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Cited by 361Nitric Oxide and Endothelin EffectsCardiovascular Health and Disease PreventionNutritional Studies and Diet

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

Open access
Lidder, Satnam, Webb, Andrew J.·2013·British Journal of Clinical Pharmacology
DOI 10.1111/j.1365-2125.2012.04420.xPMC PMC3575935
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Abstract

The discovery that dietary (inorganic) nitrate has important vascular effects came from the relatively recent realization of the 'nitrate-nitrite-nitric oxide (NO) pathway'. 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. 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. However, there is a need for good evidence for hard endpoints beyond epidemiological studies. Whilst these suggest reduction in cardiovascular risk with diets high in nitrate-rich vegetables (such as a Mediterranean diet), others have suggested possible small positive and negative associations with dietary nitrate and cancer, but these remain unproven. Interactions with other nutrients, such as vitamin C, polyphenols and fatty acids may enhance or inhibit these effects. In order to provide simple guidance on nitrate intake from different vegetables, we have developed the Nitrate 'Veg-Table' with 'Nitrate Units' [each unit being 1 mmol of nitrate (62 mg)] to achieve a nitrate intake that is likely to be sufficient to derive benefit, but also to minimize the risk of potential side effects from excessive ingestion, given the current available evidence. The lack of data concerning the long term effects of dietary nitrate is a limitation, and this will need to be addressed in future trials.

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Registry

Crossref · 10.1111/j.1365-2125.2012.04420.x

Cites

231 of 231 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

41 of 150 cited sources checked · 13 supported · 1 flagged · accuracy not yet measured

  • Premisecitation

    The process of nitrite limiting intimal hyperplasia was dependent on xanthine oxidoreductase (XOR).

    “Furthermore, the process was demonstrated to be dependent on xanthine oxidoreductase (XOR)”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • 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 source

      The Discussion (page unavailable) says the contribution of xanthine oxidoreductase to nitrite-mediated protection requires further study, rather than having been demonstrated as necessary. The paper studies heart and liver ischemia-reperfusion injury, not nitrite limiting intimal hyperplasia. (LLM, conf=0.86)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [125] 125. Webb AJ, Milsom AB, Rathod KS, Chu WL, Qureshi S, Lovell MJ, Lecomte FM, Perrett D, Raimondo C, Khoshbin E, Ahmed Z, Uppal R, Benjamin N, Hobbs AJ, Ahluwalia A. Mechanisms underlying erythrocyte and endothelial nitrite reduction to nitric oxide in hypoxia: role for xanthine oxidoreductase and endothelial nitric oxide synthase. Circ Res 2008; 103: 957-64. 126 source

      The Discussion section on blood-vessel XOR-dependent nitrite reduction reports that inhibiting XOR reduced nitrite reductase activity, supporting a role for XOR in converting nitrite to nitric oxide. The paper does not address whether nitrite limits intimal hyperplasia or whether that effect depends on XOR; searches for intimal hyperplasia and neointimal proliferation found no such result. The indexed passages have no page numbers. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Premisecitation

    Nitrite has protective effects in ischaemic hearts.

    “and in 2004 in ischaemic hearts, with protective effects [7].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [7] 7. Webb A, Bond R, McLean P, Uppal R, Benjamin N, Ahluwalia A. Reduction of nitrite to nitric oxide during ischemia protects against myocardial ischemia-reperfusion damage. Proc Natl Acad Sci U S A 2004; 101: 13683-8. source
  • Premisecitation

    Interruption of the enterosalivary circulation by asking volunteers to spit out all their saliva for 3 h immediately following beetroot juice ingestion completely blocked the rise in plasma nitrite and the reduction in BP.

    “Indeed, interruption of this process by asking volunteers to spit out all their saliva for 3 h immediately following beetroot juice ingestion completely blocked the rise in plasma nitrite and the reduction BP.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • 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
  • Premisecitation

    In 2006 Larsen et al. demonstrated that diastolic BP was reduced by 3.7 mmHg following 3 days' dietary supplementation with sodium nitrate (0.1 mmol kg-1 day-1) compared with placebo sodium chloride in 17 healthy volunteers (randomized, double-blind, crossover design).

    “in 2006 Larsen et al. demonstrated that diastolic BP was reduced by 3.7 mmHg following 3 days' dietary supplementation with sodium nitrate (0.1 mmol kg -1 day -1 ) compared with placebo sodium chloride in 17 healthy volunteers (randomized, double-blind, crossover design) [78].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • 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. source
  • Premisecitation

    Nitrate is also produced endogenously.

    “It should be remembered that nitrate is also produced endogenously.”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [50] 50. Green LC, Ruiz de Luzuriaga K, Wagner DA, Rand W, Istfan N, Young VR, Tannenbaum SR. Nitrate biosynthesis in man. Proc Natl Acad Sci U S A 1981; 78: 7764-8. source
    • cites [51] 51. Leaf CD, Wishnok JS, Tannenbaum SR. L-arginine is a precursor for nitrate biosynthesis in humans. Biochem Biophys Res Commun 1989; 163: 1032-7. source
    • cites [52] 52. Rhodes P, Leone AM, Francis PL, Struthers AD, Moncada S, Rhodes PM. The L-arginine: nitric oxide pathway is the major source of plasma nitrite in fasted humans. Biochem Biophys Res Commun 1995; 209: 590-6. source
  • May combine two claims. 44
  • Classified as probably not a substantial claim. 16
  • The quote only partly states this claim. 1

  • May combine two claims.

    Premisecitation

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

    “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.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • 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

      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)

      Experimental — accuracy not yet measured
    • 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 source

      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)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationcitation

    Dietary nitrate has 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.

    “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.”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • 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. source

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

      Experimental — accuracy not yet measured
    • 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

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

      Experimental — accuracy not yet measured
    • cites [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

  • May combine two claims.

    Premisecitation

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

    “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”
    Quote in the paperSubstantial claim2 of 4 sources checked
    • cites [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
    • cites [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
    • 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 source

      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)

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

      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)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

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

    “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.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [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
    • 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 source

      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)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Sindler et al. found decreased plasma nitrite concentrations in old male C57BL6 control mice, depleted in arteries and heart, which were restored to youthful levels by 3 weeks' supplementation with sodium nitrite (50 mg l-1 in the drinking water).

    “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].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • 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

  • May combine two claims.

    Premisecitation

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

    “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].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • 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

  • May combine two claims.

    Premisecitation

    Bahra et al. found no effect of dietary nitrate (8 mmol) on FMD at 3 h in healthy volunteers with normal endothelial function, but a reduction in pulse wave velocity of ~0.3 m s-1 accompanied the reduction in SBP of ~5 mmHg.

    “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].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • 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

  • May combine two claims.

    Premisecitation

    The half-life of nitrate is 5-8 h, much longer than that of nitrite, which has been reported as 1-5 min ex vivo and ~20-45 min in vivo.

    “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].”
    Quote in the paperNot a substantial claim3 of 7 sources checked
    • cites [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
    • 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
    • cites [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
    • 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 source

      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)

      Experimental — accuracy not yet measured
    • 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 source

      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)

      Experimental — accuracy not yet measured
    • cites [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
    • cites [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

  • May combine two claims.

    Premisecitation

    Chronic inhibition of XOR with allopurinol or 3 weeks of tungsten-rich diet increased intimal hyperplasia.

    “Chronic inhibition of XOR with allopurinol or 3 weeks of tungstenrich diet increased intimal hyperplasia.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • 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 source

      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)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In apolipoprotein E-deficient mice, subcutaneous injection of nitro-oleic acid markedly reduced atherosclerotic lesion formation, associated with antiinflammatory effects including reduction in foam cell formation through attenuation of oxidized LDL-induced phosphorylation of STAT-1.

    “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].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • 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 source

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

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Nitro-oleic acid inhibits xanthine oxidoreductase and is more potent than allopurinol in inhibiting superoxide production.

    “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]”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • 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 source

      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)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Typically around 85% of dietary nitrate is derived from vegetables, with most of the remainder from drinking water.

    “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”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [25][26][27]

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

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Possible small positive and negative associations between dietary nitrate and cancer remain unproven.

    “others have suggested possible small positive and negative associations with dietary nitrate and cancer, but these remain unproven.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Nitrate content varies across the plant: leaf > stem > root.

    “Nitrate content also varies across the plant: leaf > stem > root [37][38][39].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37][38][39]

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

  • May combine two claims.

    Premisecitation

    Nitrite provides an important alternative source of nitric oxide, particularly when oxygen levels are reduced, such as in the microcirculation, causing vasodilatation.

    “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]”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [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
    • cites [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
    • cites [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

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Dietary nitrite is mainly derived from cured meats, where it is added to prevent the development of botulinum toxin.

    “Dietary nitrite (NO2 -) is mainly derived from cured meats, where it is added to prevent the development of botulinum toxin [29]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Interactions with other nutrients, such as vitamin C, polyphenols and fatty acids, may enhance or inhibit the vascular effects of dietary nitrate.

    “Interactions with other nutrients, such as vitamin C, polyphenols and fatty acids may enhance or inhibit these effects.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

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

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Antibacterial mouthwash just prior to nitrate ingestion inhibits the increase in plasma nitrite in humans and blocks the 5 mmHg blood pressure reduction consequent to nitrate supplemented drinking water in Sprague-Dawley rats.

    “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]”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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
    • cites [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

  • May combine two claims.

    Premisecitation

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

    “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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

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

    “Vegetables notable for their low nitrate content (<100 mg kg -1 ) are onions and tomatoes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The vegetarian diet contains ~4.3 mmol nitrate day-1, close to the ADI, almost four times greater than a normal diet, which contains ~1.2 mmol nitrate.

    “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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] 49. Mitchell HH, Shonle HA, Grindley HS. The origin of the nitrates in the urine. J Biol Chem 1916; 24: 461-90. source

  • May combine two claims.

    Premisecitation

    The EFSA Acceptable Daily Intake for nitrate is 3.7 mg kg-1 (0.06 mmol kg-1), equating to ~260 mg day-1 for a 70 kg adult (~4.2 mmol).

    “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).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

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

    “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].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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
    • cites [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

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Summer grown lettuce has a lower mean nitrate concentration than winter grown lettuce.

    “For example, summer grown lettuce (longer sunshine hours and less rainfall) has lower mean nitrate concentration than winter grown [40].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

  • May combine two claims.

    Premisecitation

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

    “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]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Nitrate content is influenced by environmental, agricultural and genetic factors.

    “Nitrate content is influenced by environmental, agricultural and genetic factors [28,36].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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
    • cites [36] 36. Santamaria P. Nitrate in vegetables: toxicity, content, intake and EC regulation. J Sci Food Agric 2006; 86: 10-7. source

  • May combine two claims.

    Premisecitation

    Three days' supplementation with ~120 g of round green lettuce resulted in ~70% of the nitrate load being excreted and total urinary nitrate excretion in 24 h increased from 53 mg (~0.9 mmol) on the normal diet to 223, 241 and 243 mg on days 2, 3 and 4, equivalent to ~4 mmol nitrate.

    “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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

  • May combine two claims.

    Premisereasoning

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

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Post hoc analysis of the Kapil et al. study 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).

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

  • May combine two claims.

    Premisecitation

    The Kapil et al. study demonstrated that the peak increase in plasma nitrite at ~3 h was associated with a significant increase in cGMP, providing evidence of bioactive NO generation from nitrite.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [85] 85. Hobbs AJ. Soluble guanylate cyclase: the forgotten sibling. Trends Pharmacol Sci 1997; 18: 484-91. source

  • May combine two claims.

    Premisecitation

    The volumes of distribution of nitrate (~0.3 l kg-1) and nitrite (~0.35 l kg-1) are similar and about half that of water (~0.6 l kg-1).

    “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 ).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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
    • cites [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

  • The quote only partly states this claim.

    Premisecitation

    There was a 16% improvement in time to task failure during severe exercise with beetroot juice ingestion (5.1 mmol day-1 for 6 days).

    “There was also a 16% improvement in the time to task failure during severe exercise.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

  • May combine two claims.

    Premisecitation

    Beetroot juice (nitrate 5.2 mmol day-1) had acute effects at 2.5 h and sustained effects over 15 days on exercise performance and blood pressure lowering.

    “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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

  • May combine two claims.

    Premisecitation

    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 flavonoid-rich apple (~1.1%) or apple and spinach (~0.9%).

    “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%)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

  • May combine two claims.

    Premisecitation

    Plasma nitrite concentration reflects constitutive NOS activity in mammals and is inversely correlated with the number of cardiovascular risk factors, and positively correlated with endothelial function as assessed by flow mediated dilatation in humans.

    “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].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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
    • cites [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

  • Classified as probably not a substantial claim.

    Premisecitation

    During exercise, the oxygen cost is predictable for a given submaximal work rate.

    “A fundamental principle of exercise physiology was that during exercise, the oxygen cost is predictable for a given submaximal work rate [171][172][173].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [171][172][173]

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

  • May combine two claims.

    Premisecitation

    Stokes et al. 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.

    “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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

  • May combine two claims.

    Premisecitation

    In older adults aged ~75 years, a nitrate-rich diet enhanced regional cerebral perfusion to the frontal white matter but had no global effect on cerebral perfusion.

    “While there was no global effect, regional cerebral perfusion to the frontal white matter was enhanced”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

  • May combine two claims.

    Premisecitation

    In patients with peripheral arterial disease, a single dose of 500 ml beetroot juice (9 mmol nitrate) maintained elevated plasma nitrite concentrations and was associated with a reduction in fractional O2 extraction by the gastrocnemius.

    “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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

  • May combine two claims.

    Premisecitation

    Nitrite leads to dilatation in pulmonary vascular beds and reduces pulmonary arterial pressure in humans and animals.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [184][185][186]

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

  • May combine two claims.

    Premisecitation

    Sodium nitrite can form carcinogenic dimethylnitrosamine, which is known to disrupt nucleic acids in the rat and cause liver tumours.

    “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].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [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
    • 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

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

    • cites [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
    • cites [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

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The 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.

    “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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [230] source

  • May combine two claims.

    Interpretationreasoning

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

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

  • May combine two claims.

    Premisecitation

    Hawthorn berry extract has extremely potent nitrite reductase activity and contains polyphenols (~5%).

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

  • May combine two claims.

    Interpretationreasoning

    Most of the associations between nitrate intake and cancer are small, do not prove causality and should be interpreted with extreme caution.

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

  • May combine two claims.

    Premisecitation

    No associations have been demonstrated between total nitrate or nitrite intake (processed meat) and pancreatic cancer, adenocarcinoma of the stomach and oesophagus, non-Hodgkin lymphoma risk overall, renal cell carcinoma or bladder cancer.

    “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.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [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
    • cites [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
    • cites [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

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    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.

    “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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Some epidemiological studies have shown that fruit and vegetables have protective effects against certain cancers.

    “Some epidemiological studies have shown that fruit and vegetables have protective effects against certain cancers [210].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Inhaled ethyl nitrite results in sustained improvements in arterial oxygenation and haemodynamics in persistent pulmonary hypertension of the newborn.

    “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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

  • May combine two claims.

    Premisecitation

    High nitrate intake is associated with thyroid cancer in the NIH-AARP Diet and Health Study, and nitrate competitively inhibits iodide uptake.

    “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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

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

    “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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

  • May combine two claims.

    Premisecitation

    Apple and spinach reduced systolic blood pressure by ~3.3 mmHg and ~2.7 mmHg after 2 h respectively compared with control.

    “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”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Beetroot juice has achieved a considerable degree of acceptance as an alternative medicine for cancer patients.

    “Indeed, beetroot juice has even achieved a considerable degree of acceptance as an alternative medicine for cancer patients [231,232].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [231]
    • cites [232] source

  • May combine two claims.

    Premisecitation

    The combination of apple and spinach had no effect on systolic blood pressure and resulted in an intermediate plasma nitrite concentration.

    “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”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Nitrofatty acids have several antiinflammatory actions, inhibiting neutrophils, platelets and macrophages.

    “NO2-FAs have several antiinflammatory actions, inhibiting neutrophils, platelets and macrophages.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The vascular effects of dietary nitrate are promising and suggest that dietary nitrate underlies the apparent beneficial effects of vegetable-rich diets, such as the Mediterranean and Japanese diets, but they represent surrogate endpoints and further long-term studies with hard endpoints are required to substantiate the beneficial effects and demonstrate that they outweigh any risk of cancer.

    “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.”
    Quote in the paperSubstantial claim
57 of 57

  • The paper relies on this without support.

    In patients with peripheral arterial disease, plasma nitrite falls during exercise.

    “In patients with peripheral arterial disease (PAD), plasma nitrite falls during exercise.”
1 of 1

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Spinach dose differs by a factor of 1,000

    Minor

    The discussion gives the spinach dose in the Bondonno et al. study as 200 mg, while Table 4 lists it as 200 g.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 8

  1. Loon AIM, 1991, Nitraatinname van de Nederiandse bevolking, Voeding, 52, 96
  2. Taylor S, 1989, Relative Exposure to Nitrite, Nitrate, and N‐Nitroso Compounds from Endogenous and Exogenous Sources, Food Toxicology: A Perspective on the Relative Risks Marcel Dekker Inc, 63
  3. Penttila PL, 1995, Estimation of Food Additive and Pesticide Intakes by Means of A Stepwise Method [Dissertation]
  4. Dejonckheere W, 1994, Nitrate in food commodities of vegetable origin and the total diet in Belgium, 1992–1993, Microbiologie – Aliments – Nutrition, 12, 359
  5. Willis T, 1697, Pharmaceutice Rationalis: Or An Exercitation of the Medicines in Humane Bodies
  6. 1968, Nitrites, nitrosamines, and cancer, Lancet, 1, 1071
  7. World Health Organisation, 2002, Fifty‐ninth Report of the Joint FAO/WHO Expert Committee on Food Additives (JECFA)
  8. Alexander J, 2008, Opinion of the Scientific Panel on Contaminants in the Food chain on a request from the European Commission to perform a scientific risk assessment on nitrate in vegetables, The European Food Safety Authority Journal, 689, 1

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Authors
Lidder, S., & Webb, A. J.
Affiliations
St Thomas' Hospital (GB)
Corresponding author
Webb, Andrew J.
Venue
British Journal of Clinical Pharmacology
Publisher
Wiley
Published
2013-02-05
Volume
75
Issue
3
Pages
677-696
ISSN
  • 0306-5251 (ISSN-L)
  • 1365-2125
DOI
10.1111/j.1365-2125.2012.04420.x
PMC
PMC3575935
OpenAlex
W1549975741
Cited by
360
References
229
Citations by year
2026: 21 · 2025: 21 · 2024: 23 · 2023: 28 · 2022: 40 · 2021: 36 · 2020: 30 · 2019: 31 · 2018: 33 · 2017: 24 · 2016: 22 · 2015: 20 · 2014: 17 · 2013: 11 · 2012: 2
FWCI
10.73
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • British Journal of Clinical Pharmacology (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Research Portal (King's College London) (publishedVersion, other-oa)
Topics
  • Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Nutritional Studies and Diet
Keywords
dietary nitrate, nitrate-nitrite-nitric oxide pathway, nitric oxide, vascular effects, leafy vegetables, beetroot, blood pressure, endothelial dysfunction, platelet aggregation, exercise performance, peripheral arterial disease, ischemia-reperfusion injury, arterial stiffness, Mediterranean diet, vitamin C, polyphenols, fatty acids, cancer risk, cardiovascular risk
MeSH terms
Blood Pressure, Blood Vessels, Cardiovascular Diseases, Cardiovascular System, Diet, Humans, Nitrates, Nitric Oxide, Nitrites, Risk Factors, Vegetables, Plant Leaves, Beta vulgaris

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-11.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-11.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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