Nitrate and nitrite in biology, nutrition and therapeutics
Open accessAbstract
Inorganic nitrate and nitrite from endogenous or dietary sources are metabolized in vivo to nitric oxide (NO) and other bioactive nitrogen oxides. The nitrate-nitrite-NO pathway is emerging as an important mediator of blood flow regulation, cell signaling, energetics and tissue responses to hypoxia. The latest advances in our understanding of the biochemistry, physiology and therapeutics of nitrate, nitrite and NO were discussed during a recent 2-day meeting at the Nobel Forum, Karolinska Institutet in Stockholm.
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Claims the paper makes
15 of 47 cited sources checked · 13 supported · 0 flagged · accuracy not yet measured
- Premisecitation
The one-electron reduction of nitrite to NO can be catalyzed by many enzymatic and non-enzymatic pathways.
“It is now clear that the one-electron reduction of nitrite to NO can be catalyzed by numerous enzymatic as well as non-enzymatic pathways1,4.”
Quote in the paperSubstantial claim1 of 2 sources checked - Premisecitation
Continuous swallowing of nitrite-containing saliva produces various nitrogen oxides, including NO, in the acidic environment of the gastric lumen.
“The continuous swallowing of nitrite-containing saliva (~1.5 liters per day) generates a variety of nitrogen oxides, including NO, in the acidic milieu of the gastric lumen.”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [29] Lundberg, J.O., Weitzberg, E., Lundberg, J.M. & Alving, K. Gut 35, 1543–1546 (1994). source
The discussion under “Nitric Oxide Formation in Vitro” (page not provided) says that swallowed, nitrite-containing saliva can support continuous NO formation in the acidic stomach. It does not report production of a variety of nitrogen oxides, and gives daily saliva production as often exceeding one litre rather than approximately 1.5 litres. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites [30] Benjamin, N. et al. Nature 368, 502 (1994). source
- Rests on an assumption: The salivary glands actively remove a large fraction of ingested nitrate from the bloodstream and concentrate it in saliva.
- Premisecitation
The mitochondrion is a physiological target for NO.
“In the last 15 years it has been established that the mitochondrion is a physiological target for NO (ref. 8).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [8] Erusalimsky, J.D. & Moncada, S. Arterioscler. Thromb. Vasc. Biol. 27, 2524–2531 (2007). source
- Premisecitation
The body converts inorganic nitrate and nitrite, whether produced internally or consumed in the diet, into nitric oxide and other bioactive nitrogen oxides.
“Inorganic nitrate and nitrite from endogenous or dietary sources are metabolized in vivo to nitric oxide (NO) and other bioactive nitrogen oxides.”
Quote in the paperSubstantial claim1 of 5 sources checked- cites [1] Lundberg, J.O., Weitzberg, E. & Gladwin, M.T. Nat. Rev. Drug Discov. 7, 156–167 (2008). source
- cites [2] Gladwin, M.T. et al. Nat. Chem. Biol. 1, 308–314 (2005). source
- cites [3] Reutov, V.P. & Sorokina, E.G. Biochemistry (Mosc.) 63, 874–884 (1998).
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [4] van Faassen, E.E. et al. Med. Res. Rev. 29, 683–741 (2009). source
- cites [5] Weitzberg, E. & Lundberg, J.O. Nitric Oxide 2, 1–7 (1998). source
- Premisecitation
Nitrite therapy can prevent hypertension caused by cell-free hemoglobin-based oxygen carriers in vivo.
“Nitrite reduction to NO by deoxygenated hemoglobin may govern NO signaling in the vasculature as exemplified by experiments showing that nitrite therapy can prevent hypertension induced by cell-free hemoglobin-based oxygen carriers in vivo22.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [22] Rodriguez, C. et al. Biochem. J. 422, 423–432 (2009). source
- Premisecitation
Components of the respiratory chain can reduce nitrite to NO.
“Sruti Shiva (University of Pittsburgh) reviewed a number of studies demonstrating that components of the respiratory chain can reduce nitrite to NO (refs. 4,9)”
Quote in the paperSubstantial claim2 of 2 sources checked - Premisecitation
Under hypoxic conditions, when oxygen-dependent NO synthases may malfunction, nitrite reduction is greatly increased.
“In situations of hypoxia, when the oxygen-dependent NO synthases may become dysfunctional, nitrite reduction is instead greatly enhanced.”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [4] van Faassen, E.E. et al. Med. Res. Rev. 29, 683–741 (2009). source
- cites [9] Kozlov, A.V., Staniek, K. & Nohl, H. FEBS Lett. 454, 127–130 (1999). source
The Results (section 3; page unavailable) show nitrite-to-NO conversion under anaerobic conditions, and the Discussion (section 4; page unavailable) links this pathway to the lack of oxygen during ischemia. The paper does not establish that nitrite reduction is greatly increased relative to oxygenated conditions or state that NO synthases become dysfunctional under hypoxia. (LLM, conf=0.84)
Experimental — accuracy not yet measured
- Interpretationcitation
Nitrite reduction to NO by deoxygenated hemoglobin may control NO signaling in the vasculature.
“Nitrite reduction to NO by deoxygenated hemoglobin may govern NO signaling in the vasculature as exemplified by experiments showing that nitrite therapy can prevent hypertension induced by cell-free hemoglobin-based oxygen carriers in vivo22.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [22] Rodriguez, C. et al. Biochem. J. 422, 423–432 (2009). source
- Premisecitation
Modest dietary supplementation with sodium nitrate lowers blood pressure in healthy volunteers.
“Recently it was shown that modest dietary supplementation with sodium nitrate reduces blood pressure in healthy volunteers36.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [36] Larsen, F.J., Ekblom, B., Sahlin, K., Lundberg, J.O. & Weitzberg, E. N. Engl. J. Med. 355, 2792–2793 (2006). source
- Premisecitation
The bioactivation of nitrate begins with its reduction to nitrite by symbiotic bacteria in the oral cavity.
“The bioactivation of the more stable nitrate anion involves initial reduction to nitrite by symbiotic bacteria in the oral cavity1.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [1] Lundberg, J.O., Weitzberg, E. & Gladwin, M.T. Nat. Rev. Drug Discov. 7, 156–167 (2008). source
- Premisecitation
Mammalian tissues can reduce nitrate and nitrite to bioactive nitrogen oxides, including NO.
“However, it was only recently described that mammalian tissues can also reduce nitrate10 and nitrite11 to bioactive nitrogen oxides including NO (Fig. 2).”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
One serving of spinach, lettuce, or beetroot contains more nitrate than the amount generated endogenously over a day by all three NOSs combined.
“As an example, one serving of spinach, lettuce or beetroot contains more nitrate than that generated endogenously over a day by all three NOSs combined1.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [1] Lundberg, J.O., Weitzberg, E. & Gladwin, M.T. Nat. Rev. Drug Discov. 7, 156–167 (2008). source
- Interpretationreasoning
Nitrate can therefore be regarded as a slow-release prodrug of nitrite.
“and nitrate may therefore be considered as a ‘prodrug’ of nitrite with a slow-release profile.”
Quote in the paperSubstantial claim- Rests on an assumption: The salivary glands actively remove a large fraction of ingested nitrate from the bloodstream and concentrate it in saliva.
- Interpretationnone given
The nitrate-nitrite-NO pathway is becoming recognized as a significant regulator of blood flow, cell signaling, energy metabolism, and tissue responses to low oxygen.
“The nitrate-nitrite-NO pathway is emerging as an important mediator of blood flow regulation, cell signaling, energetics and tissue responses to hypoxia.”
Quote in the paperSubstantial claim - Premisecitation
Over the past fifty years, dietary nitrate and nitrite have become notorious because of a supposed link to disease, especially gastric cancer.
“Over the past half century, dietary nitrate and nitrite have become notorious because of their supposed association with the development of disease, most notably gastric cancer32.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [32] Tannenbaum, S.R. & Correa, P. Nature 317, 675–676 (1985). source
- Interpretationcitation
Multiple studies support a therapeutic role for nitrate and nitrite, especially in treating and preventing cardiovascular diseases such as ischemia-reperfusion injury and hypertension.
“In addition, multiple studies now support a therapeutic role for nitrate and nitrite, most notably in the treatment and prevention of cardiovascular diseases including ischemia-reperfusion (IR) injury and hypertension1.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [1] Lundberg, J.O., Weitzberg, E. & Gladwin, M.T. Nat. Rev. Drug Discov. 7, 156–167 (2008). source
- Interpretationnone given
The relative contribution of these pathways to overall NO formation differs among tissues and depends on factors such as local pH, oxygen tension, and redox status.
“The relative contribution from these pathways to overall NO formation varies between tissues and is dependent on a number of factors including local pH, oxygen tension and redox status.”
Quote in the paperNot a substantial claim - Premisecitation
A vegetable-rich diet, such as the Mediterranean or traditional Japanese diet, contains more nitrate than the acceptable daily intake recommended by the World Health Organization.
“Interestingly, a diet rich in vegetables, such as the Mediterranean and the traditional Japanese diets, contains more nitrate than that recommended as the acceptable daily intake (ADI) by the World Health Organization34.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [34] Alexander, J. et al. EFSA J. 689, 1–79 (2008).
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Premisecitation
The enterosalivary circulation of nitrate causes a sustained increase in plasma nitrite levels.
“The enterosalivary circulation of nitrate also leads to a sustained increase in plasma levels of nitrite31”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [31] Lundberg, J.O. & Govoni, M. Free Radic. Biol. Med. 37, 395–400 (2004). source
- Rests on an assumption: The salivary glands actively remove a large fraction of ingested nitrate from the bloodstream and concentrate it in saliva.
- Interpretationown data
The nitrate-nitrite-NO pathway can compensate for disruptions in endogenous NO production from NOSs.
“These data indicate that the nitrate-nitrite-NO pathway can compensate for disturbances in endogenous NO generation from NOSs.”
Quote in the paperSubstantial claim - Premisecitation
Adding nitrite to organ preservation fluid and to the organ recipient improved organ survival and function parameters in animal models of liver and heart transplantation.
“Administration of nitrite to the organ preservation fluid and to the organ recipient improved parameters of organ survival and function43.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [43] Zhan, J. et al. Surgery 146, 155–165 (2009). source
- Premisecitation
There appears to be no tolerance associated with relatively long-term nitrite or nitrate administration, unlike treatment with organic nitrates such as nitroglycerin.
“Another possible advantage is the apparent absence of tolerance connected to relatively long-term nitrite44 or nitrate38 administration in contrast to treatment with organic nitrates such as nitroglycerin.”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
Dietary nitrate and nitrite protect against ischemia-reperfusion injury in experimental myocardial infarction.
“Bryan explained that dietary nitrate and nitrite protect against IR injury in experimental myocardial infarction39”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [39] Bryan, N.S. et al. Proc. Natl. Acad. Sci. USA 104, 19144–19149 (2007). source
- Interpretationreasoning
Promising data are emerging for nitrate and nitrite across a wide range of conditions, predominantly those involving tissue ischemia.
“In aggregate, promising data are emerging in a wide variety of conditions predominantly involving tissue ischemia.”
Quote in the paperSubstantial claim - Interpretationreasoning
The emerging beneficial effects of nitrate and nitrite may also account for some of the health benefits of a vegetable-rich diet, such as the Mediterranean diet.
“Of crucial relevance, the salutary effects of nitrate and nitrite that are emerging may also explain some of the beneficial health effects of a diet rich in vegetables, such as the Mediterranean diet”
Quote in the paperSubstantial claim - Premisecitation
In mice fed a cholesterol-enriched diet, adding nitrite to drinking water prevented signs of vascular pathology.
“and in mice fed a cholesterol-enriched diet, the addition of nitrite to the drinking water prevented the signs of vascular pathology40.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [40] Stokes, K.Y. et al. Am. J. Physiol. Heart Circ. Physiol. 296, H1281–H1288 (2009). source
- Premisecitation
Chronic dietary nitrate supplementation in rats produces a sustained effect on blood pressure.
“Similar data were presented by Mattias Carlström (Uppsala University), who observed a sustained effect on blood pressure by chronic dietary nitrate supplementation in rats38.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [38] Petersson, J. et al. Free Radic. Biol. Med. 46, 1068–1075 (2009). source
- May combine two claims. 12
- Not yet classified. 1
May combine two claims.
PremisecitationNitrate and nitrite are metabolized in blood and tissues to produce NO and other bioactive nitrogen oxides, providing an alternative to the classical L-arginine-NOS-NO signaling pathway.
“However, a new view is evolving with the accumulating evidence that nitrate and nitrite metabolism occurs in blood and tissues to form NO and other bioactive nitrogen oxides, representing an alternative to ‘classical’ L-arginine–NO synthase–NO signaling1–5.”
Quote in the paperSubstantial claim1 of 5 sources checked- cites [1] Lundberg, J.O., Weitzberg, E. & Gladwin, M.T. Nat. Rev. Drug Discov. 7, 156–167 (2008). source
- cites [2] Gladwin, M.T. et al. Nat. Chem. Biol. 1, 308–314 (2005). source
- cites [3] Reutov, V.P. & Sorokina, E.G. Biochemistry (Mosc.) 63, 874–884 (1998).
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [4] van Faassen, E.E. et al. Med. Res. Rev. 29, 683–741 (2009). source
- cites [5] Weitzberg, E. & Lundberg, J.O. Nitric Oxide 2, 1–7 (1998). source
Not yet classified.
PremiseMany of nitrite's biological effects involve interactions with mitochondria.
“Recent data suggest that many of the biological effects of nitrite6,7 involve interaction with mitochondria.”
Quote in the paperNot yet classified1 of 2 sources checkedMay combine two claims.
PremisecitationSalivary nitrite increases gastric mucosal blood flow and mucus production, which supports gastroprotective mechanisms.
“Salivary nitrite increases gastric mucosal blood flow and mucus production, thereby supporting gastroprotective mechanisms35.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [35] Bjorne, H.H. et al. J. Clin. Invest. 113, 106–114 (2004). source
May combine two claims.
PremisecitationIn healthy volunteers, beetroot juice as a nitrate source reduces blood pressure by about 10 mm Hg, coinciding with peak plasma nitrite levels.
“Andrew Webb (Barts and The London Medical School) and colleagues used beetroot juice as a source of nitrate in healthy volunteers and found a reduction in blood pressure of ~10 mm Hg that coincided with peak plasma levels of nitrite37.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [37] Webb, A.J. et al. Hypertension 51, 784–790 (2008). source
May combine two claims.
InterpretationreasoningNitrate and nitrite act as storage pools that support NO signaling during metabolic stress, and their activation involves both enzymatic and non-enzymatic reactions in blood and tissues.
“Nitrate and nitrite can thus be viewed as storage pools supporting NO signaling during metabolic stress, with their bioactivation involving both enzymatic and non-enzymatic reactions in blood and tissues.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationSalivary nitrate is efficiently reduced to nitrite by oral bacteria, resulting in nitrite concentrations in saliva that are 1,000-fold higher than in plasma.
“Salivary nitrate is then efficiently reduced to nitrite by bacteria in the oral cavity, leading to 1,000-fold higher concentrations of nitrite in saliva compared to plasma28.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [28] Lundberg, J.O., Weitzberg, E., Cole, J.A. & Benjamin, N. Nat. Rev. Microbiol. 2, 593–602 (2004). source
- Rests on an assumption: The salivary glands actively remove a large fraction of ingested nitrate from the bloodstream and concentrate it in saliva.
May combine two claims.
PremisecitationNitrite administration causes vasodilatation at low concentrations, ultimately through activation of cGMP in vascular smooth muscle.
“Nitrite administration causes vasodilatation at low concentrations14, and this is ultimately mediated by activation of cGMP in the vascular smooth muscle.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [14] Cosby, K. et al. Nat. Med. 9, 1498–1505 (2003). source
May combine two claims.
PremisecitationIn healthy volunteers given a dietary nitrate load as beetroot juice, oxygen consumption was reduced, with a corresponding improvement in performance.
“Andy Jones (University of Exeter) presented data demonstrating that in healthy volunteers given a dietary nitrate load (in the form of beetroot juice), oxygen consumption was reduced, resulting in a concomitant improvement of performance41.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [41] Bailey, S.J. et al. J. Appl. Physiol. 107, 1144–1155 (2009). source
May combine two claims.
PremisecitationVery low doses of dietary nitrite reduced proteinuria and prevented renal histological damage caused by chronic administration of a NOS inhibitor.
“Koichiro Tsuchiya (University of Tokushima) presented data showing that very low doses of dietary nitrite attenuated proteinurea and prevented the renal histological damage induced by chronic administration of a NOS inhibitor42.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [42] Kanematsu, Y. et al. Am. J. Physiol. Renal Physiol. 295, F1457–F1462 (2008). source
May combine two claims.
PremisecitationDietary nitrate supplementation reduces oxygen cost and improves muscular efficiency at various levels of submaximal exercise in healthy young volunteers without increasing anaerobic metabolism.
“Recently it was demonstrated that dietary nitrate supplementation reduces oxygen cost and improves muscular efficiency at various levels of submaximal exercise in healthy young volunteers without increasing anaerobic metabolism7.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [7] Larsen, F.J., Weitzberg, E., Lundberg, J.O. & Ekblom, B. Acta Physiol. (Oxf.) 191, 59–66 (2007). source
May combine two claims.
InterpretationreasoningThe blood-pressure effects of nitrate can be prevented by having human volunteers spit for 3 hours or by giving rats an antibacterial mouthwash, demonstrating the importance of the enterosalivary circulation and oral nitrate-reducing bacteria for nitrate bioactivation.
“Both groups could prevent the effects on blood pressure either by letting the human volunteers spit for 3 h or by application of an antibacterial mouthwash to the rats. This shows the importance of the enterosalivary circulation of nitrate and the critical role of oral nitrate-reducing bacteria in its bioactivation.”
Quote in the paperSubstantial claim- Rests on an assumption: The salivary glands actively remove a large fraction of ingested nitrate from the bloodstream and concentrate it in saliva.
May combine two claims.
InterpretationreasoningNitrite bioactivation is enhanced in anatomical regions undergoing ischemia or hypoxia, which may lead to more localized therapeutic effects.
“In contrast, nitrite bioactivation is promoted in anatomic regions undergoing ischemia/hypoxia, leading to potentially more localized therapeutic effects.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationNitrite protects against ischemia-reperfusion injury in the heart, brain, kidney, and liver, as well as in chronic limb ischemia.
“In recent years data have accumulated showing that nitrite protects against IR injury in the heart, brain, kidney and liver, as well as in chronic limb ischemia (for review see refs. 1,2).”
Quote in the paperSubstantial claim0 of 2 sources checked
The paper relies on this without support.
The salivary glands actively remove a large fraction of ingested nitrate from the bloodstream and concentrate it in saliva.
“A substantial amount of ingested nitrate is actively taken up from the circulation by the salivary glands and concentrated in saliva.”
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?
While dietary nitrate can increase NO production, a high oxidative burden may reduce its effectiveness by accelerating NO degradation.
“While dietary nitrate can increase NO production, a high oxidative burden may reduce its effectiveness by accelerating NO degradation [128,234,256].”
From Dietary Nitrate-Rich Vegetables as Natural Modulators of Health: Mechanisms and Benefits in Ageing Populations (2026) · cites this paper as [128]
The 'Dietary nitrate in health and disease' section says ingested nitrate is converted to nitrite and generates nitrogen oxides, including NO. The 'Nitrate, nitrite and energetics' section mentions enhanced oxidative stress in mountaineers, but does not say that oxidative burden accelerates NO degradation or reduces the effectiveness of dietary nitrate. Page numbers are unavailable in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredAltered RBC structure and signalling may restrict the export of NO to vascular tissues, thereby reducing vasodilatory responses despite adequate nitrite levels.
“Altered RBC structure and signalling may also restrict the export of NO to vascular tissues, thereby reducing vasodilatory responses despite adequate nitrite levels [56,128,263].”
From Dietary Nitrate-Rich Vegetables as Natural Modulators of Health: Mechanisms and Benefits in Ageing Populations (2026) · cites this paper as [128]
The section “Nitrite reduction in the vasculature” says that RBCs export NO-like bioactivity involved in blood-flow control and that how NO formed in an RBC is exported to elicit vasodilatation remains controversial (page not available). It does not say that altered RBC structure or signalling restricts that export, or that vasodilatory responses fall despite adequate nitrite levels. (LLM, conf=0.85)
Experimental — accuracy not yet measuredHemoglobin, 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”
From Nitrate-Nitrite-Nitric Oxide Pathway: Implications for Anesthesiology and Intensive Care (2010) · cites this paper as [15]
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 measuredOne 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”
From Nitrate-Nitrite-Nitric Oxide Pathway: Implications for Anesthesiology and Intensive Care (2010) · cites this paper as [15]
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”
From Nitrate-Nitrite-Nitric Oxide Pathway: Implications for Anesthesiology and Intensive Care (2010) · cites this paper as [15]
There is evidence that nitrite formation in vivo may occur mainly from NO formation from eNOS compared with other sources.
“Thus, the mechanism(s) of nitrite formation in vivo remains elusive, although there is evidence that it may occur mainly from NO formation from eNOS compared with other sources (35, 38).”
From What Part of NO Don't You Understand? Some Answers to the Cardinal Questions in Nitric Oxide Biology (2010) · cites this paper as [35]
Dietary supplementation with nitrite improves pulmonary hypertension.
“This is supported by several studies describing improvements in ischemia/reperfusion injury following acute myocardial infarction, pulmonary hypertension, and organ transplantation following dietary supplementation with nitrite (35).”
From What Part of NO Don't You Understand? Some Answers to the Cardinal Questions in Nitric Oxide Biology (2010) · cites this paper as [35]
The mechanism of NO regeneration from nitrite suggests that NO2− may play an important role in generating NO under hypoxic conditions.
“For this reason, this mechanism, although presently speculative in details, suggests that NO2− may play an important role in generating NO under hypoxic conditions (35, 38, 39).”
From What Part of NO Don't You Understand? Some Answers to the Cardinal Questions in Nitric Oxide Biology (2010) · cites this paper as [35]
Nitrite (NO2−) can be reduced back to NO by heme proteins such as hemoglobin.
“Recently, it has been suggested that a major metabolite of NO, nitrite (NO2−), can be reduced back to NO by heme proteins such as hemoglobin (35).”
From What Part of NO Don't You Understand? Some Answers to the Cardinal Questions in Nitric Oxide Biology (2010) · cites this paper as [35]
Dietary supplementation with nitrite improves ischemia/reperfusion injury following acute myocardial infarction.
“This is supported by several studies describing improvements in ischemia/reperfusion injury following acute myocardial infarction, pulmonary hypertension, and organ transplantation following dietary supplementation with nitrite (35).”
From What Part of NO Don't You Understand? Some Answers to the Cardinal Questions in Nitric Oxide Biology (2010) · cites this paper as [35]
Dietary supplementation with nitrite improves organ transplantation.
“This is supported by several studies describing improvements in ischemia/reperfusion injury following acute myocardial infarction, pulmonary hypertension, and organ transplantation following dietary supplementation with nitrite (35).”
From What Part of NO Don't You Understand? Some Answers to the Cardinal Questions in Nitric Oxide Biology (2010) · cites this paper as [35]
The regeneration of NO from nitrite changes the location of NO formation and decreases the dependence on oxygen.
“The regeneration of NO from one of its metabolites would seem at first glance to be a futile exercise; however, this reaction both changes the location of NO formation and decreases the dependence on oxygen (35, 38).”
From What Part of NO Don't You Understand? Some Answers to the Cardinal Questions in Nitric Oxide Biology (2010) · cites this paper as [35]
The extremely rapid reaction of NO with HbO2 converts NO to nitrate, and NO binds very rapidly to deoxyheme to form a stable complex.
“The extremely rapid reaction with HbO2 results in conversion of the NO to nitrate, and NO binds very rapidly to the deoxyheme to form a stable complex (35, 36).”
From What Part of NO Don't You Understand? Some Answers to the Cardinal Questions in Nitric Oxide Biology (2010) · cites this paper as [35]
RBC intrinsic properties, together with mechanisms regulating vascular tone and cardiac function, contribute to regulation of blood rheology, peripheral resistance, and cardiac function.
“These RBC intrinsic properties, together with the mechanisms regulating vascular tone and cardiac function, contribute to regulation of blood rheology, peripheral resistance, and cardiac function (114, 168, 188).”
From Red Blood Cell Function and Dysfunction: Redox Regulation, Nitric Oxide Metabolism, Anemia (2017) · cites this paper as [114]
Normal RBCs have several possible modes of changing shape, including elongation, end-over-end tumbling, periodic swinging, and membrane tanktreading.
“Normal RBCs have a few possible modes of changing their shape (114, 168, 188).”
From Red Blood Cell Function and Dysfunction: Redox Regulation, Nitric Oxide Metabolism, Anemia (2017) · cites this paper as [114]
Plasma nitrite is both a marker of nitric oxide bioavailability and a bioactive nitric oxide donor.
“we observed an increase in plasma nitrite, which represents both a marker of NO bioavailability and a bioactive NO donor (10).”
Increased endothelial function and nitric oxide bioavailability may play a causal role in improving arterial blood pressure.
“While the mechanisms that underlie this effect cannot be ascertained from the present study, it is tenable that increased endothelial function and NO bioavailability play a causal role in improving arterial blood pressure (10).”
In humans, a nonenzymatic pathway converting nitrate to nitrite to nitric oxide may raise nitric oxide availability.
“A nonenzymatic pathway for the generation of NO in humans has been proposed (nitrate-nitrite-NO pathway), which may contribute to increased NO bioavailability (21).”
From Inorganic Nitrate and Beetroot Juice Supplementation Reduces Blood Pressure in Adults: A Systematic Review and Meta-Analysis (2013) · cites this paper as [21]
Nitrite serves as both a NOS-dependent and an exogenous source of nitric oxide and RNS.
“It is now clear, however, that nitrite serves as both a NOS-dependent and exogenous source of NO and RNS [122-124].”
From Signaling and stress: The redox landscape in NOS2 biology (2015) · cites this paper as [124]
Body stores of nitrate and nitrite can be increased exogenously through the diet, particularly through consumption of green leafy vegetables.
“In addition to its generation by means of the NOS system, body stores of nitrate and nitrite may also be increased exogenously through the diet, particularly through the consumption of green leafy vegetables such as lettuce, spinach, rocket, celery, cress, and beetroot”
From Dietary Nitrate Supplementation and Exercise Performance (2014) · cites this paper as [5]
Nitrate and nitrite can be reduced back to NO and other bioactive nitrogen oxides in vivo.
“However, it is now known that nitrate and nitrite can be reduced back to NO and other bioactive nitrogen oxides in vivo”
From Dietary Nitrate Supplementation and Exercise Performance (2014) · cites this paper as [5]
Inorganic nitrate is present in numerous foodstuffs and is abundant in green leafy vegetables and beetroot.
“Inorganic nitrate is present in numerous foodstuffs and is abundant in green leafy vegetables and beetroot.”
From Dietary Nitrate Supplementation and Exercise Performance (2014) · cites this paper as [5]
One serving of a nitrate-rich vegetable contains more nitrate than is endogenously generated by NOS isoforms during a full day in humans.
“One serving of such a vegetable contains more nitrate than what is endogenously generated by NOS isoforms during a full day in humans [19].”
From NO-Rich Diet for Lifestyle-Related Diseases (2015) · cites this paper as [19]
The insulin receptor shares a signaling pathway with eNOS activation to regulate postprandial blood flow and efficient nutrient disposition to peripheral tissues.
“The insulin receptor shares a signaling pathway with the activation of endothelial NOS (eNOS) [19,48,49,50,51,52] to regulate the postprandial blood flow and efficient nutrient disposition to peripheral tissues”
From NO-Rich Diet for Lifestyle-Related Diseases (2015) · cites this paper as [19]
Definitive chemical evidence for the significance of the nitrate-nitrite-NO pathway under physiological conditions is still lacking.
“This nitrate-nitrite-NO cycle offers a conceptually attractive explanation for the blood pressure lowering and cardioprotective effects of diets rich in nitrate and may provide the molecular basis for past and future therapeutic uses of nitrite/nitrate [20,25], although definitive chemical evidence for the significance of this pathway under physiological conditions is still lacking.”
From On the chemical biology of the nitrite/sulfide interaction (2015) · cites this paper as [20]
Nitrite can serve as an alternative source of NO and is a molecular entity with intrinsic signaling properties.
“Alongside the discovery of sulfide as a physiological transmitter, the past decade has witnessed the recognition that nitrite (NO2 -) can serve as an alternative source of NO and is a molecular entity with intrinsic signaling properties [20,21].”
From On the chemical biology of the nitrite/sulfide interaction (2015) · cites this paper as [20]
The nitrate-nitrite-NO cycle offers a conceptually attractive explanation for the blood pressure lowering and cardioprotective effects of diets rich in nitrate.
“This nitrate-nitrite-NO cycle offers a conceptually attractive explanation for the blood pressure lowering and cardioprotective effects of diets rich in nitrate and may provide the molecular basis for past and future therapeutic uses of nitrite/nitrate [20,25], although definitive chemical evidence for the significance of this pathway under physiological conditions is still lacking.”
From On the chemical biology of the nitrite/sulfide interaction (2015) · cites this paper as [20]
Nitrite contributes to hypoxic vasodilation, physiological blood pressure control, and redox signaling.
“It is now accepted that the anion nitrite, once considered an inert oxidation product of nitric oxide (NO), contributes to hypoxic vasodilation, physiological blood pressure control, and redox signaling.”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [3]
Nitrite serves as an in vivo reservoir for NO generation, alters mitochondrial function, and manifests a broad array of anti-inflammatory actions in model systems.
“Nitrite serves as an in vivo reservoir for ⅐ NO generation, alters mitochondrial function (54), and manifests a broad array of anti-inflammatory actions in model systems (22).”
From Conjugated linoleic acid is a preferential substrate for fatty acid nitration (2012) · cites this paper as [22]
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].”
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 [6]
Nitrite and nitrate can be recycled back to NO rather than being inert end products of NO.
“more recent studies showed that, rather than being inert end products of NO, nitrite and nitrate can be recycled back to NO [7,8].”
From Sodium nitrite downregulates vascular NADPH oxidase and exerts antihypertensive effects in hypertension (2011) · cites this paper as [8]
Nitrite produces vasodilator effects, which are ascribed to nitric oxide formation.
“Several reports have described vasodilator effects produced by nitrite, which are ascribed to nitrite oxide formation [8].”
From Sodium nitrite downregulates vascular NADPH oxidase and exerts antihypertensive effects in hypertension (2011) · cites this paper as [8]
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Self-citationOxidative stress in autoimmune rheumatic diseases
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Novel Aspects of Dietary Nitrate and Human Health
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Self-citationWhat Part of NO Don't You Understand? Some Answers to the Cardinal Questions in Nitric Oxide Biology
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Liquid Chromatography Analysis of Common Nutritional Components, in Feed and Food
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“The therapeutic potential of dietary or pharmacological nitrite is supported by multiple studies describing improvements in reperfusion injury after myocardial infarction, in pulmonary hypertension, and injury after organ transplantation [80].”
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Self-citationAcute effect of a high nitrate diet on brain perfusion in older adults
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Self-citationBiology of nitrogen oxides in the gastrointestinal tract
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Self-citationInsulin says NO to cardiovascular disease
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NO-synthase independent NO generation in mammals
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Self-citationCURRENT NUTRITIONAL RECOMMENDATIONS AND NOVEL DIETARY STRATEGIES TO MANAGE SARCOPENIA
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Green Alternatives to Nitrates and Nitrites in Meat-based Products–A Review
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Self-citationMechanisms of nitrite bioactivation
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Self-citationNitrite and nitrate chemical biology and signalling
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Self-citationSodium nitrite: The “cure” for nitric oxide insufficiency
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Self-citationCross-talk Between Nitrate-Nitrite-NO and NO Synthase Pathways in Control of Vascular NO Homeostasis
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Self-citationAssociation of Dietary Nitrate Intake With Primary Open-Angle Glaucoma
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S-nitrosylation: integrator of cardiovascular performance and oxygen delivery
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Self-citationOlives and olive oil are sources of electrophilic fatty acid nitroalkenes
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Dietary nitrate supplementation improves revascularization in chronic ischemia
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Role of Heme Oxygenase as a Modulator of Heme-Mediated Pathways
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Sunlight Has Cardiovascular Benefits Independently of Vitamin D
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- Authors
- Lundberg, J. O., Gladwin, M. T., Ahluwalia, A., Benjamin, N., Bryan, N. S., Butler, A., Cabrales, P., Fago, A., Feelisch, M., Ford, P. C., Freeman, B. A., Frenneaux, M., Friedman, J., Kelm, M., Kevil, C. G., Kim-Shapiro, D. B., Kozlov, A. V., Lancaster, J. R., Lefer, D. J., McColl, K., McCurry, K., Patel, R. P., Petersson, J., Rassaf, T., Reutov, V. P., Richter-Addo, G. B., Schechter, A., Shiva, S., Tsuchiya, K., van Faassen, E. E., Webb, A. J., Zuckerbraun, B. S., Zweier, J. L., & Weitzberg, E.
- Affiliations
- Karolinska Institutet (SE)
- University of Pittsburgh (US)
- Queen Mary University of London (GB)
- University of Exeter (GB)
- Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases (US)
- University of St Andrews (GB)
- University of California San Diego (US)
- Aarhus University (DK)
- University of Warwick (GB)
- University of California, Santa Barbara (US)
- University of Birmingham (GB)
- Albert Einstein College of Medicine (US)
- Heinrich Heine University Düsseldorf (DE)
- Louisiana State University in Shreveport (US)
- Ludwig Boltzmann Institute for Traumatology, The Research Center in Cooperation with AUVA (AT)
- University of Alabama at Birmingham (US)
- Emory University (US)
- University of Glasgow (GB)
- Cleveland Clinic (US)
- Uppsala University (SE)
- Russian Academy of Sciences (RU)
- University of Oklahoma (US)
- National Institutes of Health (US)
- Tokushima University (JP)
- The Ohio State University (US)
- Corresponding author
- Lundberg, Jon O
- Weitzberg, Eddie
- ORCID
- Lundberg, Jon O
- Gladwin, Mark T
- Ahluwalia, Amrita
- Bryan, Nathan S
- Cabrales, Pedro
- Fago, Angela
- Feelisch, Martin
- Ford, Peter C
- Frenneaux, Michael
- Friedman, Joel
- Kelm, Malte
- Kevil, Christopher G
- Kozlov, Andrey V
- Lefer, David J
- McCurry, Kenneth
- Patel, Rakesh P
- Rassaf, Tienush
- Reutov, Valentin P
- Richter-Addo, George B
- Schechter, Alan
- Shiva, Sruti
- Tsuchiya, Koichiro
- Zuckerbraun, Brian S
- Zweier, Jay L
- Weitzberg, Eddie
- Venue
- Nature Chemical Biology
- Published
- 2009-12
- Volume
- 5
- Issue
- 12
- Pages
- 865-869
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- PMC
- PMC4038383
- OpenAlex
- W2128632568
- Cited by
- 617
- References
- 45
- Citations by year
- 2026: 23 · 2025: 19 · 2024: 22 · 2023: 33 · 2022: 36 · 2021: 43 · 2020: 36 · 2019: 29 · 2018: 45 · 2017: 39 · 2016: 41 · 2015: 60 · 2014: 45 · 2013: 40 · 2012: 50
- FWCI
- 23.20
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion)
- ePrints Soton (University of Southampton) (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- UEA Digital Repository (University of East Anglia) (submittedVersion)
- Funders
- Ikaria
- University of Pittsburgh
- Hemophilia Center of Western Pennsylvania
- British Heart Foundation (SP/08/006/25110)
- European Commission
- Karolinska Institutet
- National Heart, Lung, and Blood Institute (R01HL064937, R37HL058091, R01HL058115, R01HL080482)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
- Keywords
- nitrate, nitrite, nitric oxide, nitrate-nitrite-nitric oxide pathway, blood flow regulation, signal transduction, hypoxia, energy metabolism, dietary nitrate, therapeutics
- MeSH terms
- Animals, Diet, Energy Metabolism, Humans, Mitochondria, Nitrates, Nitric Oxide, Nitrites, Signal Transduction
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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.
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