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Cited by 145Nitric Oxide and Endothelin EffectsEicosanoids and Hypertension PharmacologyRespiratory Support and Mechanisms

Nitrate-Nitrite-Nitric Oxide Pathway: Implications for Anesthesiology and Intensive Care

Open access
Weitzberg, Eddie, Hezel, Michael, Lundberg, Jon O., Warner, David S.·2010·Anesthesiology
DOI 10.1097/aln.0b013e3181fcf3cc
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Abstract

The gaseous radical nitric oxide is involved in numerous physiologic and pathophysiological events important in anesthesiology and intensive care. Nitric oxide is endogenously generated from the amino acid l-arginine and molecular oxygen in reactions catalyzed by complex nitric oxide synthases. Recently, an alternative pathway for nitric oxide generation was discovered, wherein the inorganic anions nitrate (NO3) and nitrite (NO2), most often considered inert end products from nitric oxide generation, can be reduced back to nitric oxide and other bioactive nitrogen oxide species. This nitrate-nitrite-nitric oxide pathway is regulated differently than the classic l-arginine-nitric oxide synthase nitric oxide pathway, and it is greatly enhanced during hypoxia and acidosis. Several lines of research now indicate that the nitrate-nitrite-nitric oxide pathway is involved in regulation of blood flow, cell metabolism, and signaling, as well as in tissue protection during hypoxia. The fact that nitrate is abundant in our diet gives rise to interesting nutritional aspects in health and disease. In this article, we present an overview of this field of research with emphasis on relevance in anesthesiology and intensive care.

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Crossref · 10.1097/aln.0b013e3181fcf3cc

Cites

179 of 179 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

42 of 143 cited sources checked · 10 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    Sedated and intubated intensive care patients with poor salivary production and reduced swallowing of saliva, often treated with broad-spectrum antibiotics, have virtually abolished gastric nitric oxide.

    “In this respect, it is highly interesting that sedated and intubated intensive care patients, with poor salivary production and reduced swallowing of saliva and who are often treated with broad-spectrum antibiotics, have virtually abolished gastric nitric oxide (fig.2).53,67”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [53] 53. Gago B, Lundberg JO, Barbosa RM, Laranjinha J: Red wine-dependent reduction of nitrite to nitric oxide in the stomach. Free Radic Biol Med 2007; 43:1233-42 source

      The Introduction describes salivary nitrate secretion and oral bacterial reduction, and the Results report gastric nitric oxide measurements in healthy fasting volunteers. Our copy does not address sedated or intubated intensive care patients, their antibiotic treatment, or whether their gastric nitric oxide is virtually abolished (searched: intensive care patients, intubation, antibiotics, reduced swallowing). (LLM, conf=0.77)

      Experimental — accuracy not yet measured
    • cites [67] 67. Modin A, Bjo ¨rne H, Herulf M, Alving K, Weitzberg E, Lundberg JO: Nitrite-derived nitric oxide: A possible me- diator of 'acidic-metabolic' vasodilation. Acta Physiol Scand 2001; 171:9 -16

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

  • Premisecitation

    Nitric oxide generation in the stomach is greatly enhanced after intake of nitrate.

    “Furthermore, nitric oxide generation was greatly enhanced after intake of nitrate.8”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [8] 8. Lundberg JO, Weitzberg E, Lundberg JM, Alving K: Intra- gastric nitric oxide production in humans: Measurements in expelled air. Gut 1994; 35:1543-6 source
  • Interpretationcitation

    The nitrate-nitrite-nitric oxide pathway may serve as a backup system to ensure nitric oxide generation during ischemic/hypoxic conditions when oxygen-dependent NOSs may be malfunctioning.

    “may serve as a backup system to ensure nitric oxide generation during ischemic/hypoxic conditions when the oxygen-dependent NOSs may be malfunctioning.14,15”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [14] 14. van Faassen EE, Bahrami S, Feelisch M, Hogg N, Kelm M, Kim-Shapiro DB, Kozlov AV, Li H, Lundberg JO, Mason R, Nohl H, Rassaf T, Samouilov A, Slama-Schwok A, Shiva S, Vanin AF, Weitzberg E, Zweier J, Gladwin MT: Nitrite as regulator of hypoxic signaling in mammalian physiology. Med Res Rev 2009; 29:683-741 source
    • cites [15] 15. Lundberg JO, Gladwin MT, Ahluwalia A, Benjamin N, Bryan NS, Butler A, Cabrales P, Fago A, Feelisch M, Ford PC, Freeman BA, Frenneaux M, Friedman J, Kelm M, Kevil CG, Kim-Shapiro DB, Kozlov AV, Lancaster JR Jr., Lefer DJ, McColl K, McCurry K, Patel RP, Petersson J, Rassaf T, Reutov VP, Richter-Addo GB, Schechter A, Shiva S, Tsuch- iya K, van Faassen EE, Webb AJ, Zuckerbraun BS, Zweier JL, Weitzberg E: Nitrate and nitrite in biology, nutrition and therapeutics. Nat Chem Biol 2009; 5:865-9 source
  • Premisecitation

    Xanthine oxidoreductase reduces inorganic nitrate and nitrite under low oxygen tension as occurs in ischemia.

    “In addition to its role in purine catabolism and in reduction of molecular oxygen to superoxide, xanthine oxidoreductase (XOR) has been identified to reduce inorganic nitrate and nitrite under low oxygen tension as it occurs in ischemia.84 -86”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [84] 84. Godber BL, Doel JJ, Sapkota GP, Blake DR, Stevens CR, Eisenthal R, Harrison R: Reduction of nitrite to nitric oxide catalyzed by xanthine oxidoreductase. J Biol Chem 2000; 275:7757-63 source
    • cites [85] 85. Millar TM, Stevens CR, Benjamin N, Eisenthal R, Harrison R, Blake DR: Xanthine oxidoreductase catalyses the re- duction of nitrates and nitrite to nitric oxide under hy- poxic conditions. FEBS Lett 1998; 427:225-8 source
    • cites [86] 86. Harrison R: Physiological roles of xanthine oxidoreduc- tase. Drug Metab Rev 2004; 36:363-75

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

  • Premisecitation

    One serving of a nitrate-rich vegetable contains more nitrate than is endogenously formed by all three NOS isoforms combined during a day.

    “One serving of such a vegetable contains more nitrate than what is endogenously formed by the all three NOS isoforms combined during a day.15”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [15] 15. Lundberg JO, Gladwin MT, Ahluwalia A, Benjamin N, Bryan NS, Butler A, Cabrales P, Fago A, Feelisch M, Ford PC, Freeman BA, Frenneaux M, Friedman J, Kelm M, Kevil CG, Kim-Shapiro DB, Kozlov AV, Lancaster JR Jr., Lefer DJ, McColl K, McCurry K, Patel RP, Petersson J, Rassaf T, Reutov VP, Richter-Addo GB, Schechter A, Shiva S, Tsuch- iya K, van Faassen EE, Webb AJ, Zuckerbraun BS, Zweier JL, Weitzberg E: Nitrate and nitrite in biology, nutrition and therapeutics. Nat Chem Biol 2009; 5:865-9 source
  • May combine two claims. 37
  • Classified as probably not a substantial claim. 7

  • May combine two claims.

    Premisecitation

    Hemoglobin, myoglobin, neuroglobin, xanthine oxidoreductase, aldehyde oxidase, carbonic anhydrase, eNOS, and mitochondrial enzymes have all been identified as having a role in nitrite bioactivation.

    “Hemoglobin, myoglobin, neuroglobin, xanthine oxidoreductase, aldehyde oxidase, carbonic anhydrase, eNOS, and mitochondrial enzymes have all been identified with having a role in nitrite bioactivation (fig.1).14,15”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [14] 14. van Faassen EE, Bahrami S, Feelisch M, Hogg N, Kelm M, Kim-Shapiro DB, Kozlov AV, Li H, Lundberg JO, Mason R, Nohl H, Rassaf T, Samouilov A, Slama-Schwok A, Shiva S, Vanin AF, Weitzberg E, Zweier J, Gladwin MT: Nitrite as regulator of hypoxic signaling in mammalian physiology. Med Res Rev 2009; 29:683-741 source

      Section 7 identifies hemoglobin, myoglobin, xanthine oxidase, aldehyde oxidase, eNOS, and mitochondrial respiratory-chain components as participants in nitrite reduction to NO (page numbers unavailable). The passages retrieved from our copy do not identify neuroglobin or carbonic anhydrase as nitrite-bioactivation pathways, so the full list is not supported. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [15] 15. Lundberg JO, Gladwin MT, Ahluwalia A, Benjamin N, Bryan NS, Butler A, Cabrales P, Fago A, Feelisch M, Ford PC, Freeman BA, Frenneaux M, Friedman J, Kelm M, Kevil CG, Kim-Shapiro DB, Kozlov AV, Lancaster JR Jr., Lefer DJ, McColl K, McCurry K, Patel RP, Petersson J, Rassaf T, Reutov VP, Richter-Addo GB, Schechter A, Shiva S, Tsuch- iya K, van Faassen EE, Webb AJ, Zuckerbraun BS, Zweier JL, Weitzberg E: Nitrate and nitrite in biology, nutrition and therapeutics. Nat Chem Biol 2009; 5:865-9 source

      The biochemistry and bioactivation of nitrite and Nitrite reduction in the vasculature sections describe nitrite-reducing roles for hemoglobin, myoglobin, neuroglobin, eNOS, and xanthine oxidoreductase. Nitric oxide, nitrite and mitochondria also reports that respiratory-chain components can reduce nitrite to NO. Our copy does not identify aldehyde oxidase or carbonic anhydrase as nitrite-bioactivating enzymes; its reference to anhydrase activity concerns hemoglobin, not carbonic anhydrase. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Nitric oxide gas is generated in the human stomach at high concentrations, dependent on gastric acidity and involving reduction of salivary-derived nitrite.

    “Nitric oxide gas was generated in the human stomach at high concentrations, and this production was dependent on gastric acidity and involved reduction of salivary-derived nitrite.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [8] 8. Lundberg JO, Weitzberg E, Lundberg JM, Alving K: Intra- gastric nitric oxide production in humans: Measurements in expelled air. Gut 1994; 35:1543-6 source

      The Abstract reports high NO concentrations in air expelled from the human stomach, and the Discussion reports that omeprazole nearly abolished them, supporting dependence on gastric acidity. The NITRIC OXIDE FORMATION IN VITRO section calls nitrite the probable substrate, but says it may come from swallowed saliva or gastric secretion. The claim presents reduction of salivary-derived nitrite as established rather than a proposed mechanism. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [9] 9. Benjamin N, O'Driscoll F, Dougall H, Duncan C, Smith L, Golden M, McKenzie H: Stomach NO synthesis. Nature 1994; 368:502 source

  • May combine two claims.

    Premisecitation

    In these studies, oxygen cost was also reduced during maximal performance, and time-to-exhaustion was significantly extended after beetroot juice.

    “In these studies, oxygen cost was also reduced during maximal performance, and time-to-exhaustion was significantly extended after beetroot juice.”
    Quote in the paperSubstantial claim1 of 4 sources checked
    • cites [120] 120. 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 -81 123. source
    • cites [129] 129. Gouspillou G, Bourdel-Marchasson I, Rouland R, Calmettes G, Franconi JM, Deschodt-Arsac V, Diolez P: Alteration of mito- chondrial oxidative phosphorylation in aged skeletal muscle involves modification of adenine nucleotide translocator. Bio- chim Biophys Acta 2010; 1797:143-51 133. Yellon DM, Hausenloy DJ: Myocardial reperfusion injury. N Engl J Med 2007; 357:1121-35 134. source

      The Methods (§2.3) measure oxygen consumption in isolated mitochondria, and the Results (§3.2) compare mitochondria from young and aged rats. Searches for beetroot juice, exercise oxygen cost, maximal performance, and time-to-exhaustion found no passage addressing the claimed effects. (LLM, conf=0.78)

      Experimental — accuracy not yet measured
    • cites [130] 130. Schulz R, Kelm M, Heusch G: Nitric oxide in myocardial ischemia/reperfusion injury. Cardiovasc Res 2004; 61: 402-13 135. Lefer DJ: Myocardial protective actions of nitric oxide donors after myocardial ischemia and reperfusion. New Horiz 1995; 3:105-12 136. source
    • cites [131] 131. Abdel Baky NA, Zaidi ZF, Fatani AJ, Sayed-Ahmed MM, Yaqub H: Nitric oxide pros and cons: The role of L-arginine, a nitric oxide precursor, and idebenone, a coenzyme-Q ana- logue in ameliorating cerebral hypoxia in rat. Brain Res Bull 2010; 83:49 -56 137. source

  • May combine two claims.

    Premisecitation

    In that study, there was no difference in lactate formation, indicating no compensatory increase in glycolytic energy contribution, and metabolic efficiency seemed to be improved.

    “There was no difference in lactate formation, indicating that there was no compensatory increase in glycolytic energy contribution, and thus metabolic efficiency seemed to be improved.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [124] 124. Erusalimsky JD, Moncada S: Nitric oxide and mitochon- drial signaling: From physiology to pathophysiology. Ar- terioscler Thromb Vasc Biol 2007; 27:2524 -31 127. Shiva S: Mitochondria as metabolizers and targets of ni- trite. Nitric Oxide 2010; 22:64 -74 128. source

      The 'Modulation of Glycolytic Output' section discusses increased glycolysis in certain cells, but does not report lactate formation in the study described by the claim. Searches for lactate and metabolic efficiency found no passage establishing unchanged lactate formation, no compensatory glycolytic increase, or improved metabolic efficiency. No page number is available in our copy. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Early research indicated a therapeutic role for nitric oxide in cardioprotection in myocardial infarction models, and L-arginine treatment before reperfusion was organ-protective.

    “Early research indicated a therapeutic role for nitric oxide in cardioprotection in myocardial infarction models, 135 and L-arginine treatment before reperfusion was also organ-protective.133,136,137”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [135] 135. 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; 115:1232-40 141. source

      The Discussion (page not provided) reports that nitric oxide donors and the nitric oxide precursor L-arginine protect against myocardial ischemia-reperfusion injury, supporting the cardioprotective point. It does not say L-arginine was given before reperfusion; the paper specifies that timing for nitrite, while a cited reference describes L-arginine given during reperfusion. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [133] 133. Zweier JL, Wang P, Samouilov A, Kuppusamy P: Enzyme- independent formation of nitric oxide in biological tis- sues. Nature Med 1995; 1:804 -9 139. source
    • cites [136] 136. Jung KH, Chu K, Ko SY, Lee ST, Sinn DI, Park DK, Kim JM, Song EC, Kim M, Roh JK: Early intravenous infusion of sodium nitrite protects brain against in vivo ischemia- reperfusion injury. Stroke 2006; 37:2744 -50 142. source

      The References section (page unavailable) lists a rat study reporting that L-arginine infusion reduced cerebral infarction volume. It does not establish that L-arginine was given before reperfusion. This paper’s Experimental Protocols instead describe administering sodium nitrite at reperfusion. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In more chronic rodent models of pulmonary hypertension, pulmonary hypertension was prevented by inhaled nitrite but also right ventricular hypertrophy and failure.

    “Again, pulmonary hypertension was prevented by inhaled nitrite but also right ventricular hypertrophy and failure.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [145] 145. 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 aug- ments ischemia-induced angiogenesis and arteriogenesis. Proc Natl Acad Sci U S A 2008; 105:7540 -5 151. source

      The Results describe sodium nitrite given by intraperitoneal injection in a mouse hind-limb ischemia model; the Discussion addresses restoration of limb perfusion. Searches for inhaled nitrite, pulmonary hypertension, and right-ventricular outcomes found no passage in our copy addressing the claimed prevention of pulmonary hypertension, hypertrophy, or failure. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Inhalation of nitric oxide does not only vasodilate pulmonary vessels but has also distant effects.

    “It is noteworthy that inhalation of nitric oxide does not only vasodilate pulmonary vessels but has also distant effects.159,160”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [159] 159. Mathru M, Huda R, Solanki DR, Hays S, Lang JD: Inhaled nitric oxide attenuates reperfusion inflammatory re- sponses in humans. ANESTHESIOLOGY 2007; 106:275-82 166. source
    • cites [160] 160. Dykhuizen RS, Frazer R, Duncan C, Smith CC, Golden M, Benjamin N, Leifert C: Antimicrobial effect of acidified nitrite on gut pathogens: Importance of dietary nitrate in host defense. Antimicrob Agents Chemother 1996; 40: 1422-25 167. source

  • May combine two claims.

    Premisecitation

    Humans breathing nitric oxide gas exhibit increases in peripheral forearm blood flow, which is associated with increases in plasma nitrite.

    “Humans breathing nitric oxide gas exhibit increases in peripheral forearm blood flow, which is associated with increases in plasma nitrite.161”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [161] 161. Yoon SS, Coakley R, Lau GW, Lymar SV, Gaston B, Kara- bulut AC, Hennigan RF, Hwang SH, Buettner G, Schurr MJ, Mortensen JE, Burns JL, Speert D, Boucher RC, Has- sett DJ: Anaerobic killing of mucoid Pseudomonas aerugi- nosa by acidified nitrite derivatives under cystic fibrosis airway conditions. J Clin Invest 2006; 116:436 -46 168. source

      The paper’s experimental discussion (Equation 2; page unavailable) concerns nitric oxide and killing of P. aeruginosa, not forearm blood flow in humans. Searches for forearm blood flow and for plasma nitrite after inhaled nitric oxide found no passage in our copy reporting the claimed association. (LLM, conf=0.75)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Circulating nitrite increased significantly during nitric oxide inhalation, and arteriovenous gradients were observed, indicating metabolism of this anion to nitric oxide or other bioactive nitrogen oxides.

    “It is noteworthy that circulating nitrite increased significantly during nitric oxide inhalation, and arteriovenous gradients were observed, indicating metabolism of this anion to nitric oxide or other bioactive nitrogen oxides.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [164] 164. Jepson RG, Craig JC: Cranberries for preventing urinary tract infections. Cochrane Database Syst Rev 2008; CD001321 171. source

      The Results section (page unavailable) reports urinary tract infection outcomes for cranberry products, not effects of nitric oxide inhalation. Searches for circulating nitrite, arteriovenous gradients, and nitrite metabolism found no passage addressing the claim. (LLM, conf=0.78)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In that study, inhaled nitric oxide did not affect inflammatory markers after reperfusion but significantly decreased hepatocyte apoptosis.

    “It did not affect inflammatory markers after reperfusion but significantly decreased hepatocyte apoptosis.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [164] 164. Jepson RG, Craig JC: Cranberries for preventing urinary tract infections. Cochrane Database Syst Rev 2008; CD001321 171. source

      The Results section reports cranberry products and urinary tract infections, not inhaled nitric oxide or reperfusion. Searches for inhaled nitric oxide, inflammatory markers, and hepatocyte apoptosis found no passage addressing the claimed effects; the available passages have no page numbers. (LLM, conf=0.78)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In a randomized, prospective, placebo-controlled study, Lang et al. inhaled nitric oxide (80 ppm) perioperatively and found improvement in posttransplantation liver function parameters and decreased hospital length of stay.

    “In a randomized, prospective, placebo-controlled study, Lang et al. inhaled nitric oxide (80 ppm) perioperatively and found improvement in posttransplantation liver function parameters and decreased hospital length of stay.164”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [164] 164. Jepson RG, Craig JC: Cranberries for preventing urinary tract infections. Cochrane Database Syst Rev 2008; CD001321 171. source

      The review’s study descriptions (Additional information; page unavailable) concern cranberry interventions and urinary tract infection outcomes. Searches for Lang, perioperative inhaled nitric oxide at 80 ppm, liver transplantation, and hospital length of stay found no passage addressing the attributed study or its findings. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    In that rat model, dietary nitrate increased tissue concentrations of bioactive nitrogen oxides and reduced concentrations of oxidative stress markers in plasma and urine.

    “Dietary nitrate increased tissue concentrations of bioactive nitrogen oxides and reduced the concentrations of oxidative stress markers in plasma and urine.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Up to 25% of circulating nitrate is actively taken up by the salivary glands and concentrated 10- to 20-fold in saliva.

    “Through early cancer research, it was known that up to 25% of circulating nitrate is actively taken up by the salivary glands and concentrated 10-to 20-fold in saliva, but the reason and mechanism for this were unknown, other than its proposed pathologic role in formation of carcinogenic nitrosamines.10”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] 10. Spiegelhalder B, Eisenbrand G, Preussmann R: Influence of dietary nitrate on nitrite content of human saliva: Possible relevance to in vivo formation of N-nitroso com- pounds. Food Cosmet Toxicol 1976; 14:545-8 source

  • May combine two claims.

    Premisecitation

    Widespread use of H2 blockers or proton-pump inhibitors to prevent gastric lesions in the ICU will increase gastric pH, subsequently decreasing stomach nitrite reduction.

    “With respect to gastric nitric oxide, the widespread use of H 2 blockers or proton-pump inhibitors to prevent gastric lesions in the ICU will increase gastric pH, subsequently decreasing stomach nitrite reduction.67”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [67] 67. Modin A, Bjo ¨rne H, Herulf M, Alving K, Weitzberg E, Lundberg JO: Nitrite-derived nitric oxide: A possible me- diator of 'acidic-metabolic' vasodilation. Acta Physiol Scand 2001; 171:9 -16 source

  • May combine two claims.

    Premisecitation

    Nitrate is the predominant nitric oxide oxidation product in the circulation, with plasma nitrate concentrations normally at least two orders of magnitude higher than nitrite concentrations.

    “However, nitrate is the dominating final oxidation product in plasma with concentrations (micromolar) normally at least 2 orders of magnitude higher than nitrite (nanomolar).35”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] 35. Moncada S, Palmer RM, Higgs EA: Nitric oxide: Physiol- ogy, pathophysiology, and pharmacology. Pharmacol Rev 1991; 43:109 -42 source

  • May combine two claims.

    Premisecitation

    Human nitrate reduction is highly dependent on oral commensal bacteria because human cells do not convert nitrate to nitrite to a high degree.

    “Human nitrate reduction is highly dependent on the oral commensal bacteria because our cells do not convert nitrate to nitrite to a high degree.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [45] 45. 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 [55] 55. Petersson J, Carlstro ¨m M, Schreiber O, Phillipson M, Christoffersson G, Ja ¨gare 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
    • cites [50] 50. Li H, Duncan C, Townend J, Killham K, Smith LM, Johnston P, Dykhuizen R, Kelly D, Golden M, Benjamin N, Leifert C: Nitrate-reducing bacteria on rat tongues. Appl Environ Microbiol 1997; 63:924 -30 source
    • cites [56] 56. Sobko T, Reinders C, Norin E, Midtvedt T, Gustafsson LE, Lundberg JO: Gastrointestinal nitric oxide generation in germ-free and conventional rats. Am J Physiol Gastroin- test Liver Physiol 2004; 287:G993-7 source
    • cites [57] 57. Fang FC: Antimicrobial reactive oxygen and nitrogen species: Concepts and controversies. Nat Rev Microbiol 2004; 2:820 -32

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

  • May combine two claims.

    Premisecitation

    An enterosalivary circulation of ingested nitrate exists in which circulating nitrate is actively secreted in saliva and oral commensal bacteria reduce nitrate to nitrite.

    “An enterosalivary circulation of ingested nitrate exists in which, after absorption in the gastrointestinal tract, circulating nitrate is actively secreted in saliva and oral commensal bacteria reduced nitrate to nitrite. 10”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] 10. Spiegelhalder B, Eisenbrand G, Preussmann R: Influence of dietary nitrate on nitrite content of human saliva: Possible relevance to in vivo formation of N-nitroso com- pounds. Food Cosmet Toxicol 1976; 14:545-8 source

  • May combine two claims.

    Premisecitation

    Nitrite through reduction by myoglobin has a cardioprotective effect, which is lost in myoglobin-null mice.

    “Research has shown that nitrite through reduction by myoglobin has a cardioprotective effect, which is lost in myoglobin-null mice.81”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [81] 81. Flo ¨gel U, Merx MW, Godecke A, Decking UK, Schrader J: Myoglobin: A scavenger of bioactive NO. Proc Natl Acad Sci U S A 2001; 98:735-40

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

  • May combine two claims.

    Premisecitation

    The nitrate-nitrite-nitric oxide pathway is involved in regulation of blood flow, cell metabolism, and signaling, as well as in tissue protection during hypoxia.

    “Several lines of research now indicate that the nitrate-nitrite-nitric oxide pathway is involved in regulation of blood flow, cell metabolism, and signaling, as well as in tissue protection during hypoxia.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13] 13. Lundberg JO, Weitzberg E, Gladwin MT: The nitrate- nitrite-nitric oxide pathway in physiology and therapeu- tics. Nat Rev Drug Discov 2008; 7:156 -67 source

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

    Premisecitation

    There is weak scientific evidence for any relationship between high nitrate intake and gastric cancer in humans.

    “There is, however, weak scientific evidence for any relationship between high nitrate intake and gastric cancer in humans.49”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] 49. 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. Ni- tric Oxide 2008; 19:333-7 source

  • May combine two claims.

    Premisecitation

    The vasodilatory potency of nitrite increases during hypoxia and acidosis, probably because of enhanced reduction to bioactive nitric oxide.

    “However, the vasodilatory potency of nitrite increases during hypoxia and acidosis probably because of enhanced reduction to bioactive nitric oxide.111,112,114”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [111] 111. 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; 116:1821-31 114. source
    • cites [112] 112. 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 nebu- lized nitrite is a hypoxia-sensitive NO-dependent selec- tive pulmonary vasodilator. Nat Med 2004; 10:1122-7 115. Willett WC: Diet and health: What should we eat? Science 1994; 264:532-7 116. source
    • cites [114] 114. Joshipura KJ, Hu FB, Manson JE, Stampfer MJ, Rimm EB, Nitrate-Nitrite-Nitric Oxide Pathway Weitzberg et al. Anesthesiology, V 113 • No 6 • December 2010 1473 Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/113/6/1460/253072/0000542-201012000-00038.pdf by guest on 11 July 2023

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

  • May combine two claims.

    Premisecitation

    In healthy volunteers, drinking beetroot juice reduced systolic blood pressure by 10 mmHg and diastolic blood pressure by 8 mmHg within 3 h, and the effect was still present 24 h after a single administration.

    “A reduction in both systolic (10 mmHg) and diastolic blood pressure (8 mmHg) was noted within 3 h of ingestion, and the effect was still present 24 h after a single administration.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [55] 55. Petersson J, Carlstro ¨m M, Schreiber O, Phillipson M, Christoffersson G, Ja ¨gare 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

    Factors suggested to contribute to I/R injury include endothelial and microvascular dysfunction, proinflammatory activation, and oxidative stress.

    “Among the factors that are suggested to contribute to I/R injury are endothelial and microvascular dysfunction, proinflammatory activation, and oxidative stress.133”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [133] 133. Zweier JL, Wang P, Samouilov A, Kuppusamy P: Enzyme- independent formation of nitric oxide in biological tis- sues. Nature Med 1995; 1:804 -9 139. source

  • May combine two claims.

    Premisecitation

    This mechanism also prevents mitochondrial permeability transition pore opening and cytochrome c release, which are mechanisms involved in apoptosis.

    “This mechanism also prevents mitochondrial permeability transition pore opening and cytochrome c release, which are mechanisms involved in apoptosis.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [125] 125. Unitt DC, Hollis VS, Palacios-Callender M, Frakich N, Moncada S: Inactivation of nitric oxide by cytochrome c oxidase under steady-state oxygen conditions. Biochim Biophys Acta 2010; 1797:371-7 129. source

  • May combine two claims.

    Premiseown data

    In a Phase I/II study, nitrite dose-dependently increased forearm blood flow in patients with sickle cell disease, although the response was blunted compared with healthy controls.

    “Nitrite dose-dependently increased forearm blood flow, although the response was blunted compared with healthy controls.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Nitrite-mediated protection occurs through reversible inhibition of mitochondrial complex I, which dampens electron transfer to the respiratory chain, thereby decreasing production of oxygen radicals.

    “They show that nitrite-mediated protection occurs through reversible inhibition of mitochondrial complex I, which dampens electron transfer to the respiratory chain, thereby decreasing the production of oxygen radicals.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [125] 125. Unitt DC, Hollis VS, Palacios-Callender M, Frakich N, Moncada S: Inactivation of nitric oxide by cytochrome c oxidase under steady-state oxygen conditions. Biochim Biophys Acta 2010; 1797:371-7 129. source

  • May combine two claims.

    Premisecitation

    Nitric oxide is a mediator of the ischemic preconditioning cell survival program, and nitrate administered as long as 24 h before injury was also protective.

    “It has been shown that nitric oxide is a mediator of the ischemic preconditioning cell survival program, 154 and it is worth noting that Shiva et al. found that nitrate administered as long as 24 h before injury was also protective.125”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [154] 154. Hambraeus-Jonzon K, Chen L, Frede ´n F, Wiklund P, He- denstierna G: Pulmonary vasoconstriction during re- gional nitric oxide inhalation: Evidence of a blood-borne regulator of nitric oxide synthase activity. ANESTHESIOLOGY 2001; 95:102-12 161. source
    • cites [125] 125. Unitt DC, Hollis VS, Palacios-Callender M, Frakich N, Moncada S: Inactivation of nitric oxide by cytochrome c oxidase under steady-state oxygen conditions. Biochim Biophys Acta 2010; 1797:371-7 129. source

  • May combine two claims.

    Premiseown data

    Nitrite infusions were well tolerated and did not induce hypotension or clinically significant methemoglobinemia in patients with sickle cell disease.

    “Nitrite infusions were well tolerated and did not induce hypotension or clinically significant methemoglobinemia.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Together, findings suggest a potential role for nitrite as a useful adjunctive therapy in preventing I/R injuries in several organs and tissues, and human trials are presently under way.

    “Together, these findings convincingly suggest a potential role for nitrite as a useful adjunctive therapy in preventing I/R injuries in several organs and tissues, and human trials are presently under way.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The effects of low-dose nitrite in those models were independent of NOS and abolished by coadministration of the nitric oxide scavenger cPTIO, suggesting nitrite-derived nitric oxide as an active mediator.

    “The effects were independent of NOS and abolished by coadministration of the nitric oxide scavenger cPTIO, suggesting nitrite-derived nitric oxide as an active mediator.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [140] 140. 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 arterial hypertension and smooth muscle pro- liferation via xanthine oxidoreductase-dependent nitric oxide generation. Circulation 2010; 121:98 -109 146. source

  • May combine two claims.

    Premisecitation

    During hypoxia-induced pulmonary hypertension, inhaled nitrite elicited a rapid and sustained reduction in pulmonary artery pressure with concomitant appearance of nitric oxide in exhaled air.

    “During hypoxia-induced pulmonary hypertension, inhaled nitrite elicited a rapid and sustained reduction in pulmonary artery pressure with concomitant appearance of nitric oxide in exhaled air.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [114] 114. Joshipura KJ, Hu FB, Manson JE, Stampfer MJ, Rimm EB, Nitrate-Nitrite-Nitric Oxide Pathway Weitzberg et al. Anesthesiology, V 113 • No 6 • December 2010 1473 Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/113/6/1460/253072/0000542-201012000-00038.pdf by guest on 11 July 2023

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

  • May combine two claims.

    Premisecitation

    Yoon et al. used acidified nitrite in an animal model of cystic fibrosis and were successful in clearing the airways of Pseudomonas aeruginosa.

    “Yoon et al. used acidified nitrite in an animal model of cystic fibrosis and were successful in clearing the airways of Pseudomonas aeruginosa, a common pathogen in patients with this disease.167”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [167] 167. Sobko T, Marcus C, Govoni M, Kamiya S: Dietary nitrate in Japanese traditional foods lowers diastolic blood pres- sure in healthy volunteers. Nitric Oxide 2010; 22:136 -40 source

  • May combine two claims.

    Premisecitation

    These differences were accompanied by amelioration of histopathologic changes in the allografts as well as decreased tissue messenger RNA concentrations of interferon-γ and tumor necrosis factor-α.

    “These differences were accompanied by amelioration of histopathologic changes in the allografts as well as in decreased tissue messenger RNA concentrations of interferon-␥ and tumor necrosis factor-␣.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [163] 163. Carlsson S, Wiklund NP, Engstrand L, Weitzberg E, Lun- dberg JO: Effects of pH, nitrite, and ascorbic acid on nonenzymatic nitric oxide generation and bacterial growth in urine. Nitric Oxide 2001; 5:580 -6 170. source

  • Classified as probably not a substantial claim.

    Premisecitation

    In cardiac transplantation, allograft vasculopathy remains a dreaded complication leading to rejection.

    “In cardiac transplantation, allograft vasculopathy remains a dreaded complication leading to rejection.162”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [162] 162. Lundberg JO, Carlsson S, Engstrand L, Morcos E, Wiklund NP, Weitzberg E: Urinary nitrite: More than a marker of infection. Urology 1997; 50:189 -91 169. source

  • May combine two claims.

    Premisecitation

    Epidemiologic studies convincingly show that diets rich in fruits and vegetables, such as the Mediterranean diet, protect against development of cardiovascular disease and type 2 diabetes.

    “Epidemiologic studies convincingly show that diets rich in fruits and vegetables, such as the Mediterranean diet, protect against development of cardiovascular disease and type 2 diabetes.115”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [115] 115. Speizer FE, Colditz G, Ascherio A, Rosner B, Spiegelman D, Willett WC: The effect of fruit and vegetable intake on risk for coronary heart disease. Ann Intern Med 2001; 134:1106 -14 118.

      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).

    Premisecitation

    Acidification of urine with different compounds, including vitamin C and cranberry juice, has been used in traditional medicine for prevention and treatment of urinary tract infections.

    “It is noteworthy that acidification of urine with different compounds, including vitamin C and cranberry juice, has been used in traditional medicine for prevention and treatment of urinary tract infections.170”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [170]

      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).

    Premisecitation

    Catheter-associated urinary tract infection is still one of the most common nosocomial infections despite optimal care and preventive measures.

    “In spite of optimal care and preventive measures, catheter-associated urinary tract infection is still one of the most common nosocomial infections.172”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [172]

      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).

    Premisecitation

    The use of indwelling urinary catheters is a major risk factor for catheter-associated urinary tract infection.

    “The use of indwelling urinary catheters is a major risk factor for catheter-associated urinary tract infection.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [172]

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

  • May combine two claims.

    Interpretationreasoning

    Although therapeutic effects of exogenously delivered nitrate in animal models are unequivocal, the physiologic relevance of endogenously generated nitrate and nitrite is still unresolved.

    “Although the therapeutic effects of exogenously delivered nitrate in animal models are unequivocal, the physiologic relevance of endogenously generated nitrate and nitrite is still unresolved.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    In comparison with traditional organic nitrates used in cardiovascular medicine, nitrate and nitrite do not seem to induce tolerance, and their conversion to nitric oxide and other bioactive nitrogen oxides is enhanced by low PO2 and pH.

    “In comparison with the traditional organic nitrates used in cardiovascular medicine, nitrate and nitrite do not seem to induce tolerance, and their conversion to nitric oxide and other bioactive nitrogen oxides is enhanced by low PO 2 and pH (i.e., in areas of poor perfusion).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Administration of nitrate or nitrite positively affects gastric mucosal integrity, blood pressure, endothelial function, oxygen consumption during exercise, and basal mitochondrial function.

    “Furthermore, administration of nitrate or nitrite positively affects gastric mucosal integrity, blood pressure, endiothelial function, oxygen consumption during exercise, and basal mitochondrial function.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    The several enzymatic and nonenzymatic routes that further reduce nitrite to nitric oxide are all enhanced during hypoxia and low pH situations when nitric oxide generation by the NOSs may be compromised.

    “It is noteworthy that the several enzymatic and nonenzymatic routes that further reduce nitrite to nitric oxide are all enhanced during hypoxia and low pH situations when nitric oxide generation by the NOSs may be compromised.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Interpretationreasoning

    Because accumulating evidence suggests that moderate doses of nitrate and nitrite have beneficial effects in the cardiovascular system, it is of great interest to study whether these anions can provide any improvement in anesthesiology and intensive care.

    “Because accumulating evidence suggests that moderate doses of nitrate and nitrite have beneficial effects in the cardiovascular system, it is of great interest to study whether these anions can provide any improvement in anesthesiology and intensive care.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Many patients subjected to anesthesia and intensive care have preexisting cardiovascular diseases with compromised endogenous nitric oxide production.
    • Rests on an assumption: Preoperative fasting prevents the possibility to fuel the nitrate-nitrite-nitric oxide pathway.
43 of 43

  • The authors state this as an assumption.

    Nitrate would have stronger effects in subjects with hypertension or other forms of cardiovascular disease because nitric oxide deficiency underlies these conditions.

    “It is reasonable to assume that nitrate would have even stronger effects in subjects with hypertension or other forms of cardiovascular disease because nitric oxide deficiency underlie these conditions.”

  • The paper relies on this without support.

    To date, no clinical trials have been performed in hypertensive patients.

    “To date, no clinical trials have been performed in hypertensive patients, but in a recent study, we tested this hypothesis by investigating the effects of dietary nitrate in a rat model of renal cardiovascular disease”

  • The paper relies on this without support.

    Many patients subjected to anesthesia and intensive care have preexisting cardiovascular diseases with compromised endogenous nitric oxide production.

    “Many of the patients subjected to anesthesia and intensive care have preexisting cardiovascular diseases with compromised endogenous nitric oxide production.”

  • The paper relies on this without support.

    Preoperative fasting prevents the possibility to fuel the nitrate-nitrite-nitric oxide pathway.

    “In addition, preoperative fasting does not only reduce glycogen depots but also prevents the possibility to fuel the nitrate-nitrite-nitric oxide pathway.”
4 of 4

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?

  • When nitrite-rich saliva is swallowed, it reacts with acidic gastric juices to form nitrous acid, which is exceptionally active as an antibacterial.

    “When nitrite-rich saliva is swallowed, it reacts with the acidic gastric juices to form nitrous acid (HNO 2 ), which is exceptionally active as an antibacterial.”

    From Dietary nitrate, nitric oxide, and restenosis (2011) · cites this paper as [15]

  • Dietary supplementation of nitrites can cause methemoglobinemia and interfere with oxygenation of the blood.

    “Dietary supplementation of nitrites can cause methemoglobinemia and interfere with oxygenation of the blood.”

    From Dietary nitrate, nitric oxide, and restenosis (2011) · cites this paper as [15]

  • Nitrous acid decomposes into nitrite, NO, and water.

    “Subsequently, HNO 2 decomposes into NO 2 -, NO, and water.”

    From Dietary nitrate, nitric oxide, and restenosis (2011) · cites this paper as [15]

  • The salivary glands extract nitrate from plasma, concentrating it 10- to 20-fold.

    “The salivary glands extract NO 3 -from the plasma, concentrating it 10-to 20-fold (15).”

    From Dietary nitrate, nitric oxide, and restenosis (2011) · cites this paper as [15]

  • Anaerobic bacteria in the mouth that express nitrate reductases convert nitrate to nitrite.

    “Anaerobic bacteria in the mouth that express nitrate reductases subsequently convert the nitrate to nitrite.”

    From Dietary nitrate, nitric oxide, and restenosis (2011) · cites this paper as [15]

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.

  • The proposed combination names nitrate twice instead of nitrate and nitrite

    Minor

    The proposed preemptive treatment names nitrate twice, but the next sentences describe a combination of nitrate and nitrite with distinct roles for each.

1 of 1

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Authors
Weitzberg, E., Hezel, M., Lundberg, J. O., & Warner, D. S.
Affiliations
  • Professor.
  • Postdoctoral Researcher, Section of Anesthesiology and Intensive Care.
  • Karolinska Institutet (SE)
Venue
Anesthesiology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2010-12-01
Volume
113
Issue
6
Pages
1460-1475
ISSN
0003-3022 (ISSN-L)
DOI
10.1097/aln.0b013e3181fcf3cc
OpenAlex
W2410225858
Cited by
145
References
170
Citations by year
2026: 6 · 2025: 2 · 2024: 9 · 2023: 6 · 2022: 10 · 2021: 17 · 2020: 8 · 2019: 7 · 2018: 14 · 2017: 10 · 2016: 10 · 2015: 8 · 2014: 6 · 2013: 8 · 2012: 17
FWCI
5.09
Type
journal article
Language
en
Open access
Locations
  • Anesthesiology (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Eicosanoids and Hypertension Pharmacology
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Respiratory Support and Mechanisms
Keywords
nitrate-nitrite-nitric oxide pathway, nitric oxide, nitric oxide synthase, L-arginine, nitrate, nitrite, hypoxia, acidosis
MeSH terms
Administration, Inhalation, Anesthesia, Anesthesiology, Arginine, Cardiovascular Physiological Phenomena, Critical Care, Diet, Gastric Mucosa, Humans

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.

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