The potential role of the red blood cell in nitrite-dependent regulation of blood flow
Open accessAbstract
Nitrite was once thought to have little physiological relevance. However, nitrite is now being increasingly recognized as a therapeutic or possibly even physiological precursor of nitric oxide (NO) that is utilized when needed to increase blood flow. It is likely that different mechanisms for nitrite bioconversion occur in different tissues, but in the vascular system, there is evidence that erythrocyte haemoglobin (Hb) is responsible for the oxygen-dependent reduction of nitrite to modulate blood flow. Here, we review the complex chemical interactions of Hb and nitrite and discuss evidence supporting its role in vasodilation. We also discuss ongoing work focused on defining the precise mechanisms for export of NO activity from red blood cells and of other pathways that may mediate nitrite-dependent vasodilation.
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The relative contribution of either mechanism to NO formation is likely to vary with oxygen partial pressure along the vascular tree.
“The relative contribution of either mechanism to NO formation is likely to vary with oxygen partial pressure along the vascular tree [86,87].”
From On the chemical biology of the nitrite/sulfide interaction (2015) · cites this paper as [86]
Several proposed mechanisms explain how nitrite-derived bioactivity can be exported from the red blood cell, generally involving either a compartment model with submembrane localization or formation of another nitrogen oxide such as a nitrosothiol or N2O3.
“Several proposed mechanisms have been constructed to explain how nitrite-derived bioactivity can be exported from the red blood cell and these generally involve either a compartment model with submembrane localization of the reaction allowing for inefficient free NO escape, or the formation of another nitrogen oxide such as a nitrosothiol or N2O3 that can get out of the red blood cell and carry NO”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [53]
Evidence for nitrite reactions with erythrocytic hemoglobin and stimulation of hypoxic blood flow remains more limited and is the subject of much debate.
“The evidence for nitrite reactions with erythrocytic hemoglobin and stimulation of hypoxic blood flow remains more limited and is the subject of much debate [16, 61].”
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 [16]
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“Some investigators, however, have proposed that this intermediate is more stable,16,62 whereas others have contested this proposal.76 Strictly speaking, Reaction 2 is reversible, but in the RBC, once NO comes off, it is not likely to have chance to rebind to metHb.”
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Vitturi, D. A., Teng, X., Toledo, J. C., Matalon, S., Lancaster, J. R., & Patel, R. P. (2009) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.01303.2008 · Cited by 62 · see citing works
Self-citationQuantification of intermediates formed during the reduction of nitrite by deoxyhemoglobin
Salgado, M. T., Nagababu, E., & Rifkind, J. M. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m808647200 · Cited by 56 · see citing works
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Magnetic resonance study of the transmembrane nitrite diffusion
Samouilov, A., Woldman, Y. Y., Zweier, J. L., & Khramtsov, V. V. (2007) · Nitric Oxide · doi:10.1016/j.niox.2006.12.006 · Cited by 46 · see citing works
Rates of nitric oxide dissociation from hemoglobin
Azizi, F., Kielbasa, J. E., Adeyiga, A. M., Maree, R. D., Frazier, M., Yakubu, M., Shields, H. W., King, S. B., & Kim‐Shapiro, D. B. (2005) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2005.03.001 · Cited by 44 · see citing works
Self-citationQM−MM Study of Nitrite Reduction by Nitrite Reductase of Pseudomonas aeruginosa
Marti, M. A., Crespo, A., Bari, S. E., Doctorovich, F. A., & Estrin, D. A. (2004) · The Journal of Physical Chemistry B · doi:10.1021/jp048807r · Cited by 41 · see citing works
Kozlov, A. V., Costantino, G., Sobhian, B., Szalay, L., Umar, F., Nohl, H., Bahrami, S., & Redl, H. R. (2005) · Antioxidants and Redox Signaling · doi:10.1089/ars.2005.7.515 · Cited by 39 · see citing works
Bound NO in human red blood cells: fact or artifact?
Bryan, N. S., Rassaf, T., Rodríguez, J., & Feelisch, M. (2004) · Nitric Oxide · doi:10.1016/j.niox.2004.04.008 · Cited by 39 · see citing works
Mechanistic studies of S-nitrosothiol formation by NO/O2 and by NO/methemoglobin
Herold, S., & Röck, G. (2005) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2005.02.013 · Cited by 38 · see citing works
Lui, F. E., & Kluger, R. (2009) · Biochemistry · doi:10.1021/bi9014105 · Cited by 38 · see citing works
Blood, A. B., & Power, G. G. (2007) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.01259.2006 · Cited by 35 · see citing works
Role of nitric oxide in capillary perfusion and oxygen delivery regulation during systemic hypoxia
Bertuglia, S., & Giusti, A. (2004) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00426.2004 · Cited by 35 · see citing works
Sodium nitrite therapy attenuates the hypertensive effects of HBOC-201 via nitrite reduction
Rodriguez, C., Vitturi, D. A., He, J., Vandromme, M., Brandon, A., Hutchings, A., Rue, L. W., Kerby, J. D., & Patel, R. P. (2009) · Biochemical Journal · doi:10.1042/bj20090735 · Cited by 31 · see citing works
Self-citationXXIV. Researches on the blood.—On the action of nitrites on blood
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An electron paramagnetic resonance study of the affinity of nitrite for methemoglobin
Goetz, B. I., Shields, H. W., Basu, S., Wang, P., King, S. B., Hogg, N., Gladwin, M. T., & Kim‐Shapiro, D. B. (2009) · Nitric Oxide · doi:10.1016/j.niox.2009.10.009 · Cited by 24 · see citing works
Self-citationGarcia, J. I., Seabra, A. B., Kennedy, R. S., & English, A. M. (2009) · Journal of Inorganic Biochemistry · doi:10.1016/j.jinorgbio.2009.12.009 · Cited by 23 · see citing works
Role of nitric oxide in capillary perfusion and oxygen delivery regulation during systemic hypoxia
Bertuglia, S. (2004) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00426.2005 · Cited by 23 · see citing works
Artery-to-vein differences in nitric oxide metabolites are diminished in sepsis*
Morgan, M. A. M., Frasier, L. M., Stewart, J. C., Mack, C. M., Gough, M. S., Graves, B. T., Apostolakos, M. J., Doolin, K. P., Darling, D. C., Frampton, M. W., et al. (2010) · Critical Care Medicine · doi:10.1097/ccm.0b013e3181d16a3e · Cited by 22 · see citing works
NO metabolite flux across the human coronary circulation
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Reactions of nitrite with hemoglobin measured by membrane inlet mass spectrometry
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Nitrite–methemoglobin inadequate for hypoxic vasodilation
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Blood Vessel Specific Vaso-Activity To Nitrite Under Normoxic And Hypoxic Conditions
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Reply to 'Nitrite–methemoglobin inadequate for hypoxic vasodilation'
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Self-citation
Flagged first, then by citations
Research works printed but not linked: 1
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Self-citationHemoglobin-mediated nitric oxide signaling
Helms, C., & Kim-Shapiro, D. B. (2013) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2013.04.028 · Cited by 146 · see citing works
Self-citationOn the chemical biology of the nitrite/sulfide interaction
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Inorganic 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
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Self-citationNitric oxide formation <i>versus</i> scavenging: the red blood cell balancing act
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- Authors
- Patel, R. P., Hogg, N., & Kim-Shapiro, D. B.
- Affiliations
- University of Alabama at Birmingham (US)
- Medical College of Wisconsin (US)
- Corresponding author
- Patel, Rakesh P.
- Hogg, Neil
- Venue
- Cardiovascular Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2010-10-14
- Volume
- 89
- Issue
- 3
- Pages
- 507-515
- ISSN
- 0008-6363 (ISSN-L)
- 1755-3245
- PMC
- PMC3028972
- OpenAlex
- W2050123648
- Cited by
- 70
- References
- 113
- Citations by year
- 2025: 4 · 2024: 3 · 2023: 1 · 2022: 1 · 2021: 1 · 2020: 2 · 2018: 4 · 2017: 3 · 2016: 2 · 2015: 5 · 2014: 9 · 2013: 12 · 2012: 15
- FWCI
- 1.00
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cardiovascular Research (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (HL090503, U54HL090503, R37HL058091, HL58091, HL092624, R01HL092624)
- National Institute of General Medical Sciences (GM55792)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heme Oxygenase-1 and Carbon Monoxide
- Keywords
- nitrite, nitric oxide, erythrocytes, hemoglobin, vasodilation, blood flow regulation
- MeSH terms
- Animals, Erythrocytes, Humans, Nitrites, Regional Blood Flow, Vasodilation
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