Nitrite in organ protection
Open accessAbstract
In the last decade, the nitrate‐nitrite‐nitric oxide pathway has emerged to therapeutical importance. Modulation of endogenous nitrate and nitrite levels with the subsequent S‐nitros(yl)ation of the downstream signalling cascade open the way for novel cytoprotective strategies. In the following, we summarize the actual literature and give a short overview on the potential of nitrite in organ protection.
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Written from the paper’s full text.
TL;DR
This review summarizes the nitrate–nitrite–nitric oxide pathway and argues that nitrite can be bioactivated to NO under hypoxia/ischaemia, providing cytoprotection in heart, vessel, brain, liver, lung, kidney, and shock/crush models. It highlights both promising preclinical and early clinical findings and unresolved questions about dosing, timing, tissue conversion, and potential peroxynitrite-mediated harm.
Key findings
- Nitrite has three main sources: endogenous NO oxidation, oral bacterial reduction of dietary nitrate, and dietary nitrite. Healthy fasted human plasma nitrite is 0.1–0.5 µM; Tibetan highlanders had ~10 µM, 50-fold higher than sea-level humans, and rodents can reach ~10 µM.
- Nitrite is reduced to bioactive NO under hypoxic/acidic conditions by haemoglobin, myoglobin, neuroglobin, cytoglobin, xanthine oxidoreductase, eNOS, mitochondrial enzymes, and other pathways; myoglobin-dependent bioactivation is important in cardiac ischaemia/reperfusion.
- In mice, sodium nitrite reduced myocardial infarct size by 67%; dietary nitrite supplementation for 7 days reduced infarct size by 48%; nitrate supplementation also reduced infarct size. Protection was abolished in myoglobin knockout mice, and in the authors’ experiments nitrite did not reduce infarct size in cyclophilin D knockout mice.
- Organ protection is reported across models: brain I/R infarction volume was reduced when nitrite was given within 3 h after transient occlusion and 1.5 h in permanent occlusion in rats; subarachnoid haemorrhage-induced vasospasm in macaques was reversed by IV nitrite (27 vs. 46% in vehicle); liver, lung, kidney, crush syndrome, and shock models also show benefits, though some renal and stroke studies were negative or depended on NO synthase status.
Methods
- Narrative review of the literature on nitrite biology and organ protection, not a systematic review or meta-analysis.
- Synthesizes mammalian physiology, animal models of ischaemia/reperfusion and other injuries, and human studies/trials, including dietary nitrate/nitrite interventions and inhaled nitrite.
- Main analysis is qualitative: describes sources, bioactivation pathways, mechanisms, organ-specific evidence, and clinical translation; includes some unpublished mouse experiments in Figure 2.
Limitations
- Stated: the protective or detrimental effect of NO in ischaemia/reperfusion may depend on local NO and superoxide concentrations and whether pathological peroxynitrite forms; whether nitrite treatment may cause pathological NO accumulation in ischaemic myocardium is not known and “may be a limitation.”
- Stated: the relevance and function of several nitrite reductases “have still to be elucidated”; the exact role of erythrocytes in vascular flow regulation is “still under debate”; whether nitrite treatment would reverse altered NO metabolism in hyperlipidaemia “has not been investigated so far.”
- Evident: as a narrative review, it lacks systematic search/quality assessment; some cited experiments are unpublished; mixed and negative results across stroke, kidney, and timing/dose conditions are acknowledged but not resolved.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
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Cites
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Claims the paper makes
0 of 89 cited sources checked · 0 supported · 0 flagged
- Premisecitation
Nitrite alone was demonstrated to protect phages against X-ray radiation injury, presumably acting as a reducing agent.
“As early as 1956, nitrite alone was demonstrated to protect phages against X-ray radiation injury, presumably acting as a reducing agent (Bachofer, 1956).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Bachofer, 1956
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- Premisecitation
Intravenous nitrate infusion, when given at the same dose as nitrite, conferred no reduction in infarct size following ischaemia/reperfusion in rat hearts.
“These findings were confirmed in rat hearts in vitro and in vivo, which also demonstrated that intravenous nitrate infusion -when given at the same dose as nitriteconferred no reduction in infarct size following ischaemia/ reperfusion (Baker et al., 2007).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Baker et al., 2007
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- Premisecitation
Nitrite generated from nitrate by oral bacteria and then converted to NO in the stomach was suggested to play an important role in the protection of gastric mucosa from hazardous stress.
“Nitrite, generated from nitrate by oral bacteria 'the so called enterosalivary cycle', and then converted to NO (Benjamin et al., 1994;Lundberg et al., 1994;2009;2006;2008;Kapil et al., 2010a) in the stomach was also suggested to play an important role in the protection of gastric mucosa from hazardous stress (Miyoshi et al., 2003).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Miyoshi et al., 2003
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- Premisecitation
Nitrate has blood pressure lowering effects in humans with hypertension when applied in lower doses.
“In a recent study, it has been demonstrated that nitrate has also blood pressure lowering effects in humans with hypertension when applied in lower doses (Ghosh et al., 2013).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Ghosh et al., 2013
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- Premisecitation
The cytoprotective effects of nitrate were completely abolished when mice received a mouthwash twice daily, eradicating the commensal bacterial flora necessary to reduce nitrate to nitrite.
“The cytoprotective effects of nitrate were completely abolished, however, when mice received a mouthwash twice daily, using a commercially available antibacterial solution that eradicated the commensal bacterial flora which is necessary to reduce nitrate to nitrite (Hendgen-Cotta et al., 2012).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Hendgen-Cotta et al., 2012
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- Premisecitation
In a mouse hind-limb model, dietary nitrate improved vascular regeneration compared to placebo.
“In a mouse hind-limb model, dietary nitrate improved vascular regeneration compared to placebo (Hendgen-Cotta et al., 2012).”
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- Premisecitation
The oxygen cost during standardized exercise was reduced after dietary nitrate supplementation compared to placebo.
“In further studies, Larsen et al. found that the oxygen cost during standardized exercise was reduced after dietary nitrate supplementation compared to placebo (Larsen et al., 2007;Weitzberg et al., 2010).”
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- cites Weitzberg et al., 2010
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- Interpretationcitation
Nitrite-derived NO may contribute to protection against UV-induced cell damage.
“suggesting that nitrite-derived NO may contribute to protection against UV-induced cell damage (Suschek et al., 2006).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Suschek et al., 2006
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- Premisecitation
Nitrite-mediated protection was independent of endothelial nitric oxide synthase.
“Nitrite-mediated protection was independent of endothelial nitric oxide synthase (Webb et al., 2004;Duranski et al., 2005).”
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- cites Duranski et al., 2005
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Sodium nitrite (without acidification) administered in mice undergoing ischaemia/reperfusion reduced myocardial infarct size by 67%.
“Therefore, sodium nitrite (without acidification) was administered in mice undergoing ischaemia/reperfusion and indeed nitrite reduced myocardial infarct size by 67%.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Duranski et al., 2005
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- Premisenone given
High dietary nitrate concentrations reduce blood pressure to a level similar to that achieved with a Mediterranean diet.
“Whereas the active compound being responsible for this protection has not been identified so far, it is important to note that high dietary nitrate concentrations reduce blood pressure to a level similar to that achieved with a Mediterranean diet.”
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Diastolic blood pressure was reduced by 4 mmHg after ingestion of a sodium-nitrate drink compared to placebo.
“Diastolic blood pressure was reduced by 4 mmHg after ingestion of a sodium-nitrate drink compared to placebo.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Larsen et al., 2006
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- Premisecitation
Acidified sodium nitrite reduced infarct size in a cat model of 90 min ischaemia and 270 min reperfusion when intravenous infusion was started 30 min after coronary artery occlusion.
“Acidified sodium nitrite, a releaser of NO, reduced infarct size (expressed as percentage of the area at risk) in a cat model of 90 min ischaemia and 270 min reperfusion when intravenous infusion of acidified sodium nitrite was started 30 min after coronary artery occlusion (Johnson et al., 1990).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Johnson et al., 1990
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- Premisecitation
The reduction in infarct size following administration of nitrite was completely abolished in myoglobin knockout mice.
“since the reduction in infarct size following administration of nitrite was completely abolished in myoglobin knockout mice (Hendgen-Cotta et al., 2008).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Hendgen-Cotta et al., 2008
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- Premisecitation
Nitrite affects cytochrome P450 activities, heat shock protein 70 and heme oxygenase-1 expression in a variety of tissues.
“Furthermore, nitrite affects cytochrome P450 activities, heat shock protein 70 and heme oxygenase-1 expression in a variety of tissues (Bryan et al., 2005).”
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- Premisecitation
Cardioprotective signalling of nitrite in rats involved the activation of NADPH oxidase and ATP-dependent potassium channels.
“Cardioprotective signalling of nitrite in rats involved the activation of NADPH oxidase and ATP-dependent potassium channels (Baker et al., 2007).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Baker et al., 2007
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- Premisecitation
Nitrite modifies and inhibits complex I by post-translational S-nitrosation.
“The mechanism how nitrite exerts its cytoprotective effects has been described earlier (Shiva et al., 2007); nitrite modifies and inhibits complex I by post-translational S-nitrosation.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Shiva et al., 2007
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- Premisecitation
Bioactivation of nitrite required increased activity of xanthine dehydrogenase and xanthine oxidase during ischaemia in rats.
“Bioactivation on nitrite required increased activity of xanthine dehydrogenase and xanthine oxidase during ischaemia in rats (Baker et al., 2007)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Baker et al., 2007
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- Premisecitation
Prolonged application of nitrite improved revascularization in chronically ischaemic peripheral muscles.
“and prolonged application of nitrite improved revascularization in chronically ischaemic peripheral muscles (Hendgen-Cotta et al., 2012), potentially through mobilization of circulating angiogenic cells (Heiss et al., 2012).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Hendgen-Cotta et al., 2012
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- cites Heiss et al., 2012
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- Interpretationreasoning
The protective or detrimental effect of NO from whatever sources in ischaemia/reperfusion may largely depend on the local concentrations NO and superoxide and their ratio, if it favours formation of pathological concentrations of peroxynitrite or not.
“Therefore, the protective or detrimental effect of NO from whatever sources in ischaemia/reperfusion may largely depend on the local concentrations NO and superoxide and their ratio, if it favours formation of pathological concentrations of peroxynitrite or not (see for reviews : Ferdinandy and Schulz, 2003;Ferdinandy, 2006;Pacher et al., 2007).”
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- cites Ferdinandy, 2006
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- cites Pacher et al., 2007
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- Premisecitation
A single dose of intravenous nitrite given at cardiopulmonary resuscitation improved cardiac function, survival and neurological outcomes in a placebo-controlled study in a mouse model of cardiac arrest.
“Furthermore, a single dose of intravenous nitrite given at cardiopulmonary resuscitation improved cardiac function, survival and neurological outcomes in a placebo-controlled study in a mouse model of cardiac arrest (Dezfulian et al., 2009).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Dezfulian et al., 2009
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- Premisecitation
In a clinical study by Higashino et al. (2007), a male group of hypertensive patients with complex co-morbidities of diabetes, hyperlipidaemia and renal disorder had higher nitrate/nitrite levels compared with a normotensive control group.
“In a clinical study by Higashino et al. (2007), a male group of hypertensive patients with complex co-morbidities of diabetes, hyperlipidaemia and renal disorder had higher nitrate/nitrite levels compared with a normotensive control group.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Higashino et al., 2007
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The supplementation of a low dose of nitrite through local intra-arterial infusion attenuated ischaemia-reperfusion-induced vasoconstriction, arteriole stagnation, and capillary no-reflow during reperfusion.
“The supplementation of a low dose of nitrite through local intra-arterial infusion, attenuated ischaemiareperfusion-induced vasoconstriction, arteriole stagnation, and capillary no-reflow during reperfusion (Wang et al., 2011)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Wang et al., 2011
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- Premisecitation
In cynomolgus macaques, subarachnoid haemorrhage-induced vasospasm created via implantation of a blood clot was reversed by intravenous nitrite infusion (27 vs. 46% in vehicle).
“In cynomolgus macaques, subarachnoid haemorrhageinduced vasospasm created via implantation of a blood clot was reversed by intravenous nitrite infusion (27 vs. 46% in vehicle) (Pluta et al., 2005;Fathi et al., 2011).”
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- cites Fathi et al., 2011
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- Premisecitation
Carboxy-PTIO, a direct NO scavenger, abolished the neuroprotective effects of nitrite.
“Carboxy-PTIO, a direct NO scavenger, abolished the neuroprotective effects of nitrite (Jung et al., 2006).”
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- Premisecitation
When nitrite was injected intravenously 3 h after intracerebral haemorrhage induction in rats, most doses of nitrite provided no beneficial effect on behavioural deficits, brain oedema and hematoma volumes.
“When nitrite was injected intravenously 3 h after intracerebral haemorrhage induction in rats, most doses of nitrite provided no beneficial effect on behavioural deficits, brain oedema and hematoma volumes.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Jung et al., 2011
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- Premisecitation
Pathological accumulation of NO in myocardial ischaemia may yield high flux of non-enzymatic formation of peroxynitrite upon reperfusion when there is a burst of superoxide generation.
“Nevertheless, it should be noted here that pathological accumulation of NO in myocardial ischaemia may yield high flux of non-enzymatic formation of peroxynitrite upon reperfusion when there is a burst of superoxide generation.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Yasmin et al., 1997
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- cites Csonka et al., 1999
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- cites Csonka et al., 2001
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Under hypoxic conditions, caspase-3 was de-nitrosylated and the resulting activation of caspase-3 and subsequent cleavage of β-catenin was critical for hypoxia-induced increased endothelial permeability.
“Under hypoxic conditions, caspase-3 was de-nitrosylated and the resulting activation of caspase-3 and subsequent cleavage of β-catenin was critical for hypoxia-induced increased endothelial permeability.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Lai et al., 2011
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- Premisecitation
The protective effect of topically administered sodium nitrite in that rat renal ischaemia-reperfusion model was abolished by pretreatment with a NO scavenger.
“an effect that was abolished by pretreatment with a NO scavenger.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Tripatara et al., 2007
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- Premisecitation
In mice deficient for endothelial NO synthase, nitrite treatment under these conditions even enhanced renal dysfunction.
“nitrite treatment under these conditions even enhanced renal dysfunction”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Milsom et al., 2010
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- Premisecitation
Treatment with nebulized nitrite, either once or three times per week prevented the development of pulmonary arterial hypertension.
“Treatment with nebulized nitrite, either once or three times per week prevented the development of pulmonary arterial hypertension.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Zuckerbraun et al., 2010
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- cites Zuckerbraun et al., 2011
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- Premisecitation
In rat kidney, NO was generated from nitrite during the following 40 min of ischaemia.
“In rat kidney, NO was generated from nitrite during following 40 min of ischaemia”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Okamoto et al., 2005
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- Premisecitation
In mice subjected to bilateral renal ischaemia for 30 min and 24 h reperfusion, renal dysfunction, damage and inflammation were increased.
“Similarly, in mice subjected to bilateral renal ischaemia for 30 min and 24 h reperfusion, renal dysfunction, damage and inflammation were increased”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Milsom et al., 2010
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- Premisecitation
In rat kidney, the generation of NO from nitrite during ischaemia was independent of NO synthase activity.
“which was independent from NO synthase activity”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Okamoto et al., 2005
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- Premisecitation
Renal tissue homogenates produced NO from nitrite mainly through the activity of xanthine oxidoreductase.
“Renal tissue homogenates produced NO from nitrite mainly through the activity of xanthine oxidoreductase”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Tripatara et al., 2007
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- Premisereasoning
In male rats undergoing unilateral nephrectomy followed by 45 min of ischaemia of the contralateral kidney, nitrite infusion before or during ischaemia did not attenuate the loss of brush border, the extent of tubular necrosis or red blood cell extravasation 24 and 48 h after acute renal injury.
“in male rats undergoing unilateral nephrectomy followed by 45 min of ischaemia of the contralateral kidney, nitrite infusion before or during ischaemia did not attenuate the loss of brush border, the extent of tubular necrosis or red blood cell extravasation 24 and 48 h after acute renal injury.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Basireddy et al., 2006
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- Interpretationreasoning
Sufficient metabolism of nitrite to NO appears to be a prerequisite to obtain kidney protection.
“Thus, sufficient metabolism of nitrite to NO appears to be a prerequisite to obtain kidney protection.”
Quote in the paperSubstantial claim - Premisecitation
Within 1 min of reperfusion, kidney nitrite levels were raised in that mouse model.
“Within 1 min of reperfusion kidney nitrite levels were raised.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Milsom et al., 2010
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- Interpretationcitation
The generation of NO from nitrite in rat kidney during ischaemia differs from mice.
“and thus differs from mice”
Quote in the paperSubstantial claim - Premisecitation
In rats subjected to unilateral nephrectomy and chronic high-salt diet, dietary nitrate prevented proteinuria and histological signs of renal injury.
“However, in rats subjected to unilateral nephrectomy and chronic high-salt diet, dietary nitrate prevented proteinuria and histological signs of renal injury”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Carlstrom et al., 2011
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- Premisecitation
Nitrite protects against ventilator-induced lung injury in rats.
“Further experimental studies demonstrated that nitrite protects against ventilatorinduced lung injury in rats (Pickerodt et al., 2012).”
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- Premisecitation
The beneficial effects of nitrite were absent or reduced in mice deficient for endothelial NO synthase.
“The beneficial effects of nitrite were absent or reduced in mice deficient for endothelial NO synthase”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Milsom et al., 2010
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- Premisecitation
In that rat model, nitrate infusion appeared to worsen renal injury.
“Interestingly, nitrate infusion appeared to worsen renal injury”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Basireddy et al., 2006
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- Premisecitation
In rats subjected to 60 min of bilateral renal ischaemia and 6 h of reperfusion, sodium nitrite administered topically 1 min before reperfusion significantly attenuated renal dysfunction and injury.
“In rats subjected to 60 min of bilateral renal ischaemia and 6 h of reperfusion sodium nitrite administered topically 1 min before reperfusion significantly attenuated renal dysfunction and injury”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Tripatara et al., 2007
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- Interpretationreasoning
Taken together, the nitrate-nitrite-NO pathway appears to play a crucial role in protecting the heart, vessel, brain, kidney and lung against ischaemia/reperfusion injury.
“Taken together, the nitrate-nitrite-NO pathway appears to play a crucial role in protecting the heart, vessel, brain, kidney and lung against ischaemia/reperfusion injury.”
Quote in the paperSubstantial claim - Premisecitation
In rats subjected to bilateral hind limb compression for 5 h followed by reperfusion for 0 to 6 h, nitrite administration reduced the extent of rhabdomyolysis markers such as potassium, lactate dehydrogenase and creatine phosphokinase.
“In rats subjected to bilateral hind limb compression for 5 h followed by reperfusion for 0 to 6 h, nitrite administration reduced the extent of rhabdomyolysis markers such as potassium, lactate dehydrogenase and creatine phosphokinase.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Murata et al., 2012
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- Rests on an assumption: Limb muscle compression and subsequent reperfusion are the causative factors in developing a crush syndrome.
- Premisecitation
In those rats, signs of cardiac hypertrophy and fibrosis were attenuated.
“Moreover, signs of cardiac hypertrophy and fibrosis were attenuated”
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- Premisecitation
In that rat crush injury model, nitrite treatment resulted in a dose-dependent improvement of survival rate.
“finally resulting in a dose-dependent improvement of survival rate”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Murata et al., 2012
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- Rests on an assumption: Limb muscle compression and subsequent reperfusion are the causative factors in developing a crush syndrome.
- Premisecitation
In that rat crush injury model, nitrite treatment reduced inflammatory activities in muscle and lung tissues.
“Nitrite treatment also reduced the inflammatory activities in muscle and lung tissues”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Murata et al., 2012
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- Rests on an assumption: Limb muscle compression and subsequent reperfusion are the causative factors in developing a crush syndrome.
- Premisecitation
The nitrite-dependent improvement in symptoms in that mouse shock model was dependent on the soluble guanylate cyclase system.
“but was dependent on the soluble guanylate cyclase system”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Cauwels et al., 2009
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- Premisecitation
Nitrite could also provide protection against toxicity induced by Gram-negative lipopolysaccharide.
“Nitrite could also provide protection against toxicity induced by Gram-negative lipopolysaccharide”
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- cites Cauwels and Brouckaert, 2011
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The nitrite-dependent improvement in symptoms in that mouse shock model was not associated with inhibition of mitochondrial respiratory complex activity.
“Nitrite-dependent improvement in symptoms was not associated with inhibition of mitochondrial respiratory complex activity”
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- Premisecitation
In a mouse shock model induced by a lethal tumour necrosis factor challenge, nitrite treatment significantly attenuated hypothermia, mitochondrial damage, oxidative stress and dysfunction, tissue infarction and mortality.
“Similarly, in a mouse shock model induced by a lethal tumour necrosis factor challenge, nitrite treatment significantly attenuated hypothermia, mitochondrial damage, oxidative stress and dysfunction, tissue infarction and mortality.”
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- Classified as probably not a substantial claim. 1
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Findingown dataIn our recent experiments, nitrite reduced infarct size following ischaemia/reperfusion in wild-type mice but not in Cyp D knockout mice.
“In our recent experiments, nitrite reduced infarct size following ischaemia/reperfusion in wild-type mice but not in Cyp D knockout mice suggesting that the above mechanism might hold true also in hearts in vivo (Figure 2).”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationThe presence of nitrite, but not nitrate, reduced the extent of apoptosis in cultured endothelial cells during UVA-irradiation in a concentration-dependent manner by inhibiting lipid peroxidation; this protective effect was abolished by simultaneous administration of a NO scavenger.
“Later on, the presence of nitrite, but not nitrate, reduced the extent of apoptosis in cultured endothelial cells during UVA-irradiation in a concentration-dependent manner by inhibiting lipid peroxidation; this protective effect was abolished by simultaneous administration of a NO scavenger (Suschek et al., 2003)”
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PremisecitationThe stomach content, plasma, heart and liver nitrite levels were significantly reduced after dietary nitrate and nitrite depletion, and could be restored to normal levels with nitrite supplementation.
“Indeed, the stomach content, but also the plasma, heart (Samouilov et al., 2007) and liver nitrite levels were significantly reduced after dietary nitrate and nitrite depletion (Feelisch et al., 2002), and could be restored to normal levels with nitrite supplementation (Bryan et al., 2007).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Feelisch et al., 2002
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- cites Bryan et al., 2007
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PremisecitationNitrate supplementation reversed endothelial dysfunction in healthy subjects with endothelial dysfunction, an effect associated with an increase in circulating vascular progenitor cells, endogenous nitrite and S-nitrosothiol levels.
“Applying the protocol of Larsen et al. (2006), the effects of dietary nitrate supplementation on healthy subjects with endothelial dysfunction was investigated; nitrate supplementation reversed endothelial dysfunction, an effect that was associated with an increase in circulating vascular progenitor cells (Heiss et al., 2012), endogenous nitrite and S-nitrosothiol levels.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Heiss et al., 2012
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PremisecitationThis prevents mitochondrial permeability transition pore opening and cytochrome c release.
“This prevents mitochondrial permeability transition pore opening and cytochrome c release (Shiva et al., 2007).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Shiva et al., 2007
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PremisecitationMice fed a standard diet with supplementation of nitrite in their drinking water for 7 days exhibited significantly higher plasma and myocardial levels of nitrite, nitroso and nitrosyl-heme and displayed a 48% reduction in infarct size following ischaemia/reperfusion.
“Also mice fed a standard diet with supplementation of nitrite in their drinking water for 7 days exhibited significantly higher plasma and myocardial levels of nitrite, nitroso and nitrosyl-heme and displayed a 48% reduction in infarct size following ischaemia/reperfusion.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Bryan et al., 2007
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PremisecitationIn humans, endothelial dysfunction is associated with reduced circulating nitroso compounds and the lack to increase plasma nitrite levels during exercise.
“In humans, endothelial dysfunction is also associated with reduced circulating nitroso compounds (Heiss et al., 2006) and the lack to increase plasma nitrite levels during exercise (Lauer et al., 2008;Rassaf et al., 2010)”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites Heiss et al., 2006
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- cites Lauer et al., 2008
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- cites Rassaf et al., 2010
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PremisecitationIn hyperlipidaemia, NO-mediated cardioprotective pathways are disrupted and heat-shock protein 70 response is diminished.
“In hyperlipidaemia, when NO bioavailability of the heart is diminished possibly due to oxidative stress-induced formation of peroxynitrite (Onody et al., 2003;Csont et al., 2007), NO-mediated cardioprotective pathways are disrupted (Giricz et al., 2009;Kupai et al., 2009); (for reviews see Ferdinandy, 2003;Ferdinandy et al., 2007), and heat-shock protein 70 response is diminished (Csont et al., 2”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Onody et al., 2003
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- cites Csont et al., 2007
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- cites Giricz et al., 2009
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PremisecitationCyclophilin D undergoes S-nitrosylation on cysteine 203, leading to reduced MPTP opening in mice wild-type fibroblast but not in Cyp D knockout fibroblast.
“Cyclophilin D (Cyp D), which accelerates MPTP opening, undergoes S-nitrosylation on cysteine 203 of Cyp D, leading to reduced MPTP opening in mice wild-type fibroblast but not in Cyp D knockout fibroblast (Nguyen et al., 2011).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Nguyen et al., 2011
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PremisecitationThis dampens electron transfer and reduces reactive oxygen species generation and ameliorates oxidative inactivation of complexes II-IV and aconitase.
“This dampens electron transfer and reduces reactive oxygen species generation and ameliorates oxidative inactivation of complexes II-IV and aconitase.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Shiva et al., 2007
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PremisecitationNitrite supplementation in the drinking water for 1 week restored NO homeostasis in eNOS knockout mice and protected against ischaemia/reperfusion injury.
“Nitrite supplementation in the drinking water for 1 week restored NO homeostasis also in eNOS knockout mice, normally having reduced NO and NO metabolites, and protected against ischaemia/reperfusion injury (Bryan et al., 2008).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Bryan et al., 2008
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May combine two claims.
PremisecitationSupplemental nitrate in the drinking water for 7 days also increased blood and tissue NO products and significantly reduced infarct size.
“Supplemental nitrate in the drinking water for 7 days also increased blood and tissue NO products and significantly reduced infarct size (Bryan et al., 2007).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Bryan et al., 2007
Not checked in the free run.
May combine two claims.
PremisecitationNitrite-mediated protection of the liver was dependent on NO generation and independent of endothelial NO synthase and heme oxygenase-1 enzyme activities.
“Nitrite-mediated protection of the liver was dependent on NO generation and independent of endothelial NO synthase and heme oxygenase-1 enzyme activities (Duranski et al., 2005).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Duranski et al., 2005
Not checked in the free run.
May combine two claims.
PremisecitationA high dose of nitrite decreased hematoma volume, but not brain oedema.
“A high dose of nitrite, however, decreased hematoma volume, but not brain oedema (Jung et al., 2011).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Jung et al., 2011
Not checked in the free run.
May combine two claims.
PremisecitationNitrite reduced the infarction volume and enhanced functional recovery when administered within 3 h after transient intraluminal occlusion and 1.5 h in the permanent occlusion model in rats.
“Varying the time point of infusion further indicated that nitrite reduced the infarction volume and enhanced functional recovery when nitrite was administered within 3 h after transient intraluminal occlusion and 1.5 h in the permanent occlusion model in rats respectively (Jung et al., 2009).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Jung et al., 2009
Not checked in the free run.
May combine two claims.
PremisecitationIn a cerebral ischaemia/reperfusion injury model in rats, intravenous nitrite infusion at the time of reperfusion reduced infarction volume and enhanced local cerebral blood flow and functional recovery.
“In a cerebral ischaemia/reperfusion injury model, using the intraluminal occlusion of the middle cerebral artery for 90 min in rats, intravenous nitrite infusion at the time of reperfusion reduced infarction volume (measured at 24 h) and enhanced local cerebral blood flow and functional recovery.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Jung et al., 2006
Not checked in the free run.
May combine two claims.
PremisecitationIn hepatic ischaemia/reperfusion injury in mice, nitrite exerted profound dose-dependent protective effects on cellular necrosis and apoptosis, with highly significant protective effects observed at near-physiological nitrite concentrations.
“In hepatic ischaemia/reperfusion injury in mice, nitrite exerted profound dose-dependent protective effects on cellular necrosis and apoptosis, with highly significant protective effects observed at near-physiological nitrite concentrations.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Duranski et al., 2005
Not checked in the free run.
May combine two claims.
PremisecitationNitrite treatment led to S-nitros(yl)ation and the inactivation of caspase-3, suppressing the barrier dysfunction of endothelia caused by hypoxia.
“Nitrite treatment led to S-nitros(yl)ation and the inactivation of caspase-3, suppressing the barrier dysfunction of endothelia caused by hypoxia.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Lai et al., 2011
Not checked in the free run.
May combine two claims.
PremisecitationIn patients undergoing orthotopic liver transplantation, inhaled NO doubled plasma nitrite levels, which improved liver function and reduced liver injury.
“In patients undergoing orthotopic liver transplantation, inhaled NO doubled plasma nitrite levels, which improved liver function and reduced liver injury (Lang et al., 2007).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Lang et al., 2007
Not checked in the free run.
May combine two claims.
PremisecitationIn mice with cardiac-specific overexpression of the human endothelial NO synthase gene, nitrite, nitrate and nitrosothiols levels were increased in the heart, plasma and liver, and these mice displayed a significant reduction in hepatic ischemia/reperfusion injury compared with wild-type littermates.
“Indeed, in mice with cardiac-specific overexpression of the human endothelial NO synthase gene nitrite, nitrate and nitrosothiols levels were increased in the heart, plasma and liver.These mice displayed a significant reduction in hepatic ischemia/reperfusion injury compared with wild-type littermates (Elrod et al., 2008).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Elrod et al., 2008
Not checked in the free run.
May combine two claims.
PremisecitationLiver enzyme release was significantly reduced with nitrite supplementation, the protective effect being more efficacious with longer cold preservation times.
“Liver enzyme release was significantly reduced with nitrite supplementation, the protective effect being more efficacious with longer cold preservation times.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Li et al., 2012
Not checked in the free run.
May combine two claims.
PremisecitationIn a mouse model of pulmonary arterial hypertension, inhaled nebulized nitrite has been demonstrated to be a potent pulmonary vasodilator that can effectively prevent or reverse pulmonary arterial hypertension.
“In a mouse model of pulmonary arterial hypertension, inhaled nebulized nitrite has been demonstrated to be a potent pulmonary vasodilator that can effectively prevent or reverse pulmonary arterial hypertension (Zuckerbraun et al., 2011).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Zuckerbraun et al., 2011
Not checked in the free run.
May combine two claims.
PremisecitationLiver histological examination demonstrated better preserved morphology, and less apoptosis with nitrite treatment and liver graft acute function post-transplantation was improved.
“Liver histological examination demonstrated better preserved morphology, and less apoptosis with nitrite treatment and liver graft acute function post-transplantation was improved (Li et al., 2012).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Li et al., 2012
Not checked in the free run.
May combine two claims.
PremisecitationNitrite treatment 2 weeks into the hypoxic exposure, after the establishment of pulmonary hypertension, halted the progression of pulmonary hypertension and reversed increases in right ventricular pressure.
“Additionally, nitrite treatment 2 weeks into the hypoxic exposure, after the establishment of pulmonary hypertension, halted the progression of pulmonary hypertension and reversed increases in right ventricular pressure (Zuckerbraun et al., 2010;2011).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Zuckerbraun et al., 2010
Not checked in the free run.
- cites Zuckerbraun et al., 2011
Not checked in the free run.
May combine two claims.
PremisecitationIn those mice, renal dysfunction, damage and inflammation were all reduced following nitrite treatment 1 min prior to reperfusion.
“these effects were all reduced following nitrite treatment 1 min prior to reperfusion.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Milsom et al., 2010
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
InterpretationreasoningNitrite treatment may be advantageous in well-known NO deficient states such as hyperlipidaemia.
“Nitrite treatment may be advantageous in well-known NO deficient states such as, for example hyperlipidaemia.”
Quote in the paperNot a substantial claim- Rests on an assumption: Hyperlipidaemia is a well-known NO deficient state.
May combine two claims.
InterpretationreasoningTiming and dose of nitrite application as well as the potential to convert nitrite to NO in the tissue are important to obtain a reduction in injury.
“Timing and dose of nitrite application as well as the potential to convert nitrite to NO in the tissue are important to obtain a reduction in injury.”
Quote in the paperSubstantial claim
The paper relies on this without support.
Limb muscle compression and subsequent reperfusion are the causative factors in developing a crush syndrome.
“Limb muscle compression and subsequent reperfusion are the causative factors in developing a crush syndrome.”
The paper relies on this without support.
Hyperlipidaemia is a well-known NO deficient state.
“well-known NO deficient states such as, for example hyperlipidaemia”
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?
Nitrite is protective against ischemia/reperfusion and other forms of injury in multiple tissues and organs.
“Numerous investigations have reported that nitrite is protective against I/R and other forms of injury in multiple tissues and organs (81, 125, 188), as reviewed extensively elsewhere (157).”
From Inorganic nitrite supplementation for healthy arterial aging (2014) · cites this paper as [157]
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“However, in rats subjected to unilateral nephrectomy and chronic high-salt diet, dietary nitrate prevented proteinuria and histological signs of renal injury (Carlstrom et al., 2011).”
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Self-citationTissue Processing of Nitrite in Hypoxia
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Physiological Roles of Xanthine Oxidoreductase
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Self-citationRole of the anion nitrite in ischemia-reperfusion cytoprotection and therapeutics
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“However, more nitrite reducing pathways are available under ischaemic/hypoxic conditions (for review, see Dezfulian et al., 2007; Sinha et al., 2008; Shiva et al., 2011; Tota et al., 2011).”
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“for 1 week restored NO homeostasis also in eNOS knockout mice, normally having reduced NO and NO metabolites, and protected against ischaemia/reperfusion injury (Bryan et al., 2008).”
BackgroundNitric oxide synthase reduces nitrite to NO under anoxia
Vanin, A. F., Bevers, L. M., Slama-Schwok, A., & van Faassen, E. E. (2007) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-006-6374-2 · Cited by 151 · see citing works
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Self-citationNitric oxide synthase-derived plasma nitrite predicts exercise capacity
Rassaf, T., Lauer, T., Heiss, C., Balzer, J., Mangold, S., Leyendecker, T., Rottler, J., Drexhage, C., Meyer, C., & Kelm, M. (2007) · British Journal of Sports Medicine · doi:10.1136/bjsm.2007.035758 · Cited by 122 · see citing works
Self-citationPlasma Nitroso Compounds Are Decreased in Patients With Endothelial Dysfunction
Heiß, C., Lauer, T., Dejam, A., Kleinbongard, P., Hamada, S., Rassaf, T., Matern, S., Feelisch, M., & Kelm, M. (2006) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2005.06.089 · Cited by 115 · see citing works
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Dietary nitrate supplementation improves revascularization in chronic ischemia
Hendgen-Cotta, U. B., Luedike, P., Totzeck, M., Kropp, M., Schicho, A., Stock, P., Rammos, C., Niessen, M., Heiss, C., Lundberg, J. O., et al. (2012) · Circulation · doi:10.1161/circulationaha.112.112912 · Cited by 110 · see citing works
Self-citationPositive effects of nitric oxide on left ventricular function in humans
Rassaf, T. (2006) · European Heart Journal · doi:10.1093/eurheartj/ehl096 · Cited by 102 · see citing works
Self-citationKupai, K., Csonka, C., Fekete, V., et al. (2009) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00484.2009 · Cited by 99 · see citing works
Zuckerbraun, B. S., George, M. P., & Gladwin, M. T. (2010) · Cardiovascular Research · doi:10.1093/cvr/cvq370 · Cited by 97 · see citing works
Inorganic nitrate and the cardiovascular system
Kapil, V., Webb, A. J., & Ahluwalia, A. (2010) · Heart · doi:10.1136/hrt.2009.180372 · Cited by 90 · see citing works
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Self-citationMyoglobin Protects the Heart from Inducible Nitric-oxide Synthase (iNOS)-mediated Nitrosative Stress
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Plasma nitrite reserve and endothelial function in the human forearm circulation
Rassaf, T., Heiss, C., Hendgen-Cotta, U., Balzer, J., Matern, S., Kleinbongard, P., Lee, A., Lauer, T., & Kelm, M. (2006) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2006.04.006 · Cited by 86 · see citing works
Self-citationMyocardial protection by nitrite
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Cauwels, A., Buys, E. S., Thoonen, R., Geary, L., Delanghe, J., Shiva, S., & Brouckaert, P. (2009) · Journal of Experimental Medicine · doi:10.1084/jem.20091236 · Cited by 80 · see citing works
Dietary inorganic nitrate mobilizes circulating angiogenic cells
Heiß, C., Meyer, C. G., Totzeck, M., Hendgen-Cotta, U. B., Heinen, Y., Luedike, P., Keymel, S., Ayoub, N., Lundberg, J. O., Weitzberg, E., et al. (2012) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2012.02.051 · Cited by 78 · see citing works
Self-citationPeroxynitrite: just an oxidative/nitrosative stressor or a physiological regulator as well?
Ferdinándy, P. (2006) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0706693 · Cited by 74 · see citing works
Dietary nitrate inhibits stress-induced gastric mucosal injury in the rat
Miyoshi, M., Kasahara, E., Park, A.-M., Hiramoto, K., Minamiyama, Y., Takemura, S., Sato, E. F., & Inoue, M. (2003) · Free Radical Research · doi:10.1080/1071576021000086632 · Cited by 74 · see citing works
Unmasking the Janus face of myoglobin in health and disease
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Self-citationNitrite, a naturally occurring precursor of nitric oxide that acts like a ‘prodrug’
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Effects of sodium nitrite on ischemia–reperfusion injury in the rat kidney
Basireddy, M., Isbell, T. S., Teng, X., Patel, R. P., & Agarwal, A. (2006) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00334.2005 · Cited by 72 · see citing works
Hyperlipidemia Induced by High Cholesterol Diet Inhibits Heat Shock Response in Rat Hearts
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Nitrite Reductase Activity of Nonsymbiotic Hemoglobins from <i>Arabidopsis thaliana</i>
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Nitrite and nitrate: cardiovascular risk–benefit and metabolic effect
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Nitrosyl-Heme Complexes Are Formed in the Ischemic Heart
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Self-citationPreconditioning Decreases Ischemia/Reperfusion-Induced Peroxynitrite Formation
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Cardioprotective effects of nitrite during exercise
Calvert, J. W. (2010) · Cardiovascular Research · doi:10.1093/cvr/cvq307 · Cited by 51 · see citing works
Augmentation of nitrite therapy in cerebral ischemia by NMDA receptor inhibition
Jung, K., Chu, K., Lee, S., Park, H.-K., Kim, J.-H., Kang, K., Kim, M., Lee, S. K., & Roh, J. (2008) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2008.11.081 · Cited by 48 · see citing works
Hendgen-Cotta, U. B., Kelm, M., & Rassaf, T. (2010) · Nitric Oxide · doi:10.1016/j.niox.2009.10.003 · Cited by 46 · see citing works
Self-citationMagnetic resonance study of the transmembrane nitrite diffusion
Samouilov, A., Woldman, Y. Y., Zweier, J. L., & Khramtsov, V. V. (2007) · Nitric Oxide · doi:10.1016/j.niox.2006.12.006 · Cited by 46 · see citing works
Shiva, S., Rassaf, T., Patel, R. P., & Gladwin, M. T. (2010) · Cardiovascular Research · doi:10.1093/cvr/cvq327 · Cited by 46 · see citing works
Self-citationThe presence of nitrite during UVA irradiation protects from apoptosis
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Fruit and vegetable consumption in the prevention of cancer: an update
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Assessment of the functional diversity of human myoglobin
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Self-citationThe Hepatoprotective Effect of Sodium Nitrite on Cold Ischemia-Reperfusion Injury
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Self-citationHypoxia and Anoxia Tolerance of Vertebrate Hearts: An Evolutionary Perspective
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Sodium Nitrite Mitigates Ventilator-induced Lung Injury in Rats
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Nitric oxide enhances MPP+ inhibition of complex I
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A technique to estimate the rate of whole body nitric oxide formation in conscious mice
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Serial measurements of whole blood nitrite in an intensive care setting
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“The supplementation of a low dose of nitrite through local intra-arterial infusion, attenuated ischaemiareperfusion-induced vasoconstriction, arteriole stagnation, and capillary no-reflow during reperfusion (Wang et al., 2011) and prolonged application of nitrite improved revascularization in chronically ischaemic per…”
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Relationship of catalase and sodium nitrite to protection against X-rays
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Targeting vascular (endothelial) dysfunction
Daiber, A., Steven, S., Weber, A., Shuvaev, V. V., Muzykantov, V. R., Laher, I., Li, H., Lamas, S., & Münzel, T. (2017) · British Journal of Pharmacology · doi:10.1111/bph.13517 · Cited by 501 · see citing works
Psychedelics in Psychiatry: Neuroplastic, Immunomodulatory, and Neurotransmitter Mechanisms
Inserra, A., De Gregorio, D., & Gobbi, G. (2021) · Pharmacological Reviews · doi:10.1124/pharmrev.120.000056 · Cited by 232 · see citing works
Inorganic nitrite supplementation for healthy arterial aging
Sindler, A. L., DeVan, A. E., Fleenor, B. S., & Seals, D. R. (2014) · Journal of Applied Physiology · doi:10.1152/japplphysiol.01100.2013 · Cited by 68 · see citing works
- Authors
- Rassaf, T., Ferdinandy, P., & Schulz, R.
- Affiliations
- Düsseldorf University Hospital (DE)
- Department of Pharmacology and Pharmacotherapy Semmelweis University Budapest Hungary
- Justus-Liebig-Universität Gießen (DE)
- Corresponding author
- Rassaf, Tienush
- Venue
- British Journal of Pharmacology
- Publisher
- Wiley
- Published
- 2013-12-10
- Volume
- 171
- Issue
- 1
- Pages
- 1-11
- ISSN
- 0007-1188 (ISSN-L)
- 1476-5381
- PMC
- PMC3874691
- OpenAlex
- W1582403786
- Semantic Scholar
- 92b75e5541749487acd2e29e546eb2769866509a
- Cited by
- 62
- References
- 136
- Citations by year
- 2026: 2 · 2025: 2 · 2023: 1 · 2022: 1 · 2021: 5 · 2020: 8 · 2019: 2 · 2018: 9 · 2017: 6 · 2016: 7 · 2015: 7 · 2014: 12
- FWCI
- 0.96
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- British Journal of Pharmacology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Semmelweis University Repository (Semmelweis University) (submittedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
- Keywords
- nitrite, nitrate-nitrite-nitric oxide pathway, S-nitrosylation, organ protection, cytoprotection, nitric oxide signaling, organ damage
- MeSH terms
- Animals, Humans, Nitrates, Nitric Oxide, Nitrites, Signal Transduction, Reperfusion Injury, Myocardial Reperfusion Injury, Cytoprotection, Protective Agents
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