Hypoxia, red blood cells, and nitrite regulate NO-dependent hypoxic vasodilation
Open accessAbstract
Local vasodilation in response to hypoxia is a fundamental physiologic response ensuring oxygen delivery to tissues under metabolic stress. Recent studies identify a role for the red blood cell (RBC), with hemoglobin the hypoxic sensor. Herein, we investigate the mechanisms regulating this process and explore the relative roles of adenosine triphosphate, S-nitrosohemoglobin, and nitrite as effectors. We provide evidence that hypoxic RBCs mediate vasodilation by reducing nitrite to nitric oxide (NO) and ATP release. NO dependence for nitrite-mediated vasodilation was evidenced by NO gas formation, stimulation of cGMP production, and inhibition of mitochondrial respiration in a process sensitive to the NO scavenger C-PTIO. The nitrite reductase activity of hemoglobin is modulated by heme deoxygenation and heme redox potential, with maximal activity observed at 50% hemoglobin oxygenation (P(50)). Concomitantly, vasodilation is initiated at the P(50), suggesting that oxygen sensing by hemoglobin is mechanistically linked to nitrite reduction and stimulation of vasodilation. Mutation of the conserved beta93cys residue decreases the heme redox potential (ie, decreases E(1/2)), an effect that increases nitrite reductase activity and vasodilation at any given hemoglobin saturation. These data support a function for RBC hemoglobin as an allosterically and redox-regulated nitrite reductase whose "enzyme activity" couples hypoxia to increased NO-dependent blood flow.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Accumulating studies demonstrate production of bioavailable NO from incubation of erythrocytes with nitrite.
“Although theoretical calculations suggest that this type of NO escape should be limited, accumulating studies by many research groups now demonstrate the production of bioavailable NO generated from the incubation of erythrocytes with nitrite (185, 196, 883, 975).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [196]
Relaxation by nitrite and red blood cells was associated with cGMP formation and dependent on Hb oxygen affinity, with maximal effect occurring near the Hb p50, consistent with the notion that R-state Hb reduces nitrite more effectively than T-state Hb.
“Relaxation by nitrite and red blood cells was associated with cGMP formation and dependent on Hb oxygen affinity, with maximal effect occurring near the Hb p50, consistent with the notion that R-state Hb reduces nitrite more effectively than T-state Hb [109].”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [109]
At oxygen tensions of 15 and 25 mmHg as little as 200 nM nitrite was subsequently shown to effect relaxation in aortic rings in the presence of red blood cells and relaxation was abrogated by the NO scavenger CPTIO.
“At oxygen tensions of 15 and 25 mmHg as little as 200 nM nitrite was subsequently shown to effect relaxation in aortic rings in the presence of red blood cells and relaxation was abrogated by the NO scavenger CPTIO [109].”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [109]
Differential reactivity of nitrite reduction versus oxidation controlled by oxygen tension underlies the model in which nitrite selectively produces NO during graded hypoxia.
“This differential reactivity of nitrite reduction versus oxidation being controlled by oxygen tension (i.e. presence of deoxygenated vs oxygenated hemoglobin / myoglobin) illustrates the biochemical mechanism underlying the proposed model in which nitrite can selectively produce NO during graded hypoxia [5, 25-28].”
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 [26]
Evidence for a role for NO is dependent largely on attenuation of responses by the NO-scavenger CPTIO and measurement of nitrite-dependent increases in cGMP levels.
“Evidence for a role for NO is dependent largely on attenuation of responses by the NO-scavenger CPTIO [25, 26, 52, 100] and measurement of nitrite-dependent increases in cGMP levels[26, 101].”
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 [26]
Deoxygenated red cells are able to reduce nitrite to NO which mediated vessel ring dilation.
“Lastly, Crawford et al further demonstrated that deoxygenated red cells were able to reduce nitrite to NO which mediated vessel ring dilation, solidifying the biological importance of deoxyhemoglobin reduction of nitrite [109].”
From Inorganic nitrite therapy: historical perspective and future directions (2011) · cites this paper as [109]
Human and animal studies of NO gas inhalation suggest that nitrite mediates many of the systemic therapeutic effects of inhaled NO, including peripheral vasodilation and prevention of ischemia-reperfusion-mediated tissue infarction.
“Human and animal studies of NO gas inhalation suggest that nitrite mediates many of the systemic therapeutic effects of inhaled NO, including peripheral vasodilation and prevention of ischemia-reperfusion-mediated tissue infarction [19, 109, 148, 151, 152].”
From Inorganic nitrite therapy: historical perspective and future directions (2011) · cites this paper as [109]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation
Cosby, K., Partovi, K. S., Crawford, J. H., Patel, R. P., Reiter, C. D., Martyr, S., Yang, B. K., Waclawiw, M. A., Zalos, G., Xu, X., et al. (2003) · Nature Medicine · doi:10.1038/nm954 · Cited by 1,807 · see citing works
Self-citationArnold, W. P., Mittal, C. K., Katsuki, S., & Murad, F. (1977) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.74.8.3203 · Cited by 1,459 · see citing works
Blood Flow Regulation by <i>S</i> -Nitrosohemoglobin in the Physiological Oxygen Gradient
Stamler, J. S., Jia, L., Eu, J. P., McMahon, T. J., Demchenko, I. T., Bonaventura, J., Gernert, K., & Piantadosi, C. A. (1997) · Science · doi:10.1126/science.276.5321.2034 · Cited by 1,050 · see citing works
Enzyme-independent formation of nitric oxide in biological tissues
Zweier, J. L., Wang, P., Samouilov, A., & Kuppusamy, P. (1995) · Nature Medicine · doi:10.1038/nm0895-804 · Cited by 788 · see citing works
Furchgott, R. F., & Bhadrakom, S. (1953) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)05163-8 · Cited by 655 · see citing works
Plasma nitrite reflects constitutive nitric oxide synthase activity in mammals
Kleinbongard, P., Dejam, A., Lauer, T., Rassaf, T., Schindler, A., Picker, O., Scheeren, T., Gödecke, A., Schrader, J., Schulz, R., et al. (2003) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(03)00406-4 · Cited by 586 · see citing works
Lauer, T., Preik, M., Rassaf, T., Strauer, B. E., Deussen, A., Feelisch, M., & Kelm, M. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.221381098 · Cited by 585 · see citing works
Enzymatic function of hemoglobin as a nitrite reductase that produces NO under allosteric control
Huang, Z. (2005) · Journal of Clinical Investigation · doi:10.1172/jci24650 · Cited by 520 · see citing works
Singel, D. J., & Stamler, J. S. (2005) · Annual Review of Physiology · doi:10.1146/annurev.physiol.67.060603.090918 · Cited by 481 · see citing works
Nitric oxide in the human respiratory cycle
McMahon, T., Moon, R. E., Luschinger, B. P., Carraway, M. S., Stone, A. E., Stolp, B. W., Gow, A. J., Pawloski, J. R., Watke, P., Singel, D. J., et al. (2002) · Nature Medicine · doi:10.1038/nm718 · Cited by 462 · see citing works
Oxygen Gradients in the Microcirculation
Tsai, A. G., Johnson, P. C., & Intaglietta, M. (2003) · Physiological Reviews · doi:10.1152/physrev.00034.2002 · Cited by 450 · see citing works
Gladwin, M. T., Shelhamer, J. H., Schechter, A. N., Pease-Fye, M. E., Waclawiw, M. A., Panza, J. A., Ognibene, F. P., & Cannon, R. O. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.21.11482 · Cited by 441 · see citing works
Bryan, N. S., Rassaf, T., Maloney, R. E., Rodriguez, C. M., Saijo, F., Rodriguez, J. R., & Feelisch, M. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0306706101 · Cited by 400 · see citing works
The biochemistry of nitric oxide, nitrite, and hemoglobin: role in blood flow regulation
Gladwin, M. T., Crawford, J. H., & Patel, R. P. (2004) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2003.11.032 · Cited by 378 · see citing works
Self-citationNO-dependent protein nitration: a cell signaling event or an oxidative inflammatory response?
Schopfer, F. J. (2003) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2003.10.006 · Cited by 369 · see citing works
Erythrocytes are the major intravascular storage sites of nitrite in human blood
Dejam, A. (2005) · Blood · doi:10.1182/blood-2005-02-0567 · Cited by 350 · see citing works
Nagababu, E., Ramasamy, S., Abernethy, D. R., & Rifkind, J. M. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m307572200 · Cited by 349 · see citing works
Nitrite‐derived nitric oxide: a possible mediator of ‘acidic–metabolic’ vasodilation
Modin, A., Björne, H., Herulf, M., Alving, K., Weitzberg, E., & Lundberg, J. O. N. (2001) · Acta Physiologica Scandinavica · doi:10.1046/j.1365-201x.2001.00771.x · Cited by 346 · see citing works
Nitrite reductase activity is a novel function of mammalian mitochondria
Kozlov, A. V., Staniek, K., & Nohl, H. (1999) · FEBS Letters · doi:10.1016/s0014-5793(99)00788-7 · Cited by 342 · see citing works
NO Generation From Nitrite and Its Role in Vascular Control
Lundberg, J. O., & Weitzberg, E. (2005) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/01.atv.0000161048.72004.c2 · Cited by 341 · see citing works
Kinetics and mechanism of the oxidation of human deoxyhemoglobin by nitrites.
Doyle, M. P., Pickering, R. A., DeWeert, T. M., Hoekstra, J. W., & Pater, D. (1981) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)43285-1 · Cited by 334 · see citing works
Erythrocyte and the Regulation of Human Skeletal Muscle Blood Flow and Oxygen Delivery
González‐Alonso, J., Olsen, D. B., & Saltin, B. (2002) · Circulation Research · doi:10.1161/01.res.0000044939.73286.e2 · Cited by 331 · see citing works
Ignarro, L. J., & Gruetter, C. S. (1980) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/0304-4165(80)90297-4 · Cited by 317 · see citing works
No scavenging and the hypertensive effect of hemoglobin-based blood substitutes
Olson, J. S., Foley, E. W., Rogge, C. E., Tsai, A.-L., Doyle, M. P., & Lemon, D. D. (2004) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2003.11.030 · Cited by 306 · see citing works
Cannon, R. O., Schechter, A. N., Panza, J. A., Ognibene, F. P., Pease-Fye, M. E., Waclawiw, M. A., Shelhamer, J. H., & Gladwin, M. T. (2001) · Journal of Clinical Investigation · doi:10.1172/jci200112761 · Cited by 298 · see citing works
Cannon, R. O., Schechter, A. N., Panza, J. A., Ognibene, F. P., Pease‐Fye, M. E., Waclawiw, M. A., Shelhamer, J. H., & Gladwin, M. T. (2001) · Journal of Clinical Investigation · doi:10.1172/jci12761 · Cited by 289 · see citing works
ATP: the red blood cell link to NO and local control of the pulmonary circulation
Sprague, R. S., Ellsworth, M. L., Stephenson, A. H., & Lonigro, A. J. (1996) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.1996.271.6.h2717 · Cited by 266 · see citing works
The Reaction between Nitrite and Deoxyhemoglobin
Huang, K. T., Keszler, A., Patel, N., Patel, R. P., Gladwin, M. T., Kim-Shapiro, D. B., & Hogg, N. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m501496200 · Cited by 253 · see citing works
Reactions of PTIO and Carboxy-PTIO with ·NO, ·NO2, and O 2 . ¯
Goldstein, S., Russo, A., & Samuni, A. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m308317200 · Cited by 215 · see citing works
Luchsinger, B. P., Rich, E. N., Gow, A. J., Williams, E. M., Stamler, J. S., & Singel, D. J. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0233287100 · Cited by 202 · see citing works
Kim‐Shapiro, D. B., Gladwin, M. T., Patel, R. P., & Hogg, N. (2004) · Journal of Inorganic Biochemistry · doi:10.1016/j.jinorgbio.2004.10.034 · Cited by 172 · see citing works
Circulating no pool: assessment of nitrite and nitroso species in blood and tissues
Rassaf, T., Feelisch, M., & Kelm, M. (2003) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2003.11.011 · Cited by 155 · see citing works
Red Blood Cell–Derived ATP as a Regulator of Skeletal Muscle Perfusion
Ellsworth, M. L. (2004) · Medicine & Science in Sports & Exercise · doi:10.1249/01.mss.0000106284.80300.b2 · Cited by 147 · see citing works
Biochemical Characterization of HumanS-Nitrosohemoglobin
Patel, R. P., Hogg, N., Spencer, N. Y., Kalyanaraman, B., Matalon, S., & Darley-Usmar, V. M. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.22.15487 · Cited by 133 · see citing works
Vasorelaxation by Red Blood Cells and Impairment in Diabetes
James, P. E., Lang, D., Tufnell-Barret, T., Milsom, A. B., & Frenneaux, M. P. (2004) · Circulation Research · doi:10.1161/01.res.0000122044.21787.01 · Cited by 125 · see citing works
Biochemical Characterization ofS-Nitrosohemoglobin
Wolzt, M., MacAllister, R. J., Davis, D., Feelisch, M., Moncada, S., Vallance, P. J., & Hobbs, A. J. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.41.28983 · Cited by 120 · see citing works
NO-synthase and nitrite-reductase components of nitric oxide cycle.
Reutov, V. P., & Sorokina, E. G. (1998) · PubMed · Cited by 118 · see citing works
Crawford, J. H., Chacko, B. K., Pruitt, H. M., Piknova, B., Hogg, N., & Patel, R. P. (2004) · Blood · doi:10.1182/blood-2004-03-0880 · Cited by 111 · see citing works
Self-citationHemoglobin-Mediated, Hypoxia-Induced Vasodilation via Nitric Oxide
Robinson, J. M., & Lancaster, J. R. (2005) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.f292 · Cited by 104 · see citing works
Extracellular ATP signaling in the rabbit lung: erythrocytes as determinants of vascular resistance
Sprague, R. S., Olearczyk, J. J., Spence, D. M., Stephenson, A. H., Sprung, R. W., & Lonigro, A. J. (2003) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.01026.2002 · Cited by 98 · see citing works
Nitrite-derived nitric oxide: a possible mediator of 'acidic-metabolic' vasodilation
Modin, A., Björne, H., Herulf, M., et al. (2001) · Acta Physiologica Scandinavica · doi:10.1046/j.1365-201x.2001.171001009.x · Cited by 94 · see citing works
Luchsinger, B. P., Rich, E. N., Yan, Y., Williams, E. M., Stamler, J. S., & Singel, D. J. (2005) · Journal of Inorganic Biochemistry · doi:10.1016/j.jinorgbio.2004.12.010 · Cited by 89 · see citing works
Winterbourn, C. C., & Carrell, R. W. (1977) · Biochemical Journal · doi:10.1042/bj1650141 · Cited by 82 · see citing works
Haldane, hot dogs, halitosis, and hypoxic vasodilation: the emerging biology of the nitrite anion
Gladwin, M. T. (2004) · Journal of Clinical Investigation · doi:10.1172/jci20664 · Cited by 65 · see citing works
Vasoactivity of S-nitrosohemoglobin: role of oxygen, heme, and NO oxidation states
Crawford, J. H., White, C. R., & Patel, R. P. (2003) · Blood · doi:10.1182/blood-2002-12-3825 · Cited by 59 · see citing works
Self-citationCheng, Y., Shen, T.-J., Simplăceanu, V., & Ho, C. (2002) · Biochemistry · doi:10.1021/bi0202880 · Cited by 53 · see citing works
Nitric Oxide Inhibits ATP Release from Erythrocytes
Olearczyk, J. J., Ellsworth, M. L., Stephenson, A. H., Lonigro, A. J., & Sprague, R. S. (2004) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.103.064709 · Cited by 45 · see citing works
Concentration-dependent Effects of Anions on the Anaerobic Oxidation of Hemoglobin and Myoglobin
Taboy, C. H., Faulkner, K. M., Kraiter, D. C., Bonaventura, C., & Crumbliss, A. L. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m004547200 · Cited by 39 · see citing works
CO Ligation Intermediates and the Mechanism of Hemoglobin Cooperativity
Perrella, M., & Di, E. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.5.2605 · Cited by 38 · see citing works
Bonaventura, C., Tesh, S., Faulkner, K. M., et al. (1998) · Biochemistry · doi:10.1021/bi971574s · Cited by 36 · 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
Bonaventura, C., Godette, G., Tesh, S., Holm, D. E., Bonaventura, J., Crumbliss, A. L., Pearce, L. L., & Peterson, J. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.9.5499 · Cited by 28 · see citing works
Anaerobic Oxidations of Myoglobin and Hemoglobin by Spectroelectrochemistry
Taboy, C. H., Bonaventura, C., & Crumbliss, A. L. (2002) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(02)53048-2 · Cited by 27 · see citing works
Shiva, S. S., & Darley-Usmar, V. M. (2003) · IUBMB Life · doi:10.1080/152165430310001640489 · Cited by 27 · see citing works
ATP-induced stimulation of calcium binding to cardiac sarcolemma
Mas‐Oliva, J., Williams, A. J., & Nayler, W. G. (1979) · Biochemical and Biophysical Research Communications · doi:10.1016/0006-291x(79)91815-1 · Cited by 25 · 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
Oxidation of human hemoglobin by sodium nitrite-effect of β-93 thiol groups
Mansouri, A. (1979) · Biochemical and Biophysical Research Communications · doi:10.1016/0006-291x(79)90649-1 · Cited by 22 · see citing works
Grocott, H. P., Bart, R. D., Sheng, H., et al. (1998) · Stroke · doi:10.1161/01.str.29.8.1650 · Cited by 21 · see citing works
Зинчук, В. В., & Dorokhina, L. V. (2002) · Nitric Oxide · doi:10.1006/niox.2001.0377 · Cited by 16 · see citing works
Assessing NO‐Dependent Vasodilatation Using Vessel Bioassays at Defined Oxygen Tensions
Isbell, T. S., Koenitzer, J. R., Crawford, J. H., White, C. R., Kraus, D. W., & Patel, R. P. (2005) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(05)96047-3 · Cited by 14 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 1
- Patel RP, Hogg N, Spencer NY, Kalyanaraman B, Matalon S, Darley-Usmar VM. Biochemical char- acterization of human S-nitrosohemoglobin: ef- fects on oxygen binding and transnitrosation. J Biol Chem. 1999;274:15487-15492.
Cited by
Sorted by citations
The emerging biology of the nitrite anion
Gladwin, M. T., Schechter, A. N., Kim-Shapiro, D. B., Patel, R. P., Hogg, N., Shiva, S., Cannon, R. O., Kelm, M., Wink, D. A., Espey, M. G., et al. (2005) · Nature Chemical Biology · doi:10.1038/nchembio1105-308 · Cited by 609 · see citing works
Shiva, S., Huang, Z., Grubina, R., Sun, J., Ringwood, L. A., MacArthur, P. H., Xu, X., Murphy, E., Darley-Usmar, V. M., & Gladwin, M. T. (2007) · Circulation Research · doi:10.1161/01.res.0000260171.52224.6b · Cited by 599 · see citing works
Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation
Tejero, J., Shiva, S., & Gladwin, M. T. (2019) · Physiological Reviews · doi:10.1152/physrev.00036.2017 · Cited by 541 · see citing works
Red blood cells in sports: Effects of exercise and training on oxygen supply by red blood cells
Mairbäurl, H. (2013) · Frontiers in Physiology · doi:10.3389/fphys.2013.00332 · Cited by 482 · see citing works
Nitrite as Regulator of Hypoxic Signaling in Mammalian Physiology
van Faassen, E. E., Bahrami, S., Feelisch, M., Hogg, N., Kelm, M., Kim‐Shapiro, D. B., Kozlov, A. V., Li, H., Lundberg, J. O., Mason, R., et al. (2009) · Medicinal Research Reviews · doi:10.1002/med.20151 · Cited by 435 · see citing works
Hendgen-Cotta, U. B., Merx, M. W., Shiva, S., Schmitz, J., Becher, S., Klare, J. P., Steinhoff, H.-J., Goedecke, A., Schrader, J., Gladwin, M. T., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0801336105 · Cited by 418 · see citing works
Maia, L. B., & Moura, J. J. G. (2014) · Chemical Reviews · doi:10.1021/cr400518y · Cited by 401 · see citing works
Ceruloplasmin is a NO oxidase and nitrite synthase that determines endocrine NO homeostasis
Shiva, S., Wang, X., Ringwood, L. A., Xu, X., Yuditskaya, S., Annavajjhala, V., Miyajima, H., Hogg, N., Harris, Z. L., & Gladwin, M. T. (2006) · Nature Chemical Biology · doi:10.1038/nchembio813 · Cited by 359 · see citing works
Gladwin, M. T., Raat, N. J. H., Shiva, S., Dezfulian, C., Hogg, N., Kim-Shapiro, D. B., & Patel, R. P. (2006) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00407.2006 · Cited by 329 · see citing works
Unraveling the Reactions of Nitric Oxide, Nitrite, and Hemoglobin in Physiology and Therapeutics
Kim-Shapiro, D. B., Schechter, A. N., & Gladwin, M. T. (2006) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/01.atv.0000204350.44226.9a · Cited by 308 · see citing works
The functional nitrite reductase activity of the heme-globins
Gladwin, M. T., & Kim-Shapiro, D. B. (2008) · Blood · doi:10.1182/blood-2008-01-115261 · Cited by 293 · see citing works
Human neuroglobin functions as a redox-regulated nitrite reductase
Tiso, M., Tejero, J., Basu, S., Azarov, I., Wang, X., Simplaceanu, V., Frizzell, S., Jayaraman, T., Geary, L., Shapiro, C., et al. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.159541 · Cited by 287 · see citing works
Kapil, V., Khambata, R. S., Jones, D. A., Rathod, K., Primus, C., Massimo, G., Fukuto, J. M., & Ahluwalia, A. (2020) · Pharmacological Reviews · doi:10.1124/pr.120.019240 · Cited by 248 · see citing works
Catalytic generation of N2O3 by the concerted nitrite reductase and anhydrase activity of hemoglobin
Basu, S., Grubina, R., Huang, J., Conradie, J., Huang, Z., Jeffers, A., Jiang, A., He, X., Azarov, I., Seibert, R., et al. (2007) · Nature Chemical Biology · doi:10.1038/nchembio.2007.46 · Cited by 224 · see citing works
Tissue Processing of Nitrite in Hypoxia
Feelisch, M., Fernandez, B. O., Bryan, N. S., Garcia-Saura, M. F., Bauer, S., Whitlock, D. R., Ford, P. C., Janero, D. R., Rodriguez, J., & Ashrafian, H. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m806654200 · Cited by 218 · see citing works
Webb, A. J., Milsom, A. B., Rathod, K. S., Chu, W. L., Qureshi, S., Lovell, M. J., Lecomte, F. M. J., Perrett, D., Raimondo, C., Khoshbin, E., et al. (2008) · Circulation Research · doi:10.1161/circresaha.108.175810 · Cited by 203 · see citing works
Role of the anion nitrite in ischemia-reperfusion cytoprotection and therapeutics
DEZFULIAN, C., RAAT, N., SHIVA, S., & GLADWIN, M. (2007) · Cardiovascular Research · doi:10.1016/j.cardiores.2007.05.001 · Cited by 198 · see citing works
Gladwin, M. T., Grubina, R., & Doyle, M. P. (2009) · Accounts of Chemical Research · doi:10.1021/ar800089j · Cited by 194 · see citing works
Chronic sodium nitrite therapy augments ischemia-induced angiogenesis and arteriogenesis
Kumar, D., Branch, B. G., Pattillo, C. B., Hood, J., Thoma, S., Simpson, S., Illum, S., Arora, N., Chidlow, J. H., Langston, W., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0711480105 · Cited by 187 · see citing works
Cortese-Krott, M. M., Rodriguez-Mateos, A., Sansone, R., Kuhnle, G. G. C., Thasian-Sivarajah, S., Krenz, T., Horn, P., Krisp, C., Wolters, D., Heiß, C., et al. (2012) · Blood · doi:10.1182/blood-2012-07-442277 · Cited by 183 · see citing works
Hemoglobin, nitric oxide and molecular mechanisms of hypoxic vasodilation
Allen, B. W., Stamler, J. S., & Piantadosi, C. A. (2009) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2009.08.002 · Cited by 165 · see citing works
SNO-hemoglobin is not essential for red blood cell–dependent hypoxic vasodilation
Isbell, T. S., Sun, C.-W., Wu, L.-C., Teng, X., Vitturi, D. A., Branch, B. G., Kevil, C. G., Peng, N., Wyss, J. M., Ambalavanan, N., et al. (2008) · Nature Medicine · doi:10.1038/nm1771 · Cited by 157 · see citing works
Mechanisms of nitrite bioactivation
Kim-Shapiro, D. B., & Gladwin, M. T. (2014) · Nitric Oxide · doi:10.1016/j.niox.2013.11.002 · Cited by 157 · see citing works
Hemoglobin-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
Reactions of ferrous neuroglobin and cytoglobin with nitrite under anaerobic conditions
Petersen, M. G., Dewilde, S., & Fago, A. (2008) · Journal of Inorganic Biochemistry · doi:10.1016/j.jinorgbio.2008.05.008 · Cited by 144 · see citing works
Anemia and splenomegaly in cGKI-deficient mice
Föller, M., Feil, S., Ghoreschi, K., Koka, S., Gerling, A., Thunemann, M., Hofmann, F., Schuler, B., Vogel, J., Pichler, B., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0708940105 · Cited by 136 · see citing works
Li, H., Hemann, C., Abdelghany, T. M., El-Mahdy, M. A., & Zweier, J. L. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.342378 · Cited by 132 · see citing works
Mechanisms of nitrite reduction to nitric oxide in the heart and vessel wall
Zweier, J. L., Li, H., Samouilov, A., & Liu, X. (2010) · Nitric Oxide · doi:10.1016/j.niox.2009.12.004 · Cited by 132 · see citing works
Nitric oxide synthase-derived plasma nitrite predicts exercise capacity
Rassaf, T., Lauer, T., Heiss, C., Balzer, J., Mangold, S., Leyendecker, T., Rottler, J., Drexhage, C., Meyer, C., & Kelm, M. (2007) · British Journal of Sports Medicine · doi:10.1136/bjsm.2007.035758 · Cited by 122 · see citing works
Nitrite Reduction and Cardiovascular Protection
Omar, S. A., & Webb, A. J. (2014) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2014.01.012 · Cited by 121 · see citing works
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
Dalsgaard, T., Simonsen, U., & Fago, A. (2007) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.01298.2006 · Cited by 110 · see citing works
Platelet Inhibition by Nitrite Is Dependent on Erythrocytes and Deoxygenation
Srihirun, S., Sriwantana, T., Unchern, S., Kittikool, D., Noulsri, E., Pattanapanyasat, K., Fucharoen, S., Piknova, B., Schechter, A. N., & Sibmooh, N. (2012) · PLoS ONE · doi:10.1371/journal.pone.0030380 · Cited by 109 · see citing works
A comparison of organic and inorganic nitrates/nitrites
Omar, S. A., Artime, E., & Webb, A. J. (2012) · Nitric Oxide · doi:10.1016/j.niox.2012.03.008 · Cited by 106 · see citing works
Sodium Nitrate Supplementation Does Not Enhance Performance of Endurance Athletes
BESCÓS, R., FERRER-ROCA, V., GALILEA, P. A., ROIG, A., DROBNIC, F., SUREDA, A., MARTORELL, M., CORDOVA, A., TUR, J. A., & PONS, A. (2012) · Medicine & Science in Sports & Exercise · doi:10.1249/mss.0b013e3182687e5c · Cited by 107 · see citing works
Lauer, T., Heiss, C., Balzer, J., Kehmeier, E., Mangold, S., Leyendecker, T., Rottler, J., Meyer, C., Merx, M. W., Kelm, M., et al. (2008) · Basic Research in Cardiology · doi:10.1007/s00395-008-0714-3 · Cited by 88 · see citing works
Mitochondria as metabolizers and targets of nitrite
Shiva, S. (2010) · Nitric Oxide · doi:10.1016/j.niox.2009.09.002 · Cited by 87 · see citing works
Wang, J., Krizowski, S., Fischer-Schrader, K., Niks, D., Tejero, J., Sparacino-Watkins, C., Wang, L., Ragireddy, V., Frizzell, S., Kelley, E. E., et al. (2015) · Antioxidants & Redox Signaling · doi:10.1089/ars.2013.5397 · Cited by 84 · see citing works
Dias-Junior, C. A. C., Gladwin, M. T., & Tanus-Santos, J. E. (2006) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2006.08.022 · Cited by 82 · see citing works
Effects of sodium nitrite on ischemia–reperfusion injury in the rat kidney
Basireddy, M., Isbell, T. S., Teng, X., Patel, R. P., & Agarwal, A. (2006) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00334.2005 · Cited by 72 · see citing works
The potential role of the red blood cell in nitrite-dependent regulation of blood flow
Patel, R. P., Hogg, N., & Kim-Shapiro, D. B. (2011) · Cardiovascular Research · doi:10.1093/cvr/cvq323 · Cited by 70 · see citing works
Jensen, F. B., & Rohde, S. (2010) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00813.2009 · Cited by 63 · see citing works
Regulation of nitrite transport in red blood cells by hemoglobin oxygen fractional saturation
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
Kurhaluk, N., & Tkaczenko, H. (2025) · Nutrients · doi:10.3390/nu17040665 · Cited by 62 · see citing works
The role of vascular myoglobin in nitrite-mediated blood vessel relaxation
Ormerod, J. O. M., Ashrafian, H., Maher, A. R., Arif, S., Steeples, V., Born, G. V. R., Egginton, S., Feelisch, M., Watkins, H., & Frenneaux, M. P. (2011) · Cardiovascular Research · doi:10.1093/cvr/cvq299 · Cited by 61 · see citing works
Vitturi, D. A., & Patel, R. P. (2011) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2011.05.037 · Cited by 59 · see citing works
Mikula, I., Durocher, S., Martasek, P., Mutus, B., & Slama-Schwok, A. (2009) · Biochemical Journal · doi:10.1042/bj20080987 · Cited by 51 · see citing works
Machha, A., & Schechter, A. N. (2012) · Nutrition Reviews · doi:10.1111/j.1753-4887.2012.00477.x · Cited by 51 · see citing works
Frérart, F., Sonveaux, P., Rath, G., Smoos, A., Meqor, A., Charlier, N., Jordan, B. F., Saliez, J., Noël, A., Dessy, C., et al. (2008) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-07-4001 · Cited by 49 · see citing works
Nitric oxide formation <i>versus</i> scavenging: the red blood cell balancing act
Owusu, B. Y., Stapley, R., & Patel, R. P. (2012) · The Journal of Physiology · doi:10.1113/jphysiol.2012.234906 · Cited by 48 · see citing works
Dufour, S. P., Patel, R. P., Brandon, A., Teng, X., Pearson, J., Barker, H., Ali, L., Yuen, A. H. Y., Smolenski, R. T., & González-Alonso, J. (2010) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00389.2010 · Cited by 45 · see citing works
Vanhatalo, A., Jones, A. M., Blackwell, J. R., Winyard, P. G., & Fulford, J. (2014) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00096.2014 · Cited by 39 · see citing works
Why do women have similar erythropoietin levels to men but lower hemoglobin levels?
Murphy, W. G., Tong, E., & Murphy, C. (2010) · Blood · doi:10.1182/blood-2010-07-294595 · Cited by 40 · see citing works
Nitrite reduction to nitric oxide in the vasculature
Lundberg, J. O., & Weitzberg, E. (2008) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00611.2008 · Cited by 39 · 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
Liu, M., Zollbrecht, C., Peleli, M., Lundberg, J. O., Weitzberg, E., & Carlström, M. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.03.025 · Cited by 30 · see citing works
Kelpke, S. S., Chen, B., Bradley, K. M., Teng, X., Chumley, P., Brandon, A., Yancey, B., Moore, B., Head, H., Viera, L., et al. (2012) · Kidney International · doi:10.1038/ki.2012.116 · Cited by 28 · see citing works
Maher, A. R., Arif, S., Madhani, M., Abozguia, K., Ahmed, I., Fernandez, B. O., Feelisch, M., O'Sullivan, A., Christopoulos, A., Sverdlov, A. L., et al. (2013) · British Journal of Pharmacology · doi:10.1111/bph.12152 · Cited by 26 · see citing works
Rifkind, J. M., Nagababu, E., Cao, Z., Barbiro-Michaely, E., & Mayevsky, A. (2009) · Advances in experimental medicine and biology · doi:10.1007/978-0-387-85998-9_5 · Cited by 10 · see citing works
- Authors
- Crawford, J. H.
- Affiliations
- University of Alabama at Birmingham (US)
- Corresponding author
- Crawford, J. H.
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2006-01-15
- Volume
- 107
- Issue
- 2
- Pages
- 566-574
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC1895612
- OpenAlex
- W2138011583
- Cited by
- 497
- References
- 60
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 12 · 2023: 13 · 2022: 7 · 2021: 24 · 2020: 16 · 2019: 13 · 2018: 24 · 2017: 27 · 2016: 17 · 2015: 28 · 2014: 24 · 2013: 34 · 2012: 39
- FWCI
- 14.51
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Blood (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Heart Association
- National Institutes of Health (HL70146)
- National Heart, Lung, and Blood Institute (R01HL070146, HL 70146, HL24525)
- National Institute of General Medical Sciences (T32GM008361, T32 GM 08361)
- 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
- hypoxic vasodilation, erythrocytes, nitrite, nitric oxide, hemoglobin, nitrite reductase, heme redox potential, ATP release, cyclic GMP, mitochondrial respiration, oxygen sensing, oxygen delivery
- MeSH terms
- Adenosine Triphosphate, Allosteric Regulation, Erythrocytes, Cyclic GMP, Heme, Hemoglobins, Humans, Mitochondria, Mutation, Nitric Oxide, Nitrite Reductases, Nitrites, Oxidation-Reduction, Oxygen, Respiration, Vasodilation, Cell Hypoxia
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
