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Cited by 59Nitric Oxide and Endothelin EffectsRedox biology and oxidative stressHemoglobin structure and function

Current perspectives and challenges in understanding the role of nitrite as an integral player in nitric oxide biology and therapy

Open access
Vitturi, Dario A., Patel, Rakesh P.·2011·Free Radical Biology and Medicine
DOI 10.1016/j.freeradbiomed.2011.05.037PMC PMC3148353
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Abstract

Beyond an inert oxidation product of nitric oxide (NO) metabolism, current thinking posits a key role for nitrite as a mediator of NO-signaling, especially during hypoxia. This concept has been discussed both in the context of nitrite serving a role as an endogenous modulator of NO-homeostasis, but also from a novel clinical perspective whereby nitrite therapy may replete NO-signaling and prevent ischemic tissue injury. Indeed, the relatively rapid translation of studies delineating mechanisms of action to ongoing and planned clinical trials has been critical in fuelling interest in nitrite biology and several excellent reviews have been written on this topic. In this article we limit our discussions to current concepts, and what we feel are questions that remain unanswered within the paradigm of nitrite being a mediator of NO biology.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that nitrite is not merely an inert NO oxidation product but can act as an endogenous and therapeutic source of NO signaling, especially under hypoxia and acidosis. It focuses on unresolved mechanistic questions, including how nitrite-derived NO escapes heme scavenging, how multiple nitrite reductases are regulated, and how to define safe nitrite therapy.

Key findings

  • Nitrite reduction to NO occurs under low oxygen and acidic conditions and is mediated by heme proteins such as deoxyhemoglobin and deoxymyoglobin, as well as non-heme proteins including xanthine oxidoreductase, aldehyde oxidase, neuroglobin, eNOS, cytochrome c, carbonic anhydrase, cytochrome c oxidase, complex III, and cytochrome P450. Myoglobin knockout mice lose nitrite-mediated cardioprotection after ischemia-reperfusion, coinciding with loss of NO formation by EPR.
  • A central paradox is that ferrous heme reacts rapidly with NO (rate constants ~10^7 M^-1 s^-1), and hemoglobin/myoglobin concentrations are high (RBC hemoglobin ~20 mM; cardiac/skeletal muscle myoglobin ~300–900 μM), so any nitrite-derived NO should be scavenged. Proposed escape mechanisms include T-state deoxyhemoglobin, membrane-associated metabolons, N2O3 formation, S-nitrosothiol formation, and oxidative denitrosylation.
  • The N2O3/RSNO model faces kinetic constraints: the methemoglobin-nitrite adduct dissociation constant has been reported around 1 mM at pH 6.4, 25°C, reassessed at 50–150 μM at pH 6.5, 37°C or 0.5–2 mM at pH 7.4, 37°C; with physiological nitrite ~300 nM and methemoglobin ~100 μM, the complex may be only 15–50 nM. N2O3 reacts rapidly with thiols (k = 6.6×10^7 M^-1 s^-1), and RBC glutathione is ~2–5 mM.
  • Nitrite effects are largely NO-dependent and can be sGC-dependent or sGC-independent; examples include cGMP increases, vasodilation, protection against ischemia-reperfusion injury or LPS-induced endotoxemia, inhibition of smooth muscle proliferation via p21Waf1/Cip1, hsp70 induction, estrogen receptor alpha activation, and increased mitochondrial efficiency. Nitrite therapy shows a U-shaped dose response in murine hepatic and myocardial ischemia-reperfusion, with protective doses around ~50 nmoles and a protective window spanning more than two or three orders of magnitude.

Methods

  • Narrative review/conceptual synthesis of prior basic, translational, and clinical literature on nitrite biology and therapy; no primary experimental cohort or trial is reported.
  • The paper discusses biochemical mechanisms, in vitro and in vivo studies, knockout models, and clinical trial rationale, but does not perform a systematic review or meta-analysis.
  • Main analysis is interpretive: it organizes current concepts and highlights unanswered questions around nitrite reduction, NO escape from heme scavenging, transport, signaling pathways, nitration, and therapeutic dosing.

Limitations

  • The paper explicitly states many unanswered questions: how NO-signaling escapes ferrous heme scavenging; whether hemoglobin/RBC nitrite reductase is physiologically relevant; how multiple redundant nitrite reductases are regulated; how nitrite transport is controlled; and how factors such as organ, hypoxia severity, disease, sex, race, age, diet, and dosing route affect the therapeutic window.
  • It notes that a specific nitrite scavenger functioning at physiologic pH does not exist, and that isolating hemoglobin’s nitrite reductase activity without affecting oxygen binding or NOS activity has proven difficult.
  • Evident from the text: this is a narrative review without systematic search criteria or new data, and some statements rely on unpublished observations; therefore it cannot quantify effect sizes or resolve the mechanistic controversies it describes.

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

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Registry

Crossref · 10.1016/j.freeradbiomed.2011.05.037

Cites

Statistics

Nothing to recompute.

Claims the paper makes

0 of 155 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Nitrite reduction to NO can occur under anoxic and/or acidic conditions.

    “initial studies documented the potential for nitrite reduction to NO under anoxic and / or acidic conditions [1-4].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [1] Zweier JL Wang P Samouilov A Kuppusamy P Enzyme-independent formation of nitric oxide in biological tissues. Nat Med 1995 1 804 809 7585184 source

      Not checked in the free run.

    • cites [2] Modin A Bjorne H Herulf M Alving K Weitzberg E Lundberg JO Nitrite-derived nitric oxide: a possible mediator of ‘acidic-metabolic’ vasodilation. Acta Physiol Scand 2001 171 9 16 11350258

      Not checked in the free run.

    • cites [3] Benjamin N O'Driscoll F Dougall H Duncan C Smith L Golden M McKenzie H Stomach NO synthesis. Nature 1994 368 502 502 8139683 source

      Not checked in the free run.

    • cites [4] Lundberg JO Weitzberg E Lundberg JM Alving K Intragastric nitric oxide production in humans: measurements in expelled air. Gut 1994 35 1543 1546 7828969 PMC1375608 source

      Not checked in the free run.

  • Premisecitation

    Generation of NO from nitrite reduction can occur under conditions that span a range of oxygen tensions and pH observed over the pathophysiological spectrum.

    “The more recent interest in nitrite biology stems largely from the realization that the generation of NO from nitrite reduction can occur under conditions that span a range of oxygen tensions and pH observed over the pathophysiological spectrum [5-7].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [5] 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 PMC2725214 19219851 source

      Not checked in the free run.

    • cites [6] 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 Tsuchiya K van Faassen EE Webb AJ Zuckerbraun BS Zweier JL Weitzberg E Nitrate and nitrite in biology, nutrition and therapeutics. Nat Chem Biol 2009 5 865 869 19915529 PMC4038383 source

      Not checked in the free run.

    • cites [7] Lundberg JO Weitzberg E Gladwin MT The nitrate-nitrite-nitric oxide pathway in physiology and therapeutics. Nat Rev Drug Discov 2008 7 156 167 18167491 source

      Not checked in the free run.

  • Premisecitation

    Xanthine oxidoreductase can mediate the one-electron reduction of nitrite to NO under anoxic conditions.

    “Despite early studies by Zhang et al [21, 22] and Millar et al [23] demonstrating that xanthine oxidoreductse can mediate the one-electron reduction of nitrite to NO under anoxic conditions”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [21] Zhang Z Naughton D Winyard PG Benjamin N Blake DR Symons MC Generation of nitric oxide by a nitrite reductase activity of xanthine oxidase: a potential pathway for nitric oxide formation in the absence of nitric oxide synthase activity. Biochem Biophys Res Commun 1998 249 767 772 9731211 source

      Not checked in the free run.

    • cites [22] Zhang Z Naughton DP Blake DR Benjamin N Stevens CR Winyard PG Symons MC Harrison R Human xanthine oxidase converts nitrite ions into nitric oxide (NO). Biochem Soc Trans 1997 25 524S 9388740 source

      Not checked in the free run.

    • cites [23] Millar TM Stevens CR Benjamin N Eisenthal R Harrison R Blake DR Xanthine oxidoreductase catalyses the reduction of nitrates and nitrite to nitric oxide under hypoxic conditions. FEBS Letters 1998 427 225 228 9607316 source

      Not checked in the free run.

  • Interpretationcitation

    Differential reactivity of nitrite reduction versus oxidation controlled by oxygen tension underlies the model in which nitrite selectively produces NO during graded hypoxia.

    “This differential reactivity of nitrite reduction versus oxidation being controlled by oxygen tension (i.e. presence of deoxygenated vs oxygenated hemoglobin / myoglobin) illustrates the biochemical mechanism underlying the proposed model in which nitrite can selectively produce NO during graded hypoxia [5, 25-28].”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [5] 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 PMC2725214 19219851 source

      Not checked in the free run.

    • cites [25] Cosby K Partovi KS Crawford JH Patel RP Reiter CD Martyr S Yang BK Waclawiw MA Zalos G Xu X Huang KT Shields H Kim-Shapiro DB Schechter AN Cannon RO 3rd Gladwin MT Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation. Nat Med 2003 9 1498 1505 14595407 source

      Not checked in the free run.

    • cites [26] 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 2006 107 566 574 16195332 PMC1895612 source

      Not checked in the free run.

    • cites [27] Huang Z Shiva S Kim-Shapiro DB Patel RP Ringwood LA Irby CE Huang KT Ho C Hogg N Schechter AN Gladwin MT Enzymatic function of hemoglobin as a nitrite reductase that produces NO under allosteric control. J Clin Invest 2005 115 2099 2107 16041407 PMC1177999 source

      Not checked in the free run.

    • cites [28] Shiva S Huang Z Grubina R Sun J Ringwood LA MacArthur PH Xu X Murphy E Darley-Usmar VM Gladwin MT Deoxymyoglobin is a nitrite reductase that generates nitric oxide and regulates mitochondrial respiration. Circ Res 2007 100 654 661 17293481 source

      Not checked in the free run.

  • Premisenone given

    Heme proteins mediate nitrite reduction at physiologic oxygen tensions and pH, exemplified by reactions of nitrite with the ferrous heme of deoxyhemoglobin or deoxymyoglobin.

    “Most insights into this paradigm have implicated a key role for heme proteins in mediating nitrite reduction as exemplified by the reactions of nitrite (NO2-) with the ferrous heme (FeII) of either deoxyhemoglobin or deoxymyoglobin.”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 5
  • May combine two claims. 21

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

    Findingown data

    The route of nitrite dosing in rats (continuous vs. bolus administration) can differentially affect hemodynamics in the presence or absence of anesthesia.

    “Moreover, we have noticed that the route of nitrite dosing in rats (continuous vs. bolus administration) can differentially affect hemodynamics in the presence or absence of anesthesia (unpublished observations).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    In the paradigm, nitrite is a source for NO, with more NO being produced the more ischemic and acidic the tissue becomes.

    “In this paradigm, nitrite is a source for NO, with more NO being produced the more ischemic and acidic the tissue becomes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Both ferrous deoxy and oxyheme react relatively rapidly with NO to produce nitrosyl heme or nitrate respectively.

    “both ferrous deoxy and oxyheme react relatively rapidly (rate constants ~107 M-1s-1) with NO to produce nitrosyl heme (Scheme 1) or nitrate respectively [29, 30].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [29] Cassoly R Gibson Q Conformation, co-operativity and ligand binding in human hemoglobin. J Mol Biol 1975 91 301 313 171411 source

      Not checked in the free run.

    • cites [30] Herold S Exner M Nauser T Kinetic and mechanistic studies of the NO*- mediated oxidation of oxymyoglobin and oxyhemoglobin. Biochemistry 2001 40 3385 3395 11258960 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    High concentrations of hemoglobin and myoglobin in red blood cells and cardiac/skeletal muscle determine that the reaction between their hemes and NO will be fast and might inhibit NO-signaling.

    “the high concentrations of hemoglobin and myoglobin in red blood cells (20 mM) and cardiac/skeletal muscle (300-900 μM) [31, 32], determines that the reaction between their hemes and NO will be fast and might inhibit NO-signaling.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [31] Bekedam MA van Beek-Harmsen BJ van Mechelen W Boonstra A van der Laarse WJ Myoglobin concentration in skeletal muscle fibers of chronic heart failure patients. Journal of Applied Physiology 2009 107 1138 1143 19661455 PMC2763838 source

      Not checked in the free run.

    • cites [32] Wittenberg JB Wittenberg BA Myoglobin function reassessed. J Exp Biol 2003 206 2011 2020 12756283 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Nitrite can be an hypoxic source for NO and opens the door for nitrite therapeutics for ischemic injury.

    “The potential for nitrite to be an hypoxic source for NO has also opened the door for nitrite therapeutics for various conditions characterized by ischemic injury”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Xanthine oxidase dependent reduction of nitrite requires substantial hypoxia or anoxia, or high concentrations of SOD to prevent NO scavenging by superoxide.

    “xanthine oxidase dependent reduction of nitrite requires substantial hypoxia (or anoxia) or the presence of high concentrations of SOD to prevent NO scavenging by superoxide produced via oxygen reduction catalyzed by the same xanthine oxidoreductase [70, 71].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [70] Li H Samouilov A Liu X Zweier JL Characterization of the Effects of Oxygen on Xanthine Oxidase-mediated Nitric Oxide Formation. Journal of Biological Chemistry 2004 279 16939 16946 14766900 source

      Not checked in the free run.

    • cites [71] Li H Samouilov A Liu X Zweier JL Characterization of the magnitude and kinetics of xanthine oxidase-catalyzed nitrite reduction. Evaluation of its role in nitric oxide generation in anoxic tissues. J Biol Chem 2001 276 24482 24489 11312267 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The high reactivity of N2O3 with thiols and the presence of glutathione in red blood cells may limit the ability of N2O3 to reach the vascular compartment.

    “the fact that N2O3 reacts with high rate constants with thiols (k = 6.6×107 M-1s-1 [58]) coupled to the presence of ~2-5mM glutathione in red blood cells may limit the ability of N2O3 to reach the vascular compartment.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [58] Keshive M Singh S Wishnok JS Tannenbaum SR Deen WM Kinetics of S-nitrosation of thiols in nitric oxide solutions. Chem Res Toxicol 1996 9 988 993 8870986 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Evidence for nitrite reactions with erythrocytic hemoglobin and stimulation of hypoxic blood flow remains more limited and is the subject of much debate.

    “The evidence for nitrite reactions with erythrocytic hemoglobin and stimulation of hypoxic blood flow remains more limited and is the subject of much debate [16, 61].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [16] Patel RP Hogg N Kim-Shapiro DB The potential role of the red blood cell in nitrite-dependent regulation of blood flow. Cardiovasc Res 2011 89 507 515 20952416 PMC3028972 source

      Not checked in the free run.

    • cites [61] Allen BW Stamler JS Piantadosi CA Hemoglobin, nitric oxide and molecular mechanisms of hypoxic vasodilation. Trends in Molecular Medicine 2009 15 452 460 19781996 PMC2785508 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Protection afforded by nitrite administration in a model of cardiac ischemia-reperfusion is lost in myoglobin knockout mice and coincides with loss of NO formation detected by EPR.

    “protection afforded by nitrite administration in a model of ischemia-reperfusion in the heart is lost when myoglobin knock-out mice are used instead of wild type animals and this coincides with a loss of NO formation detected by EPR [33].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [33] Hendgen-Cotta UB Merx MW Shiva S Schmitz J Becher S Klare JP Steinhoff HJ Goedecke A Schrader J Gladwin MT Kelm M Rassaf T Nitrite reductase activity of myoglobin regulates respiration and cellular viability in myocardial ischemia-reperfusion injury. Proc Natl Acad Sci U S A 2008 105 10256 10261 18632562 PMC2481313 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Nitrite entry into the red blood cell is likely mediated mostly by passive diffusion as nitrous acid, while AE-1 might control net fluxes of nitrite transport by mediating nitrite export via an oxygen-sensitive process coupled to hemoglobin oxygenation state.

    “we recently suggested that whereas nitrite entry into the red blood cell is likely to be mediated mostly by passive diffusion in the form of nitrous acid, AE-1 might be involved in controlling net fluxes of nitrite transport across the red blood cell membrane by mediating nitrite export via an oxygen-sensitive process coupled to the hemoglobin oxygenation state [99].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [99] 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. Am J Physiol Heart Circ Physiol 2009 296 H1398 1407 19286940 PMC2685350 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Nitrite may function more as an NO-buffer, continually matching decreases in oxygen tension with increased NO formation.

    “it is possible that beyond being a hypoxia-activated reservoir for NO, nitrite could in fact be functioning more as an NO-buffer, continually matching decreases in oxygen tension with increased NO formation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    These mechanisms suggest that nitrite reduction to NO by these proteins might be upregulated under conditions of oxidative stress and potentially be involved in cellular protection.

    “These mechanisms suggest that nitrite reduction to NO by these proteins might be upregulated under conditions of oxidative stress and potentially be involved in cellular protection analogous to known pathways of anti-apoptotic and anti-inflammatory effects of NO.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Hypoxemia is an integral part of vascular physiology and is further enhanced during ischemic stress.

    “hypoxemia is an integral part of vascular physiology which is further enhanced during ischemic stress.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Current perspectives postulate that nitrite diffuses across the plasma membrane by becoming protonated to nitrous acid and, in red cells from some species, by interacting with anion exchanger 1 (AE-1).

    “Current perspectives postulate that nitrite diffuses across the plasma membrane by becoming protonated to nitrous acid [97] and, in the context of red cells from some species, by interacting with the anion exchanger 1 (AE-1) [98, 99].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [97] Samouilov A Woldman YY Zweier JL Khramtsov VV Magnetic resonance study of the transmembrane nitrite diffusion. Nitric oxide: biology and chemistry / official journal of the Nitric Oxide Society 2007 16 362 370 17306575 PMC2709508 source

      Not checked in the free run.

    • cites [98] Jensen FB Rohde S Comparative analysis of nitrite uptake and hemoglobin-nitrite reactions in erythrocytes: sorting out uptake mechanisms and oxygenation dependencies. Am J Physiol Regul Integr Comp Physiol 2010 298 R972 982 20130222 source

      Not checked in the free run.

    • cites [99] 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. Am J Physiol Heart Circ Physiol 2009 296 H1398 1407 19286940 PMC2685350 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Evidence for a role for NO is dependent largely on attenuation of responses by the NO-scavenger CPTIO and measurement of nitrite-dependent increases in cGMP levels.

    “Evidence for a role for NO is dependent largely on attenuation of responses by the NO-scavenger CPTIO [25, 26, 52, 100] and measurement of nitrite-dependent increases in cGMP levels[26, 101].”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [25] Cosby K Partovi KS Crawford JH Patel RP Reiter CD Martyr S Yang BK Waclawiw MA Zalos G Xu X Huang KT Shields H Kim-Shapiro DB Schechter AN Cannon RO 3rd Gladwin MT Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation. Nat Med 2003 9 1498 1505 14595407 source

      Not checked in the free run.

    • cites [26] 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 2006 107 566 574 16195332 PMC1895612 source

      Not checked in the free run.

    • cites [52] 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 1240 15841216 PMC1077170 source

      Not checked in the free run.

    • cites [100] 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. Proc Natl Acad Sci U S A 2008 105 7540 7545 18508974 PMC2396555 source

      Not checked in the free run.

    • cites [101] Cauwels A Buys ES Thoonen R Geary L Delanghe J Shiva S Brouckaert P Nitrite protects against morbidity and mortality associated with TNF- or LPS-induced shock in a soluble guanylate cyclase-dependent manner. J Exp Med 2009 206 2915 2924 19934018 PMC2806477 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The majority of studies have shown that nitrite effects are NO-dependent and can be either sGC dependent or independent.

    “the majority of studies have shown that nitrite effects are NO-dependent and can be either sGC dependent or independent consistent with current paradigms of how nitric oxide synthase derived NO works.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Although nitrite-derived NO formation might be inefficient, it is still biologically and therapeutically important.

    “although nitrite-derived NO formation might be inefficient [75], it is still biologically and therapeutically important”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [75] Feelisch M Fernandez BO Bryan NS Garcia-Saura MF Bauer S Whitlock DR Ford PC Janero DR Rodriguez J Ashrafian H Tissue Processing of Nitrite in Hypoxia: AN INTRICATE INTERPLAY OF NITRIC OXIDE-GENERATING AND -SCAVENGING SYSTEMS. J Biol Chem 2008 283 33927 33934 18835812 PMC2590701 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Both hypoxia and nitrite supplementation function by increasing the availability of substrates and thereby increasing the flux through the nitrite reduction pathway.

    “both hypoxia and nitrite supplementation function by increasing the availability of substrates thereby increasing the flux through the nitrite reduction pathway.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In vitro and in vivo studies using inhibitors and transgenic mouse models show that the hypoxic effects of nitrite are mediated in large part through the sGC-cGMP-PKG pathway and include vasodilation, protection against ischemia reperfusion injury, or LPS-induced endotoxemia.

    “both in vitro and in vivo studies using inhibitors and transgenic mouse models that target the classical NO-dependent activation of the sGC-cGMP-PKG signaling pathway further show that the hypoxic effects of nitrite are mediated in large part through this mechanism and include vasodilation, protecting against ischemia reperfusion injury or LPS-induced endotoxemia[101].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [101] Cauwels A Buys ES Thoonen R Geary L Delanghe J Shiva S Brouckaert P Nitrite protects against morbidity and mortality associated with TNF- or LPS-induced shock in a soluble guanylate cyclase-dependent manner. J Exp Med 2009 206 2915 2924 19934018 PMC2806477 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    There are two likely pathways by which nitrite may mediate S-nitrosation in vivo: abstraction of a hydrogen atom from the target thiol followed by nitrite-derived NO addition, and direct nitrosation of the thiol by nitrite-derived dinitrogen trioxide.

    “There are two likely pathways by which nitrite may mediate S-nitrosation in vivo [107], one involves the abstraction of a hydrogen atom from the target thiol followed by nitrite-derived NO addition (Scheme 3a) and the other is the direct nitrosation of the thiol by nitrite-derived dinitrogen trioxide (Scheme 3b).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [107] Goldstein S Czapski G Mechanism of the nitrosation of thiols and amines by oxygenated NO solutions: the nature of the nitrosating intermediates. J Am Chem Soc 1996 118 3419 3425 source

      Not checked in the free run.

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

    Premisenone given

    Protein nitration has usually been considered a deleterious process that alters protein function or targets it for degradation, which is the basis for use of 3-nitrotyrosine as a marker for oxidative and nitrative stress in vivo.

    “Protein nitration has usually been considered a deleterious process that either alters protein function or targets it for degradation, which is basis for the use of 3-nitrotyrosine as a marker for oxidative and nitrative stress in vivo.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Nitrite supplementation stimulates hsp70 expression and activates the estrogen receptor alpha in a human breast cancer line.

    “stimulate of hsp70 expression and activate the estrogen receptor alpha in a human breast cancer line [102].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [102] Veselik DJ Divekar S Dakshanamurthy S Storchan GB Turner JMA Graham KL Huang L Stoica A Martin MB Activation of Estrogen Receptor-α by the Anion Nitrite. Cancer Research 2008 68 3950 3958 18483281 PMC3676890 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Nitrite could be used as an effective treatment to improve the outcome of major procedures such as organ transplants.

    “the realization that nitrite can both mimic ischemic pre-conditioning and potentiate angiogenesis suggests the possibility that nitrite could be used as an effective treatment to improve the outcome of major procedures such as organ transplants.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Nitrite can mimic ischemic pre-conditioning and potentiate angiogenesis.

  • May combine two claims.

    Premisecitation

    After nitrite administration, nitrite levels sometimes increase and sometimes do not change despite evidence of NO-dependent signaling induction.

    “In some cases, increased nitrite levels are measured after administration, but in others no change in nitrite is observed despite clear evidence of NO-dependent signaling induction (a notable example being nitrite dependent stimulation of ischemic angiogenesis) [100, 123].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [100] 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. Proc Natl Acad Sci U S A 2008 105 7540 7545 18508974 PMC2396555 source

      Not checked in the free run.

    • cites [123] 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. Am J Physiol Heart Circ Physiol 2010 298 H331 339 19940079 PMC2822592 source

      Not checked in the free run.

24 of 24

  • The paper relies on this without support.

    At pH 7, the predominant form of nitrite (>99.9%) is the nitrite anion, with a pK of 3.4.

    “especially when you consider that the predominant form of nitrite (>99.9%) at pH 7 is the nitrite anion (pK = 3.4).”

  • The paper relies on this without support.

    Nitrite can mimic ischemic pre-conditioning and potentiate angiogenesis.

    “the realization that nitrite can both mimic ischemic pre-conditioning and potentiate angiogenesis”
2 of 2

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?

  • NO can be produced endogenously from nitrite, and reduction of nitrite to NO is increased under acidic and hypoxic conditions by heme proteins such as deoxyhemoglobin or deoxymyoglobin.

    “In addition to direct production via NOS enzymes, NO can be produced endogenously from the more oxidized nitrogen oxide, nitrite. Reduction of nitrite to NO is increased under acidic and hypoxic conditions, with the reduction occurring enzymatically by heme proteins such as deoxyhemoglobin or deoxymyoglobin [79].”

    From Regulation of obesity and insulin resistance by nitric oxide (2014) · cites this paper as [79]

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 reference is assigned two publication years

    Minor

    References 18 and 118 have the same authors, title, journal, volume, pages, and identifier, but list the publication year as 2011 and 2010, respectively.

1 of 1

The citation lists haven’t been fetched yet

References 122 · Cited by 59

Research works printed but not linked: 2

  1. Dejam, 2007, Nitrite infusion in humans and nonhuman primates: endocrine effects, pharmacokinetics, and tolerance formation, Circulation, 116, 1821, 10.1161/CIRCULATIONAHA.107.712133 · DOI · Paper page
  2. Tang, 2010, Nitrite and nitrate: cardiovascular risk-benefit and metabolic effect, Curr. Opin. Lipidol., 22, 11, 10.1097/MOL.0b013e328341942c · DOI · Paper page

Authors
Vitturi, D. A., & Patel, R. P.
Affiliations
University of Alabama at Birmingham (US)
Corresponding author
Patel, Rakesh P.
ORCID
Patel, Rakesh P.
Venue
Free Radical Biology and Medicine
Publisher
Elsevier BV
Published
2011-08
Volume
51
Issue
4
Pages
805-812
ISSN
0891-5849 (ISSN-L)
DOI
10.1016/j.freeradbiomed.2011.05.037
PMC
PMC3148353
OpenAlex
W2072332580
Semantic Scholar
464925bf23574f8ffa3c440185633195d71798e2
Cited by
59
References
122
Citations by year
2026: 1 · 2025: 1 · 2024: 4 · 2023: 3 · 2022: 1 · 2021: 6 · 2020: 3 · 2019: 1 · 2018: 3 · 2017: 4 · 2016: 4 · 2015: 5 · 2014: 8 · 2013: 6 · 2012: 7
FWCI
0.80
Type
journal article
Language
en
Open access
Licence
Locations
  • Free Radical Biology and Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • National Heart, Lung, and Blood Institute (R01HL095468, HL095468)
  • National Institute of Environmental Health Sciences (U54ES017218)
Topics
  • Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
Keywords
nitrite, nitric oxide signaling, hypoxia, nitric oxide homeostasis, nitrite therapy, ischemic injury, nitric oxide metabolism, clinical translation
MeSH terms
Animals, Hypoxia, Blood Flow Velocity, Clinical Trials as Topic, Humans, Nitrites, Nitrogen Oxides, Oxidation-Reduction, Vasodilation, Signal Transduction, Reperfusion Injury, Nitrosation, Oxidative Stress, Reactive Nitrogen Species, Molecular Targeted Therapy

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 ›

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