Vascular effects of dietary nitrate (as found in green leafy vegetables and beetroot) via the nitrate-nitrite-nitric oxide pathway

In the paper

“Pre-clinical studies with nitrate or nitrite also show the potential to protect against ischaemia-reperfusion injury and reduce arterial stiffness, inflammation and intimal thickness.”

What the sources say

• Partly supported

  The Introduction reports that sodium nitrite protects against ischaemia-reperfusion injury, and the Discussion reports reduced large-artery stiffness and inflammatory markers in old mice. Our copy does not report a reduction in intimal thickness; that part of the claim is unsupported. (LLM, conf=0.87)

  cites [150] 150. Sindler AL, Fleenor BS, Calvert JW, Marshall KD, Zigler ML, Lefer DJ, Seals DR. Nitrite supplementation reverses vascular endothelial dysfunction and large elastic artery stiffness with aging. Aging Cell 2011; 10: 429-37. 151 sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction and Discussion report that nitrite protected mice from hepatic and cardiac ischaemia-reperfusion injury, compared with vehicle or nitrate controls. The paper does not report reductions in arterial stiffness, inflammation or intimal thickness, and it does not establish nitrate as protective. (LLM, conf=0.88)

  cites [160] 160. Duranski MR, Greer JJ, Dejam A, Jaganmohan S, Hogg N, Langston W, Patel RP, Yet SF, Wang X, Kevil CG, Gladwin MT, Lefer DJ. Cytoprotective effects of nitrite during in vivo ischemia-reperfusion of the heart and liver. J Clin Invest 2005; 115: 1232-40. 162 sourceExperimental — accuracy not yet measured

In the paper

“Dietary nitrate has been demonstrated to have a range of beneficial vascular effects, including reducing blood pressure, inhibiting platelet aggregation, preserving or improving endothelial dysfunction, enhancing exercise performance in healthy individuals and patients with peripheral arterial disease.”

What the sources say

• Partly supported

  Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

  cites [78] 78. Larsen FJ, Ekblom B, Sahlin K, Lundberg JO, Weitzberg E. Effects of dietary nitrate on blood pressure in healthy volunteers. N Engl J Med 2006; 355: 2792-3. sourceExperimental — accuracy not yet measured
• Partly supported

  Split into 2 atoms — 1 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

  cites [79] 79. Webb AJ, Patel N, Loukogeorgakis S, Okorie M, Aboud Z, Misra S, Rashid R, Miall P, Deanfield J, Benjamin N, MacAllister R, Hobbs AJ, Ahluwalia A. Acute blood pressure lowering, vasoprotective, and antiplatelet properties of dietary nitrate via bioconversion to nitrite. Hypertension 2008; 51: 784-90. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [97] 97. Richardson G, Hicks SL, O'Byrne S, Frost MT, Moore K, Benjamin N, McKnight GM. The ingestion of inorganic nitrate increases gastric S-nitrosothiol levels and inhibits platelet function in humans. Nitric Oxide 2002; 7: 24-9. source

In the paper

“Nitrite appears to mediate the majority of its effects through bioactivation to NO.This occurs mainly via nitrite reductases, which have selective activity under oxygen/hypoxic/ischaemic conditions”

What the sources say

• ?Not checked — no full text of the sourcecites [6] 6. Cosby K, Partovi KS, Crawford JH, Patel RP, Reiter CD, Martyr S, Yang BK, Waclawiw MA, Zalos G, Xu X, Huang KT, Shields H, Kim-Shapiro DB, Schechter AN, Cannon RO 3rd, Gladwin MT. Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation. Nat Med 2003; 9: 1498-505. source
• ?Not checked — no full text of the sourcecites [119] 119. Gladwin MT, Schechter AN, Kim-Shapiro DB, Patel RP, Hogg N, Shiva S, Cannon RO 3rd, Kelm M, Wink DA, Espey MG, Oldfield EH, Pluta RM, Freeman BA, Lancaster JR Jr, Feelisch M, Lundberg JO. The emerging biology of the nitrite anion. Nat Chem Biol 2005; 1: 308-14. 120 source
• Partly supported

  The Introduction links nitrite-associated vasodilation to its conversion to NO by deoxyhemoglobin, and the results report that hemoglobin’s nitrite-reductase rate varies with oxygen saturation. The paper does not establish that the majority of nitrite’s effects occur through NO bioactivation or that nitrite reductases are the main route across those effects; the Physiological implications section also discusses nonenzymatic reduction. Page numbers were not available in our copy. (LLM, conf=0.86)

  cites [120] 120. Huang Z, Shiva S, Kim-Shapiro DB, Patel RP, Ringwood LA, Irby CE, Huang KT, Ho C, Hogg N, Schechter AN, Gladwin MT. Enzymatic function of hemoglobin as a nitrite reductase that produces NO under allosteric control. J Clin Invest 2005; 115: 2099-107. 121 sourceExperimental — accuracy not yet measured
• Partly supported

  The section on myoglobin as a nitrite reductase describes nitrite reduction to NO at different oxygen tensions and reports that myoglobin accounts for more than 70% of the effects examined in cardiac tissue. The section on hypoxic vasodilation also links nitrite-to-NO conversion to hypoxia. These passages support the proposed pathway under low-oxygen and ischemic conditions, but do not establish that it mediates the majority of nitrite’s effects generally. (LLM, conf=0.84)

  cites [121] 121. Gladwin MT, Kim-Shapiro DB. The functional nitrite reductase activity of the heme-globins. Blood 2008; 112: 2636-47. 122 sourceExperimental — accuracy not yet measured

In the paper

“Only a small fraction of nitrate reaches the large bowel, as <1% of ingested nitrate is excreted in the faeces [113] and <2% is present in ileostomy fluid in patients with a total colectomy [113,114], with negligible nitrite concentrations.”

What the sources say

• ?Not checked — no full text of the sourcecites [113] 113. Bartholomew B, Hill MJ. The pharmacology of dietary nitrate and the origin of urinary nitrate. Food Chem Toxicol 1984; 22: 789-95. 114 source
• Partly supported

  The Results report very low nitrate in ileal effluent and no detectable nitrite, supporting the claim’s general point. They do not establish that ileal nitrate was below 2% of intake across the studied diets: mean ileal excretion was 0.038 mmol/day while intake ranged from 0.83 to 5.2 mmol/day. The Discussion reports less than 0.2% of labelled nitrate-derived nitrogen in faeces from another study, not a direct finding that less than 1% of ingested nitrate was excreted as faecal nitrate. (LLM, conf=0.88)

  cites [114] 114. Florin TH, Neale G, Cummings JH. The effect of dietary nitrate on nitrate and nitrite excretion in man. Br J Nutr 1990; 64: 387-97. 115 sourceExperimental — accuracy not yet measured

In the paper

“Sindler et al. also detected depleted concentrations in the arteries and heart, which were restored to youthful levels (4-6 month controls) by 3 weeks' supplementation with sodium nitrite (50 mg l -1 in the drinking water) [150].”

What the sources say

• Supported

  Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [150] 150. Sindler AL, Fleenor BS, Calvert JW, Marshall KD, Zigler ML, Lefer DJ, Seals DR. Nitrite supplementation reverses vascular endothelial dysfunction and large elastic artery stiffness with aging. Aging Cell 2011; 10: 429-37. 151 source

In the paper

“Thus, Sindler et al. found that nitrite reduced the elevated pulse wave velocity and levels of inflammatory cytokines IL-1b, IL6, INFg and TNFa [150].”

What the sources say

• Supported

  The Results section reports that sodium nitrite reversed the age-associated increase in aortic pulse wave velocity in old mice. It also reports that short-term treatment reduced aortic IL-1β, IL-6, IFNγ and TNF-α to levels observed in young controls. Page numbers are unavailable in our copy. (LLM, conf=0.94)

  cites [150] 150. Sindler AL, Fleenor BS, Calvert JW, Marshall KD, Zigler ML, Lefer DJ, Seals DR. Nitrite supplementation reverses vascular endothelial dysfunction and large elastic artery stiffness with aging. Aging Cell 2011; 10: 429-37. 151 source

In the paper

“Bahra et al. found no effect in healthy volunteers with normal endothelial function.FMD was not altered at 3 h following the ingestion of dietary nitrate (8 mmol).However, a reduction in pulse wave velocity of ~0.3 m s -1 accompanied the reduction in SBP of ~5 mmHg [148].”

What the sources say

• Supported

  The Study protocol reports an 8 mmol potassium nitrate dose in healthy volunteers, with measurements at 3 h. The Abstract reports no change in FMD, while aortic pulse wave velocity fell from 6.5 to 6.2 m/s and systolic blood pressure fell from 116.9 to 112.1 mm Hg. (LLM, conf=0.94)

  cites [148] 148. Bahra M, Kapil V, Pearl V, Ghosh S, Ahluwalia A. Inorganic nitrate ingestion improves vascular compliance but does not alter flow-mediated dilatation in healthy volunteers. Nitric Oxide 2012; 26: 197-202. 149 source

In the paper

“The half-life of nitrate is 5-8 h [77,79,111,141,142], which is much longer than that of nitrite, which has been reported as being 1-5 min ex vivo [77,142] and ~20-45 min in vivo [86,112].”

What the sources say

• ?Not checked — no full text of the sourcecites [77] 77. Lundberg JO, Govoni M. Inorganic nitrate is a possible source for systemic generation of nitric oxide. Free Radic Biol Med 2004; 37: 395-400. source
• Supported

  The Discussion reports a nitrate half-life of approximately 8 hours and an ex vivo nitrite half-life of less than 2 minutes, consistent with the ranges for which this paper is cited. The citing sentence attributes the 20–45-minute in vivo estimate to different references, so that estimate is not part of this verdict. (LLM, conf=0.91)

  cites [79] 79. Webb AJ, Patel N, Loukogeorgakis S, Okorie M, Aboud Z, Misra S, Rashid R, Miall P, Deanfield J, Benjamin N, MacAllister R, Hobbs AJ, Ahluwalia A. Acute blood pressure lowering, vasoprotective, and antiplatelet properties of dietary nitrate via bioconversion to nitrite. Hypertension 2008; 51: 784-90. source
• ?Not checked — no full text of the sourcecites [111] 111. van Velzen AG, Sips AJ, Schothorst RC, Lambers AC, Meulenbelt J. The oral bioavailability of nitrate from nitrate-rich vegetables in humans. Toxicol Lett 2008; 181: 177-81. 112 source
• ?Could not verify

  The Results report that nitrate concentrations remained elevated over the six-hour study, while the rise in gastric nitrite was not sustained. Neither the Results nor the Discussion gives a nitrate half-life of 5–8 hours or the claimed ex vivo or in vivo nitrite half-lives; searches for those values found no supporting passage. (LLM, conf=0.76)

  cites [141] 141. McKnight GM, Smith LM, Drummond RS, Duncan CW, Golden M, Benjamin N. Chemical synthesis of nitric oxide in the stomach from dietary nitrate in humans. Gut 1997; 40: 211-4. 142 sourceExperimental — accuracy not yet measured
• Partly supported

  The half-lives table in “Nitrite Reduction to NO In Vivo” (page unavailable) lists 5–8 hours for nitrate and 1–5 minutes for nitrite, supporting the values attributed to this paper. It describes these as approximate blood/plasma values from human studies, however, and does not identify the 1–5-minute value as ex vivo. The separate 20–45-minute in vivo figure is cited to other sources in the citing sentence. (LLM, conf=0.84)

  cites [142] 142. Lundberg JO, Weitzberg E. NO generation from nitrite and its role in vascular control. Arterioscler Thromb Vasc Biol 2005; 25: 915-22. 143 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [86] 86. Dejam A, Hunter CJ, Tremonti C, Pluta RM, Hon YY, Grimes G, Partovi K, Pelletier MM, Oldfield EH, Cannon RO 3rd, Schechter AN, Gladwin MT. Nitrite infusion in humans and nonhuman primates: endocrine effects, pharmacokinetics, and tolerance formation. Circulation 2007; 116: 1821-31. source
• ?Not checked — no full text of the sourcecites [112] 112. Hunault CC, van Velzen AG, Sips AJ, Schothorst RC, Meulenbelt J. Bioavailability of sodium nitrite from an aqueous solution in healthy adults. Toxicol Lett 2009; 190: 48-53. 113 source

In the paper

“Chronic inhibition of XOR with allopurinol or 3 weeks of tungstenrich diet increased intimal hyperplasia.”

What the sources say

• ?Could not verify

  The Discussion (page unavailable) mentions xanthine oxidoreductase-dependent nitrite reduction, but not chronic XOR inhibition or intimal hyperplasia. Searches for allopurinol, tungsten, and intimal hyperplasia found no passage in our copy reporting the claimed result. (LLM, conf=0.76)

  cites [160] 160. Duranski MR, Greer JJ, Dejam A, Jaganmohan S, Hogg N, Langston W, Patel RP, Yet SF, Wang X, Kevil CG, Gladwin MT, Lefer DJ. Cytoprotective effects of nitrite during in vivo ischemia-reperfusion of the heart and liver. J Clin Invest 2005; 115: 1232-40. 162 sourceExperimental — accuracy not yet measured

In the paper

“Rudolph et al. demonstrated that subcutaneous injection of nitro-oleic acid markedly reduced atherosclerotic lesion formation in apoliproprotein E-deficient mice associated with a variety of antiinflammatory effects including reduction in foam cell formation through attenuation of oxidized LDL-induced phosphorylation of signal transducer and activator of transcription-1 (STAT-1) [139].”

What the sources say

• Partly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [139] 139. Rudolph TK, Rudolph V, Edreira MM, Cole MP, Bonacci G, Schopfer FJ, Woodcock SR, Franek A, Pekarova M, Khoo NK, Hasty AH, Baldus S, Freeman BA. Nitro-fatty acids reduce atherosclerosis in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 2010; 30: 938-45. 140 sourceExperimental — accuracy not yet measured

In the paper

“Also, Kelley et al., have found that nitro-oleic acid inhibits XOR, and is surprisingly more potent than allopurinol in terms of inhibition of superoxide production [197]”

What the sources say

• Partly supported

  The Results (page unavailable) report that nitro-oleic acid lessened markers of ROS generation in mice after renal ischemia/reperfusion. The Discussion (page unavailable) addresses NADPH oxidase and neutrophil superoxide generation, but does not establish inhibition of xanthine oxidoreductase or compare nitro-oleic acid with allopurinol. (LLM, conf=0.82)

  cites [197] 197. Liu H, Jia Z, Soodvilai S, Guan G, Wang MH, Dong Z, Symons JD, Yang T. Nitro-oleic acid protects the mouse kidney from ischemia and reperfusion injury. Am J Physiol Renal Physiol 2008; 295: F942-9. 199 Nitrites, nitrosamines, and cancer. Lancet 1968; 1: 1071-2. 200 sourceExperimental — accuracy not yet measured

In the paper

“Typically, around 85% of dietary nitrate (the inorganic nitrate anion, NO3 -) is derived from vegetables [25][26][27], with most of the remainder from drinking water”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [25][26][27]

In the paper

“others have suggested possible small positive and negative associations with dietary nitrate and cancer, but these remain unproven.”

In the paper

“Nitrate content also varies across the plant: leaf > stem > root [37][38][39].”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [37][38][39]

In the paper

“From 2001, nitrite was discovered to provide an important alternative source of nitric oxide, particularly when oxygen levels are reduced [4,5], such as in the microcirculation, causing vasodilatation [6]”

What the sources say

• ?Not checked — no full text of the sourcecites [4] 4. Modin A, Bjorne H, Herulf M, Alving K, Weitzberg E, Lundberg JO. Nitrite-derived nitric oxide: a possible mediator of 'acidic-metabolic' vasodilation. Acta Physiol Scand 2001; 171: 9-16. source
• ?Not checked — no full text of the sourcecites [5] 5. Demoncheaux EA, Higenbottam TW, Foster PJ, Borland CD, Smith AP, Marriott HM, Bee D, Akamine S, Davies MB. Circulating nitrite anions are a directly acting vasodilator and are donors for nitric oxide. Clin Sci 2002; 102: 77-83. source
• ?Not checked — no full text of the sourcecites [6] 6. Cosby K, Partovi KS, Crawford JH, Patel RP, Reiter CD, Martyr S, Yang BK, Waclawiw MA, Zalos G, Xu X, Huang KT, Shields H, Kim-Shapiro DB, Schechter AN, Cannon RO 3rd, Gladwin MT. Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation. Nat Med 2003; 9: 1498-505. source

In the paper

“Dietary nitrite (NO2 -) is mainly derived from cured meats, where it is added to prevent the development of botulinum toxin [29]”

What the sources say

• ?Not checked — no full text of the sourcecites [29] 29. Binkerd EF, Kolari OE. The history and use of nitrate and nitrite in the curing of meat. Food Cosmet Toxicol 1975; 13: 655-61. source

In the paper

“Interactions with other nutrients, such as vitamin C, polyphenols and fatty acids may enhance or inhibit these effects.”

In the paper

“A portion of a medium nitrate-containing vegetable will provide ~0.5 mmol nitrate, whereas low nitrate containing vegetables (onions and tomatoes) would provide just 0.1 mmol nitrate.”

In the paper

“This increase in plasma nitrite is also inhibited by the use of an antibacterial mouthwash just prior to nitrate ingestion in humans [80] and also blocks the 5 mmHg blood pressure reduction consequent to nitrate supplemented drinking water in Sprague-Dawley rats [81]”

What the sources say

• ?Not checked — no full text of the sourcecites [80] 80. 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; 19: 333-7. source
• ?Not checked — no full text of the sourcecites [81] 81. Petersson J, Carlstrom M, Schreiber O, Phillipson M, Christoffersson G, Jagare A, Roos S, Jansson EA, Persson AE, Lundberg JO, Holm L. Gastroprotective and blood pressure lowering effects of dietary nitrate are abolished by an antiseptic mouthwash. Free Radic Biol Med 2009; 46: 1068-75. source

In the paper

“after 2 days at room temperature the nitrite concentration of beetroot juice increases dramatically to almost 600 mg l -1 , though remains low if kept refrigerated below 4°C [47].”

What the sources say

• ?Not checked — no full text of the sourcecites [47] 47. Tamme T, Reinik M, Pussa T, Roasto M, Meremae K, Kiis A. Dynamics of nitrate and nitrite content during storage of home-made and small-scale industrially produced raw vegetable juices and their dietary intake. Food Addit Contam Part A Chem Anal Control Expo Risk Assess 2010; 27: 487-95. 48 Katan MB. Nitrate in foods: harmful or healthy? Am J Clin Nutr 2009; 90: 11-2. source

In the paper

“Vegetables notable for their low nitrate content (<100 mg kg -1 ) are onions and tomatoes.”

In the paper

“The vegetarian diet has been demonstrated to contain ~4.3 mmol nitrate day -1 , close to the ADI, almost four times greater than a 'normal' diet, which contains ~1.2 mmol nitrate [49].”

What the sources say

• ?Not checked — no full text of the sourcecites [49] 49. Mitchell HH, Shonle HA, Grindley HS. The origin of the nitrates in the urine. J Biol Chem 1916; 24: 461-90. source

In the paper

“The Acceptable Daily Intake (ADI) set by the European Food Safety Authority for nitrate is 3.7 mg kg -1 (0.06 mmol kg -1 ).This equates to ~260 mg day -1 for a 70 kg adult (~4.2 mmol).”

In the paper

“Indeed, nitrite is rapidly absorbed, with a plasma tmax of 15-45 min following oral nitrite administration [112], but this increases to ~3 h, when nitrite is derived from oral nitrate ingestion via the enterosalivary circulation [82].”

What the sources say

• ?Not checked — no full text of the sourcecites [112] 112. Hunault CC, van Velzen AG, Sips AJ, Schothorst RC, Meulenbelt J. Bioavailability of sodium nitrite from an aqueous solution in healthy adults. Toxicol Lett 2009; 190: 48-53. 113 source
• ?Not checked — no full text of the sourcecites [82] 82. Kapil V, Milsom AB, Okorie M, Maleki-Toyserkani S, Akram F, Rehman F, Arghandawi S, Pearl V, Benjamin N, Loukogeorgakis S, Macallister R, Hobbs AJ, Webb AJ, Ahluwalia A. Inorganic nitrate supplementation lowers blood pressure in humans: role for nitrite-derived NO. Hypertension 2010; 56: 274-81. source

In the paper

“For example, summer grown lettuce (longer sunshine hours and less rainfall) has lower mean nitrate concentration than winter grown [40].”

What the sources say

• ?Not checked — no full text of the sourcecites [40] 40. Ysart G, Clifford R, Harrison N. Monitoring for nitrate in UK-grown lettuce and spinach. Food Addit Contam 1999; 16: 301-6. source

In the paper

“Kapil et al.,used potassium nitrate capsules, and demonstrated a dose dependent reduction in BP (with 4, 12 and 24 mmol nitrate) equivalent to beetroot juice [nitrate] with no effect seen with potassium chloride as control [82]”

What the sources say

• ?Not checked — no full text of the sourcecites [82] 82. Kapil V, Milsom AB, Okorie M, Maleki-Toyserkani S, Akram F, Rehman F, Arghandawi S, Pearl V, Benjamin N, Loukogeorgakis S, Macallister R, Hobbs AJ, Webb AJ, Ahluwalia A. Inorganic nitrate supplementation lowers blood pressure in humans: role for nitrite-derived NO. Hypertension 2010; 56: 274-81. source

In the paper

“Nitrate content is influenced by environmental, agricultural and genetic factors [28,36].”

What the sources say

• ?Not checked — no full text of the sourcecites [28] 28. Knight TM, Forman D, Al-Dabbagh SA, Doll R. Estimation of dietary intake of nitrate and nitrite in Great Britain. Food and Chemical Toxicology : An International Journal Published for the British Industrial Biological Research Association 1987; 25: 277-85. source
• ?Not checked — no full text of the sourcecites [36] 36. Santamaria P. Nitrate in vegetables: toxicity, content, intake and EC regulation. J Sci Food Agric 2006; 86: 10-7. source

In the paper

“A study of 3 days' supplementation with ~120 g of round green lettuce demonstrated that ~70% of the nitrate load was excreted and the total amount of urinary nitrate excretion in a 24 h period increased from 53 mg (~0.9 mmol) on the normal diet to 223, 241 and 243 mg on days 2, 3 and 4 respectively; equivalent to ~4 mmol nitrate [8].”

What the sources say

• ?Not checked — no full text of the sourcecites [8] 8. Pannala AS, Mani AR, Spencer JP, Skinner V, Bruckdorfer KR, Moore KP, Rice-Evans CA. The effect of dietary nitrate on salivary, plasma, and urinary nitrate metabolism in humans. Free Radic Biol Med 2003; 34: 576-84. source

In the paper

“A UK portion (80 g) of a high nitrate-containing vegetable, such as beetroot or a green leafy vegetable, will therefore contain ~2 mmol (or 2 units) of nitrate, about half the current ADI in a 70 kg person, which is 4.2 mmol.”

In the paper

“Post hoc analysis revealed that nitrate reduced blood pressure in males -from a higher baseline (associated with a lower baseline plasma nitrite concentration) compared with BP in females, who had no response to nitrate (possibly a result of their higher baseline plasma nitrite concentrations).”

What the sources say

• ?Not checked — no full text of the sourcecites [82] 82. Kapil V, Milsom AB, Okorie M, Maleki-Toyserkani S, Akram F, Rehman F, Arghandawi S, Pearl V, Benjamin N, Loukogeorgakis S, Macallister R, Hobbs AJ, Webb AJ, Ahluwalia A. Inorganic nitrate supplementation lowers blood pressure in humans: role for nitrite-derived NO. Hypertension 2010; 56: 274-81. source

In the paper

“This study also demonstrated that the peak increase in plasma nitrite at ~3 h was associated with a significant increase in cGMP, the most sensitive indicator of NO bioactivity [85], thus providing evidence of bioactive NO generation from nitrite.”

What the sources say

• ?Not checked — no full text of the sourcecites [85] 85. Hobbs AJ. Soluble guanylate cyclase: the forgotten sibling. Trends Pharmacol Sci 1997; 18: 484-91. source

In the paper

“The volumes of distribution of nitrate (~0.3 l kg -1 ) [111] and nitrite (~0.35 l kg -1 ) [86], are similar and about half that of water (~0.6 l kg -1 ).”

What the sources say

• ?Not checked — no full text of the sourcecites [111] 111. van Velzen AG, Sips AJ, Schothorst RC, Lambers AC, Meulenbelt J. The oral bioavailability of nitrate from nitrate-rich vegetables in humans. Toxicol Lett 2008; 181: 177-81. 112 source
• ?Not checked — no full text of the sourcecites [86] 86. Dejam A, Hunter CJ, Tremonti C, Pluta RM, Hon YY, Grimes G, Partovi K, Pelletier MM, Oldfield EH, Cannon RO 3rd, Schechter AN, Gladwin MT. Nitrite infusion in humans and nonhuman primates: endocrine effects, pharmacokinetics, and tolerance formation. Circulation 2007; 116: 1821-31. source

In the paper

“There was also a 16% improvement in the time to task failure during severe exercise.”

What the sources say

• ?Not checked — no full text of the sourcecites [177] 177. Lansley KE, Winyard PG, Fulford J, Vanhatalo A, Bailey SJ, Blackwell JR, DiMenna FJ, Gilchrist M, Benjamin N, Jones AM. Dietary nitrate supplementation reduces the O2 cost of walking and running: a placebo-controlled study. J Appl Physiol 2011; 110: 591-600. 179 source

In the paper

“Vanhatalo et al. extended the duration of observed beneficial effects of beetroot juice (nitrate 5.2 mmol day -1 ) on exercise performance and blood pressure lowering from acute effects at 2.5 h, to sustained effects over 15 days [88].”

What the sources say

• ?Not checked — no full text of the sourcecites [88] 88. 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: R1121-31. source

In the paper

“Bondonno et al., (2012) found a small increase in mean FMD over 4 min of ~0.5% in 30 healthy volunteers following ingestion of 200 mg spinach, but this was not as great as flavanoid-rich apple (~1.1%) or apple and spinach (~0.9%)”

What the sources say

• ?Not checked — no full text of the sourcecites [89] 89. Bondonno CP, Yang X, Croft KD, Considine MJ, Ward NC, Rich L, Puddey IB, Swinny E, Mubarak A, Hodgson JM. 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 2012; 52: 95-102. source

In the paper

“Plasma nitrite concentration has been shown to reflect constitutive NOS activity in mammals [144] and is inversely correlated with the number of cardiovascular risk factors, and positively correlated with endothelial function as assessed by flow mediated dilatation (FMD) in humans [145].”

What the sources say

• ?Not checked — no full text of the sourcecites [144] 144. Kleinbongard P, Dejam A, Lauer T, Rassaf T, Schindler A, Picker O, Scheeren T, Godecke A, Schrader J, Schulz R, Heusch G, Schaub GA, Bryan NS, Feelisch M, Kelm M. Plasma nitrite reflects constitutive nitric oxide synthase activity in mammals. Free Radic Biol Med 2003; 35: 790-6. 145 source
• ?Not checked — no full text of the sourcecites [145] 145. Kleinbongard P, Dejam A, Lauer T, Jax T, Kerber S, Gharini P, Balzer J, Zotz RB, Scharf RE, Willers R, Schechter AN, Feelisch M, Kelm M. Plasma nitrite concentrations reflect the degree of endothelial dysfunction in humans. Free Radic Biol Med 2006; 40: 295-302. 146 source

In the paper

“A fundamental principle of exercise physiology was that during exercise, the oxygen cost is predictable for a given submaximal work rate [171][172][173].”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [171][172][173]

In the paper

“Stokes et al. who fed mice a cholesterol-enriched diet for 3 weeks, resulting in impaired endothelium-dependent arteriolar vasodilator responses to acetylcholine which were restored to normal by administration of nitrite in the drinking water [147].”

What the sources say

• ?Not checked — no full text of the sourcecites [147] 147. Stokes KY, Dugas TR, Tang Y, Garg H, Guidry E, Bryan NS. Dietary nitrite prevents hypercholesterolemic microvascular inflammation and reverses endothelial dysfunction. Am J Physiol Heart Circ Physiol 2009; 296: H1281-8. 148 source

In the paper

“While there was no global effect, regional cerebral perfusion to the frontal white matter was enhanced”

What the sources say

• ?Not checked — no full text of the sourcecites [168] 168. Lauer T, Heiss C, Balzer J, Kehmeier E, Mangold S, Leyendecker T, Rottler J, Meyer C, Merx M, Kelm M, Rassaf T. Age-dependent endothelial dysfunction is associated with failure to increase plasma nitrite in response to exercise. Basic Res Cardiol 2008; 103: 291-97. 170 source

In the paper

“Kenjale et al. demonstrated that a single dose of 500 ml beetroot juice (9 mmol nitrate) increased both the time before onset of claudication by 18% and the total walking time by 17% in patients with PAD whilst maintaining elevated plasma nitrite concentrations, associated with a reduction in fractional O2 extraction by the gastrocnemius [170].”

What the sources say

• ?Not checked — no full text of the sourcecites [170] 170. Barstow TJ, Lamarra N, Whipp BJ. Modulation of muscle and pulmonary O 2 uptakes by circulatory dynamics during exercise. J Appl Physiol 1990; 68: 979-89. 172 source

In the paper

“Nitrite also leads to dilatation in pulmonary vascular beds reducing pulmonary arterial pressure in humans and animals [184][185][186], and therefore has the potential to ameliorate pulmonary hypertension.”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [184][185][186]

In the paper

“Major concern emerged in the 1960s [199], with the demonstration of carcinogenic dimethylnitrosamine formation (known to disrupt nucleic acids in the rat and cause liver tumours [200]) from sodium nitrite [201,202].”

What the sources say

• ?Not checked — no full text of the sourcecites [199] 199. Sakshaug J, Sognen E, Hansen MA, Koppang N. Dimethylnitrosamine; its hepatotoxic effect in sheep and its occurrence in toxic batches of herring meal. Nature 1965; 206: 1261-2. 202 source
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [200] 200. Sander J. [Can nitrites in the human diet be the cause of cancerogenesis through formation of nitrosamines?]. Arch Hyg Bakteriol 1967; 151: 22-8. 203
• ?Not checked — no full text of the sourcecites [201] 201. Druckrey H, Schildbach A, Schmaehl D, Preussmann R, Ivankovic S. [Quantitative Analysis of the Carcinogenic Effect of Diethylnitrosamine]. Arzneimittelforschung 1963; 13: 841-51. 204
• ?Not checked — no full text of the sourcecites [202] 202. Bartsch H, Ohshima H, Pignatelli B. Inhibitors of endogenous nitrosation. Mechanisms and implications in human cancer prevention. Mutat Res 1988; 202: 307-24. 205 World Health Organisation. Fifty-ninth Report of the Joint FAO/WHO Expert Committee on Food Additives (JECFA). Geneva: Evaluation of Certain Food Additives, 2002. 206 source

In the paper

“These effects of beetroot (juice) have generally been ascribed to betanin, the major betacyanin constituent, which has strong antioxidant activity, and is particularly high in betalain extracts obtained from hairy root cultures of the red beetroot B. vulgaris [230].”

What the sources say

• ?Not checked — no full text of the sourcecites [230] source

In the paper

“Beetroot may represent a particularly safe source of dietary nitrate, with the potential to reduce, rather than increase cancer risk.”

In the paper

“Hawthorn berry extract has been found to have extremely potent nitrite reductase activity, in addition to containing polyphenols (~5%)”

In the paper

“However, most of the associations are small, do not prove causality and should be interpreted with extreme caution.”

In the paper

“However, no associations have been demonstrated between total nitrate or nitrite intake (processed meat) and pancreatic cancer [222], adenocarcinoma of the stomach and oesophagus [223], non-Hodgkin lymphoma risk overall [224], renal cell carcinoma [225] or bladder cancer.”

What the sources say

• ?Not checked — no full text of the sourcecites [222] 222. Kapadia GJ, Azuine MA, Rao GS, Arai T, Iida A, Tokuda H. Cytotoxic effect of the red beetroot (Beta vulgaris L.) extract compared to doxorubicin (Adriamycin) in the human prostate (PC-3) and breast (MCF-7) cancer cell lines. Anticancer Agents Med Chem 2011; 11: 280-4. 227 source
• ?Not checked — no full text of the sourcecites [223] 223. Kapadia GJ, Tokuda H, Konoshima T, Nishino H. Chemoprevention of lung and skin cancer by Beta vulgaris (beet) root extract. Cancer Lett 1996; 100: 211-4. 228 source
• ?Not checked — no full text of the sourcecites [224] 224. Kapadia GJ, Azuine MA, Sridhar R, Okuda Y, Tsuruta A, Ichiishi E, Mukainake T, Takasaki M, Konoshima T, Nishino H, Tokuda H. Chemoprevention of DMBA-induced UV-B promoted, NOR-1-induced TPA promoted skin carcinogenesis, and DEN-induced phenobarbital promoted liver tumors in mice by extract of beetroot. Pharmacol Res 2003; 47: 141-48. 229 source

In the paper

“The World Cancer Research Fund/American Institute of Cancer Research, Second Report 2007, did not show any increased risk of cancers, such as stomach or ovarian, with green leafy vegetables, and even showed trends towards beneficial effects [209].”

What the sources say

• ?Not checked — no full text of the sourcecites [209] 209. Kuroiwa Y, Yamada M, Matsui K, Okamura T, Ishii Y, Masumura K, Tasaki M, Umemura T, Mitsumori K, Nohmi T, Hirose M, Nishikawa A. Combined ascorbic acid and sodium nitrite treatment induces oxidative DNA damage-associated mutagenicity in vitro, but lacks initiation activity in rat forestomach epithelium. Toxicol Sci 2008; 104: 274-82. 214 source

In the paper

“Some epidemiological studies have shown that fruit and vegetables have protective effects against certain cancers [210].”

What the sources say

• ?Not checked — no full text of the sourcecites [210] 210. Hirose M, Tanaka H, Takahashi S, Futakuchi M, Fukushima S, Ito N. Effects of sodium nitrite and catechol, 3-methoxycatechol, or butylated hydroxyanisole in combination in a rat multiorgan carcinogenesis model. Cancer Res 1993; 53: 32-7. 215

In the paper

“Indeed, Moya et al. have previously demonstrated that inhaled ethyl nitrite results in sustained improvements in arterial oxygenation and haemodynamics in persistent pulmonary hypertension of the newborn [192].”

What the sources say

• ?Not checked — no full text of the sourcecites [192] 192. O'Donnell VB, Eiserich JP, Chumley PH, Jablonsky MJ, Krishna NR, Kirk M, Barnes S, Darley-Usmar VM, Freeman BA. Nitration of unsaturated fatty acids by nitric oxide-derived reactive nitrogen species peroxynitrite, nitrous acid, nitrogen dioxide, and nitronium ion. Chem Res Toxicol 1998; 12: 83-92. 194 source

In the paper

“The National Institutes of Health-American Association of Retired Persons (NIH-AARP) Diet and Health Study prospectively studied large cohorts and have recently identified some potential associations between high nitrate intake, assessed using a 124-item food frequency questionnaire, and epithelial ovarian cancer [220] and thyroid cancer (nitrate competitively inhibits iodide uptake) [221].”

What the sources say

• ?Not checked — no full text of the sourcecites [221] 221. Ward M, Rusiecki J, Lynch C, Cantor K. Nitrate in public water supplies and the risk of renal cell carcinoma. Cancer Causes Control 2007; 18: 1141-51. 226 source

In the paper

“In addition, in wine, ethanol is nitrosated resulting in the formation of ethylnitrite, an organic nitrite, which has been shown to be a potent vasodilator [191].”

What the sources say

• ?Not checked — no full text of the sourcecites [191] 191. Moya MP, Gow AJ, Califf RM, Goldberg RN, Stamler JS. Inhaled ethyl nitrite gas for persistent pulmonary hypertension of the newborn. Lancet 2002; 360: 141-43. 193 source

In the paper

“Whilst apple and spinach reduced SBP (by ~-3.3 mmHg and ~-2.7 mmHg after 2 h respectively) compared with control, the combination of apple and spinach had no effect and resulted in an intermediate plasma nitrite con- centration suggesting possible extravascular (e.g.stomach) reduction of nitrite by the apple flavonoids and ascorbic acid, as intravascular reduction might be expected to enhance BP”

What the sources say

• ?Not checked — no full text of the sourcecites [89] 89. Bondonno CP, Yang X, Croft KD, Considine MJ, Ward NC, Rich L, Puddey IB, Swinny E, Mubarak A, Hodgson JM. 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 2012; 52: 95-102. source

In the paper

“Indeed, beetroot juice has even achieved a considerable degree of acceptance as an alternative medicine for cancer patients [231,232].”

What the sources say

• ?Not checked — no full text of the sourcecites [231]
• ?Not checked — no full text of the sourcecites [232] source

In the paper

“Whilst apple and spinach reduced SBP (by ~-3.3 mmHg and ~-2.7 mmHg after 2 h respectively) compared with control, the combination of apple and spinach had no effect and resulted in an intermediate plasma nitrite con- centration suggesting possible extravascular (e.g.stomach) reduction of nitrite by the apple flavonoids and ascorbic acid, as intravascular reduction might be expected to enhance BP”

What the sources say

• ?Not checked — no full text of the sourcecites [89] 89. Bondonno CP, Yang X, Croft KD, Considine MJ, Ward NC, Rich L, Puddey IB, Swinny E, Mubarak A, Hodgson JM. 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 2012; 52: 95-102. source

In the paper

“NO2-FAs have several antiinflammatory actions, inhibiting neutrophils, platelets and macrophages.”

In the paper

“Whilst these effects are promising and suggestive that dietary nitrate underlies the apparent beneficial effects of vegetable rich diets, such as the Mediterranean and Japanese diets, they represent surrogate endpoints and further long term studies with hard endpoints will eventually be required to substantiate the beneficial effects and demonstrate that they outweigh any risk of cancer.”