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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The process of nitrite limiting intimal hyperplasia was dependent on xanthine oxidoreductase (XOR).
“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]
The Discussion (page unavailable) says the contribution of xanthine oxidoreductase to nitrite-mediated protection requires further study, rather than having been demonstrated as necessary. The paper studies heart and liver ischemia-reperfusion injury, not nitrite limiting intimal hyperplasia. (LLM, conf=0.86)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredEarly research indicated a therapeutic role for nitric oxide in cardioprotection in myocardial infarction models, and L-arginine treatment before reperfusion was organ-protective.
“Early research indicated a therapeutic role for nitric oxide in cardioprotection in myocardial infarction models, 135 and L-arginine treatment before reperfusion was also organ-protective.133,136,137”
From Nitrate-Nitrite-Nitric Oxide Pathway: Implications for Anesthesiology and Intensive Care (2010) · cites this paper as [135]
The Discussion (page not provided) reports that nitric oxide donors and the nitric oxide precursor L-arginine protect against myocardial ischemia-reperfusion injury, supporting the cardioprotective point. It does not say L-arginine was given before reperfusion; the paper specifies that timing for nitrite, while a cited reference describes L-arginine given during reperfusion. (LLM, conf=0.86)
Experimental — accuracy not yet measuredPre-clinical studies with nitrate or nitrite show the potential to protect against ischaemia-reperfusion injury and reduce arterial stiffness, inflammation and intimal thickness.
“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]
The Introduction and Discussion report that nitrite protected mice from hepatic and cardiac ischaemia-reperfusion injury, compared with vehicle or nitrate controls. The paper does not report reductions in arterial stiffness, inflammation or intimal thickness, and it does not establish nitrate as protective. (LLM, conf=0.88)
Experimental — accuracy not yet measuredChronic inhibition of XOR with allopurinol or 3 weeks of tungsten-rich diet increased intimal hyperplasia.
“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]
The Discussion (page unavailable) mentions xanthine oxidoreductase-dependent nitrite reduction, but not chronic XOR inhibition or intimal hyperplasia. Searches for allopurinol, tungsten, and intimal hyperplasia found no passage in our copy reporting the claimed result. (LLM, conf=0.76)
Experimental — accuracy not yet measuredEven the late introduction of nitrite was able to reverse intimal hyperplasia.
“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]
The Introduction describes mouse models of liver and heart ischemia-reperfusion injury, and the section ‘Intraventricular nitrite limits myocardial I/R injury’ reports reduced infarct size when nitrite was given five minutes before reperfusion. Neither section addresses intimal hyperplasia or its reversal; searches for those terms found no relevant passage in our copy. (LLM, conf=0.76)
Experimental — accuracy not yet measured
Nitrite protects from ischemia-reperfusion injury in vivo and is thought to act as an S-nitrosating agent in ischemic myocardium.
“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]
Nitrite is a dietary constituent that protects the heart against I/R injury in many animal models during both ischemia and preconditioning stage.
“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]
Nitrate supplementation prevents or limits ischemia-reperfusion injury and endothelial dysfunction in both animal and human models of ischemia-reperfusion.
“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]
The nitrate/nitrite content of fruits and vegetables could contribute to their cardiovascular health benefits in animals and humans.
“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]
Physiologically relevant levels of nitrite counter ischemic-reperfusion injury.
“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]
Low concentrations of nitrite mediate cytoprotection in a variety of tissues in animal models including heart, liver, brain, kidney, hindlimb, and human forearm.
“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]
Pretreatment with sodium nitrite protects against ischemia/reperfusion injury in the heart in preclinical models.
“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]
Nitrite administration reduces skeletal muscle, renal, and liver injury after ischemia.
“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]
Exogenous administration of nitrite correlates with increased levels of S-nitrosothiols in red blood cells and other tissues both in vivo and in vitro.
“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]
Evidence for a role for NO is dependent largely on attenuation of responses by the NO-scavenger CPTIO and measurement of nitrite-dependent increases in cGMP levels.
“Evidence for a role for NO is dependent largely on attenuation of responses by the NO-scavenger CPTIO [25, 26, 52, 100] and measurement of nitrite-dependent increases in cGMP levels[26, 101].”
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]
Murine based studies of hepatic and myocardial ischemia-reperfusion injury have shown a U-shaped profile for nitrite effects: protection increases with increasing dose up to a point, then as the dose is increased further protection is lost and higher doses can exacerbate injury.
“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]
Nitration reactions could explain the loss of protection observed when higher doses of nitrite are administered in the context of ischemia-reperfusion injury.
“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]
The nitrite dose range encompassing protection versus loss of protection in these studies was greater than two or three orders of magnitude.
“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]
Relatively low doses of nitrite are sufficient to induce dramatic protective effects in vivo.
“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]
Doses of ~50 nmoles of nitrite have been shown to be protective in models of ischemia reperfusion and hemorrhagic shock in mice.
“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]
Nitrite therapy protects against ischemic tissue injury through a heme oxygenase-1 pathway.
“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]
cPTIO treatment attenuates nitrite-mediated protection against ischemia-reperfusion injury in vivo, indicating that protective mechanisms likely involve NO-dependent signaling pathways and molecular responses.
“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]
Near physiological doses of sodium nitrite (high nanomolar) are highly cytoprotective in both myocardial and hepatic ischemia-reperfusion.
“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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“Nitrite has been shown to reduce ischemia-reperfusion injury (66).”
BackgroundMyocardial ischaemia–reperfusion injury and cardioprotection in perspective
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“NOS-independent NO production seems to complement the endogenous NO production especially during ischaemia and acidosis when oxygen availability is low and the NO synthases operate poorly (Zweier et al. 1995, Weitzberg & Lundberg 1998, Duranski et al. 2005, Lundberg & Weitzberg 2005).”
BackgroundCardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I
Chouchani, E. T., Methner, C., Nadtochiy, S. M., Logan, A., Pell, V. R., Ding, S., James, A. M., Cochemé, H. M., Reinhold, J., Lilley, K. S., et al. (2013) · Nature Medicine · doi:10.1038/nm.3212 · Cited by 619 · see citing works
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Self-citationRenal ischemia/reperfusion injury; from pathophysiology to treatment.
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“Several recent reports have demonstrated NO and nitrite-mediated cytoprotection in IRI models (91-94).”
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“Indeed, a similar or even smaller increase is associated with reduction in blood pressure in healthy humans [21] and cardioprotective effects in a murine model of myocardial infarction [13].”
BackgroundMalaria biology and disease pathogenesis: insights for new treatments
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Self-citationNitrite is a signaling molecule and regulator of gene expression in mammalian tissues
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Enzymatic function of hemoglobin as a nitrite reductase that produces NO under allosteric control
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“In this regard, H 2 S therapy is similar to NO therapy in the setting of I/R injury.(28)”
MethodSelf-citationNitrite as Regulator of Hypoxic Signaling in Mammalian Physiology
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“125 The role of Mb in vivo has been investigated by comparison of WT mice with Mbdeficient mutants (Mb / ).130,131 In these mutants, multiple compensatory mechanisms were activated to compensate for the loss of the oxygen-storage and -transport function of Mb.”
BackgroundInfluentialSelf-citationThe ubiquitous role of nitric oxide in cardioprotection
Jones, S. P., & Bolli, R. (2006) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2005.09.011 · Cited by 434 · see citing works
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“Recently, inhaled NO administration was shown to accelerate the restoration of liver function in transplantation patients, presumably through increased circulating levels of nitrite [112], a newly recognized vascular endocrine transporter of NO [113] that protects against heart and liver ischemia–reperfusion injury [1…”
BackgroundFigueira, T. R., de Barros, M. H., Camargo, A. A., Castilho, R. F., Ferreira, J. C. B., Kowaltowski, A. J., Sluse, F. E., de Souza-Pinto, N. C., & Vercesi, A. E. (2012) · Antioxidants and Redox Signaling · doi:10.1089/ars.2012.4729 · Cited by 417 · see citing works
“Indeed, there is evidence that increased NO 2 - bioavailability exerts beneficial effects in vivo (22, 23, 79, 116, 127, 149, 229, 301, 303, 415, 472, 522).”
Physiological role for nitrate-reducing oral bacteria in blood pressure control
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“The application of 48 nmol sodium nitrite (50 l) into the left ventricular cavity occurred 5 min before reperfusion (16).”
BackgroundMethodInfluentialSelf-citationIschemia/Reperfusion Injury Revisited: An Overview of the Latest Pharmacological Strategies
Soares, R. O. D. S., Losada, D. M., Jordani, M. C., Évora, P. R. B., & Castro-e-Silva, O. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20205034 · Cited by 415 · see citing works
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“While the strong majority of the hormetic mechanism studies are performed within an in vitro system, some experiments employed whole animals (Boccia et al., 1998; Duranski et al., 2005; Homayoun et al., 2002; Houshmand et al., 2009; Kawabata et al., 1994; Kelly et al., 2010; Kim et al., 2008; Ogura et al., 2009; Roger…”
BackgroundCeruloplasmin is a NO oxidase and nitrite synthase that determines endocrine NO homeostasis
Shiva, S., Wang, X., Ringwood, L. A., Xu, X., Yuditskaya, S., Annavajjhala, V., Miyajima, H., Hogg, N., Harris, Z. L., & Gladwin, M. T. (2006) · Nature Chemical Biology · doi:10.1038/nchembio813 · Cited by 359 · see citing works
“In tissues, near-physiological concentrations of nitrite (”
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A mammalian functional nitrate reductase that regulates nitrite and nitric oxide homeostasis
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“Nitrate prevents hypoperfusion after ischemia A number of recent studies have demonstrated the importance of nitrite in protection against I/R injur”
BackgroundRoles of dietary inorganic nitrate in cardiovascular health and disease
Lundberg, J. O., Carlström, M., Larsen, F. J., & Weitzberg, E. (2011) · Cardiovascular Research · doi:10.1093/cvr/cvq325 · Cited by 355 · see citing works
“Soon after, Duranski et al.(32) demonstrated potent cytoprotective”
BackgroundInfluentialDietary nitrite supplementation protects against myocardial ischemia-reperfusion injury
Bryan, N. S., Calvert, J. W., Elrod, J. W., Gundewar, S., Ji, S. Y., & Lefer, D. J. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0706579104 · Cited by 347 · see citing works
Self-citationCirculating Nitrite Contributes to Cardioprotection by Remote Ischemic Preconditioning
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“Duranski and colleagues (18) reported that nitrite limited ischemia-reperfusion cytotoxicity at doses as low as 1.”
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Unraveling the Reactions of Nitric Oxide, Nitrite, and Hemoglobin in Physiology and Therapeutics
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Self-citationNitric oxide in liver diseases
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“The protective effect of eNOS-derived NO is exerted at least in part through the sGCcGMP-protein kinase G (PKG) pathway [138, 139].”
BackgroundThe functional nitrite reductase activity of the heme-globins
Gladwin, M. T., & Kim-Shapiro, D. B. (2008) · Blood · doi:10.1182/blood-2008-01-115261 · Cited by 293 · see citing works
Self-citationCritical Issues for the Translation of Cardioprotection
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AMPK, Mitochondrial Function, and Cardiovascular Disease
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Direct evidence for S-nitrosation of mitochondrial complex I
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“been abolished by the NO scavenger PTIO or by an inhibitor of guanylyl cyclase (GC).(27,49) In addition to the activation of GC and formation of cGMP, NO or its reaction products can nitros(yl)ate”
MethodNitrite in nitric oxide biology: Cause or consequence?
Bryan, N. S. (2006) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2006.05.019 · Cited by 260 · see citing works
“also describe nitrite-based signaling by reduction of near-physiological levels of nitrite, albeit through the classical NO-dependent signaling pathways and not through nitrite itself [82].”
BackgroundDiscovery of the nitric oxide signaling pathway and targets for drug development
Nathan, S. B. (2009) · Frontiers in bioscience · doi:10.2741/3228 · Cited by 256 · see citing works
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“Nitrite-mediated protection of the liver was dependent on ·NOgeneration and independent of eNOS and hemoxygenase-1 enzymeactivities (Duranski et al., 2005).”
BackgroundMethodResultInfluentialSickle cell disease vasculopathy: A state of nitric oxide resistance
Wood, K. C., Hsu, L. L.-Y., & Gladwin, M. T. (2008) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2008.01.008 · Cited by 246 · see citing works
“, rat, mouse, dog, and primate) to reduce organ infarct volume by more than 50% at very low doses (mouse, 48 nmol [235]; rat, 480 nmol [244]) and blood concentrations (200 nM–10 μM) [235].”
BackgroundSelf-citationNitrate and nitrite in the diet: How to assess their benefit and risk for human health
Habermeyer, M., Roth, A., Guth, S., Diel, P. R., Engel, K., Epe, B., Fürst, P., Heinz, V., Humpf, H., Joost, H., et al. (2014) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201400286 · Cited by 244 · see citing works
“confirmed in the heart and liver of mice [134] and in the brain of rats [110].”
BackgroundCalabrese, E. J. (2016) · Pharmacological Research · doi:10.1016/j.phrs.2015.12.021 · Cited by 241 · see citing works
S -Nitrosylation: NO-Related Redox Signaling to Protect Against Oxidative Stress
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“In animal models it protects against ischemia–reperfusion injury [18,19].”
Tripatara, P., Patel, N. S. A., Webb, A., Rathod, K., Lecomte, F. M. J., Mazzon, E., Cuzzocrea, S., Yaqoob, M. M., Ahluwalia, A., & Thiemermann, C. (2007) · Journal of the American Society of Nephrology · doi:10.1681/asn.2006050450 · Cited by 226 · see citing works
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“This was in contrast to systemic administration of sodium nitrite, which had no effect on renal I-R injury (Basireddy et al. 2006; Tripatara et al. 2007), but similar to the protection afforded by nitrite against I-R injury of the heart and liver (Webb et al. 2004; Duranski et al. 2005).”
BackgroundResultNitric Oxide for Inhalation in the Acute Treatment of Sickle Cell Pain Crisis
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“Aspartate aminotransferase, U/L 69 36 (28-55) 72 41 (30-56) .”
Self-citationCardioprotection: A radical view
Penna, C. R. R., Mancardi, D., Rastaldo, R., & Pagliaro, P. (2009) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2009.02.008 · Cited by 219 · see citing works
“However, mice treated with sodium nitrite at the end of myocardial ischemia showed marked reduction in infarct size compared with nitrate-treated mouse hearts, an effect abolished by the NO· scavenger, 2-phenyl4,4,5,5,-tetramethylimidazoline-1-oxyl 3-oxide (PTIO) [197].”
BackgroundHypoxic Modulation of Exogenous Nitrite-Induced Vasodilation in Humans
Maher, A. R., Milsom, A. B., Gunaruwan, P., Abozguia, K., Ahmed, I., Weaver, R. A., Thomas, P., Ashrafian, H., Born, G. V. R., James, P. E., et al. (2008) · Circulation · doi:10.1161/circulationaha.107.719591 · Cited by 210 · see citing works
Nitrite: A physiological store of nitric oxide and modulator of mitochondrial function
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Nitrite regulates hypoxic vasodilation via myoglobin-dependent nitric oxide generation
Totzeck, M., Hendgen-Cotta, U. B., Luedike, P., Berenbrink, M., Klare, J. P., Steinhoff, H.-J., Semmler, D., Shiva, S., Williams, D., Kipar, A., et al. (2012) · Circulation · doi:10.1161/circulationaha.111.087155 · Cited by 202 · see citing works
“the cardiopulmonary resuscitation syndrome(47) and for chronic and acute intervention regimens.(48,49) by gest on July (2)5, 2017 http://ciajournals.”
Self-citationThe oral microbiome and nitric oxide homoeostasis
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Protein <i>S</i> -Nitrosylation and Cardioprotection
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Biology of nitrogen oxides in the gastrointestinal tract
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Role of the anion nitrite in ischemia-reperfusion cytoprotection and therapeutics
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“Additionally, nitrite-derived NO may have antiinflammatory [23,89–91,113,114] and anti-thrombotic [115,116] properties which could be beneficial in situations such as cardiopulmonary bypass.”
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Self-citationRed wine-dependent reduction of nitrite to nitric oxide in the stomach
Gago, B., Lundberg, J. O., Barbosa, R. M., & Laranjinha, J. (2007) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2007.06.007 · Cited by 186 · see citing works
Chronic sodium nitrite therapy augments ischemia-induced angiogenesis and arteriogenesis
Kumar, D., Branch, B. G., Pattillo, C. B., Hood, J., Thoma, S., Simpson, S., Illum, S., Arora, N., Chidlow, J. H., Langston, W., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0711480105 · Cited by 187 · see citing works
“Moreover, we and others have reported that sodium nitrite protects against acute ischemia/reperfusion injury and other disease states associated with acute tissue ischemia and NO deficiency (25, 29).”
BackgroundMethodInfluentialSelf-citationKoch, C. D., Gladwin, M. T., Freeman, B. A., Lundberg, J. O., Weitzberg, E., & Morris, A. (2017) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2016.12.015 · Cited by 186 · see citing works
Self-citationEndothelial nitric oxide synthase in red blood cells: Key to a new erythrocrine function?
Cortese-Krott, M. M., & Kelm, M. (2014) · Redox Biology · doi:10.1016/j.redox.2013.12.027 · Cited by 184 · see citing works
Cardioprotective effects of vegetables: is nitrate the answer?
Lundberg, J. O., Feelisch, M., Björne, H., Jansson, E. Å., & Weitzberg, E. (2006) · Nitric Oxide · doi:10.1016/j.niox.2006.01.013 · Cited by 185 · see citing works
Dezfulian, C., Shiva, S., Alekseyenko, A., Pendyal, A., Beiser, D. G., Munasinghe, J. P., Anderson, S. A., Chesley, C. F., Vanden Hoek, T. L., & Gladwin, M. T. (2009) · Circulation · doi:10.1161/circulationaha.109.853267 · Cited by 174 · see citing works
Self-citationGonzalez, F. M., Shiva, S., Vincent, P. S., Ringwood, L. A., Hsu, L.-Y., Hon, Y. Y., Aletras, A. H., Cannon, R. O., Gladwin, M. T., & Arai, A. E. (2008) · Circulation · doi:10.1161/circulationaha.107.748814 · Cited by 175 · see citing works
Self-citationTherapeutic effects of inorganic nitrate and nitrite in cardiovascular and metabolic diseases
Omar, S. A., Webb, A. J., Lundberg, J. O., & Weitzberg, E. (2016) · Journal of Internal Medicine · doi:10.1111/joim.12441 · Cited by 175 · see citing works
Kim‐Shapiro, D. B., Gladwin, M. T., Patel, R. P., & Hogg, N. (2004) · Journal of Inorganic Biochemistry · doi:10.1016/j.jinorgbio.2004.10.034 · Cited by 172 · see citing works
Self-citationThe measurement of blood and plasma nitrite by chemiluminescence: Pitfalls and solutions
Pelletier, M. M., Kleinbongard, P., Ringwood, L. A., Hito, R., Hunter, C. J., Schechter, A. N., Gladwin, M. T., & Dejam, A. (2006) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2006.05.001 · Cited by 173 · see citing works
Self-citationBurwell, L. S., & Brookes, P. S. (2007) · Antioxidants and Redox Signaling · doi:10.1089/ars.2007.1845 · Cited by 172 · see citing works
“The pathways by which various protective agents elicit cardioprotection also are shown (64, 76, 181, 247, 248).”
NO-synthase independent NO generation in mammals
Lundberg, J. O., & Weitzberg, E. (2010) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2010.02.136 · Cited by 172 · see citing works
“scavenger carboxy-PTIO [59,60,62,64] supporting a role of NO in the protective effects.”
BackgroundStokes, K. Y., Dugas, T. R., Tang, Y., Garg, H., Guidry, E., & Bryan, N. S. (2009) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.01291.2008 · Cited by 171 · see citing works
“Furthermore, exogenous nitrite has been shown to be protective in both hepatic and cardiac ischemia-reperfusion models in animals (19, 67) and can reverse hypertension due to NOS inhibition (65).”
BackgroundBir, S. C., Kolluru, G. K., McCarthy, P., Shen, X., Pardue, S., Pattillo, C. B., & Kevil, C. G. (2012) · Journal of the American Heart Association · doi:10.1161/jaha.112.004093 · Cited by 162 · see citing works
“We and others have reported that nitrite anion reduction to NO mediates cytoprotection during acute ischemia-reperfusion injury and chronic tissue ischemia.(19,38) We previously have reported that nitrite-dependent NO formation rapidly Figure 13.”
BackgroundSelf-citationBryan, N. S., Calvert, J. W., Gundewar, S., & Lefer, D. J. (2008) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2008.04.040 · Cited by 161 · see citing works
“Surgical procedures used in themyocardial I/R protocol were similar to methods described previously [22,23].”
MethodFerdinandy, P., Andreadou, I., Baxter, G. F., Bøtker, H. E., Davidson, S. M., Dobrev, D., Gersh, B. J., Heusch, G., Lecour, S., Ruiz‐Meana, M., et al. (2022) · Pharmacological Reviews · doi:10.1124/pharmrev.121.000348 · Cited by 162 · see citing works
Hataishi, R., Rodrigues, A. C. T., Neilan, T. G., Morgan, J. G., Buys, E. S., Shiva, S., Tambouret, R., Jassal, D. S., Raher, M. J., Furutani, E., et al. (2006) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.01172.2005 · Cited by 159 · see citing works
“(12) reported that a bolus administration of nitrite directly into the LV before reperfusion decreased MI size.”
BackgroundSelf-citationInhaled NO as a therapeutic agent
Bloch, K. D., Ichinose, F., ROBERTSJR, J., & Zapol, W. M. (2007) · Cardiovascular Research · doi:10.1016/j.cardiores.2007.04.014 · Cited by 159 · see citing works
“The potential importance of nitrite as a mediator of inhaled NO’s impact on I-R injury was highlighted in recent studies of Duranski and colleagues [85]: they observed that small increases in blood nitrite levels (such as might be attained during NO inhalation) were sufficient to decrease I-R injury in the liver and h…”
BackgroundMechanisms of nitrite bioactivation
Kim-Shapiro, D. B., & Gladwin, M. T. (2014) · Nitric Oxide · doi:10.1016/j.niox.2013.11.002 · Cited by 157 · see citing works
Self-citationChen, Y.-Y., Chu, H., Pan, K., Teng, C.-H., Wang, D.-L., Wang, A. H. ‐., Khoo, K., & Meng, T. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m805287200 · Cited by 156 · see citing works
Siddiqi, N., Neil, C., Bruce, M., MacLennan, G., Cotton, S. C., Papadopoulou, S., Feelisch, M., Bunce, N. H., Lim, P. O., Hildick‐Smith, D., et al. (2014) · European Heart Journal · doi:10.1093/eurheartj/ehu096 · Cited by 155 · see citing works
“These effects are seen in the nanomolar concentration range in a murine model.(22) An i.”
BackgroundInfluentialNitrite and nitrate chemical biology and signalling
DeMartino, A. W., Kim‐Shapiro, D. B., Patel, R. P., & Gladwin, M. T. (2018) · British Journal of Pharmacology · doi:10.1111/bph.14484 · Cited by 156 · see citing works
“, 2017), and changes in plasma nitrite are protective down to 200 nM (Duranski et al., 2005).”
BackgroundSelf-citationSodium nitrite: The “cure” for nitric oxide insufficiency
Parthasarathy, D. K., & Bryan, N. S. (2012) · Meat Science · doi:10.1016/j.meatsci.2012.03.001 · Cited by 157 · see citing works
“Published studies also demonstrated that nitrite therapy given intravenously prior to reperfusion protects against hepatic and myocardial ischemia/reperfusion (I/R) injury (Duranski et al., 2005).”
BackgroundNO generation from inorganic nitrate and nitrite: Role in physiology, nutrition and therapeutics
Lundberg, J. O., & Weitzberg, E. (2009) · Archives of Pharmacal Research · doi:10.1007/s12272-009-1803-z · Cited by 153 · see citing works
Yang, J., Gonon, A. T., Sjöquist, P.-O., Lundberg, J. O., & Pernow, J. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1307058110 · Cited by 147 · see citing works
Grubina, R., Huang, Z., Shiva, S., Joshi, M. S., Azarov, I., Basu, S., Ringwood, L. A., Jiang, A., Hogg, N., Kim‐Shapiro, D. B., et al. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m700546200 · Cited by 147 · see citing works
Self-citationDietary nitrite and nitrate: a review of potential mechanisms of cardiovascular benefits
Machha, A., & Schechter, A. N. (2011) · European Journal of Nutrition · doi:10.1007/s00394-011-0192-5 · Cited by 146 · see citing works
“In another study, using mice subjected to left coronary artery occlusion (model for myocardial ischemia), Duranski et al. [ 18 ] reported that nitrite administered at near physiological blood concentrations (2.4‐960 nM) exerted dose-dependent protective effects against cellular necrosis and myocardial IR injury.”
MethodInfluentialNitrate-Nitrite-Nitric Oxide Pathway: Implications for Anesthesiology and Intensive Care
Weitzberg, E., Hezel, M., Lundberg, J. O., & Warner, D. S. (2010) · Anesthesiology · doi:10.1097/aln.0b013e3181fcf3cc · Cited by 145 · see citing works
“then demonstrated potent cytoprotective effects of low-dose nitrite in vivo in mouse models of myocardial infarction and liver ischemia.(140) The effects were independent of NOS and abolished by coadministration of the nitric oxide scavenger cPTIO, suggesting nitrite-derived nitric oxide as an active mediator.”
Background
- 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 › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › 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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