Nitrite therapy after cardiac arrest reduces reactive oxygen species generation, improves cardiac and neurological function, and enhances survival via reversible inhibition of mitochondrial complex I
Open accessAbstract
BACKGROUND: Three-fourths of cardiac arrest survivors die before hospital discharge or suffer significant neurological injury. Except for therapeutic hypothermia and revascularization, no novel therapies have been developed that improve survival or cardiac and neurological function after resuscitation. Nitrite (NO(2)(-)) increases cellular resilience to focal ischemia/reperfusion injury in multiple organs. We hypothesized that nitrite therapy may improve outcomes after the unique global ischemia/reperfusion insult of cardiopulmonary arrest. METHODS AND RESULTS: We developed a mouse model of cardiac arrest characterized by 12 minutes of normothermic asystole and a high cardiopulmonary resuscitation rate. In this model, global ischemia and cardiopulmonary resuscitation were associated with blood and organ nitrite depletion, reversible myocardial dysfunction, impaired alveolar gas exchange, neurological injury, and an approximately 50% mortality. A single low dose of intravenous nitrite (50 nmol=1.85 micromol/kg=0.13 mg/kg) compared with blinded saline placebo given at cardiopulmonary resuscitation initiation with epinephrine improved cardiac function, survival, and neurological outcomes. From a mechanistic standpoint, nitrite treatment restored intracardiac nitrite and increased S-nitrosothiol levels, decreased pathological cardiac mitochondrial oxygen consumption resulting from reactive oxygen species formation, and prevented oxidative enzymatic injury via reversible specific inhibition of respiratory chain complex I. CONCLUSIONS: Nitrite therapy after resuscitation from 12 minutes of asystole rapidly and reversibly modulated mitochondrial reactive oxygen species generation during early reperfusion, limiting acute cardiac dysfunction, death, and neurological impairment in survivors.
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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 [122]
NO2- supplemented diets are associated with a variety of beneficial anti-inflammatory and metabolic actions, including regulation of mitochondrial function, adipogenesis, oxygen delivery to tissues, and blood pressure.
“Importantly, NO 2 Ϫ -supplemented diets are associated with a variety of beneficial anti-inflammatory and metabolic actions, including the regulation of mitochondrial function, adipogenesis, oxygen delivery to tissues, and blood pressure (20).”
From Conjugated linoleic acid is a preferential substrate for fatty acid nitration (2012) · cites this paper as [20]
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 [40]
Nitrite-induced S-nitrosation of complex I of the electron transport chain decreases mitochondrial reactive species formation and subsequently confers protection against ischemia-reperfusion injury.
“the nitrite-induced S-nitrosation of complex I of the electron transport chain which decreases mitochondrial reactive species formation and subsequently confers protection against ischemia-reperfusion injury [104] [33, 86, 105, 106].”
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 [106]
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References 45 · Cited by 174
- Authors
- 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.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- From Pulmonary and Critical Care Medicine, Department of Medicine, and Cerebral Vascular Disease Research Center, Department of Neurology, University of Miami Miller School of Medicine, Miami, Fla (C.D.); Hemostasis and Vascular Biology Research Institute (S.S., M.T.G.) and Department of Pharmacology and Chemical Biology (S.S.), University of Pittsburgh, Pittsburgh, Pa; University of North Carolina School of Medicine, Chapel Hill (A.P.); Emergency Resuscitation Center and Section of Emergency...
- ORCID
- Venue
- Circulation
- Published
- 2009-09-08
- Volume
- 120
- Issue
- 10
- Pages
- 897-905
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- PMC
- PMC2755623
- OpenAlex
- W2110687748
- Cited by
- 174
- References
- 45
- Citations by year
- 2025: 7 · 2024: 3 · 2023: 4 · 2022: 7 · 2021: 8 · 2020: 7 · 2019: 6 · 2018: 12 · 2017: 11 · 2016: 8 · 2015: 17 · 2014: 17 · 2013: 16 · 2012: 17
- FWCI
- 17.55
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- University of South Dakota
- National Institutes of Health
- National Heart, Lung, and Blood Institute (Z01HL005111)
- Topics
- Health Sciences › Medicine › Emergency Medicine › Cardiac Arrest and Resuscitation
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Keywords
- nitrite therapy, cardiac arrest, cardiac arrest resuscitation, global cerebral ischemia, ischemia-reperfusion injury, reactive oxygen species, mitochondrial complex I inhibition, S-nitrosothiols, cardiac dysfunction, neurological injury, survival, epinephrine, mitochondrial oxygen consumption, oxidative damage
- MeSH terms
- Animals, Heart, Heart Arrest, Injections, Intravenous, Male, Mice, Inbred C57BL, Nervous System, Sodium Nitrite, Time Factors, Survival Rate, Cardiopulmonary Resuscitation, Reactive Oxygen Species, Electron Transport Complex I, Mice
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