Role of the anion nitrite in ischemia-reperfusion cytoprotection and therapeutics
Open accessAbstract
The anion nitrite (NO(2)(-)) constitutes a biochemical reservoir for nitric oxide (NO). Nitrite reduction to NO may be catalyzed by hemoglobin, myoglobin or other metal-containing enzymes and occurs at increasing rates under conditions of physiologic hypoxia or ischemia. A number of laboratories have now demonstrated in animal models the ability of nitrite to provide potent cytoprotection following focal ischemia-reperfusion (IR) injury of the heart, liver, brain, and kidney. While the mechanism of nitrite-mediated cytoprotection remains to be fully characterized, the release of nitrite-derived NO following IR appears to be central to this mechanism. The evidence of nitrite-mediated cytoprotection against IR injury in multiple animal models opens the door to potential therapeutic opportunities in human disease. Here we review the mechanisms for nitrite formation in blood and tissue, its metabolic equilibrium with NO, nitrate, and NO-modified proteins, the evidence supporting nitrite-mediated cytoprotection, and the potential mechanisms driving cytoprotection, and we explore the opportunities for the therapeutic application of nitrite for human disease.
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Nitrite administered before or during cardiac ischemia protects cardiac function and attenuates infarct size in small and large animal models.
“Nitrite administered before or during cardiac ischemia has been shown to protect cardiac function and attenuate infarct size in a number of small and large animal models (226, 374, 864).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [226]
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 [189]
Nitrite or nitrate have been associated with beneficial effects including protection against ischemia-reperfusion injury, vasorelaxant properties, pulmonary vasodilator effects, and antihypertensive effects in experimental and clinical studies.
“relevant biological effects were associated with nitrite or nitrate, including beneficial effects against ischemia-reperfusion injury [11,18,19], vasorelaxant properties [20], pulmonary vasodilator effects [21][22][23], and antihypertensive effects in experimental [24][25][26][27] and in clinical studies [28][29][30].”
From Sodium nitrite downregulates vascular NADPH oxidase and exerts antihypertensive effects in hypertension (2011) · cites this paper as [19]
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Kinetics of the reactions of nitrogen monoxide and nitrite with ferryl hemoglobin
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Nitrite uptake and metabolism and oxidant stress in human erythrocytes
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eNOS Gene Therapy Exacerbates Hepatic Ischemia-Reperfusion Injury in Diabetes
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Peroxynitrite: just an oxidative/nitrosative stressor or a physiological regulator as well?
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Effects of sodium nitrite on ischemia–reperfusion injury in the rat kidney
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Nitrosyl-Heme Complexes Are Formed in the Ischemic Heart
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Cellular, biochemical, and molecular aspects of reperfusion injury
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Nitrite as an intrinsic signaling molecule
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Self-citationNitric Oxide and Mitochondrial Complex IV
Sarti, P., Arese, M., Bacchi, A., Barone, M. C., Forte, E., Mastronicola, D., Brunori, M., & Giuffrè, A. (2003) · IUBMB Life · doi:10.1080/15216540310001628726 · Cited by 56 · see citing works
Intragastric nitric oxide is abolished in intubated patients and restored by nitrite*
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Hemoglobin as a Nitrite Reductase Regulating Red Cell–Dependent Hypoxic Vasodilation
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Self-citationNitrite Reductase Activity of Sol-Gel-encapsulated Deoxyhemoglobin
Roche, C. J., Dantsker, D., Samuni, U., & Friedman, J. M. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m603914200 · Cited by 39 · see citing works
Nitrite-derived nitric oxide formation following ischemia-reperfusion injury in kidney
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Peroxynitrite: Toxic or Protective in the Heart?
Ferdinandy, P., & Schulz, R. (2001) · Circulation Research · doi:10.1161/01.res.88.2.e12 · Cited by 30 · see citing works
Nitrite transport into pig erythrocytes and its potential biological role
Jensen, F. B. (2005) · Acta Physiologica Scandinavica · doi:10.1111/j.1365-201x.2005.01448.x · Cited by 28 · see citing works
Do neutrophils contribute to myocardial reperfusion injury?
Lefer, D. J. (2002) · Basic Research in Cardiology · doi:10.1007/s00395-002-0363-x · Cited by 27 · see citing works
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Effect of Exogenous Nitric Oxide during Cardiopulmonary Bypass on Lung Postperfusion Histology
Palatianos, G. M., Paziouros, K. E., Vassili, M. I., Stratigi, P., Kaklamanis, L., Prapas, S. N., Panagiotou, M., Iliopoulou, E., Mardaki, S., & Melissari, E. N. (2005) · ASAIO Journal · doi:10.1097/01.mat.0000169274.42302.14 · Cited by 2 · see citing works
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The nitrate-nitrite-nitric oxide pathway in physiology and therapeutics
Lundberg, J. O., Weitzberg, E., & Gladwin, M. T. (2008) · Nature Reviews Drug Discovery · doi:10.1038/nrd2466 · Cited by 2,739 · see citing works
Self-citationBailey, S. J., Fulford, J., Vanhatalo, A., Winyard, P. G., Blackwell, J. R., DiMenna, F. J., Wilkerson, D. P., Benjamin, N., & Jones, A. M. (2010) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00046.2010 · Cited by 607 · see citing works
“For example, it is possible that the protective effect of NO2 on infarct size that has been reported in experimental models of myocardial ischemia (20, 63, 73) might be due to an NO-mediated reduction in the energy (and O2) cost of contraction rather than, or perhaps in addition to, enhanced perfusion of ischemic area…”
BackgroundSources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation
Tejero, J., Shiva, S., & Gladwin, M. T. (2019) · Physiological Reviews · doi:10.1152/physrev.00036.2017 · Cited by 541 · see citing works
Self-citationNitrite as Regulator of Hypoxic Signaling in Mammalian Physiology
van Faassen, E. E., Bahrami, S., Feelisch, M., Hogg, N., Kelm, M., Kim‐Shapiro, D. B., Kozlov, A. V., Li, H., Lundberg, J. O., Mason, R., et al. (2009) · Medicinal Research Reviews · doi:10.1002/med.20151 · Cited by 435 · see citing works
“4 nitrite seems inert under normoxic conditions, but starts to act as a source of NO if oxygen levels in the tissue drop below a certain threshold.(10,11) Various mechanisms for nitrite reduction have now been identified.”
BackgroundSelf-citationLansley, K. E., Winyard, P. G., Fulford, J., Vanhatalo, A., Bailey, S. J., Blackwell, J. R., DiMenna, F. J., Gilchrist, M., Benjamin, N., & Jones, A. M. (2011) · Journal of Applied Physiology · doi:10.1152/japplphysiol.01070.2010 · Cited by 404 · see citing works
“Systolic and diastolic blood pressure were unchanged during PL supplementation, suggesting that the reduction in systolic blood pressure with NO3 -rich BR was mediated through the systemic reduction of NO3 -derived NO2 to NO (6, 11, 18).”
BackgroundMaia, L. B., & Moura, J. J. G. (2014) · Chemical Reviews · doi:10.1021/cr400518y · Cited by 401 · see citing works
Acute Dietary Nitrate Supplementation Improves Cycling Time Trial Performance
LANSLEY, K. E., WINYARD, P. G., BAILEY, S. J., VANHATALO, A., WILKERSON, D. P., BLACKWELL, J. R., GILCHRIST, M., BENJAMIN, N., & JONES, A. M. (2011) · Medicine & Science in Sports & Exercise · doi:10.1249/mss.0b013e31821597b4 · Cited by 388 · see citing works
“This suggests that the physiological effects observed after BR were mediated through the systemic reduction of nitrate-derived nitrite to the potent vasodilator and signaling molecule, nitric oxide (4,8,12,31).”
Lidder, S., & Webb, A. J. (2013) · British Journal of Clinical Pharmacology · doi:10.1111/j.1365-2125.2012.04420.x · Cited by 360 · see citing works
Dietary 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
Nitric oxide signaling: Classical, less classical, and nonclassical mechanisms
Martı́nez-Ruiz, A., Cadenas, S., & Lamas, S. (2011) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2011.04.010 · Cited by 336 · see citing works
The 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-citationAMPK, Mitochondrial Function, and Cardiovascular Disease
Wu, S., & Zou, M.-H. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21144987 · Cited by 286 · see citing works
Lehnert, N., Kim, E., Dong, H. T., Harland, J. B., Hunt, A. P., Manickas, E. C., Oakley, K. M., Pham, J., Reed, G. C., & Alfaro, V. S. (2021) · Chemical Reviews · doi:10.1021/acs.chemrev.1c00253 · Cited by 277 · see citing works
Sickle 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
“, initiation, progression, and resolution of vessel occlusion with downstream ischemia) [8]; and (c) a reputed mechanistic function for nitrite that parallels those for NO-mediated cytoprotection in this setting [240].”
BackgroundSelf-citationHermes‐Lima, M., Moreira, D. C., Rivera‐Ingraham, G. A., Giraud‐Billoud, M., Genaro‐Mattos, T. C., & Campos, E. G. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.07.156 · Cited by 241 · see citing works
“Nitrite, which has also been demonstrated to be an important cytoprotector on ischemia– reperfusion events (Dezfulian et al., 2007), increased in a tissue-specific way in turtles exposed to anoxia (Jensen et al., 2014).”
Andreadou, I., Iliodromitis, E. K., Rassaf, T., Schulz, R., Papapetropoulos, A., & Ferdinandy, P. (2014) · British Journal of Pharmacology · doi:10.1111/bph.12811 · Cited by 213 · see citing works
“The administration of sodium nitrite exerts cytoprotective effects in myocardial I/R injury (Webb et al., 2004; Dezfulian et al., 2007; Hendgen-Cotta et al., 2008).”
BackgroundNitrite: A physiological store of nitric oxide and modulator of mitochondrial function
Shiva, S. (2013) · Redox Biology · doi:10.1016/j.redox.2012.11.005 · Cited by 207 · see citing works
Self-citationZuckerbraun, B. S., Shiva, S., Ifedigbo, E., Mathier, M. A., Mollen, K. P., Rao, J., Bauer, P. M., Choi, J. J. W., Curtis, E., Choi, A. M. K., et al. (2010) · Circulation · doi:10.1161/circulationaha.109.891077 · Cited by 192 · see citing works
Self-citationChronic 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
“The identity of the electron donor remains an active area of investigation, with xanthine oxidoreductase, oxygen-binding heme proteins (hemoglobin and myoglobin), mitochondrial heme proteins, and nitrite disproportionation at acidic pH all being possible candidates (25).”
BackgroundEndothelial 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
Therapeutic Uses of Inorganic Nitrite and Nitrate: From the Past to the Future
Butler, A. R., & Feelisch, M. (2008) · Circulation · doi:10.1161/circulationaha.107.753814 · Cited by 184 · 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-citationAbe, Y., Hines, I. N., Zibari, G. B., Pavlick, K. P., GRAY, L., Kitagawa, Y., & Grisham, M. B. (2008) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2008.09.029 · Cited by 176 · see citing works
“Furthermore, the mouse model of liver I/R has been especially informative in demonstrating that endogenous or exogenous NO protects the liver from post-ischemic injury by normalizing the redox potential of the liver, attenuating the transcriptional activation of a number of injurious and pro-inflammatory genes, limiti…”
BackgroundDaiber, A., & Münzel, T. F. (2015) · Antioxidants and Redox Signaling · doi:10.1089/ars.2015.6376 · Cited by 167 · see citing works
“Interestingly, there is consistent evidence that this compound has potent cytoprotective properties, especially in IR injury (29, 72, 148), potentially mediated by nitrosative inhibition of mitochondrial respiratory chain I, which causes a reduced ROS production at reperfusion.”
BackgroundMontenegro, M. F., Amaral, J. H., Pinheiro, L. C., Sakamoto, E. K., Ferreira, G. C., Reis, R. I., Marçal, D. M. O., Pereira, R. P., & Tanus-Santos, J. E. (2011) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2011.04.005 · Cited by 152 · see citing works
“Many studies have explored the therapeutic potential of activating nitrate–nitrite–NO pathways, and relevant biological effects were associated with nitrite or nitrate, including beneficial effects against ischemia–reperfusion injury [11,18,19], vasorelaxant properties [20], pulmonary vasodilator effects [21–23], and…”
BackgroundDietary 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
Woessner, M., Smoliga, J. M., Tarzia, B., Stabler, T., Van Bruggen, M., & Allen, J. D. (2016) · Nitric Oxide · doi:10.1016/j.niox.2016.01.002 · Cited by 137 · see citing works
Nitric oxide promotes distant organ protection: evidence for an endocrine role of nitric oxide
Elrod, J. W., Calvert, J. W., Gundewar, S., Bryan, N. S., & Lefer, D. J. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0800700105 · Cited by 137 · see citing works
“The reduction of nitrite to NO has been cited to occur in a variety of biological tissues and has been prominently featured in protection against ischemic injury (32).”
BackgroundImpact of hypoxic hepatitis on mortality in the intensive care unit
Fuhrmann, V., Kneidinger, N., Herkner, H., Heinz, G., Nikfardjam, M., Bojic, A., Schellongowski, P., Angermayr, B., Schöniger–Hekele, M., Madl, C., et al. (2011) · Intensive Care Medicine · doi:10.1007/s00134-011-2248-7 · Cited by 137 · see citing works
“There is also evidence that nitrite may mediate cytoprotection in hepatic ischemia reperfusion injury [ 39 , 40].”
BackgroundLi, H., Hemann, C., Abdelghany, T. M., El-Mahdy, M. A., & Zweier, J. L. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.342378 · Cited by 132 · see citing works
“Several members of the globin family, including Hb, Mb, and Ngb, have shown the ability to reduce nitrite to NO, eliciting vasodilatation under ischemic conditions (16, 21, 28, 39, 40, 43).”
BackgroundGhosh, J., Das, J., Manna, P., & Sil, P. C. (2009) · Toxicology · doi:10.1016/j.tox.2009.11.011 · Cited by 125 · see citing works
Milkowski, A., Garg, H. K., Coughlin, J. R., & Bryan, N. S. (2010) · Nitric Oxide · doi:10.1016/j.niox.2009.08.004 · Cited by 123 · see citing works
“lished work over the past 10 years [72,95–101].”
BackgroundNadtochiy, S. M., & Redman, E. (2011) · Nutrition · doi:10.1016/j.nut.2010.12.006 · Cited by 121 · see citing works
“These discrepancies indicate that the actual amount of daily NO3/NO2 intake should be considered with caution because the data may vary depending on study design or targeted population [19,23].”
BackgroundCardiovascular surgery and organ damage: Time to reconsider the role of hemolysis
Windsant, I. C. V., Hanssen, S. J., Buurman, W. A., & Jacobs, M. J. H. M. (2011) · Journal of Thoracic and Cardiovascular Surgery · doi:10.1016/j.jtcvs.2011.02.012 · Cited by 122 · see citing works
“The process of NO reduction is most efficient at low PO2 and low pH and thus occurs preferentially during hypoxia or anoxia.(70,72,73) This is of particular importance because NO synthase activity is greatly limited at low Po2 values.”
BackgroundWood, K. C., Cortese-Krott, M. M., Kovacic, J. C., Noguchi, A. C., Liu, V. B., Wang, X., Raghavachari, N., Boehm, M., Kato, G. J., Kelm, M., et al. (2013) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.112.301068 · Cited by 123 · see citing works
Self-citationInorganic nitrite therapy: historical perspective and future directions
Kevil, C. G., Kolluru, G. K., Pattillo, C. B., & Giordano, T. (2011) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2011.04.042 · Cited by 113 · see citing works
A comparison of organic and inorganic nitrates/nitrites
Omar, S. A., Artime, E., & Webb, A. J. (2012) · Nitric Oxide · doi:10.1016/j.niox.2012.03.008 · Cited by 106 · see citing works
Alef, M. J., Vallabhaneni, R., Carchman, E., Morris, S. M., Shiva, S., Wang, Y., Kelley, E. E., Tarpey, M. M., Gladwin, M. T., Tzeng, E., et al. (2011) · Journal of Clinical Investigation · doi:10.1172/jci44079 · Cited by 101 · see citing works
Self-citationPride, C. K., Mo, L., Quesnelle, K., Dagda, R. K., Murillo, D., Geary, L., Corey, C., Portella, R., Zharikov, S., St Croix, C., et al. (2014) · Cardiovascular Research · doi:10.1093/cvr/cvt224 · Cited by 97 · see citing works
Self-citationZuckerbraun, B. S., George, M. P., & Gladwin, M. T. (2010) · Cardiovascular Research · doi:10.1093/cvr/cvq370 · Cited by 97 · see citing works
Self-citationNitrite 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 · see citing works
“The ability of nitrite to decrease infarct size has now been recapitulated by a number of other investigators in both in vivo and in vitro models of cardiac I/R (Table 1). Remarkably, the dose response of nitrite is highly reproducible across these studies, with the administration of 48 nmol (which increases plasma ni…”
BackgroundInfluentialSelf-citationMitochondria as metabolizers and targets of nitrite
Shiva, S. (2010) · Nitric Oxide · doi:10.1016/j.niox.2009.09.002 · Cited by 87 · see citing works
“Moreover, this phenomenon was absent in experiments in which the myoglobin was oxi- dized or in which the NO scavenger PTIO (2-phenyl-4,4,5,5tetramethylimidazoline-3-oxide-1-oxyl) was present, confirming that the inhibition of respiration under these conditions was indeed due to an interaction of nitrite and myoglobin…”
Self-citationRegulation of mitochondrial function and energetics by reactive nitrogen oxides
Larsen, F. J., Schiffer, T. A., Weitzberg, E., & Lundberg, J. O. (2012) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2012.08.580 · Cited by 87 · see citing works
δ-Opioid receptor activation attenuates oxidative injury in the ischemic rat brain
Yang, Y., Xia, X., Zhang, Y., Wang, Q., Li, L., Luo, G., & Xia, Y. (2009) · BMC Biology · doi:10.1186/1741-7007-7-55 · Cited by 87 · see citing works
Nitrite 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 86 · see citing works
Nediani, C., Raimondi, L., Borchi, E., & Cerbai, E. (2010) · Antioxidants and Redox Signaling · doi:10.1089/ars.2010.3198 · Cited by 83 · see citing works
“Although the NO effect is mainly compartmentalized, emerging evidence suggests that NO generated at one compartment can be converted to inert NO metabolites such as nitrite and nitrate and transferred to other compartment and then reduced back to NO in the presence of myoglobin (101).”
Myocardial protection by nitrite
Calvert, J. W., & Lefer, D. J. (2009) · Cardiovascular Research · doi:10.1093/cvr/cvp079 · Cited by 82 · see citing works
Castiglione, N., Rinaldo, S., Giardina, G., Stelitano, V., & Cutruzzolà, F. (2012) · Antioxidants and Redox Signaling · doi:10.1089/ars.2011.4196 · Cited by 79 · see citing works
“NO can also exert its cytoprotective role by inhibiting caspase through S-nitrosation and via cGMP to avoid the release of cytochrome c from mitochondria, thus preventing apoptosis (91).”
InfluentialBice, 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 · see citing works
“…NO have given rise to a multitude of experimental and clinical studies focusing on the delivery of exogenous NO, in the form of various NO species and NO-donor compounds, to limit ischemia/reperfusion injury [7] with the general hypothesis being that NO ameliorates ischemia/reperfusion injury.”
A Review of the Pathophysiology and Novel Treatments for Erectile Dysfunction
Lasker, G. F., Maley, J. H., & Kadowitz, P. J. (2010) · Advances in Pharmacological Sciences · doi:10.1155/2010/730861 · Cited by 72 · see citing works
“[99] C.”
BackgroundManna, P., Ghosh, J., Das, J., & Sil, P. C. (2010) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2009.12.024 · Cited by 71 · see citing works
Bueno, M., Wang, J., Mora, A. L., & Gladwin, M. T. (2013) · Antioxidants & Redox Signaling · doi:10.1089/ars.2012.4833 · Cited by 68 · see citing works
“Nitrite has protective effects in different ischemia reperfusion injury models (19).”
BackgroundNO2– Activation and Reduction to NO by a Nonheme Fe(NO2)2 Complex
Sanders, B., Hassan, S. M., & Harrop, T. C. (2014) · Journal of the American Chemical Society · doi:10.1021/ja505236x · Cited by 67 · see citing works
Milsom, A. B., Patel, N. S. A., Mazzon, E., Tripatara, P., Storey, A., Mota-Filipe, H., Sepodes, B., Webb, A. J., Cuzzocrea, S., Hobbs, A. J., et al. (2010) · Nitric Oxide · doi:10.1016/j.niox.2009.10.010 · Cited by 67 · see citing works
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Jin, L., Qin, L., Xia, D., Liu, X., Fan, Z., Zhang, C., Gu, L., He, J., Ambudkar, I. S., Deng, D., et al. (2013) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2012.12.015 · Cited by 64 · see citing works
“Both nitrate and nitrite have therapeutic effects in animal models of ischemia–reperfusion injury [27,28], reduced cellular oxygen consumption [29], reversal of metabolic syndrome, reduced oxidative stress [30], and protection against gastric ulcerations [31,32].”
Heme/Copper Assembly Mediated Nitrite and Nitric Oxide Interconversion
Hematian, S., Siegler, M. A., & Karlin, K. D. (2012) · Journal of the American Chemical Society · doi:10.1021/ja3083818 · Cited by 64 · see citing works
Moayeri, M., Crown, D., Dorward, D. W., Gardner, D., Ward, J. M., Li, Y., Cui, X., Eichacker, P. Q., & Leppla, S. H. (2009) · PLoS Pathogens · doi:10.1371/journal.ppat.1000456 · Cited by 64 · see citing works
“Nitrite therapy has received much attention in recent years as a cytoprotective therapy in ischemia/reperfusion injury or disease states associated with NO deficiency [41,42].”
BackgroundMo, L., Wang, Y., Geary, L., Corey, C., Alef, M. J., Beer-Stolz, D., Zuckerbraun, B. S., & Shiva, S. (2012) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2012.07.080 · Cited by 62 · see citing works
“Mechanistically, the reduction of NO2 to NO is thought to be the initial step in a number of vascular responses that NO2 mediates in vivo, including stimulation of angiogenesis [21], protection from ischemia/reperfusion injury [22-25] and reversal of intimal hyperplasia after vascular injury [26].”
BackgroundSelf-citationRassaf, T., Ferdinandy, P., & Schulz, R. (2014) · British Journal of Pharmacology · doi:10.1111/bph.12291 · Cited by 62 · see citing works
“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).”
BackgroundBarreto‐Torres, G., Parodi‐Rullán, R. M., & Javadov, S. A. (2012) · International Journal of Molecular Sciences · doi:10.3390/ijms13067694 · Cited by 61 · see citing works
“NO can also reduce mitochondrial ROS through direct inhibition of complex I during ischemia thereby minimizing ROS production at reperfusion [36].”
BackgroundPharmacology and therapeutic role of inorganic nitrite and nitrate in vasodilatation
Bailey, J., Feelisch, M., Horowitz, J. D., Frenneaux, M. P., & Madhani, M. (2014) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2014.06.009 · Cited by 60 · see citing works
“…groups that nitrite-derived bioactivity is cardioprotective by minimising cell death by apoptosis (Webb et al., 2004; Duranski et al., 2005; Dezfulian et al., 2007; Shiva et al., 2007a, 2007b; Tripatara et al., 2007), exerts anti-aggregatory effects (Srihirun et al., 2012; Corti et al.,…”
Vitturi, D. A., & Patel, R. P. (2011) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2011.05.037 · Cited by 59 · see citing works
“The potential for nitrite to be an hypoxic source for NO has also opened the door for nitrite therapeutics for various conditions characterized by ischemic injury, the pathogenesis of which is mediated in part by a loss of NO-signaling as exemplified by ischemia-reperfusion injury [8-11].”
Kemmner, S., Lorenz, G., Wobst, J., Kessler, T., Wen, M., Günthner, R., Stock, K., Heemann, U., Burkhardt, K., Baumann, M., et al. (2017) · Nitric Oxide · doi:10.1016/j.niox.2017.01.011 · Cited by 74 · see citing works
Inhaled nitric oxide: Current clinical concepts
Bhatraju, P. K., Crawford, J. H., Hall, M. K., & Lang, J. D. (2015) · Nitric Oxide · doi:10.1016/j.niox.2015.08.007 · Cited by 57 · see citing works
Sandvik, G. K., Nilsson, G., & Jensen, F. B. (2011) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00538.2011 · Cited by 57 · see citing works
“Several studies have shown that exogenously administrated nitrite limits tissue damage during ischemia-reperfusion events in mammalian models (18, 63), and nitrite is currently being tested as a therapeutic agent against various cardiovascular problems (5, 48).”
BackgroundActivation of Hypoxia Response in Endothelial Cells Contributes to Ischemic Cardioprotection
Kerkelä, R., Karsikas, S., Szabó, Z., Serpi, R., Magga, J. M., Gao, E., Alitalo, K. K., Anisimov, A., Sormunen, R. T., Pietilä, I., et al. (2013) · Molecular and Cellular Biology · doi:10.1128/mcb.00432-13 · Cited by 55 · see citing works
“NO is known to mediate several beneficial effects promoting cardiac ischemia survival (29).”
BackgroundMaia, L. B., & Moura, J. J. G. (2018) · Redox Biology · doi:10.1016/j.redox.2018.08.020 · Cited by 56 · see citing works
McArthur, J. G., Svenstrup, N., Chen, C., Fricot, A., Carvalho, C., Nguyen, J., Nguyen, P., Parachikova, A. I., Abdulla, F. A., Vercellotti, G. M., et al. (2019) · Haematologica · doi:10.3324/haematol.2018.213462 · Cited by 54 · see citing works
“Red cell lysis results in the release of Hb which consumes the plasma pool of NO and increases the vasculopathy associated with SCD7 nitrite generated in the plasma from an excess of NO produced by endothelial NO synthase (eNOS), can be converted back to NO as levels drop, acting as a biochemical reserve for NO.47 In…”
BackgroundInfluentialApelin/APJ System: A Novel Therapeutic Target for Myocardial Ischemia/Reperfusion Injury
Chen, Z., Wu, D., Li, L., & Chen, L. (2016) · DNA and Cell Biology · doi:10.1089/dna.2016.3391 · Cited by 53 · see citing works
“Nitrite reduction to NO may be catalyzed by myoglobin, hemoglobin, or other metal-containing enzymes and occurs at increasing rates under conditions of physiologic hypoxia or ischemia (Dezfulian et al. , 2007).”
Nitrite therapy is neuroprotective and safe in cardiac arrest survivors
Dezfulian, C., Alekseyenko, A., Dave, K. R., Raval, A. P., Do, R., Kim, F., & Pérez‐Pinzón, M. A. (2012) · Nitric Oxide · doi:10.1016/j.niox.2012.03.007 · Cited by 51 · see citing works
“In less than a decade nitrite therapy has been demonstrated to mitigate reperfusion injury in multiple animal models of ischemiareperfusion in a variety of organs [14,15].”
BackgroundSelf-citationMitigation of chlorine gas lung injury in rats by postexposure administration of sodium nitrite
Yadav, A. K., Doran, S. F., Samal, A. A., Sharma, R., Vedagiri, K., Postlethwait, E. M., Squadrito, G. L., Fanucchi, M. V., Roberts, L. J., Patel, R. P., et al. (2010) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00278.2010 · Cited by 50 · see citing works
“NO2 -mediated protection against inflammatory tissue injury is thought to occur primarily by its reduction to NO by reduced hemoglobin in hypoxic red blood cells, which in turn could affect ALI by several mechanisms, including modulation of leukocyte adhesion and infiltration, inhibition of endothelial/ epithelial cel…”
BackgroundDietary intake and bio-activation of nitrite and nitrate in newborn infants
Jones, J. A., Hopper, A. O., Power, G. G., & Blood, A. B. (2014) · Pediatric Research · doi:10.1038/pr.2014.168 · Cited by 47 · see citing works
“suggested that nitrite reduction to NO in acidic tissues exacerbates postischemic injury (65), nitrite has since been consistently shown in experimental animals to be protective against I/R injury in the heart, brain, liver, and kidney (29,68).”
Shiva, S., Rassaf, T., Patel, R. P., & Gladwin, M. T. (2010) · Cardiovascular Research · doi:10.1093/cvr/cvq327 · Cited by 46 · see citing works
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Hepatocellular protection by nitric oxide or nitrite in ischemia and reperfusion injury
Abe, Y., Hines, I. N., Zibari, G. B., & Grisham, M. B. (2008) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2008.10.006 · Cited by 44 · see citing works
Gori, T., & Daiber, A. (2009) · American Journal of Cardiovascular Drugs · doi:10.1007/bf03256591 · Cited by 44 · see citing works
Pattillo, C. B., Bir, S. C., Rajaram, V., & Kevil, C. G. (2010) · Cardiovascular Research · doi:10.1093/cvr/cvq297 · Cited by 43 · see citing works
“The preponderance of studies have shown that beneficial effects of near physiological plasma concentrations (high nanomolar) of sodium nitrite therapy emanate from the reduction of nitrite back to NO as the NO scavengers carboxy-PTIO (2-phenyl-4,4,5,5,tetramethylimidazoline-1-oxyl-3-oxide) or cell free haemoglobin blu…”
BackgroundMechanistic characterization of nitrite‐mediated neuroprotection after experimental cardiac arrest
Dezfulian, C., Kenny, E., Lamade, A. M., Missé, A., Krehel, N. M., Croix, C. M. S., Kelley, E. E., Jackson, T. C., Uray, T., Rackley, J., et al. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13764 · Cited by 42 · see citing works
“As a result, nitrite generation of NO required for activation of sGC or S-nitrosation occurs selectively during ischemia-reperfusion (Dezfulian et al. 2007) making it a potential precision medicine therapy for CA.”
BackgroundSelf-citationLim, C. C., Bryan, N. S., Jain, M., Garcia-Saura, M. F., Fernandez, B. O., Sawyer, D. B., Handy, D. E., Loscalzo, J., Feelisch, M., & Liao, R. (2009) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00673.2009 · Cited by 43 · see citing works
Nitrite Reduces Acute Lung Injury and Improves Survival in a Rat Lung Transplantation Model
Sugimoto, R., Okamoto, T., Nakao, A., Zhan, J., Wang, Y., Kohmoto, J., Tokita, D., Farver, C. F., Tarpey, M. M., Billiar, T. R., et al. (2012) · American Journal of Transplantation · doi:10.1111/j.1600-6143.2012.04169.x · Cited by 40 · see citing works
Self-citationRole of β-Adrenergic Receptors and Nitric Oxide Signaling in Exercise-Mediated Cardioprotection
Calvert, J. W., & Lefer, D. J. (2013) · Physiology · doi:10.1152/physiol.00011.2013 · Cited by 39 · see citing works
Singh, M., Arya, A., Kumar, R., Bhargava, K., & Sethy, N. K. (2012) · Nitric Oxide · doi:10.1016/j.niox.2011.12.002 · Cited by 38 · see citing works
Sinha, S. S., Shiva, S., & Gladwin, M. T. (2008) · Trends in Cardiovascular Medicine · doi:10.1016/j.tcm.2008.05.001 · Cited by 37 · see citing works
“…is its ability to mediate cytoprotection after ischemia-reperfusion (I/R) in a number of organs and species (Baker et al. 2007, Bryan et al. 2007, Dezfulian et al. 2007, Duranski et al. 2005, Gonzalez et al. 2008, Jung et al. 2006, Lu et al. 2005, Shiva et al. 2007b, Tripatara et al. 2007,…”
BackgroundSelf-citationSkeletal Muscle Nitrate as a Regulator of Systemic Nitric Oxide Homeostasis
Piknova, B., Schechter, A. N., Park, J. W., Vanhatalo, A., & Jones, A. M. (2021) · Exercise and Sport Sciences Reviews · doi:10.1249/jes.0000000000000272 · Cited by 36 · see citing works
Murata, I., Nozaki, R., Ooi, K., Ohtake, K., Kimura, S., Ueda, H., Nakano, G., Sonoda, K., Inoue, Y., Uchida, H., et al. (2012) · Journal of Trauma and Acute Care Surgery · doi:10.1097/ta.0b013e31824a76b5 · Cited by 33 · see citing works
“nitrite administered before or during reperfusion has been demonstrated to protect against I/R injury in a number of animal models of myocardial infarction, stroke, liver infarction, and renal I/R injury.(6) However, there has been so far no experimental evidence indicating the therapeutic consequences of nitrite admi…”
BackgroundHematian, S., Kenkel, I., Shubina, T. E., Dürr, M., Liu, J. J., Siegler, M. A., Ivanović‐Burmazović, I., & Karlin, K. D. (2015) · Journal of the American Chemical Society · doi:10.1021/jacs.5b02174 · Cited by 33 · see citing works
Hathazi, D., Scurtu, F., Bischin, C., Mot, A. C., Attia, A. A. A., Kongsted, J., & Silaghi-Dumitrescu, R. L. (2018) · Molecules · doi:10.3390/molecules23020350 · Cited by 32 · see citing works
Kovács, M., Kiss, A., Gönczi, M., Miskolczi, G., Seprényi, G., Kaszaki, J., Kohr, M. J., Murphy, E., & Végh, Á. (2015) · PLoS ONE · doi:10.1371/journal.pone.0122243 · Cited by 30 · see citing works
Silva, M. R., Correia, A. O., dos Santos, G. C. A., Parente, L. L. T., de Siqueira, K. P., Lima, D. G. S., Moura, J. A., Ribeiro, A. E. D. S., da Costa, R. O., Lucetti, D. L., et al. (2018) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2018.02.001 · Cited by 30 · see citing works
“The anion nitrite (NO2) is considered a biochemical reservoir for nitric oxide (NO), and nitrite reduction to NO occurs at increasing rates in brain ischemia (Dezfulian et al., 2007).”
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Heart Failure Management: The Present and the Future
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“NO and the NO-modified proteins and lipids then exert their downstream beneficial effects through the following mechanisms (38): 1.”
Emerging role of nitrite in myocardial protection
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Effect of Out-of-Hospital Sodium Nitrite on Survival to Hospital Admission After Cardiac Arrest
Kim, F., Maynard, C. C., Dezfulian, C., Sayre, M. R., Kudenchuk, P. J., Rea, T. D., Sampson, D., Olsufka, M., May, S. J., & Nichol, G. (2021) · JAMA · doi:10.1001/jama.2020.24326 · Cited by 26 · see citing works
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Current Pharmacological Advances in the Treatment of Cardiac Arrest
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“Nitrite therapy limits cellular injury and apoptosis after ischemia and reperfusion (I/R).(116) It has been proven to be cytoprotective in numerous animal models of focal I/R injury, including rodent heart, brain, liver and kidney, canine heart, and primate brain.”
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Nanotechnology for Electroanalytical Biosensors of Reactive Oxygen and Nitrogen Species
Seenivasan, R., Kolodziej, C., Karunakaran, C., & Burda, C. (2017) · The Chemical Record · doi:10.1002/tcr.201600143 · Cited by 24 · see citing works
Nebulized nitrite protects rat lung grafts from ischemia reperfusion injury
Okamoto, T., Tang, X., Janocha, A., Farver, C. F., Gladwin, M. T., & McCurry, K. R. (2013) · The Journal of Thoracic and Cardiovascular Surgery · doi:10.1016/j.jtcvs.2012.04.006 · Cited by 22 · see citing works
Self-citation
- Authors
- DEZFULIAN, C., RAAT, N., SHIVA, S., & GLADWIN, M.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- GLADWIN, M
- Venue
- Cardiovascular Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2007-07-15
- Volume
- 75
- Issue
- 2
- Pages
- 327-338
- ISSN
- 0008-6363 (ISSN-L)
- PMC
- PMC2002522
- OpenAlex
- W2128346933
- Cited by
- 198
- References
- 115
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 4 · 2023: 6 · 2022: 2 · 2021: 6 · 2020: 3 · 2019: 4 · 2018: 8 · 2017: 10 · 2016: 11 · 2015: 12 · 2014: 15 · 2013: 15 · 2012: 21
- FWCI
- 12.24
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cardiovascular Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (Z99CL999999)
- 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, cytoprotection, nitrite reduction, nitrate, hypoxia, heart, liver, brain, kidney
- MeSH terms
- Animals, Anions, Humans, Nitric Oxide, Nitrites, Signal Transduction, Reperfusion Injury, Cytoprotection, Models, Animal, Muscle Cells
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