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Cytoprotective effects of nitrite during in vivo ischemia-reperfusion of the heart and liver
Open accessAbstract
Nitrite represents a circulating and tissue storage form of NO whose bioactivation is mediated by the enzymatic action of xanthine oxidoreductase, nonenzymatic disproportionation, and reduction by deoxyhemoglobin, myoglobin, and tissue heme proteins. Because the rate of NO generation from nitrite is linearly dependent on reductions in oxygen and pH levels, we hypothesized that nitrite would be reduced to NO in ischemic tissue and exert NO-dependent protective effects. Solutions of sodium nitrite were administered in the setting of hepatic and cardiac ischemia-reperfusion (I/R) injury in mice. In hepatic I/R, nitrite exerted profound dose-dependent protective effects on cellular necrosis and apoptosis, with highly significant protective effects observed at near-physiological nitrite concentrations. In myocardial I/R injury, nitrite reduced cardiac infarct size by 67%. Consistent with hypoxia-dependent nitrite bioactivation, nitrite was reduced to NO, S-nitrosothiols, N-nitros-amines, and iron-nitrosylated heme proteins within 1-30 minutes of reperfusion. Nitrite-mediated protection of both the liver and the heart was dependent on NO generation and independent of eNOS and heme oxygenase-1 enzyme activities. These results suggest that nitrite is a biological storage reserve of NO subserving a critical function in tissue protection from ischemic injury. These studies reveal an unexpected and novel therapy for diseases such as myocardial infarction, organ preservation and transplantation, and shock states.
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In the citing paper
“Furthermore, the process was demonstrated to be dependent on xanthine oxidoreductase (XOR)”
From Vascular effects of dietary nitrate (as found in green leafy vegetables and beetroot) via the nitrate-nitrite-nitric oxide pathway (2013) · cites this paper as [160]
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Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Early research indicated a therapeutic role for nitric oxide in cardioprotection in myocardial infarction models, 135 and L-arginine treatment before reperfusion was also organ-protective.133,136,137”
From Nitrate-Nitrite-Nitric Oxide Pathway: Implications for Anesthesiology and Intensive Care (2010) · cites this paper as [135]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Pre-clinical studies with nitrate or nitrite also show the potential to protect against ischaemia-reperfusion injury and reduce arterial stiffness, inflammation and intimal thickness.”
From Vascular effects of dietary nitrate (as found in green leafy vegetables and beetroot) via the nitrate-nitrite-nitric oxide pathway (2013) · cites this paper as [160]
Experimental — accuracy not yet measuredThe check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“Chronic inhibition of XOR with allopurinol or 3 weeks of tungstenrich diet increased intimal hyperplasia.”
From Vascular effects of dietary nitrate (as found in green leafy vegetables and beetroot) via the nitrate-nitrite-nitric oxide pathway (2013) · cites this paper as [160]
Experimental — accuracy not yet measuredThe check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“Even the late introduction of nitrite was able to reverse intimal hyperplasia [160].”
From Vascular effects of dietary nitrate (as found in green leafy vegetables and beetroot) via the nitrate-nitrite-nitric oxide pathway (2013) · cites this paper as [160]
Experimental — accuracy not yet measured
In the citing paper
“The nitrite (NO2−) anion protects from ischemia-reperfusion injury in vivo1–3,37 and is thought to act as an S-nitrosating agent in the ischemic myocardium2.”
From Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I (2013) · cites this paper as [1]
In the citing paper
“Nitrite is a dietary constituent that protects the heart against I/R injury in many animal models during both ischemia and preconditioning stage [186,187,188,189,190,191,192].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [186]
In the citing paper
“while nitrate supplementation prevents or limits ischemia-reperfusion injury and endothelial dysfunction in both animal[98,120–124] and human[97,125] models of ischemia-reperfusion.”
From Enterosalivary nitrate metabolism and the microbiome: Intersection of microbial metabolism, nitric oxide and diet in cardiac and pulmonary vascular health (2017) · cites this paper as [121]
In the citing paper
“the nitrate/nitrite content of the fruits and vegetables could contribute to their cardiovascular health benefits in animals [29,33,78,79,80,81,82,83] and humans [31,84,85,86].”
From NO-Rich Diet for Lifestyle-Related Diseases (2015) · cites this paper as [79]
In the citing paper
“Physiologically relevant levels of nitrite have been shown to counter ischemic-reperfusion injury [8–10]”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [9]
In the citing paper
“The efficacy of low concentrations of nitrite in mediating cytoprotection has been demonstrated in a variety of tissues in animal models including heart [8, 9, 55, 118–122] liver [9, 120, 123], brain [124–126], kidney [127, 128], hindlimb [129], and human forearm [23].”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [9]
In the citing paper
“pretreatment with this compound, delivered as a salt in the form of sodium nitrite, protects against ischemia/reperfusion (I/R) injury in the heart in preclinical models (7, 19, 20, 40, 46, 60, 79, 189).”
From Inorganic nitrite supplementation for healthy arterial aging (2014) · cites this paper as [46]
In the citing paper
“nitrite administration reduces skeletal muscle (188), renal (125, 179), and liver (46, 154, 169) injury after ischemia.”
From Inorganic nitrite supplementation for healthy arterial aging (2014) · cites this paper as [46]
In the citing paper
“exogenous administration of nitrite correlates with increased levels of S-nitrosothiols in red blood cells and other tissues both in vivo and in vitro [25, 43, 46-53].”
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 [52]
In the citing paper
“Evidence for a role for NO is dependent largely on attenuation of responses by the NO-scavenger CPTIO [25, 26, 52, 100] and measurement of nitrite-dependent increases in cGMP levels[26, 101].”
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 [52]
In the citing paper
“Murine based studies of hepatic and myocardial IR injury have shown a ‘U’ shaped profile for nitrite effects; namely protection increases with increasing dose up to a point and then as the dose is increased further, protection is lost and can -if even higher doses are administered, exacerbate injury [52, 114].”
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 [52]
In the citing paper
“nitration reactions could also explain the loss of protection observed when higher doses of nitrite are administered in the context of IR injury [52, 114].”
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 [52]
In the citing paper
“the nitrite dose range encompassing protection versus loss of protection in these studies was greater than two or three orders of magnitude.”
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 [52]
In the citing paper
“experimental observations show that relatively low doses of nitrite are sufficient to induce dramatic protective effects in vivo.”
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 [52]
In the citing paper
“Typically doses of ~50 nmoles have been shown to be protective in models of ischemia reperfusion [52, 114] as well hemorrhagic shock in mice [122] for example.”
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 [52]
In the citing paper
“Duranski et al showed that nitrite therapy protects against ischemic tissue injury through a heme oxygenase-1 pathway which further implicated the generation of nitrite dependent NO during therapy.”
From Inorganic nitrite therapy: historical perspective and future directions (2011) · cites this paper as [156]
In the citing paper
“cPTIO treatment was shown by numerous groups to attenuate nitrite mediated protection against ischemia-reperfusion injury in vivo indicating that protective mechanisms likely involve NO dependent signaling pathways and molecular responses [47, 89, 156, 162].”
From Inorganic nitrite therapy: historical perspective and future directions (2011) · cites this paper as [156]
In the citing paper
“This paper proved that near physiological doses of sodium nitrite (high nanomolar) were highly cytoprotective in both myocardial and hepatic ischemia-reperfusion extending previous work from Cosby et al demonstrating that near physiological levels of nitrite anion mediated hypoxic vasodilation responses [19].”
From Inorganic nitrite therapy: historical perspective and future directions (2011) · cites this paper as [156]
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Citations
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“5 to 10 μmol/L after bolus administration: a range broadly associated with cardioprotection in reperfusion injury achieved through bolus dose administration in preclinical studies.(15,18) Manufacture of the interventions, blinding, coding, and randomization were conducted by the Pharmacy Manufacturing Unit at Ipswich…”
MethodSchopfer, M. P., Wang, J., & Karlin, K. D. (2010) · Inorganic Chemistry · doi:10.1021/ic100033y · Cited by 104
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“2 nmol in murine models of myocardial infarction and hepatic IR (33).”
BackgroundSelf-citationBrief Periods of Nitric Oxide Inhalation Protect against Myocardial Ischemia–Reperfusion Injury
Nagasaka, Y., Fernandez, B. O., Garcia-Saura, M. F., Petersen, B., Ichinose, F., Bloch, K. D., Feelisch, M., & Zapol, W. M. (2008) · Anesthesiology · doi:10.1097/aln.0b013e318186316e · Cited by 101
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“in a manner mimicking ischaemic pre-conditioning (IPC), nitrite not only confers cardioprotection when administered during ischaemia, but also when transiently present hours prior to the onset of the ischaemic episode.(1,9,14,15) While this phenomenon suggests that nitrite is able”
Cysteine-mediated redox signalling in the mitochondria
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“Nitrite supplementation results in a 48% reduction in infarct size post I/R insult [32-35].”
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“Hypoxia has been shown to increase xanthine oxidoreductase activity in rat microvascular endothelial cells in vitro or in lung tissue in vivo.(75,94) Furthermore, arginine supplementation has been shown to decrease and pharmaco-”
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NO-Rich Diet for Lifestyle-Related Diseases
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“Infused nitrite similarly protected mice against both hepatic and cardiac ischemia-reperfusion injury.(17) More recently, efforts to translate these latter observations to the clinical setting have produced mixed results in patients presenting with STelevated myocardial infarction.”
BackgroundSelf-citationAbu‐Amara, M., Yang, S. Y., Seifalian, A. M., Davidson, B. R., & Fuller, B. J. (2012) · Liver International · doi:10.1111/j.1478-3231.2012.02755.x · Cited by 91
“This has been shown in vivo (22, 65) and in cultured hepatocytes models (64, 66).”
BackgroundInorganic nitrate and the cardiovascular system
Kapil, V., Webb, A. J., & Ahluwalia, A. (2010) · Heart · doi:10.1136/hrt.2009.180372 · Cited by 90
“NO2 /NO3 L AND ISCHAEMIA-REPERFUSION (IR) INJURY/MYOCARDIAL INFARCTION (MI) Numerous studies show the benefits of physiological levels of NO2 in IR injury of solid organs, including notably the brain,(81) kidney(82) and liver.(83) 84 However, the first evidence that the ‘alternative reductive’pathway forNOgenerationmi…”
BackgroundNitrite mediates cytoprotection after ischemia/reperfusion by modulating mitochondrial function
Shiva, S., & Gladwin, M. T. (2009) · Basic Research in Cardiology · doi:10.1007/s00395-009-0009-3 · Cited by 91
“injection midway through ischemia AST/ALT, Histopathology Hepatocellular necrosis and apoptosis [ 20 ]”
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Blood Pressure–Lowering Effect of Orally Ingested Nitrite Is Abolished by a Proton Pump Inhibitor
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Cardioprotection Through S -Nitros(yl)ation of Macrophage Migration Inhibitory Factor
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Molecular Mechanisms in Exercise-Induced Cardioprotection
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“The beneficial effect of nitrite therapy (which generates NO-independent of eNOS) has been shown in animal models of cardiac I/R injury [108, 109].”
BackgroundGenetic overexpression of eNOS attenuates hepatic ischemia-reperfusion injury
Duranski, M. R., Elrod, J. W., Calvert, J. W., Bryan, N. S., Feelisch, M., & Lefer, D. J. (2006) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.01173.2005 · Cited by 89
Self-citationMitochondria as metabolizers and targets of nitrite
Shiva, S. (2010) · Nitric Oxide · doi:10.1016/j.niox.2009.09.002 · Cited by 87
“of hepatic I/R and myocardial infarction, an increase in plasma nitrite of 200 nM decreased liver injury by approximately 40% and infarct size by 50%, respectively [10].”
InfluentialNitrite reduction by molybdoenzymes: a new class of nitric oxide-forming nitrite reductases
Maia, L. B., & Moura, J. J. G. (2015) · JBIC Journal of Biological Inorganic Chemistry · doi:10.1007/s00775-014-1234-2 · Cited by 88
Myoglobin and mitochondria: A relationship bound by oxygen and nitric oxide
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Nitric oxide deficiency in pulmonary hypertension: pathobiology and implications for therapy
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“The NOS pathway is oxygen dependent while the nitrate-nitrite-NO pathway is hypoxia activated.[69,70]”
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“A study by Duranski and colleagues showed that a low dose of nitrite is strongly cardio-protective when given systemically in an animal model of myocardial infarction [47].”
BackgroundeNOS gene T-786C polymorphism modulates atorvastatin-induced increase in blood nitrite
Nagassaki, S., Sertorio, J. T. C., Metzger, I. F., Bem, A. F. D., da Rocha, J. B. T., & Tanus-Santos, J. E. (2006) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2006.04.026 · Cited by 85
Carnosine modulates nitric oxide in stimulated murine RAW 264.7 macrophages
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“It may also be possible that part of the beneficial effects of Car are due to just an increase in nitrite, since it has been demonstrated that nitrite can alleviate the effects of cerebral vasospasms [43] and can attenuate ischemia–reperfusion injury in the heart and liver [43, 44].”
Evolution of Novel Small-Molecule Therapeutics Targeting Sickle Cell Vasculopathy
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Self-citationMyocardial protection by nitrite
Calvert, J. W., & Lefer, D. J. (2009) · Cardiovascular Research · doi:10.1093/cvr/cvp079 · Cited by 82
“Duranski et al.52 reported that nitrite was cardioprotective in an in vivo mouse model of myocardial I/R injury.”
BackgroundInfluentialCardioprotection of pharmacological postconditioning on myocardial ischemia/reperfusion injury
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“THE ROLE OF NITRITE in vascular biology has recently received much attention with the demonstration in numerous experimental and clinical models that this inorganic anion may represent an endogenous and/or therapeutic reservoir for nitric oxide (NO) bioactivity during physiological and pathological hypoxia (2, 5, 6, 1…”
BackgroundSelf-citationDeVan, A. E., Johnson, L. C., Brooks, F. A., Evans, T. D., Justice, J. N., Cruickshank-Quinn, C. I., Reisdorph, N. A., Bryan, N. S., McQueen, M. B., Santos‐Parker, J. R., et al. (2015) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00879.2015 · Cited by 84
“Interest in sodium nitrite as a treatment for CVD was rekindled in recent years after chronic oral supplementation was shown to protect the heart from ischemia-reperfusion injury in preclinical models (4, 8, 17) and after infusion produced transient vasodilation of conduit and resistance arteries in humans (34).”
BackgroundHypoxia Tolerance, Nitric Oxide, and Nitrite: Lessons From Extreme Animals
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Effects of nitrite on modulating ROS generation following ischemia and reperfusion
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“Nitrite can also exert potent cytoprotective effects after I/R injury on liver in a dose-dependent fashion by limiting serum increase of the liver transaminases, hepatocellular injury, and apoptosis (102).”
InfluentialYang, T., Zhang, X., Tarnawski, L., Peleli, M., Zhuge, Z., Terrando, N., Harris, R. A., Olofsson, P. S., Larsson, E., Persson, A. E. G., et al. (2017) · Redox Biology · doi:10.1016/j.redox.2017.06.002 · Cited by 82
“The organ protective effects of nitrite in IR injury have been demonstrated in multiple organs such as liver [25], brain [26], lung [27,28], and particularly in the heart [17,25,29].”
BackgroundRole of nitric oxide in hepatic ischemia-reperfusion injury
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Strategic localization of heart mitochondrial NOS: a review of the evidence
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Photobiomodulation and nitric oxide signaling
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Plasma nitrite response and arterial reactivity differentiate vascular health and performance
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“Recent studies suggest nitrite protects against ischemia–reperfusion injury [39,40] and may regulate gene expression [41].”
BackgroundcGMP at the centre of attention: emerging strategies for activating the cardioprotective PKG pathway
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“Indeed exogenous nitrite reduced cardiac infarct size in mice subjected to myocardial I/R injury by upregulating NO [17, 29].”
BackgroundRapid actions of aldosterone in vascular health and disease—friend or foe?
Skøtt, O., Uhrenholt, T. R., Schjerning, J., Hansen, P., Rasmussen, L. E., & Jensen, B. L. (2006) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2005.10.010 · Cited by 76
Pharmacologic Therapy That Simulates Conditioning for Cardiac Ischemic/Reperfusion Injury
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Ambrosio, G., Pinto, M. D., Tritto, I., Agnelli, G., Bentivoglio, M., Zuchi, C., Anderson, F. A., Gore, J. M., López-Sendón, J., Wyman, A., et al. (2009) · European Heart Journal · doi:10.1093/eurheartj/ehp457 · Cited by 74
eNOS Gene Therapy Exacerbates Hepatic Ischemia-Reperfusion Injury in Diabetes
Elrod, J. W., Duranski, M. R., Langston, W., Greer, J. J. M., Tao, L., Dugas, T. R., Kevil, C. G., Champion, H. C., & Lefer, D. J. (2006) · Circulation Research · doi:10.1161/01.res.0000231306.03510.77 · Cited by 75
Self-citationNitrite reduction by xanthine oxidase family enzymes: a new class of nitrite reductases
Maia, L. B., & Moura, J. J. G. (2011) · JBIC Journal of Biological Inorganic Chemistry · doi:10.1007/s00775-010-0741-z · Cited by 75
Bice, J. S., Jones, B. R., Chamberlain, G. R., & Baxter, G. F. (2016) · Basic Research in Cardiology · doi:10.1007/s00395-016-0540-y · Cited by 72
“The production of NO from NO 2 - has been shown to reduce myocardial injury [8, 33] and the reduction of NO 2 - is thought to be facilitated by molecules including deoxymyoglobin [5] and the enzyme xanthine oxidoreductase [66] among others.”
Metadata
- Authors
- Duranski, M. R., Greer, J. J. M., Dejam, A., Jaganmohan, S., Hogg, N., Langston, W., Patel, R. P., Yet, S.-F., Wang, X., Kevil, C. G., Gladwin, M. T., & Lefer, D. J.
- Affiliations
- Louisiana State University Health Sciences Center Shreveport (US)
- Medical College of Wisconsin (US)
- University of Alabama at Birmingham (US)
- Brigham and Women's Hospital (US)
- National Institutes of Health (US)
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2005-04-14
- Volume
- 115
- Issue
- 5
- Pages
- 1232-1240
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC1077170
- OpenAlex
- W2098453482
- Cited by
- 674
- References
- 70
- Citations by year
- 2026: 5 · 2025: 12 · 2024: 9 · 2023: 7 · 2022: 21 · 2021: 22 · 2020: 20 · 2019: 18 · 2018: 23 · 2017: 40 · 2016: 31 · 2015: 45 · 2014: 42 · 2013: 42 · 2012: 59
- FWCI
- 28.36
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Diabetes Association
- National Institutes of Health
- National Heart, Lung, and Blood Institute (2R01-HL60849, R01HL060849)
- National Institute of Diabetes and Digestive and Kidney Diseases (P01-1 DK-43785, P01DK043785)
- Topics
- Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Ischemia and Reperfusion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Hemoglobin structure and function
- Keywords
- nitrite, nitric oxide, ischemia-reperfusion injury, cardioprotection, hepatoprotection, sodium nitrite, S-nitrosothiols, nitrosamines, liver necrosis, apoptosis, organ preservation, myocardial infarction
- MeSH terms
- Animals, Heme Oxygenase (Decyclizing), Liver, Membrane Proteins, Mice, Inbred C57BL, Myocardium, Nitrites, Peritoneum, Reperfusion Injury, Nitric Oxide Synthase, Mice, Heme Oxygenase-1
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