CoChat
Sign Up
Cited by 113Nitric Oxide and Endothelin EffectsRedox biology and oxidative stressCardiovascular Health and Disease Prevention

Inorganic nitrite therapy: historical perspective and future directions

Open access
Kevil, Christopher G., Kolluru, Gopi K., Pattillo, Christopher B., Giordano, Tony·2011·Free Radical Biology and Medicine
DOI 10.1016/j.freeradbiomed.2011.04.042PMC PMC4414241
Open this paper in CoChat — free account

Abstract

Over the past several years, investigators studying nitric oxide (NO) biology and metabolism have come to learn that the one electron oxidation product of NO, nitrite anion, serves as a unique player in modulating tissue NO bioavailability. Numerous studies have examined how this oxidized metabolite of NO can act as a salvage pathway for maintaining NO equivalents through multiple reduction mechanisms in permissive tissue environments. Moreover, it is now clear that nitrite anion production and distribution throughout the body can act in an endocrine manner to augment NO bioavailability that is important for physiological and pathological processes. These discoveries have led to renewed hope and efforts for an effective NO based therapeutic agent through the unique action of sodium nitrite as an NO pro-drug. More recent studies also indicate that sodium nitrate may also increase plasma nitrite levels via the enterosalivary circulatory system resulting in nitrate reduction to nitrite by microorganisms found within the oral cavity. In this review, we discuss the importance of nitrite anion in several disease models along with an appraisal of sodium nitrite therapy in the clinic, potential caveats of such clinical uses, and future possibilities of nitrite based therapies.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that inorganic nitrite is not an inert NO byproduct but a recyclable NO reservoir/salvage pathway, with sodium nitrite showing therapeutic potential across ischemic, inflammatory, cardiovascular, and infectious conditions. It surveys historical, biochemical, preclinical, and clinical evidence while cautioning that dose, route, tissue conditions, and trial design critically determine benefit.

Key findings

  • Nitrite is reduced back to NO under hypoxia/ischemia via deoxyhemoglobin/myoglobin, xanthine oxidase, acidic disproportionation, mitochondrial cytochrome c oxidase, and other mechanisms; plasma nitrite is usually 200–600 nM, up to 70–90% derives from eNOS, and exogenous nitrite half-life is 20–30 minutes.
  • Sodium nitrite is protective in preclinical ischemia-reperfusion (heart, liver, brain, kidney), chronic hindlimb ischemia/angiogenesis, sickle cell disease, hypertension/pulmonary hypertension, cerebral vasospasm, colitis, cystic fibrosis biofilm infections, and shock; effective doses range from high nanomolar/low micromolar for ischemia to high micromolar/low millimolar for colitis and cystic fibrosis.
  • Oral sodium nitrite has >98% bioavailability, peak plasma levels at 15–30 minutes, and a circulating half-life of 25–35 minutes; nitrate peaks at ~1.5 hours with an 8–13 hour half-life, and methemoglobinemia of 1–3% may occur at doses >2–3 mg/kg. For cyanide poisoning, sodium nitrite 30 mg/ml over 5–20 minutes (~300 mg total) raises metHb to ~20%.
  • The NTP 2-year study found no carcinogenicity in male or female F344/N rats or male B6C3F1 mice given 35–150 mg/kg sodium nitrite, with equivocal female B6C3F1 forestomach epithelial hyperplasia at 150 mg/kg; nitrite may also transiently increase tumor pO2 and improve radiotherapy efficacy.

Methods

  • Narrative review, not a systematic review or meta-analysis; it synthesizes historical accounts, NO/nitrite biochemistry, endogenous and exogenous nitrite sources, reduction pathways, disease models, and clinical trial information.
  • Draws on cited preclinical and human studies, including pharmacokinetic data from Hunault et al. and references to Clinicaltrials.gov tables (Tables 1–2 are referenced but not included in the supplied text).
  • No primary experiments, systematic search strategy, or formal quantitative synthesis are described.

Limitations

  • The paper states that many mechanisms remain incompletely understood, including nitrite-heme export/adduct formation, compartment-specific contributions to nitrite reduction, immune modulation, and effects on cancer; it calls for additional study and well-controlled trials.
  • It notes that the number of clinical trials involving sodium nitrite is relatively small and that trial designs vary widely, warning that poorly designed or executed trials could impede progress.
  • Evident from the text: as a narrative review, it lacks systematic search/inclusion criteria and formal risk-of-bias assessment; the referenced Tables 1–2 are not present in the provided text.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.freeradbiomed.2011.04.042

Cites

288 of 288 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 277 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    Nitrite-mediated changes in blood flow and endothelial cell growth are blocked by the NO scavenger cPTIO.

    “nitrite mediated changes in blood flow and endothelial cell growth were blocked by the NO scavenger cPTIO”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [47] Kumar D Branch BG Pattillo CB Hood J Thoma S Simpson S Illum S Arora N Chidlow JH Jr Langston W Teng X Lefer DJ Patel RP Kevil CG Chronic sodium nitrite therapy augments ischemia-induced angiogenesis and arteriogenesis Proceedings of the National Academy of Sciences of the United States of America 105 7540 7545 2008 18508974 PMC2396555 source

      Not checked in the free run.

  • Findingcitation

    Delayed sodium nitrite therapy 5 days after ischemic induction still augments ischemic tissue reperfusion and arteriogenesis development.

    “delayed sodium nitrite therapy 5 days after ischemic induction still augments ischemic tissue reperfusion and arteriogenesis development (Pattillo in press).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Pattillo in press

      Not checked in the free run.

  • Findingcitation

    Nitrite therapy significantly increases ischemic tissue nitrite/nitrosothiol levels.

    “nitrite therapy significantly increased ischemic tissue nitrite/nitrosothiol levels”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [47] Kumar D Branch BG Pattillo CB Hood J Thoma S Simpson S Illum S Arora N Chidlow JH Jr Langston W Teng X Lefer DJ Patel RP Kevil CG Chronic sodium nitrite therapy augments ischemia-induced angiogenesis and arteriogenesis Proceedings of the National Academy of Sciences of the United States of America 105 7540 7545 2008 18508974 PMC2396555 source

      Not checked in the free run.

  • Findingcitation

    Sodium nitrate therapy is unable to mediate similar responses to nitrite therapy over the duration of study.

    “sodium nitrate therapy was unable to mediate similar responses to nitrite therapy over the duration of study”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [47] Kumar D Branch BG Pattillo CB Hood J Thoma S Simpson S Illum S Arora N Chidlow JH Jr Langston W Teng X Lefer DJ Patel RP Kevil CG Chronic sodium nitrite therapy augments ischemia-induced angiogenesis and arteriogenesis Proceedings of the National Academy of Sciences of the United States of America 105 7540 7545 2008 18508974 PMC2396555 source

      Not checked in the free run.

  • Findingown data

    A single dose of sodium nitrite after induction of ischemia does not augment hind limb reperfusion.

    “administration of a single dose of sodium nitrite after induction of ischemia did not augment hind limb reperfusion (unpublished observations)”
    Quote in the paperSubstantial claim
  • May combine two claims. 72
  • Classified as probably not a substantial claim. 13

  • May combine two claims.

    Findingown data

    The beneficial effects of dipyridamole are PKA and eNOS dependent, as the effects are absent in eNOS knockout mice.

    “These beneficial effects were PKA and eNOS dependent as the effects of dipyridamole were absent in eNOS knockout mice.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [170] Venkatesh PK Pattillo CB Branch B Hood J Thoma S Illum S Pardue S Teng X Patel RP Kevil CG Dipyridamole enhances ischaemia-induced arteriogenesis through an endocrine nitrite/nitric oxide-dependent pathway Cardiovascular research 85 661 670 2010 20061326 PMC2819839 source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Low dose sodium nitrite therapy quickly restores ischemic hind-limb blood flow within several days and does not affect flow in the contralateral non-ischemic limb.

    “low dose sodium nitrite therapy quickly restored ischemic hind-limb blood flow within several days and did not affect flow in the contralateral non-ischemic limb”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [47] Kumar D Branch BG Pattillo CB Hood J Thoma S Simpson S Illum S Arora N Chidlow JH Jr Langston W Teng X Lefer DJ Patel RP Kevil CG Chronic sodium nitrite therapy augments ischemia-induced angiogenesis and arteriogenesis Proceedings of the National Academy of Sciences of the United States of America 105 7540 7545 2008 18508974 PMC2396555 source

      Not checked in the free run.

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

    Findingnone given

    Many recent treatment studies involve multiple institutional sponsors and exhibit a wide range of designs with respect to randomization, blindedness, and controls.

    “Many of these treatment studies involve multiple institutional sponsors and it is clear that the trials exhibit a wide range of designs with respect to randomization, blindedness, and controls.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    All three NOS isoforms progressively oxidize L-arginine to L-citrulline resulting in NO production.

    “All three of these isoforms progressively oxidize and reduce L-arginine to L-citrulline resulting in NO production [13].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13] Moncada S Higgs A The L-arginine-nitric oxide pathway N Engl J Med 329 2002 2012 1993 7504210 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Nitrite anion is a reversible metabolite of NO that facilitates endogenous signaling responses differentially affecting gene expression.

    “However, nitrite anion has emerged as a reversible metabolite of NO that facilitates endogenous signaling responses differentially affecting gene expression [3, 4], serves as a diagnostic marker of cardiovascular health, and acts as a potential therapeutic agent for several disease states.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [3] Pattillo CB Fang K Pardue S Kevil CG Genome expression profiling and network analysis of nitrite therapy during chronic ischemia: possible mechanisms and interesting molecules Nitric Oxide 22 168 179 2010 19963074 PMC4599788 source

      Not checked in the free run.

    • cites [4] Raat NJ Noguchi AC Liu VB Raghavachari N Liu D Xu X Shiva S Munson PJ Gladwin MT Dietary nitrate and nitrite modulate blood and organ nitrite and the cellular ischemic stress response Free radical biology & medicine 47 510 517 2009 19464364 PMC2744499 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Nitrite reduction back to NO under appropriate pathophysiological conditions can generate many nitroso species, or nitrite itself may mediate intracellular nitrosation reactions such as RSNO formation.

    “Recent studies show the potential role of nitrite reduction back to NO under appropriate pathophysiological conditions to generate many nitroso species or that nitrite itself may mediate intracellular nitrosation reactions (e.g. RSNO formation) [22, 23].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [22] Bryan NS Fernandez BO Bauer SM Garcia-Saura MF Milsom AB Rassaf T Maloney RE Bharti A Rodriguez J Feelisch M Nitrite is a signaling molecule and regulator of gene expression in mammalian tissues Nat Chem Biol 1 290 297 2005 16408059 source

      Not checked in the free run.

    • cites [23] Ng ES Jourd’heuil D McCord JM Hernandez D Yasui M Knight D Kubes P Enhanced S-nitroso-albumin formation from inhaled NO during ischemia/reperfusion Circulation research 94 559 565 2004 14739156 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Conditions during tissue ischemia-reperfusion or chronic ischemia are optimal for the reduction of nitrite to NO, where multiple reduction mechanisms may be invoked.

    “However, conditions during tissue ischemia-reperfusion or chronic ischemia are optimal for the reduction of nitrite to NO, where multiple reduction mechanisms may be invoked (e.g. deoxyhemoglobin/myoglobin, xanthine oxidoreductase, acidosis, and others).”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Endothelium-derived NO plays an important role in vascular homeostasis and cardiac function.

    “It is well known that endothelium-derived nitric oxide (NO) plays an important role in vascular homeostasis and cardiac function based on seminal studies leading to the Nobel Prize in Physiology or Medicine in 1998 [9, 10].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [9] Bian K Doursout MF Murad F Vascular system: role of nitric oxide in cardiovascular diseases J Clin Hypertens (Greenwich) 10 304 310 2008 18401228 PMC8109995 source

      Not checked in the free run.

    • cites [10] Mizuno A Baretti R Buckberg GD Young HH Vinten-Johansen J Ma XL Ignarro LJ Endothelial stunning and myocyte recovery after reperfusion of jeopardized muscle: a role of L-arginine blood cardioplegia J Thorac Cardiovasc Surg 113 379 389 1997 9040633 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Humans lack defined enzymatic machinery to efficiently reduce nitrate to nitrite, although mammalian tissues can reduce nitrate on a less efficient scale.

    “Unlike prokaryotes, humans lack defined enzymatic machinery to efficiently reduce nitrate to nitrite although it has been reported that mammalian tissues can reduce nitrate on a less efficient scale [48].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [48] Jansson EA Huang L Malkey R Govoni M Nihlen C Olsson A Stensdotter M Petersson J Holm L Weitzberg E Holm L Lundberg JO A mammalian functional nitrate reductase that regulates nitrite and nitric oxide homeostasis Nat Chem Biol 4 417 417 2008 18516050 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NO inhibits cytochrome c oxidase, decreases mitochondrial ROS formation, and limits apoptotic cytochrome c release.

    “NO is a well-characterized regulator of mitochondrial function that inhibits cytochrome c oxidase, decreases mitochondrial ROS formation, and limits apoptotic cytochrome c release [32–36].”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [32] Poderoso JJ Carreras MC Lisdero C Riobo N Schopfer F Boveris A Nitric oxide inhibits electron transfer and increases superoxide radical production in rat heart mitochondria and submitochondrial particles Arch Biochem Biophys 328 85 92 1996 8638942 source

      Not checked in the free run.

    • cites [33] Brookes PD-UV Hypothesis: the mitochondrial NO(*) signaling pathway, and the transduction of nitrosative to oxidative cell signals: an alternative function for cytochrome C oxidase Free radical biology & medicine 32 370 374 2002 11841927 source

      Not checked in the free run.

    • cites [34] Brookes PS Salinas EP Darley-Usmar K Eiserich JP Freeman BA Darley-Usmar VM Anderson PG Concentration-dependent effects of nitric oxide on mitochondrial permeability transition and cytochrome c release The Journal of biological chemistry 275 20474 20479 2000 10791954 source

      Not checked in the free run.

    • cites [35] Burwell LS Nadtochiy SM Brookes PS Cardioprotection by metabolic shut-down and gradual wake-up J Mol Cell Cardiol 46 804 810 2009 19285082 PMC2683198 source

      Not checked in the free run.

    • cites [36] Kim YM Kim TH Seol DW Talanian RV Billiar TR Nitric oxide suppression of apoptosis occurs in association with an inhibition of Bcl-2 cleavage and cytochrome c release The Journal of biological chemistry 273 31437 31441 1998 9813055 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NO is readily oxidized to nitrite and subsequently nitrate in an oxygen dependent manner; physiological concentrations of nitrite vary between tissues reflecting the degree of NOS activity as well as oxidation pathways of NO.

    “NO is readily oxidized to nitrite and subsequently nitrate in an oxygen dependent manner; thus, the physiological concentrations of nitrite vary between tissues reflecting the degree of NOS activity as well as oxidation pathways of NO [20, 45].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [20] Bryan NS Rassaf T Maloney RE Rodriguez CM Saijo F Rodriguez JR Feelisch M Cellular targets and mechanisms of nitros(yl)ation: an insight into their nature and kinetics in vivo Proceedings of the National Academy of Sciences of the United States of America 101 4308 4313 2004 15014175 PMC384737 source

      Not checked in the free run.

    • cites [45] Rodriguez J Maloney RE Rassaf T Bryan NS Feelisch M Chemical nature of nitric oxide storage forms in rat vascular tissue Proceedings of the National Academy of Sciences of the United States of America 100 336 341 2003 12502793 PMC140970 source

      Not checked in the free run.

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

    Premisecitation

    Usual concentrations of plasma nitrite range from 200-600 nM in many mammals including humans.

    “Usual concentrations of plasma nitrite range from 200–600 nM in many mammals including humans [17].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] 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 radical biology & medicine 35 790 796 2003 14583343 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The presence of deoxygenated hemoglobin reduces nitrite to NO, which may activate soluble guanylate cyclase to mediate vasodilation.

    “However, Cosby et al has shown that the presence of deoxygenated hemoglobin reduced nitrite to NO, which may activate soluble guanylate cyclase to mediate vasodilation [19].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [19] 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 Nature medicine 9 1498 1505 2003 14595407 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Nitrite concentrations in plasma and in tissues correlate closely following administration, as transport of nitrite is aided by anion transporters across membranes due to the high concentration gradient from plasma to cells.

    “Nitrite concentrations in plasma and in tissues correlate closely following administration, as transport of nitrite is aided by anion transporters across membranes due to the high concentration gradient from plasma to cells [71].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [71] Vitturi DA Teng X Toledo JC Matalon S Lancaster JR Jr Patel RP Regulation of nitrite transport in red blood cells by hemoglobin oxygen fractional saturation American journal of physiology 296 H1398 1407 2009 19286940 PMC2685350

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Endogenous nitrite generation primarily involves two pathways: one electron oxidation of endogenously produced NO to nitrite, and reduction of salivary nitrate to nitrite by commensal bacteria and reabsorption back into the organism.

    “Endogenous nitrite generation primarily involves two pathways; 1) one electron oxidation of endogenously produced NO to nitrite, and 2) reduction of salivary nitrate to nitrite by commensal bacteria and reabsorption back into the organism.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    NOS3 dependent NO production plays an important role in regulating steady state plasma nitrite levels, while also influencing nitrate, nitroso, and nitrosyl products in tissues.

    “NOS3 dependent NO production plays an important role in regulating steady state plasma nitrite levels, while also influencing nitrate, nitroso, and nitrosyl products in tissues [72, 73].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [72] Carlstrom M Larsen FJ Nystrom T Hezel M Borniquel S Weitzberg E Lundberg JO Dietary inorganic nitrate reverses features of metabolic syndrome in endothelial nitric oxide synthase-deficient mice Proceedings of the National Academy of Sciences of the United States of America 107 17716 17720 2010 20876122 PMC2955084 source

      Not checked in the free run.

    • cites [73] Lundberg JO Weitzberg E NO generation from nitrite and its role in vascular control Arteriosclerosis, thrombosis, and vascular biology 25 915 922 2005 15746440 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The dominant oxidation product of NO in aqueous solution is nitrite and nitrate formation requires additional oxidation by heme proteins.

    “This report clearly demonstrated that the dominant oxidation product of NO in aqueous solution is nitrite and that nitrate formation requires additional oxidation by heme proteins.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [76] Ignarro LJ Fukuto JM Griscavage JM Rogers NE Byrns RE Oxidation of nitric oxide in aqueous solution to nitrite but not nitrate: comparison with enzymatically formed nitric oxide from L-arginine Proceedings of the National Academy of Sciences of the United States of America 90 8103 8107 1993 7690141 PMC47296 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ingestion of foods rich in nitrates results in elevated plasma levels of both nitrate and nitrite and may help explain the health benefits of certain diets such as Mediterranean.

    “Ingestion of foods rich in nitrates results in elevated plasma levels of both nitrate and nitrite and may help explain the health benefits of certain diets (e.g. Mediterranean) [58].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [58] Lundberg JO Feelisch M Bjorne H Jansson EA Weitzberg E Cardioprotective effects of vegetables: is nitrate the answer? Nitric Oxide 15 359 362 2006 16563818 source

      Not checked in the free run.

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

    Premisecitation

    Nitrate intake from sources other than food was estimated to be around 35-44 mg/person/day.

    “Nitrate intake from sources other than food was estimated to be around 35–44 mg/person/day [64].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [64] EFSA Nitrate in vegetables: scientific opinion of the panel on contaminants in the food chain The EFSA Journal 689 1 79 2008 PMC10193653 37213838

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NO readily reacts with molecular oxygen through a single electron oxidation to HNO; further oxidation results in formation of nitrite, with the major pathway for NO metabolism being oxidation to nitrite and nitrate under normal physiological conditions.

    “NO readily reacts with molecular oxygen through a single electron oxidation to HNO. Further oxidation of this species results in the formation of nitrite (NO2−) with the major pathway for NO metabolism being oxidation to nitrite and nitrate under normal physiological conditions [67].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [67] Yoshida K Kasama K Kitabatake M Imai M Biotransformation of nitric oxide, nitrite and nitrate Int Arch Occup Environ Health 52 103 115 1983 6629503 source

      Not checked in the free run.

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

    Premisecitation

    Nitrite is found in environmental toxicants such as cigarette smoke and car exhaust.

    “Apart from food sources, nitrite (NO2−) is also found in environmental toxicants such as cigarette smoke and car exhaust [63].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [63] Norman V KC Nitrogen oxides in tobacco smoke Nature 205 915 916 1965 source

      Not checked in the free run.

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

    Premisecitation

    Intake of nitrite from environmental sources occurs through contaminated ground water, commonly due to fertilizers, livestock and human excreta, which pose a potential hazard to health.

    “Intake of nitrite from environmental sources also occurs through contaminated ground water, commonly due to fertilizers, livestock and human excreta, which pose a potential hazard to health [59, 65].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [59] Hord NG Tang Y Bryan NS Food sources of nitrates and nitrites: the physiologic context for potential health benefits Am J Clin Nutr 90 1 10 2009 19439460 source

      Not checked in the free run.

    • cites [65] Johnson CJ Kross BC Continuing importance of nitrate contamination of groundwater and wells in rural areas Am J Ind Med 18 449 456 1990 2248249 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Nitrite administration can precondition liver and heart tissue against subsequent ischemic injury by protecting against mitochondrial dysfunction, enhancing tissue reperfusion respiration and energetics, and limiting ROS-mediated cellular dysfunction.

    “Moreover, nitrite administration can precondition liver and heart tissue against subsequent ischemic injury by protecting against mitochondrial dysfunction, enhancing tissue reperfusion respiration and energetics, and limiting ROS-mediated cellular dysfunction [40].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [40] Shiva S Sack MN Greer JJ Duranski M Ringwood LA Burwell L Wang X MacArthur PH Shoja A Raghavachari N Calvert JW Brookes PS Lefer DJ Gladwin MT Nitrite augments tolerance to ischemia/reperfusion injury via the modulation of mitochondrial electron transfer J Exp Med 204 2089 2102 2007 17682069 PMC2118713 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The main source of endogenous nitrite in mammals is produced through the L-arginine-NO pathway, which is constitutively active in multiple cell types throughout the body.

    “The main source of endogenous nitrite in mammals is produced through the L-arginine-NO pathway, which is constitutively active in multiple cell types throughout the body [41].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [41] Leaf CD WJ Tannenbaum SR L-arginine is a precursor for nitrate biosynthesis in humans Biochem Biophys Res Commun 163 1032 1037 1989 2783109 source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Under acidic conditions (pH 3.2-3.4), nitrite converts to HNO2, which is unstable and forms N2O3 that can subsequently generate free NO.

    “Under acidic conditions (pH 3.2–3.4), nitrite converts to HNO2, which is unstable and forms N2O3 that can subsequently generate free NO (reactions (1), (2) and (3)).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Nitrite reduction to NO in ischemic rat hearts occurred in a NOS independent manner but was associated with tissue pH of 5.5 or below.

    “Work from the Zweier lab demonstrated that nitrite reduction to NO in ischemic rat hearts occurred in a NOS independent manner but was associated with tissue pH of 5.5 or below [84].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [84] Zweier JL Wang P Kuppusamy P Direct measurement of nitric oxide generation in the ischemic heart using electron paramagnetic resonance spectroscopy The Journal of biological chemistry 270 304 307 1995 7814391 source

      Not checked in the free run.

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

    Premisecitation

    Peroxynitrite markedly inhibits XO activity in a dose-dependent manner.

    “It has been reported that peroxynitrite markedly inhibits XO activity in a dose-dependent manner, thus it is possible that subsequent nitrosation of XO due to nitrite reduction to NO in the presence of superoxide may also influence XO activity [104].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [104] Lee CI Liu X Zweier JL Regulation of xanthine oxidase by nitric oxide and peroxynitrite The Journal of biological chemistry 275 9369 9376 2000 10734080 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Oral ingestion of nitrite into the acidic environment of the stomach produces NO that augments mucus secretion, antibacterial effects of gastric fluids, and ulcer healing.

    “Moreover, oral ingestion of nitrite into the acidic environment of the stomach produces NO that augments mucus secretion, antibacterial effects of gastric fluids, and ulcer healing [93–97].”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [93] Bjorne HH Petersson J Phillipson M Weitzberg E Holm L Lundberg JO Nitrite in saliva increases gastric mucosal blood flow and mucus thickness The Journal of clinical investigation 113 106 114 2004 14702114 PMC300767 source

      Not checked in the free run.

    • cites [94] Larauche M Anton PM Garcia-Villar R Theodorou V Frexinos J Bueno L Fioramonti J Protective effect of dietary nitrate on experimental gastritis in rats Br J Nutr 89 777 786 2003 12828794 source

      Not checked in the free run.

    • cites [95] Miyoshi M Kasahara E Park AM Hiramoto K Minamiyama Y Takemura S Sato EF Inoue M Dietary nitrate inhibits stress-induced gastric mucosal injury in the rat Free Radic Res 37 85 90 2003 12653221 source

      Not checked in the free run.

    • cites [96] Duncan C Dougall H Johnston P Green S Brogan R Leifert C Smith L Golden M Benjamin N Chemical generation of nitric oxide in the mouth from the enterosalivary circulation of dietary nitrate Nat Med 1 564 551 1995 7585121 source

      Not checked in the free run.

    • cites [97] Lundberg JO Weitzberg E Lundberg JM Alving K Intragastric nitric oxide production in humans: measurements in expelled air Gut 35 1543 1546 1994 7828969 PMC1375608 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Xanthine oxidase is structurally related to bacterial nitrate and nitrite reductases and can reduce both nitrate and nitrite.

    “Xanthine oxidase is structurally related to bacterial nitrate and nitrite reductases and can reduce both nitrate and nitrite [102].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [102] Alikulov ZA L’Vov NP Kretovich VL Nitrate and nitrite reductase activity of milk xanthine oxidase Biokhimiia 45 1714 1718 1980 6894704

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mice deficient for ceruloplasmin show lower basal concentrations of plasma nitrite and less plasma nitrite elevation upon NO administration.

    “This concept is confirmed in mice deficient for ceruloplasmin that showed lower basal concentrations of plasma nitrite and less plasma nitrite elevation upon NO administration [78].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [78] Shiva S WX Ringwood LA Xu X Yuditskaya S Annavajjhala V Miyajima H Hogg N Harris ZL Gladwin MT Ceruloplasmin is a NO oxidase and nitrite synthase that determines endocrine NO homeostasis Nat Chem Biol 2 486 493 2006 16906150 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Vessel relaxation by nitrite at pH 6.6 was blocked by the soluble guanylyl cyclase inhibitor ODQ, supporting the conclusion that NO was responsible for these effects.

    “Vessel relaxation was blocked by the soluble guanylyl cyclase inhibitor, ODQ, supporting the conclusion that NO was responsible for these effects.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [92] 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 171 9 16 2001 11350258

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Nitrite present in blood can react either with oxyhemoglobin to form nitrate and methemoglobin or with deoxyhemoglobin to form NO, nitrosylhemoglobin, and NO adducts.

    “Thus, nitrite present in blood can react either with oxyhemoglobin (oxyHb) to form nitrate (NO3−) and methemoglobin (metHb) or with deoxyhemoglobin (deoxyHb) to form NO, nitrosylhemoglobin (NO-Hb), and NO adducts.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Vascular nitrite reduction can occur under moderately acidic pH changes, indicating that this pathway may be important for augmenting tissue NO levels.

    “A later study by Modin et al demonstrated that vascular nitrite reduction could occur under moderately acidic pH changes indicating that this pathway may indeed be important for augmenting tissue NO levels [92].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [92] 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 171 9 16 2001 11350258

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Intra-arterial infusion of nitrite at near-physiological levels causes vasodilation in an arterio-venous gradient manner that is influenced by R-T state conversion and oxygen tension implicating red cell reduction of nitrite to NO.

    “However, experiments by Cosby et al showed that intra-arterial infusion of nitrite at near-physiological levels causes vasodilation in an arterio-venous gradient manner that is influenced by R-T state conversion and oxygen tension implicating red cell reduction of nitrite to NO [19, 106, 107].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [19] 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 Nature medicine 9 1498 1505 2003 14595407 source

      Not checked in the free run.

    • cites [106] Huang KT Keszler A Patel N Patel RP Gladwin MT Kim-Shapiro DB Hogg N The reaction between nitrite and deoxyhemoglobin. Reassessment of reaction kinetics and stoichiometry The Journal of biological chemistry 280 31126 31131 2005 15837788 source

      Not checked in the free run.

    • cites [107] 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 The Journal of clinical investigation 115 2099 2107 2005 16041407 PMC1177999 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Therapeutic use of inorganic nitrite may be of widespread benefit given the reciprocal relationship between nitrite and NO plus the fact that NO bioavailability contributes to numerous disease states.

    “However, given the appreciation of the reciprocal relationship between nitrite and NO plus the fact that NO bioavailability is well known to contribute to numerous disease states [136, 137], therapeutic use of inorganic nitrite may be of widespread benefit.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [136] Arnal JF Dinh-Xuan AT Pueyo M Darblade B Rami J Endothelium-derived nitric oxide and vascular physiology and pathology Cell Mol Life Sci 55 1078 1087 1999 10442089 PMC11146781 source

      Not checked in the free run.

    • cites [137] Li H Forstermann U Nitric oxide in the pathogenesis of vascular disease The Journal of pathology 190 244 254 2000 10685059 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Dietary nitrate administration through beetroot juice consumption decreased oxygen cost during exercise that was also associated with increased plasma nitrite levels and extended time to exhaustion.

    “Likewise, work from the Jones laboratory also found that dietary nitrate administration through beetroot juice consumption decreased oxygen cost during exercise that was also associated with increased plasma nitrite levels and extended time to exhaustion [125–127].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [125] Bailey SJ Winyard P Vanhatalo A Blackwell JR Dimenna FJ Wilkerson DP Tarr J Benjamin N Jones AM Dietary nitrate supplementation reduces the O2 cost of low-intesity exercise and enhances tolerance to high-intensity exercise in humans J Appl Physiol 107 1144 1155 2009 19661447 source

      Not checked in the free run.

    • cites [126] Bailey SJ Fulford J Vanhatalo A Winyard PG Blackwell JR DiMenna FJ Wilkerson DP Benjamin N Jones AM Dietary nitrate supplementation enhances muscle contractile efficiency during knee-extensor excercise in humans J Appl Physiol 109 135 148 2010 20466802 source

      Not checked in the free run.

    • cites [127] 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 110 591 600 2011 21071588 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Dietary nitrate consumption increased plasma nitrite levels and decreased muscle oxygen cost during both sub-maximal and maximal exercise.

    “In two studies by Larsen et al, it is clear that dietary nitrate consumption increased plasma nitrite levels and decreased muscle oxygen cost during both sub-maximal and maximal exercise [123, 124].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [123] Larsen FJ Weitzberg E Lundberg JO Ekbolm B Effects of dietary nitrate on oxygen cost during exercise Acta Physiol (Oxf) 191 59 66 2007 17635415 source

      Not checked in the free run.

    • cites [124] Larsen FJ Weitzberg E Lundberg JO Ekbolm B Dietary nitrate reduces maximal oxygen consumption while maintaining work performance in maximal exercise Free Radic Biol Med 48 342 347 2010 19913611 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Sodium nitrite mediated metHb formation is slower than other cyanide antidotes (e.g. 4-dimethylaminophenol) and has lead to the notion that the cardiovascular effects of nitrite may also be protective against cyanide mediated increases in central venous pressure.

    “However, sodium nitrite mediated metHb formation is slower than other cyanide antidotes (e.g. 4-dimethylaminophenol) and has lead to the notion that the cardiovascular effects of nitrite may also be protective against cyanide mediated increases in central venous pressure [135].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [135] Beasley DM Glass WI Cyanide poisoning: pathophysiology and treatment recommendations Occup Med (Lond) 48 427 431 1998 10024740 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Therapeutic administration of sodium nitrite 30 mg/ml over 5-20 minutes (~300 mg total) significantly increases metHb levels (~20%) that can bind with cyanide to form cyanmethemoglobin thus competing with cytochrome oxidase a3.

    “Therapeutic administration of sodium nitrite 30 mg/ml over 5–20 minutes (~300 mg total) significantly increases metHb (i.e. ferric heme) levels (~20%) that can bind with cyanide to form cyanmethemoglobin thus competing with cytochrome oxidase a3 [134].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [134] Baskin SI Horowitz AM Nealley EW The antidotal action of sodium nitrite and sodium thiosulfate against cyanide poisoning J Clin Pharmacol 32 368 375 1992 1569239 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The effect of dietary nitrate did not alter heart rate, lactate accumulation, or ventilation, and correlated with an increased time to exhaustion.

    “These studies further demonstrated that the effect of dietary nitrate did not alter heart rate, lactate accumulation, or ventilation, and correlated with an increased time to exhaustion.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [123] Larsen FJ Weitzberg E Lundberg JO Ekbolm B Effects of dietary nitrate on oxygen cost during exercise Acta Physiol (Oxf) 191 59 66 2007 17635415 source

      Not checked in the free run.

    • cites [124] Larsen FJ Weitzberg E Lundberg JO Ekbolm B Dietary nitrate reduces maximal oxygen consumption while maintaining work performance in maximal exercise Free Radic Biol Med 48 342 347 2010 19913611 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The beneficial effect of sodium nitrite stems from the fact that cyanide has a high binding affinity for ferric iron, which is the basis of cyanide inhibition of cytochrome oxidase a3 thus decreasing mitochondrial respiration.

    “The beneficial effect of sodium nitrite stems from the fact that cyanide has a high binding affinity for ferric iron, which is the basis of cyanide inhibition of cytochrome oxidase a3 thus decreasing mitochondrial respiration [133].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [133] Gracia R Shepard G Cyanide poisoning and its treatment Pharmacother 24 1358 1365 2004 15628833 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Nitrite/nitrate positively affects mitochondrial function to alter muscle metabolism, which could similarly affect mitochondrial function of other tissues.

    “Together, these studies demonstrate that nitrite/nitrate positively affects mitochondrial function to alter muscle metabolism, which could similarly affect mitochondrial function of other tissues.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Deoxygenated red cells are able to reduce nitrite to NO which mediated vessel ring dilation.

    “Lastly, Crawford et al further demonstrated that deoxygenated red cells were able to reduce nitrite to NO which mediated vessel ring dilation, solidifying the biological importance of deoxyhemoglobin reduction of nitrite [109].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [109] Crawford JH Isbell TS Huang Z Shiva S Chacko BK Schechter AN Darley-Usmar VM Kerby JD Lang JD Jr Kraus D Ho C Gladwin MT Patel RP Hypoxia, red blood cells, and nitrite regulate NO-dependent hypoxic vasodilation Blood 107 566 574 2006 16195332 PMC1895612 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Decreased NO levels contribute to endothelial cell dysfunction, atherosclerotic plaque development, arteriosclerosis, vessel restenosis, peripheral vascular disease, and ischemia-reperfusion injury.

    “It is well accepted that decreased NO levels contribute to endothelial cell dysfunction, atherosclerotic plaque development, arteriosclerosis, vessel restenosis, peripheral vascular disease, and ischemia-reperfusion injury [14, 15, 138–140].”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [14] Garcia-Cardena G Martasek P Masters BS Skidd PM Couet J Li S Lisanti MP Sessa WC Dissecting the interaction between nitric oxide synthase (NOS) and caveolin. Functional significance of the nos caveolin binding domain in vivo The Journal of biological chemistry 272 25437 25440 1997 9325253 source

      Not checked in the free run.

    • cites [15] Kolluru GK Siamwala JH Chatterjee S eNOS phosphorylation in health and disease Biochimie 92 1186 1198 2010 20363286 source

      Not checked in the free run.

    • cites [138] Maxwell AJ Cooke JP The role of nitric oxide in atherosclerosis Coronary artery disease 10 277 286 1999 10421966 source

      Not checked in the free run.

    • cites [139] Naseem KM The role of nitric oxide in cardiovascular diseases Molecular aspects of medicine 26 33 65 2005 15722114 source

      Not checked in the free run.

    • cites [140] Grisham MB Granger DN Lefer DJ Modulation of leukocyte-endothelial interactions by reactive metabolites of oxygen and nitrogen: relevance to ischemic heart diseases Free Radic Biol Med 25 404 433 1998 9741579 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Nitrite-derived NO production by rat liver mitochondria was inhibited by cyanide and enhanced cytochrome c oxidase in a pH dependent manner.

    “Castello and coworkers have also shown nitrite-derived NO production by rat liver mitochondria was inhibited by cyanide and enhanced cytochrome c oxidase in a pH dependent manner [84, 117].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [84] Zweier JL Wang P Kuppusamy P Direct measurement of nitric oxide generation in the ischemic heart using electron paramagnetic resonance spectroscopy The Journal of biological chemistry 270 304 307 1995 7814391 source

      Not checked in the free run.

    • cites [117] Meyer DJ Enzymatic/non-enzymatic formation of nitric oxide Nature medicine 1 1103 1104 1995 7584968 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Upon oral consumption, inorganic nitrite absorption occurs quickly and primarily in the upper small intestinal region (duodenum and jejunem) typically reaching a peak plasma level between 15-30 minutes that may be influenced by the amount administered and the presence of food in the stomach.

    “Upon oral consumption, inorganic nitrite absorption occurs quickly and primarily in the upper small intestinal region (duodenum and jejunem) typically reaching a peak plasma level between 15–30 minutes that may be influenced by the amount administered and the presence of food in the stomach.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [69] Hunault CC van Velzen AG Sips AJ Schothorst RC Meulenbelt J Bioavailability of sodium nitrite from an aqueous solution in healthy adults Toxicology letters 190 48 53 2009 19576277 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Nitrite anion itself can stimulate cGC activity and other signaling mediators, as treatment with NO scavenger carboxy-PTIO was unable to prevent these effects.

    “work from Bryan et al demonstrated that nitrite anion itself could stimulate cGC activity and other signaling mediators as treatment with the NO scavenger carboxy-PTIO was unable to prevent these effects by nitrite administration [20].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Bryan NS Rassaf T Maloney RE Rodriguez CM Saijo F Rodriguez JR Feelisch M Cellular targets and mechanisms of nitros(yl)ation: an insight into their nature and kinetics in vivo Proceedings of the National Academy of Sciences of the United States of America 101 4308 4313 2004 15014175 PMC384737 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    cPTIO treatment attenuates nitrite-mediated protection against ischemia-reperfusion injury in vivo, indicating that protective mechanisms likely involve NO-dependent signaling pathways and molecular responses.

    “cPTIO treatment was shown by numerous groups to attenuate nitrite mediated protection against ischemia-reperfusion injury in vivo indicating that protective mechanisms likely involve NO dependent signaling pathways and molecular responses [47, 89, 156, 162].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [47] Kumar D Branch BG Pattillo CB Hood J Thoma S Simpson S Illum S Arora N Chidlow JH Jr Langston W Teng X Lefer DJ Patel RP Kevil CG Chronic sodium nitrite therapy augments ischemia-induced angiogenesis and arteriogenesis Proceedings of the National Academy of Sciences of the United States of America 105 7540 7545 2008 18508974 PMC2396555 source

      Not checked in the free run.

    • cites [89] 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 Proceedings of the National Academy of Sciences of the United States of America 101 13683 13688 2004 15347817 PMC518813 source

      Not checked in the free run.

    • cites [156] 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 The Journal of clinical investigation 115 1232 1240 2005 15841216 PMC1077170 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Nitrite contributes to intravascular endocrine nitric oxide transport, hypoxic vasodilation, signaling responses, and tissue cytoprotection after ischemia-reperfusion.

    “Specifically, nitrite contributes to intravascular endocrine nitric oxide (NO) transport, hypoxic vasodilation, signaling responses, and tissue cytoprotection after ischemia-reperfusion.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Peak plasma nitrate levels from sodium nitrite consumption are observed on average by 1.5 hours with a circulating half-life of 8-13 hours depending on dose and route of administration.

    “Conversely, peak plasma nitrate levels from sodium nitrite consumption are observed on average by 1.5 hours with a circulating half-life of 8–13 hours depending on dose and route of administration.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [69] Hunault CC van Velzen AG Sips AJ Schothorst RC Meulenbelt J Bioavailability of sodium nitrite from an aqueous solution in healthy adults Toxicology letters 190 48 53 2009 19576277 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Pharmacological scavengers PTIO and NEM inhibit the protective effects in CS-eNOS-Tg mice, indicating a role for nitrite reduction to NO and S-nitrosylation for cytoprotection.

    “Experiments also showed that pharmacological scavengers PTIO and NEM inhibited the protective effects in CS-eNOS-Tg mice, indicating a role for nitrite reduction to NO and S-nitrosylation for cytoprotection [164].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [164] Elrod JW Calvert JW Gundewar S Bryan NS Lefer DJ Nitric oxide promotes distant organ protection: evidence for an endocrine role of nitric oxide Proceedings of the National Academy of Sciences of the United States of America 105 11430 11435 2008 18685092 PMC2516252 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Nitrite therapy potently decreases mitochondrial respiration during ischemia, thereby preventing uncoupling of electron transport that increases reactive oxygen species formation leading to cytochrome c release and apoptosis activation.

    “Subsequent work by the same group revealed that nitrite therapy potently decreases mitochondrial respiration during ischemia thereby preventing uncoupling of electron transport that increases reactive oxygen species formation leading to cytochrome c release and apoptosis activation [4, 39, 40].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [4] Raat NJ Noguchi AC Liu VB Raghavachari N Liu D Xu X Shiva S Munson PJ Gladwin MT Dietary nitrate and nitrite modulate blood and organ nitrite and the cellular ischemic stress response Free radical biology & medicine 47 510 517 2009 19464364 PMC2744499 source

      Not checked in the free run.

    • cites [39] Shiva S HZ Grubina R Sun J Ringwood LA MacArthur PH Xu X Murphy E Darley-Usmar VM Gladwin MT Deoxymyoglobin is a nitrite reducatse that generates nitric oxide and regulates mitochondrial respiration Circulation research 100 654 661 2007 17293481 source

      Not checked in the free run.

    • cites [40] Shiva S Sack MN Greer JJ Duranski M Ringwood LA Burwell L Wang X MacArthur PH Shoja A Raghavachari N Calvert JW Brookes PS Lefer DJ Gladwin MT Nitrite augments tolerance to ischemia/reperfusion injury via the modulation of mitochondrial electron transfer J Exp Med 204 2089 2102 2007 17682069 PMC2118713 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The route of administration does not significantly alter the protective outcome of nitrite therapy, as oral administration of sodium nitrite attenuates myocardial ischemia-reperfusion injury.

    “the route of administration did not significantly alter the protective outcome of nitrite therapy as oral administration of sodium nitrite was able to attenuate myocardial ischemia-reperfusion injury [163].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [163] Bryan NS Calvert JW Elrod JW Gundewar S Ji SY Lefer DJ Dietary nitrite supplementation protects against myocardial ischemia-reperfusion injury Proceedings of the National Academy of Sciences of the United States of America 104 19144 19149 2007 18025468 PMC2141922 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Sodium nitrite could ameliorate endothelial cell dysfunction and ischemic injury in SCD patients.

    “These data are encouraging and strongly suggest that sodium nitrite could ameliorate endothelial cell dysfunction and ischemic injury in this patient population.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Findings from animal models of ischemia-reperfusion and other diseases are relevant to human patients.

  • May combine two claims.

    Premisecitation

    Sodium nitrite can stimulate hypoxic vasodilation of the pulmonary vasculature, indicating that nitrite therapy might be clinically useful for PAH.

    “Reports from several laboratories demonstrate that sodium nitrite can stimulate hypoxic vasodilation of the pulmonary vasculature indicating that nitrite therapy might be clinically useful for PAH [87, 195, 196].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [87] Hunter CJ Dejam A Blood AB Shields H Kim-Shapiro DB Machado RF Tarekegn S Mulla N Hopper AO Schechter AN Power GG Gladwin MT Inhaled nebulized nitrite is a hypoxia-sensitive NO-dependent selective pulmonary vasodilator Nature medicine 10 1122 1127 2004 15361865 source

      Not checked in the free run.

    • cites [195] Casey DB Badejo AM Jr Dhaliwal JS Murthy SN Hyman AL Nossaman BD Kadowitz PJ Pulmonary vasodilator responses to sodium nitrite are mediated by an allopurinol-sensitive mechanism in the rat American journal of physiology 296 H524 533 2009 19074675 PMC2643888 source

      Not checked in the free run.

    • cites [196] Ingram TE Pinder AG Bailey DM Fraser AG James PE Low-dose sodium nitrite vasodilates hypoxic human pulmonary vasculature by a means that is not dependent on a simultaneous elevation in plasma nitrite American journal of physiology 298 H331 339 2010 19940079 PMC2822592 source

      Not checked in the free run.

    • Rests on an assumption: Findings from animal models of ischemia-reperfusion and other diseases are relevant to human patients.

  • May combine two claims.

    Premisecitation

    Acidified sodium nitrite mediates anaerobic killing of mucoid Pseudomonas aeruginosa in cultured biofilms and enhances killing against this and antibiotic-resistant strains in lungs in vivo.

    “Work by Yoon et al demonstrated that acidified sodium nitrite mediated anaerobic killing of mucoid Pseudomonas aeruginosa in cultured biofilms and enhanced killing against this and antibiotic resistant strains in lungs in vivo [200].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [200] Yoon SS Coakley R Lau GW Lymar SV Gaston B Karabulut AC Hennigan RF Hwang SH Buettner G Schurr MJ Mortensen JE Burns JL Speert D Boucher RC Hassett DJ Anaerobic killing of mucoid Pseudomonas aeruginosa by acidified nitrite derivatives under cystic fibrosis airway conditions The Journal of clinical investigation 116 436 446 2006 16440061 PMC1350997 source

      Not checked in the free run.

    • Rests on an assumption: Findings from animal models of ischemia-reperfusion and other diseases are relevant to human patients.

  • May combine two claims.

    Premisecitation

    Three-day dietary nitrite supplementation of healthy volunteers with sodium nitrate (0.1 mmol/kg/day) significantly increases plasma nitrite/nitrate levels and decreases diastolic pressure by 3.7 mm Hg.

    “An initial study by Larsen et al reported that 3 day dietary nitrite supplementation of healthy volunteers with sodium nitrate (0.1 mmol/kg/day) significantly increased plasma nitrite/nitrate levels and decreased diastolic pressure by 3.7 mm Hg [190].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [190] Larsen FJ Ekblom B Sahlin K Lundberg JO Weitzberg E Effects of dietary nitrate on blood pressure in healthy volunteers N Engl J Med 355 2792 2793 2006 17192551 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Supplementation of nitrite reduces allograft inflammation, apoptosis, and macrophage recruitment and mitigates donor-specific alloimmune responses to prolong allograft survival.

    “It was shown that supplementation of nitrite reduced allograft inflammation, apoptosis, and macrophage recruitment and mitigated donor-specific alloimmune responses to prolong allograft survival.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [165] Zhan J Nakao A Sugimoto R Dhupar R Wang Y Wang Z Billiar TR McCurry KR Orally administered nitrite attenuates cardiac allograft rejection in rats Surgery 146 155 165 2009 19628069 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Nitrite-mediated therapy partially involves p21 cyclin-dependent kinase inhibitor, as hypoxia pulmonary hypertension is still evident upon nitrite therapy in p21 deficient mice yet reduced pulmonary pressures and ventricular remodeling responses are still reduced.

    “It was also found that nitrite mediated therapy partially involved p21 cyclin-dependent kinase inhibitor as hypoxia pulmonary hypertension was still evident upon nitrite therapy in p21 deficient mice yet reduced pulmonary pressures and ventricular remodeling responses were still reduced.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [197] Zuckerbraun BS Shiva S Ifedigbo E Mathier MA Mollen KP Rao J Bauer PM Choi JJ Curtis E Choi AM Gladwin MT Nitrite potently inhibits hypoxic and inflammatory pulmonary artery hypertension and smooth muscle proliferation via xanthine oxidoreductase-dependent nitric oxide generation Circulation 121 98 109 2010 20026772

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In human subjects with SCD, small doses of sodium nitrite are adequate to provide detectable changes in systemic plasma nitrite levels and augment forearm blood flow.

    “Mack et al has shown that in human subjects with SCD, small doses of sodium nitrite were adequate to provide detectable changes in systemic plasma nitrite levels and augment forearm blood flow [187].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [187] Mack AK McGowan VR II Tremonti CK Ackah D Barnett C Machado RF Gladwin MT Kato GJ Sodium nitrite promotes regional blood flow in patients with sickle cell disease: a phase I/II study British journal of haematology 142 971 978 2008 18671702 PMC2766260 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Sodium nitrite therapy minimally increases plasma and lung nitrite levels but still ameliorates disease.

    “Interestingly, sodium nitrite therapy minimally increased plasma and lung nitrite levels but still ameliorated disease.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [197] Zuckerbraun BS Shiva S Ifedigbo E Mathier MA Mollen KP Rao J Bauer PM Choi JJ Curtis E Choi AM Gladwin MT Nitrite potently inhibits hypoxic and inflammatory pulmonary artery hypertension and smooth muscle proliferation via xanthine oxidoreductase-dependent nitric oxide generation Circulation 121 98 109 2010 20026772

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Consumption of beetroot juice (~500 mls) acutely lowers arterial BP, augments endothelial function during ischemia, and inhibits platelet aggregation as a result of bioconversion to NO in healthy individuals.

    “Webb et al investigated the possibility of increasing plasma nitrite levels through dietary nitrate by consumption of beetroot juice (~500 mls) that was also found to acutely lower arterial BP, augment endothelial function during ischemia, and inhibit platelet aggregation as a result of bioconversion to NO in healthy individuals [191].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [191] 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 51 784 790 2008 18250365 PMC2839282 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Nitrite-mediated protection is independent of eNOS function but is lost in sGC knockout animals.

    “It was also determined that nitrite mediated protection was independent of eNOS function but was lost in sGC knockout animals.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [214] Buys ES Cauwels A Raher MJ Passeri JJ Hobai I Cawley SM Rauwerdink KM Thibault H Sips PY Thoonen R Scherrer-Crosbie M Ichinose F Brouckaert P Bloch KD sGC(alpha)1(beta)1 attenuates cardiac dysfunction and mortality in murine inflammatory shock models American journal of physiology 297 H654 663 2009 19502556 PMC2724210 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Oral nitrite therapy reverses the loss of colonic nitrite levels and decreases TNF-α expression, which is associated with clinical and histological improvements.

    “Oral nitrite therapy reversed the loss of colonic nitrite levels and decreased TNF-α expression, which was associated with clinical and histological improvements.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [233] Ohtake K Koga M Uchida H Sonoda K Ito J Uchida M Natsume H Kobayashi J Oral nitrite ameliorates dextran sulfate sodium-induced acute experimental colitis in mice Nitric Oxide 23 65 73 2010 20399279 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Certain nitrosamines can cross react with nitrite and naturally occur as secondary amines in food, compounds that act as carcinogens in rodents.

    “In 1956, Magee and Barnes reported that certain nitrosamines could cross react with nitrite and naturally occur as secondary amines in food, compounds that act as carcinogens in rodents [256].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [256] Magee PN Barnes JM The production of malignant primary hepatic tumours in the rat by feeding dimethylnitrosamine Br J Cancer 10 114 122 1956 13342328 PMC2074083 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The protective effect of nitrite is not restricted to TNF-α but also protects against LPS-induced sepsis.

    “Lastly, the protective effect of nitrite was not restricted to TNF-α but also protected against LPS induce sepsis.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [214] Buys ES Cauwels A Raher MJ Passeri JJ Hobai I Cawley SM Rauwerdink KM Thibault H Sips PY Thoonen R Scherrer-Crosbie M Ichinose F Brouckaert P Bloch KD sGC(alpha)1(beta)1 attenuates cardiac dysfunction and mortality in murine inflammatory shock models American journal of physiology 297 H654 663 2009 19502556 PMC2724210 source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Organic inhalant nitrites are completely different from inorganic nitrite anion, including separate metabolic pathways for NO formation and lack of tissue specificity.

    “However, it is important to understand that organic inhalant nitrites are completely different than inorganic nitrite anion including separate metabolic pathways for NO formation and lack of tissue specificity.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    5-aminosalicylic acid attenuates depletion of colon tissue nitrite levels, increases systemic nitrite levels, and reduces oxidative stress during DSS colitis.

    “the effects of 5-aminosalicylic acid (5-ASA- an anti-inflammatory agent for the treatment of inflammatory bowel disease) attenuated depletion of colon tissue nitrite levels, increased systemic nitrite levels, and oxidative stress during DSS colitis.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [234] Saijo F Milsom AB Bryan NS Bauer SM Vowinkel T Ivanovic M Andry C Granger DN Rodriguez J Feelisch M On the dynamics of nitrite, nitrate and other biomarkers of nitric oxide production in inflammatory bowel disease Nitric Oxide 22 155 167 2010 20005300 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Nitrite protects mitochondria against oxidative stress, thus shielding organs from shock-induced damage.

    “Nitrite was shown to protect mitochondria against oxidative stress thus shielding organs from shock-induced damage.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [214] Buys ES Cauwels A Raher MJ Passeri JJ Hobai I Cawley SM Rauwerdink KM Thibault H Sips PY Thoonen R Scherrer-Crosbie M Ichinose F Brouckaert P Bloch KD sGC(alpha)1(beta)1 attenuates cardiac dysfunction and mortality in murine inflammatory shock models American journal of physiology 297 H654 663 2009 19502556 PMC2724210 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The development of DSS colitis involves an early loss of colon tissue nitrite levels with a concomitant increase in systemic nitrite.

    “This study found that the development of DSS colitis involves an early loss of colon tissue nitrite levels with a concomitant increase in systemic nitrite.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [234] Saijo F Milsom AB Bryan NS Bauer SM Vowinkel T Ivanovic M Andry C Granger DN Rodriguez J Feelisch M On the dynamics of nitrite, nitrate and other biomarkers of nitric oxide production in inflammatory bowel disease Nitric Oxide 22 155 167 2010 20005300 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Salivary nitrite increases gastric mucosal blood flow and mucus production.

    “Bjorne et al demonstrated that salivary nitrite increases gastric mucosal blood flow and mucus production [93].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [93] Bjorne HH Petersson J Phillipson M Weitzberg E Holm L Lundberg JO Nitrite in saliva increases gastric mucosal blood flow and mucus thickness The Journal of clinical investigation 113 106 114 2004 14702114 PMC300767 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Daily administration of 85 mg/L−1 nitrate in drinking water for 8-10 weeks decreases body weight, plasma triglycerides, and visceral fat while improving glucose tolerance and fasting blood glucose levels in eNOS deficient mice.

    “It was found that daily administration of 85 mg/L−1 in the drinking water for 8–10 weeks decreased body weight, plasma triglycerides, and visceral fat while improving glucose tolerance and fasting blood glucose levels in eNOS deficient mice.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [72] Carlstrom M Larsen FJ Nystrom T Hezel M Borniquel S Weitzberg E Lundberg JO Dietary inorganic nitrate reverses features of metabolic syndrome in endothelial nitric oxide synthase-deficient mice Proceedings of the National Academy of Sciences of the United States of America 107 17716 17720 2010 20876122 PMC2955084 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Exogenous sodium nitrite treatment significantly attenuates hypothermia, mitochondrial damage, oxidative stress, tissue ischemia, and mortality in a TNF-α induced murine shock model.

    “A recent study by Cauwels et al shows that exogenous sodium nitrite treatment, in sharp contrast to exacerbation by NOS inhibition, significantly attenuates hypothermia, mitochondrial damage, oxidative stress, tissue ischemia, and mortality in a TNF-α induced murine shock model [214].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [214] Buys ES Cauwels A Raher MJ Passeri JJ Hobai I Cawley SM Rauwerdink KM Thibault H Sips PY Thoonen R Scherrer-Crosbie M Ichinose F Brouckaert P Bloch KD sGC(alpha)1(beta)1 attenuates cardiac dysfunction and mortality in murine inflammatory shock models American journal of physiology 297 H654 663 2009 19502556 PMC2724210 source

      Not checked in the free run.

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

    Premisenone given

    The relationship between nitrite and nitrate exposure and human cancer remains equivocal.

    “However, the relationship between nitrite and nitrate exposure and human cancer remains equivocal.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    During the development of colitis, tissue levels of nitrite drop quickly along with a concomitant increase in colonic TNF-α expression by day three followed by increased myeloperoxidase activity, and iNOS and HO-1 expression at day 7.

    “It was reported that during the development of colitis, tissue levels of nitrite dropped quickly along with a concomitant increase in colonic TNF-α expression by day three followed by increased myeloperoxidase activity, and iNOS and HO-1 expression at day 7.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [233] Ohtake K Koga M Uchida H Sonoda K Ito J Uchida M Natsume H Kobayashi J Oral nitrite ameliorates dextran sulfate sodium-induced acute experimental colitis in mice Nitric Oxide 23 65 73 2010 20399279 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The duration and route of administration of inorganic nitrite clearly influences observed beneficial effects such that continuous dosing is required to alleviate chronic tissue ischemia versus single dose therapy for acute ischemia, and that topical/oral administration of nitrite can differentially affect biological responses versus intravascular or intraperitoneal delivery.

    “Third, the duration and route of administration of inorganic nitrite clearly influences observed beneficial effects such that continuous dosing is required to alleviate chronic tissue ischemia versus single dose therapy for acute ischemia, and that topical/oral administration (skin, mucosal surfaces, or internal organs) of nitrite can differentially affect biological responses versus intravascular”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The required dose of nitrite necessary for beneficial effects differs significantly amongst disorders such that high nanomolar to low micromolar nitrite levels are protective during tissue ischemia, yet high micromolar to low millimolar doses appear to be required for attenuating colitis pathology and bacterial growth associated with cystic fibrosis.

    “Second, the required dose of nitrite necessary for beneficial effects differs significantly amongst disorders such that high nanomolar to low micromolar nitrite levels are protective during tissue ischemia, yet high micromolar to low millimolar doses appear to be required for attenuating colitis pathology and bacterial growth associated with cystic fibrosis.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: High doses of sodium nitrite are toxic in humans.

  • May combine two claims.

    Interpretationcitation

    Sodium nitrite therapy may be an effective anti-tumor therapy through NO mediated radiosensitization or tumoricidal properties.

    “As discussed above, sodium nitrite therapy may actually be an effective anti-tumor therapy through NO mediated radiosenitization or tumoricidal properties [278, 279].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [278] Brantley EC Guo L Zhang C Lin Q Yokoi K Langley RR Kruzel E Maya M Kim SW Kim SJ Fan D Fidler IJ Nitric oxide-mediated tumoricidal activity of murine microglial cells Translational oncology 3 380 388 2010 21151477 PMC3000463 source

      Not checked in the free run.

    • cites [279] Maksimovic-Ivanic D Mijatovic S Harhaji L Miljkovic D Dabideen D Fan Cheng K Mangano K Malaponte G Al-Abed Y Libra M Garotta G Nicoletti F Stosic-Grujicic S Anticancer properties of the novel nitric oxide-donating compound (S,R)-3-phenyl-4,5-dihydro-5-isoxazole acetic acid-nitric oxide in vitro and in vivo Molecular cancer therapeutics 7 510 520 2008 18347138 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    These completed clinical trials established biochemical and physiological parameters and addressed some safety concerns that provide useful baseline information for the field.

    “In short, these studies established biochemical and physiological parameters as well as addressing some safety concerns that provide useful baseline information for the field moving forward.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Clinical trial design parameters strongly influence data outcome, interpretation, and conclusions.

    “It is very important to emphasize that clinical trial design parameters strongly influence data outcome, interpretation, and conclusions [267, 268].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [267] Pocock SJ Clinical trials with multiple outcomes: a statistical perspective on their design, analysis, and interpretation Controlled clinical trials 18 530 545 discussion 546-539 1997 9408716 source

      Not checked in the free run.

    • cites [268] Wade DT Outcome measures for clinical rehabilitation trials: impairment, function, quality of life, or value? American journal of physical medicine & rehabilitation/Association of Academic Physiatrists 82 S26 31 2003 14502036 source

      Not checked in the free run.

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

    Premisecitation

    Nitrite can inhibit cell division of certain tumor cell lines.

    “Conversely, it has been reported that sodium nitrite administration to tumor bearing mice does not significantly affect growth rates and that nitrite can inhibit cell division of certain tumor cell lines [263, 277].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [263] Morcos E Carlsson S Weitzberg E Wiklund NP Lundberg JO Inhibition of cancer cell replication by inorganic nitrite Nutrition and cancer 62 501 504 2010 20432171 source

      Not checked in the free run.

    • cites [277] Kitamura Y Yamagihi M Okazaki K Furukawa F Imazawa T Nishikawa A Hirose M Lack of enhancing effects of sodium nitrite on 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine (PhIP) induced mammary carcinogenesis in female Sprague-Dawley rats Cancer Lett 235 69 74 2006 15951105 source

      Not checked in the free run.

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

    Premisecitation

    Sodium nitrite administration to tumor bearing mice does not significantly affect growth rates.

    “Conversely, it has been reported that sodium nitrite administration to tumor bearing mice does not significantly affect growth rates and that nitrite can inhibit cell division of certain tumor cell lines [263, 277].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [263] Morcos E Carlsson S Weitzberg E Wiklund NP Lundberg JO Inhibition of cancer cell replication by inorganic nitrite Nutrition and cancer 62 501 504 2010 20432171 source

      Not checked in the free run.

    • cites [277] Kitamura Y Yamagihi M Okazaki K Furukawa F Imazawa T Nishikawa A Hirose M Lack of enhancing effects of sodium nitrite on 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine (PhIP) induced mammary carcinogenesis in female Sprague-Dawley rats Cancer Lett 235 69 74 2006 15951105 source

      Not checked in the free run.

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

    Premisecitation

    Nitrite could potentially bind and activate ER-α+ breast cancer cells thereby influencing their growth.

    “Studies have addressed this concern with Veselik et al indicating that nitrite could potentially bind and activate ER-α+ breast cancer cells thereby influencing their growth [273–275].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [273] Furukawa F Nishikawa A Miyauchi M Nakamura H Son HY Yamagishi M Hirose M Concurrent administration of fish meal and sodium nitrite does not promote renal carcinogenesis in rats after initiation with N-ethyl-N-hydroxyethylnitrosamine Cancer Lett 154 45 51 2000 10799738 source

      Not checked in the free run.

    • cites [274] Masuda S Terashima Y Sano A Kuruto R Sugiyama Y Shimoi K Tanji K Yoshioka H Terao Y Kinae N Changes in the mutagenic and estrogenic activities of bisphenol A upon treatment with nitrite Mutation research 585 137 146 2005 15936980 source

      Not checked in the free run.

    • cites [275] Miyauchi M Nakamura H Furukawa F Son HY Nishikawa A Hirose M Promoting effects of combined antioxidant and sodium nitrite treatment on forestomach carcinogenesis in rats after initiation with N-methyl-N-nitro-N-nitrosoguanidine Cancer Lett 178 19 24 2002 11849737 source

      Not checked in the free run.

83 of 83

  • The paper relies on this without support.

    Findings from animal models of ischemia-reperfusion and other diseases are relevant to human patients.

    “indicating that nitrite therapy might be clinically useful for PAH”
    “suggesting that aerosolized sodium nitrite therapy might be beneficial for controlling CF associated bacterial infections.”

  • The paper relies on this without support.

    High doses of sodium nitrite are toxic in humans.

    “This is an important distinction given the fact that high doses of sodium nitrite can be toxic thus making nitrite therapy for certain diseases largely unrealistic.”

  • The paper relies on this without support.

    Nitrite/nitrate levels measured in plasma or tissues reflect NO bioavailability and functional NO signaling.

    “plasma nitrite levels may be an important indicator of vascular health and function in PAD patients”

  • The paper relies on this without support.

    Nitrite anion is an important source of bioactive NO under low pH conditions.

    “Nitrite anion is known to represent an important source of bioactive NO under low pH conditions.”

  • The paper relies on this without support.

    NO drives local vasodilation and increases perfusion.

    “The characteristic of NO, by driving local vasodilation and increasing perfusion, suggests that it may have therapeutic potential in tumors to allow transient increase in the delivery and efficacy of anti-cancer drugs.”

  • The paper relies on this without support.

    Inflammatory activity influences nearly every aspect of human disease.

    “In particular, recent developments regarding nitrite modulation of immune responses are very intriguing and merit further investigation as it is now known that inflammatory activity influences nearly every aspect of human disease.”
6 of 6

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?

  • The plethora of studies documenting protective effects of nitrite in cell culture or animal models, together with human use of nitrite in cyanide antidote kits, has laid the foundation for clinical evaluation of nitrite therapy for a variety of ischemia-related disorders.

    “The plethora of studies documenting protective effects of nitrite in cell culture or animal models, together with human use of nitrite in cyanide antidote kits, has laid the foundation for clinical evaluation of nitrite therapy for a variety of ischemia related disorders (summarized in [8, 11, 117]).”

    From Current perspectives and challenges in understanding the role of nitrite as an integral player in nitric oxide biology and therapy (2011) · cites this paper as [117]

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.

  • Same article has conflicting page ranges

    Minor

    References 54 and 96 have the same title, authors, year, and PMID, but give different starting pages. Reference 96 also lists an ending page earlier than its starting page.

  • Soderberg study names different inhalant nitrites

    Minor

    The text describes the cited Soderberg study as an amyl nitrite exposure study, while its reference title identifies the exposure as isobutyl nitrite.

2 of 2

Cites

Flagged first, then by citations

Research works printed but not linked: 3

  1. Duncan, 1995, Chemical generation of nitric oxide in the mouth from the enterosalivary circulation of dietary nitrate, Nat. Med., 1, 564-551, 10.1038/nm0695-546 · DOI · Paper page
  2. Li, 2009, The protective effect of nitrite on liver cold ischemia reperfusion injury, Liver Transpl., 15, S236
  3. Pearse, 1891, The treatment of paroxysmal nerve disorders, Practitioner, 46, 29

Cited by

Sorted by citations

Related

Authors
Kevil, C. G., Kolluru, G. K., Pattillo, C. B., & Giordano, T.
Affiliations
  • Louisiana State University (US)
  • Louisiana State University Health Sciences Center Shreveport (US)
Corresponding author
Kevil, Christopher G.
ORCID
Venue
Free Radical Biology and Medicine
Publisher
Elsevier BV
Published
2011-08
Volume
51
Issue
3
Pages
576-593
ISSN
0891-5849 (ISSN-L)
DOI
10.1016/j.freeradbiomed.2011.04.042
PMC
PMC4414241
OpenAlex
W2075903936
Semantic Scholar
50af9f1071748c47ba52cfe0f274e85cae813cfb
Cited by
113
References
285
Citations by year
2026: 2 · 2025: 2 · 2024: 1 · 2023: 7 · 2022: 6 · 2021: 6 · 2020: 3 · 2019: 10 · 2018: 8 · 2017: 8 · 2016: 6 · 2015: 17 · 2014: 11 · 2013: 10 · 2012: 14
FWCI
1.29
Type
journal article
Language
en
Open access
Licence
Locations
  • Free Radical Biology and Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
NIH (HL80482, HL094021, DK043785)
Topics
  • Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
Keywords
nitrite, nitric oxide, sodium nitrite, sodium nitrate, nitric oxide prodrug, nitric oxide bioavailability
MeSH terms
Animals, Autoimmune Diseases, Bacteria, Humans, Inflammation, Inorganic Chemicals, Ischemia, Mouth, Neoplasms, Nitric Oxide, Oxidation-Reduction, Sodium Nitrite

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 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

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 ›

Are you an author, or do you see a problem with this page? Request a review