Nitrite as a vascular endocrine nitric oxide reservoir that contributes to hypoxic signaling, cytoprotection, and vasodilation
Abstract
Accumulating evidence suggests that the simple and ubiquitous anion salt, nitrite (NO 2−), is a physiological signaling molecule with potential roles in intravascular endocrine nitric oxide (NO) transport, hypoxic vasodilation, signaling, and cytoprotection after ischemia-reperfusion. Human and animal studies of nitrite treatment and NO gas inhalation provide evidence that nitrite mediates many of the systemic therapeutic effects of NO gas inhalation, including peripheral vasodilation and prevention of ischemia-reperfusion-mediated tissue infarction. With regard to nitrite-dependent hypoxic signaling, biochemical and physiological studies suggest that hemoglobin possesses an allosterically regulated nitrite reductase activity that reduces nitrite to NO along the physiological oxygen gradient, potentially contributing to hypoxic vasodilation. An expanded consideration of nitrite as a hypoxia-dependent intrinsic signaling molecule has opened up a new field of research and therapeutic opportunities for diseases associated with regional hypoxia and vasoconstriction.
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Mathematical modeling of the reaction of Hb with nitrite at different oxygen tensions yields a bell-shaped dependence of observed rates versus oxygen concentration, with maximal NO generation around 50% Hb oxygen saturation, consistent with experimental data.
“In fact, the reaction of Hb with nitrite has been modeled mathematically at different oxygen tensions. The combination of a faster rate at higher oxygen, but increased availability of deoxyHb at low oxygen, leads to bell-shaped dependence of the observed rates versus the oxygen concentration with the maximal rates of NO generation around 50% Hb oxygen saturation, consistent with experimental data”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [368]
Inorganic nitrite demonstrates robust NO-signaling effects and contributes to basal vascular tone, blood pressure, protection from endothelial dysfunction and vascular inflammation under conditions of metabolic and inflammatory stress.
“As with NOS-derived NO, inorganic nitrite demonstrates robust NO-signaling effects[52,53,57,59] and contributes to basal vascular tone[51,55,60,61], blood pressure[62–66], protection from endothelial dysfunction[67–71] and vascular inflammation[72] under conditions of metabolic and inflammatory stress.”
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 [59]
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References 106 · Cited by 329
- Authors
- Gladwin, M. T., Raat, N. J. H., Shiva, S., Dezfulian, C., Hogg, N., Kim-Shapiro, D. B., & Patel, R. P.
- Affiliations
- National Institutes of Health (US)
- Venue
- American Journal of Physiology-Heart and Circulatory Physiology
- Publisher
- American Physiological Society
- Published
- 2006-11
- Volume
- 291
- Issue
- 5
- Pages
- H2026-H2035
- ISSN
- 0363-6135 (ISSN-L)
- 1522-1539
- OpenAlex
- W2152287206
- Cited by
- 329
- References
- 106
- Citations by year
- 2026: 7 · 2025: 4 · 2024: 7 · 2023: 8 · 2022: 9 · 2021: 13 · 2020: 12 · 2019: 10 · 2018: 13 · 2017: 16 · 2016: 15 · 2015: 12 · 2014: 19 · 2013: 22 · 2012: 31
- FWCI
- 2.99
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Physiology-Heart and Circulatory Physiology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heme Oxygenase-1 and Carbon Monoxide
- Keywords
- nitrite, nitric oxide, hypoxic vasodilation, hypoxia signaling, cytoprotection, ischemia-reperfusion injury, regional hypoxia, vasoconstriction
- MeSH terms
- Animals, Endocrine System, Hemoglobins, Humans, Models, Biological, Nitric Oxide, Nitrites, Vasodilation, Cell Hypoxia, Cytoprotection
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