Early Intravenous Infusion of Sodium Nitrite Protects Brain Against In Vivo Ischemia-Reperfusion Injury
Abstract
Background and Purpose— The rate of nitric oxide (NO) generation from nitrite is linearly dependent on reductions in oxygen and pH levels. Recently, nitrite-derived NO has been reported to exert a profound protection against liver and heart ischemia-reperfusion injury. In this study, we hypothesized that nitrite would be reduced to NO in the ischemic brain and exert NO-dependent neuroprotective effects. Methods— Cerebral ischemia-reperfusion injury was induced by intraluminal thread occlusion of middle cerebral artery in the adult male rats. Solutions of sodium nitrite were infused intravenously at the time of reperfusion. Sodium nitrate and carboxy-PTIO (30 minutes before ischemic surgery), a direct NO scavenger, were infused for comparisons. Results— Nitrite reduced infarction volume and enhanced local cerebral blood flow and functional recovery. The effects were observed at concentrations of 48 nmol and 480 nmol, but not at 4800 nmol nitrite and 480 nmol nitrate. The neuroprotective effects of nitrite were inhibited completely by the carboxy-PTIO. The 480 nmol nitrite attenuated dihydroethidium activity, 3-nitrotyrosine formation, and lipid peroxidation in the ischemic brain. Conclusions— Nitrite exerted profound neuroprotective effects with antioxidant properties in the ischemic brains. These results suggest that nitrite, as a biological storage reserve of NO, may be a novel therapeutic agent in the setting of acute stroke.
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Early 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 [136]
The References section (page unavailable) lists a rat study reporting that L-arginine infusion reduced cerebral infarction volume. It does not establish that L-arginine was given before reperfusion. This paper’s Experimental Protocols instead describe administering sodium nitrite at reperfusion. (LLM, conf=0.82)
Experimental — accuracy not yet measuredThe protective effect of nitrite in ischaemia-reperfusion injury has been replicated by many in vivo and in vitro studies showing protection in most organs tested, including liver, brain, heart and kidneys.
“This protective effect of nitrite in ischaemiareperfusion injury has now been replicated by many other in vivo and in vitro studies showing protection in most organs tested such as the liver [161, 162], brain [163], heart [164] and kidneys [165] and reviewed by Dezfulian C et al. [166] and Webb & Ahluwalia [167].”
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 [163]
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 [188]
Nitrite is protective against ischemia/reperfusion and other forms of injury in multiple tissues and organs.
“Numerous investigations have reported that nitrite is protective against I/R and other forms of injury in multiple tissues and organs (81, 125, 188), as reviewed extensively elsewhere (157).”
From Inorganic nitrite supplementation for healthy arterial aging (2014) · cites this paper as [81]
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 [114]
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 [114]
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 [114]
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 [114]
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 [114]
Nitrite therapy is protective against ischemia-reperfusion injury in the brain.
“Several other studies extended the idea that nitrite therapy is protective against ischemia-reperfusion injury in different organs including the brain [157] and kidney (depending on route of administration) [158, 159].”
From Inorganic nitrite therapy: historical perspective and future directions (2011) · cites this paper as [157]
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- Authors
- Jung, K.-H., Chu, K., Ko, S.-Y., Lee, S.-T., Sinn, D.-I., Park, D.-K., Kim, J.-M., Song, E.-C., Kim, M., & Roh, J.-K.
- Affiliations
- Seoul National University (KR)
- Venue
- Stroke
- Published
- 2006-11
- Volume
- 37
- Issue
- 11
- Pages
- 2744-2750
- ISSN
- 0039-2499 (ISSN-L)
- 1524-4628
- OpenAlex
- W2118917131
- Cited by
- 253
- References
- 23
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 6 · 2023: 4 · 2022: 8 · 2021: 13 · 2020: 6 · 2019: 11 · 2018: 8 · 2017: 17 · 2016: 10 · 2015: 16 · 2014: 13 · 2013: 21 · 2012: 20
- FWCI
- 10.96
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Stroke (publishedVersion)
- PubMed (publishedVersion)
- Seoul National University Open Repository (Seoul National University) (submittedVersion)
- Funders
- Ministry of Education and Human Resources Development
- Topics
- Life Sciences › Neuroscience › Neurology › Neurological Disorders and Treatments
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Epidemiology › Acute Ischemic Stroke Management
- Keywords
- sodium nitrite, nitric oxide, cerebral ischemia-reperfusion injury, neuroprotection, acute stroke, cPTIO, nitrate, lipid peroxidation, nitrotyrosine, infarct size, middle cerebral artery occlusion, antioxidant activity
- MeSH terms
- Animals, Brain, Infusions, Intravenous, Male, Sodium Nitrite, Time Factors, Reperfusion Injury, Neuroprotective Agents, Rats
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