Comparative analysis of nitrite uptake and hemoglobin–nitrite reactions in erythrocytes: sorting out uptake mechanisms and oxygenation dependencies
Abstract
Nitrite uptake into red blood cells (RBCs) precedes its intracellular reactions with hemoglobin (Hb) that forms nitric oxide (NO) during hypoxia. We investigated the uptake of nitrite and its reactions with Hb at different oxygen saturations (So(2)), using RBCs with (carp and rabbit) and without (hagfish and lamprey) anion exchanger-1 (AE1) in the membrane, with the aim to unravel the mechanisms and oxygenation dependencies of nitrite transport. Added nitrite rapidly diffused into the RBCs until equilibrium. The distribution ratio of nitrite across the membrane agreed with that expected from HNO(2) diffusion and AE1-mediated facilitated NO(2)(-) diffusion. Participation of HNO(2) diffusion was emphasized by rapid transmembrane nitrite equilibration also in the natural AE1 knockouts. Following the equilibration, nitrite was consumed by reacting with Hb, which created a continued inward diffusion controlled by intracellular reaction rates. Changes in nitrite uptake with So(2), pH, or species were accordingly explained by corresponding changes in reaction rates. In carp, nitrite uptake rates increased linearly with decreasing So(2) over the entire So(2) range. In rabbit, nitrite uptake rates were highest at intermediate So(2), producing a bell-shaped relationship with So(2). Nitrite consumption increased approximately 10-fold with a 1 unit decrease in pH, as expected from the involvement of protons in the reactions with Hb. The reaction of nitrite with deoxyhemoglobin was favored over that with oxyhemoglobin at intermediate So(2). We propose a model for RBC nitrite uptake that involves both HNO(2) diffusion and AE1-mediated transport and that explains both the present and previous (sometimes puzzling) results.
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Current perspectives postulate that nitrite diffuses across the plasma membrane by becoming protonated to nitrous acid and, in red cells from some species, by interacting with anion exchanger 1 (AE-1).
“Current perspectives postulate that nitrite diffuses across the plasma membrane by becoming protonated to nitrous acid [97] and, in the context of red cells from some species, by interacting with the anion exchanger 1 (AE-1) [98, 99].”
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 [98]
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Truong, G. T., Schröder, H. J., Liu, T., Zhang, M., Kanda, E., Bragg, S. L., Power, G. G., & Blood, A. B. (2014) · The Journal of Physiology · doi:10.1113/jphysiol.2013.269340 · Cited by 10 · see citing works
“The possibility of compartmentalization of Reaction 1 has been proposed previously (Gladwin et al. 2006; Vitturi et al. 2009; Jensen & Rohde, 2010; Salhany, 2013), and gains circumstantial credibility from reports demonstrating that deoxyhaemoglobin associates closely with the anion exchanger…”
BackgroundRole of temperature in regulation of the life cycle of temperate fish
Si, D., Żukow, W., & Brudnicki, R. (2013) · Russian Journal of Marine Biology · doi:10.1134/s1063074013020041 · Cited by 10 · see citing works
Jensen, F. B., Kolind, R. A. H., Jensen, N. S., Montesanti, G., & Wang, T. (2017) · Comparative Biochemistry and Physiology Part A Molecular & Integrative Physiology · doi:10.1016/j.cbpa.2017.01.010 · Cited by 9 · see citing works
The SLC4 Anion Exchanger Gene Family
Stewart, A. K., & Alper, S. L. (2012) · Elsevier eBooks · doi:10.1016/b978-0-12-381462-3.00054-9 · Cited by 9 · see citing works
Exploring pathways of NO and H2S signaling in metabolic depression: The case of anoxic turtles
Bundgaard, A., Jensen, B. S., Jensen, F. B., & Fago, A. (2020) · Comparative Biochemistry and Physiology Part A Molecular & Integrative Physiology · doi:10.1016/j.cbpa.2020.110857 · Cited by 8 · see citing works
Blood Rheology and Microcirculation
Tikhomirova, I. A. (2023) · Успехи физиологических наук · doi:10.31857/s0301179823010071 · Cited by 8 · see citing works
Role of nitrates in the adaptation of fish to hypoxic conditions
Si, D., Żukow, W., Dzierżanowski, M., Mieszkowski, J., Muszkieta, R., & Klimczyk, M. (2016) · Water Resources · doi:10.1134/s0097807816120046 · Cited by 8 · see citing works
Vega‐Villa, K. R., Pluta, R. M., Lonser, R. R., & Woo, S. (2013) · CPT Pharmacometrics & Systems Pharmacology · doi:10.1038/psp.2013.35 · Cited by 7 · see citing works
Aquaculture of air-breathing fishes
Bayley, M., Damsgaard, C., Cong, N. V., Phương, N. T., & Huong, D. T. T. (2020) · Fish physiology · doi:10.1016/bs.fp.2020.09.005 · Cited by 7 · see citing works
Nitrite and Nitric Oxide as Potential Diagnostic Markers in Acute Vascular Diseases
Silver, J. H. (2011) · Journal of Neurology & Neurophysiology · doi:10.4172/2155-9562.s1-005 · Cited by 6 · see citing works
“Nitrite uptake into RBCs involves both diffusion of protonated nitrite (HNO2) and facilitated diffusion of NO2 - via anion-exchanger-1 (AE1) [29].”
BackgroundДоломатов, С. И., Żukow, W., & Skomarovskiy, D. (2011) · Zenodo (CERN European Organization for Nuclear Research) · doi:10.5281/zenodo.4540668 · Cited by 4 · see citing works
Ishibashi, T., Nishizawa, N., Nakamoto-Nomura, M., Abe, F., Liu, H., Yoshida, J., Kawada, T., & Nishio, M. (2011) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.34.528 · Cited by 3 · see citing works
Tang, H.-B., Si, Y.-X., Li, H., Dang, W., & Lu, H. (2025) · BMC Microbiology · doi:10.1186/s12866-025-04198-8 · Cited by 2 · see citing works
“Aqueous nitrite can reduce blood oxy-gen-carrying capacity by oxidizing hemoglobin, induce physiological metabolism disorder and histopathological damage, influence immune function and even result in a large number of deaths in fish [3–6].”
Erythroid anion Exchanger-1 (band 3) transports nitrite for nitric oxide metabolism
Chen, P.-L., Huang, K., Chen, L., & Hsu, K. (2023) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2023.11.028 · Cited by 3 · see citing works
Sodium nitrite intoxications: Quantification of nitrite and nitrate levels in postmortem blood
Schmitz, D., Stach, P., Juebner, M., Scholtis, S., Iwersen‐Bergmann, S., Krüger, J., Klíma, M., Andresen‐Streichert, H., & Lucuta, L. (2025) · Journal of Analytical Toxicology · doi:10.1093/jat/bkaf081 · Cited by 1 · see citing works
Vasoactivity of nitrite in the iliac artery of the toadRhinella marina
Forgan, L. G., Sofele, M., McNeill, B. A., Cameron, M. S., & Donald, J. A. (2017) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00315.2016 · Cited by 1 · see citing works
Gam, L. T. H., Phuong, N. T. H., Huong, D. T. T., Vu, N. T. T., & Nhu, P. N. (2018) · Can Tho University Journal of Science · doi:10.22144/ctu.jen.2018.001 · Cited by 1 · see citing works
Phan, V. T., Huỳnh, T. N. L., Đỗ, T. T. H., & Nguyễn, T. P. (2022) · Can Tho University Journal of Science · doi:10.22144/ctu.jvn.2022.057
“Điều này tương tự khi cá chép (Cyprinus carpio) và cá mút đá Đại Tây Dương (Atlantic hagfish, Myxine glutinosa) tiếp xúc với nitrite làm giảm pH ngoại bào bởi sự tăng lượng nitrite tích lũy trong máu (Jensen & Rohde, 2010).”
Li, T., Bai, S., Kong, L., Bi, B., & Hu, Q. (2025) · Aquaculture · doi:10.1016/j.aquaculture.2025.742767
Alshahrani, M. H. D., & Sidorov, A. V. (2025) · Inland Water Biology · doi:10.1134/s1995082925601431
“…the skin of the animal: interaction with respiratory proteins of the hemolymph (hemocy-anin) (Tahon et al., 1990) and/or its capture by cells (Jensen and Rohde, 2010), including nerve cells, with subsequent conversion into nitric oxide, a highly reactive molecule with pronounced free-radical…”
Physiological responses to nitrite toxicity in freshwater pearl mussel (Lamellidens marginalis)
Tripathy, V., Chhandaprajnadarsini, E. M., Tiwari, P. K., Choudhary, P., Nayak, Y., & Saurabh, S. (2026) · Ecotoxicology · doi:10.1007/s10646-026-03112-w
“Due to its competitive interaction with chloride ions, nitrite can enter the organism via chloride transport pathways, leading to its internal accumulation (Jensen et al. 2002 ; Jensen and Rohde 2010).”
Investigating the role of nitric oxide clones in cardiovascular conditions
Arif, S. (2014) · University of Birmingham Institutional Research Archive (University of Birmingham)
- Authors
- Jensen, F. B., & Rohde, S.
- Affiliations
- University of Southern Denmark (DK)
- Corresponding author
- Jensen, Frank B.
- ORCID
- Jensen, Frank B.
- Venue
- American Journal of Physiology-Regulatory, Integrative and Comparative Physiology
- Publisher
- American Physiological Society
- Published
- 2010-04
- Volume
- 298
- Issue
- 4
- Pages
- R972-R982
- ISSN
- 0363-6119 (ISSN-L)
- 1522-1490
- OpenAlex
- W1995820213
- Cited by
- 63
- References
- 47
- Citations by year
- 2026: 1 · 2025: 5 · 2023: 2 · 2022: 4 · 2021: 3 · 2020: 4 · 2019: 3 · 2018: 4 · 2017: 6 · 2016: 2 · 2015: 2 · 2014: 5 · 2013: 4 · 2012: 7
- FWCI
- 3.08
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Physiology-Regulatory, Integrative and Comparative Physiology (publishedVersion)
- PubMed (publishedVersion)
- University of Southern Denmark Research Portal (University of Southern Denmark) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Physiology › Erythrocyte Function and Pathophysiology
- Keywords
- nitrite uptake, erythrocytes, nitric oxide, band 3, oxygen saturation, hypoxia, pH dependence, deoxyhemoglobin, oxyhemoglobin, carp, rabbits, hagfish, lamprey, nitrite transport
- MeSH terms
- Animals, Carps, Denmark, Erythrocytes, Hagfishes, Hemoglobins, Kinetics, Lampreys, Nitrites, Oxygen, Oxygen Consumption, Oxyhemoglobins, Rabbits, Species Specificity
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