before the age-related decline in women. J. Am. Coll. Cardiol.1994, 24, 471–476.
92. Taddei, S.; Virdis, A.; Ghiadoni, L.; Salvetti, G.; Bernini, G.; Magagna, A.; Salvetti, A. Age-related reduction of NO availability and oxidative stress in humans. Hypertension2001, 38, 274–279.
93. Taddei, S.; Virdis, A.; Mattei, P.; Ghiadoni, L.; Fasolo, C.B.; Sudano, I.; Salvetti, A. Hypertension causes premature aging of endothelial function in humans. Hypertension1997, 29, 736–743.
94. Taddei, S.; Virdis, A.; Mattei, P.; Ghiadoni, L.; Gennari, A.; Fasolo, C.B.; Sudano, I.; Salvetti, A. Aging and endothelial function in normotensive subjects and patients with essential hypertension. Circulation1995, 91, 1981–1987.
95. Milkowski, A.; Garg, H.K.; Coughlin, J.R.; Bryan, N.S. Nutritional epidemiology in the context of nitric oxide biology: A risk-benefit evaluation for dietary nitrite and nitrate. Nitric Oxide2010, 22, 110–119.
96. Lidder, S.; Webb, A.J. Vascular effects of dietary nitrate (as found in green leafy vegetables and beetroot) via the nitrate-nitrite-nitric oxide pathway. Br. J. Clin. Pharmacol.2013, 75, 677–696.
97. Belch, J.J.; Topol, E.J.; Agnelli, G.; Bertrand, M.; Califf, R.M.; Clement, D.L.; Creager, M.A.; Easton, J.D.; Gavin, J.R., III; Greenland, P. et al. Critical issues in peripheral arterial disease detection and management: A call to action. Arch. Intern. Med.2003, 163, 884–892.
98. Hirsch, A.T.; Haskal, Z.J.; Hertzer, N.R.; Bakal, C.W.; Creager, M.A.; Halperin, J.L.; Hiratzka, L.F.; Murphy, W.R.; Olin, J.W.; Puschett, J.B. et al. ACC/AHA 2005 practice guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): A collaborative report from the american association for vascular Surgery/Society for vascular surgery, society for cardiovascular angiography and interventions, society for vascular medicine and biology, society of interventional radiology, and the ACC/AHA task force on practice guidelines (writing committee to develop guidelines for the management of patients with peripheral arterial disease): Endorsed by the american association of cardiovascular and pulmonary rehabilitation; national heart, lung, and blood institute; society for vascular nursing; TransAtlantic inter-society consensus; and vascular disease foundation. Circulation2006, 113, e463–e654.
99. Govoni, M.; Jansson, E.A.; Weitzberg, E.; Lundberg, J.O. The increase in plasma nitrite after a dietary nitrate load is markedly attenuated by an antibacterial mouthwash. Nitric Oxide2008, 19, 333–337.
100. Hoon, M.W.; Hopkins, W.G.; Jones, A.M.; Martin, D.T.; Halson, S.L.; West, N.P.; Johnson, N.A.; Burke, L.M. Nitrate supplementation and high-intensity performance in competitive cyclists. Appl. Physiol. Nutr. Metab.2014, 39, 1043–1049.
101. Masschelein, E.; van Thienen, R.; Wang, X.; van Schepdael, A.; Thomis, M.; Hespel, P. Dietary nitrate improves muscle but not cerebral oxygenation status during exercise in hypoxia. J. Appl. Physiol.2012, 113, 736–745.
102. Wylie, L.J.; Kelly, J.; Bailey, S.J.; Blackwell, J.R.; Skiba, P.F.; Winyard, P.G.; Jeukendrup, A.E.; Vanhatalo, A.; Jones, A.M. Beetroot juice and exercise: Pharmacodynamic and dose-response relationships. J. Appl. Physiol. 2013, 115, 325–336.
103. Muggeridge, D.J.; Howe, C.C.; Spendiff, O.; Pedlar, C.; James, P.E.; Easton, C. A single dose of beetroot juice enhances cycling performance in simulated altitude. Med. Sci. Sports Exerc.2014, 46, 143–150.
104. Martin, D.S.; Gilbert-Kawai, E.T.; Meale, P.M.; Fernandez, B.O.; Cobb, A.; Khosravi, M.; Mitchell, K.; Grocott, M.P.; Levett, D.Z.; Mythen, M.G. et al. Design and conduct of “xtreme alps”: A double-blind, randomised controlled study of the effects of dietary nitrate supplementation on acclimatisation to high altitude. Contemp. Clin. Trials2013, 36, 450–459.
105. Hoon, M.W.; Jones, A.M.; Johnson, N.A.; Blackwell, J.R.; Broad, E.M.; Lundy, B.; Rice, A.J.; Burke, L.M. The effect of variable doses of inorganic nitrate-rich beetroot juice on simulated 2000 m rowing performance in trained athletes. Int. J. Sports Physiol. Perform.2014, 9, 615–620.
106. Wilkerson, D.P.; Hayward, G.M.; Bailey, S.J.; Vanhatalo, A.; Blackwell, J.R.; Jones, A.M. Influence of acute dietary nitrate supplementation on 50 mile time trial performance in well-trained cyclists. Eur. J. Appl. Physiol.2012, 112, 4127–4134.