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Enhanced Vasodilator Activity of Nitrite in Hypertension: Critical Role for Erythrocytic Xanthine Oxidoreductase and Translational Potential
Open accessAbstract
Elevation of circulating nitrite (NO 2 − ) levels causes vasodilatation and lowers blood pressure in healthy volunteers. Whether these effects and the underpinning mechanisms persist in hypertension is unknown. Therefore, we investigated the consequences of systemic nitrite elevation in spontaneously hypertensive rats and conducted proof-of-principle studies in patients. Nitrite caused dose-dependent blood pressure–lowering that was profoundly enhanced in spontaneously hypertensive rats versus normotensive Wistar Kyoto controls. This effect was virtually abolished by the xanthine oxidoreductase (XOR) inhibitor, allopurinol, and associated with hypertension-specific XOR-dependent nitrite reductase activity localized to the erythrocyte but not the blood vessel wall. To determine whether these pathways translate to human hypertension, we investigated the effects of elevation of circulating nitrite levels in 15 drug naïve grade 1 hypertensives. To elevate nitrite, we used a dose of dietary nitrate (≈3.5 mmol) that elevated nitrite levels ≈1.5-fold ( P <0.01); a rise shown previously to exert no significant blood pressure–lowering effects in normotensives. This dose caused substantial reductions in systolic (≈12 mm Hg) and diastolic blood pressures ( P <0.001) and pulse wave velocity ( P <0.05); effects associated with elevations in erythrocytic XOR expression and XOR-dependent nitrite reductase activity. Our observations demonstrate the improved efficacy of inorganic nitrate and nitrite in hypertension as a consequence of increased erythrocytic XOR nitrite reductase activity and support the concept of dietary nitrate supplementation as an effective, but simple and inexpensive, antihypertensive strategy.
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Endogenous Hemoprotein-Dependent Signaling Pathways of Nitric Oxide and Nitrite
Dent, M. R., DeMartino, A. W., Tejero, J., & Gladwin, M. T. (2021) · Inorganic Chemistry · doi:10.1021/acs.inorgchem.1c01048 · Cited by 35
Rizzi, É., Amaral, J. H., Guimarães, D. A., Conde-Tella, S. O., Pinheiro, L. C., Gerlach, R. F., de Castro, M. M., & Tanus-Santos, J. E. (2018) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2018.11.002 · Cited by 35
Pinheiro, L. C., Oliveira‐Paula, G. H., Ferreira, G. C., de Paula, T. D., Duarte, D. Â., Costa-Neto, C. M., & Tanus-Santos, J. E. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101769 · Cited by 35
Extending the translational potential of targeting NO/ cGMP ‐regulated pathways in the CVS
Papapetropoulos, A., Hobbs, A. J., & Topouzis, S. (2014) · British Journal of Pharmacology · doi:10.1111/bph.12980 · Cited by 35
“…Larsen et al., 2006; Webb et al., 2008b; Kapil et al., 2010a) and dietary nitrate supplementation reduces blood pressure in hypertensive patients (Ghosh et al., 2013) with a significantly increased potency, suggesting the beneficial effects of modulating nitrate-nitrite-NO signalling for…”
BackgroundSelf-citationNitrite-stimulated Gastric Formation of S-nitrosothiols As An Antihypertensive Therapeutic Strategy
Oliveira‐Paula, G. H., & Tanus-Santos, J. E. (2018) · Current Drug Targets · doi:10.2174/1389450119666180816120816 · Cited by 33
Abu-Alghayth, M. H., Vanhatalo, A., Wylie, L. J., McDonagh, S. T. J., Thompson, C., Kadach, S., Kerr, P., Smallwood, M. J., JONES, A. M., & Winyard, P. G. (2021) · Redox Biology · doi:10.1016/j.redox.2021.101974 · Cited by 32
Tropea, T., Wareing, M., Greenwood, S. L., Feelisch, M., Sibley, C. P., & Cottrell, E. C. (2018) · Nitric Oxide · doi:10.1016/j.niox.2018.08.009 · Cited by 32
“The complete inhibition of vasorelaxation by the sGC blocker ODQ suggests a key role of NO-mediated activation of sGC, in line with several other studies [7,13,21,41].”
ResultTropea, T., Renshall, L. J., Nihlén, C., Weitzberg, E., Lundberg, J. O., David, A. L., Tsatsaris, V., Stuckey, D. J., Wareing, M., Greenwood, S. L., et al. (2020) · The Journal of Physiology · doi:10.1113/jp279655 · Cited by 32
“…from both preclinical and clinical studies has shown beneficial effects of BRJ supplementation, attributed to its high nitrate content, to lower blood pressure (Kapil et al. 2010, 2015; Ferguson et al. 2013; Ghosh et al. 2013) and improve blood flow (Ferguson et al. 2013; Walker et al. 2019).”
BackgroundInfluentialLiu, T., Schroeder, H. J., Power, G. G., & Blood, A. B. (2022) · Redox Biology · doi:10.1016/j.redox.2022.102327 · Cited by 31
“In line with this idea, the vasodilatory effects of treatment with nitrite are found to persist even after plasma nitrite levels have returned to baseline [42,43].”
BackgroundKhambata, R. S., Ghosh, S. M., & Ahluwalia, A. (2015) · Antioxidants and Redox Signaling · doi:10.1089/ars.2015.6254 · Cited by 30
“Crucially, at this dose, nitrite had minimal effects on BP in the normotensive Wistar Kyoto (WKY) control (33).”
Self-citationBroxterman, R. M., Salle, D. T. L., Zhao, J., Reese, V. R., Richardson, R. S., & Trinity, J. D. (2019) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00371.2019 · Cited by 32
Stamm, P., Oelze, M. W., Steven, S., Kröller‐Schön, S., Kvandová, M., Kalinovic, S., Jasztal, A., Kij, A., Kuntić, M., Jiménez, M. T. B., et al. (2021) · Nitric Oxide · doi:10.1016/j.niox.2021.06.001 · Cited by 29
Local delivery of nitric oxide prevents endothelial dysfunction in periodontitis
Fernandes, D., Khambata, R. S., Massimo, G., Ruivo, E., Gee, L. C., Foster, J., Goddard, A., Curtis, M., Barnes, M. R., Wade, W. G., et al. (2022) · Pharmacological Research · doi:10.1016/j.phrs.2022.106616 · Cited by 31
“These benefits have been evidenced in models of ischaemia-induced endothelial dysfunction [5] and hypertension/hypercholesterolaemia-associated endothelial dysfunction [6,52] and our observations herein now add endothelial dysfunction associated with periodontitis to the list.”
BackgroundSelf-citationOliveira‐Paula, G. H., Pinheiro, L. C., Guimarães, D. A., Conde-Tella, S. O., Blanco, A. L. F., de Angelis, C. D., Schechter, A. N., & Tanus-Santos, J. E. (2016) · Redox Biology · doi:10.1016/j.redox.2016.04.001 · Cited by 27
“In this respect, XOR has been implicated in NO generation from nitrite [20,21], particularly in hypertension because XOR up-regulation has been shown in”
BackgroundResultInfluentialInorganic Nitrate in Angina Study: A Randomized Double‐Blind Placebo‐Controlled Trial
Schwarz, K., Singh, S., Parasuraman, S. K., Rudd, A. E., Shepstone, L., Feelisch, M., Minnion, M., Ahmad, S., Madhani, M., Horowitz, J. D., et al. (2017) · Journal of the American Heart Association · doi:10.1161/jaha.117.006478 · Cited by 27
“The 600-mg sodium nitrate dose was based on previous evidence that 300 mg to 600 mg of oral nitrate was effective in multiple studies assessing effects on blood pressure and exercise capacity in human volunteers.(10,11,20,21,30)”
Pinheiro, L. C., Amaral, J. H., Ferreira, G. C., Montenegro, M. F., Oliveira‐Paula, G. H., & Tanus-Santos, J. E. (2014) · Nitric Oxide · doi:10.1016/j.niox.2014.05.009 · Cited by 26
Haun, C. T., Kephart, W. C., Holland, A. M., Mobley, C. B., McCloskey, A. E., Shake, J. J., Pascoe, D. D., Roberts, M. D., & Martin, J. S. (2016) · European Journal of Applied Physiology · doi:10.1007/s00421-016-3478-8 · Cited by 26
Skeletal Muscle Vascular Control During Exercise
Ferguson, S. K., Glean, A. A., Holdsworth, C. T., Wright, J. L., Fees, A. J., Colburn, T. D., Stäbler, T., Allen, J. D., JONES, A. M., Musch, T. I., et al. (2015) · Journal of Cardiovascular Pharmacology and Therapeutics · doi:10.1177/1074248415599061 · Cited by 25
Kerley, C. P., Dolan, E., & Cormican, L. J. (2017) · Irish Journal of Medical Science (1971 -) · doi:10.1007/s11845-016-1551-2 · Cited by 25
“17 significantly increased NO metabolites [22-31] These studies utilized nitrate doses 378”
MethodVenkatesan, S., Smirne, C., Aquino, C. I., Surico, D., Remorgida, V., Pour, M. M. O., Pirisi, M., & Grossini, E. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27020629 · Cited by 30
“Despite promising results, clinical efficacy remains variable, suggesting that differences in nitrite reductase activity and nitrite bioavailability may influence individual responses [163].”
Remington, J., & Winters, K. P. (2019) · The JBI Database of Systematic Reviews and Implementation Reports · doi:10.11124/jbisrir-2017-003842 · Cited by 24
Peng, R., Luo, M., Tian, R., & Lu, N. (2020) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2020.108453 · Cited by 24
Inorganic nitrate attenuates cardiac dysfunction: roles for xanthine oxidoreductase and nitric oxide
Gee, L. C., Massimo, G., Lau, C. W. Z., Primus, C., Fernandes, D., Chen, J., Rathod, K. S., Hamers, A. J. P., Filomena, F., Nuredini, G., et al. (2021) · British Journal of Pharmacology · doi:10.1111/bph.15636 · Cited by 22
“…was deproteinated using Vivaspin 500 filter columns (Sartorius Stedim Biotech, SA) at 14,000 g for 60 mins at 4 C, before ozone chemiluminescence was conducted on samples using a 280i Nitric Oxide Analyzer (Sievers, USA) as previously described (Ghosh et al., 2013; Ignarro et al., 1993).”
MethodSelf-citationIbadallah, B. X., Abdullah, N., & Shuib, A. S. (2015) · Planta Medica · doi:10.1055/s-0034-1383409 · Cited by 24
Recent insights into nitrite signaling processes in blood
Helms, C. C., Liu, X., & Kim‐Shapiro, D. B. (2016) · Biological Chemistry · doi:10.1515/hsz-2016-0263 · Cited by 23
“Other groups have also observed NO detected by chemiluminescence after reacting NO with RBCs (Ghosh et al., 2013; Liu et al., 2015).”
Background
Metadata
- Authors
- Ghosh, S. M., Kapil, V., Fuentes-Calvo, I., Bubb, K. J., Pearl, V., Milsom, A. B., Khambata, R., Maleki-Toyserkani, S., Yousuf, M., Benjamin, N., Webb, A. J., Caulfield, M. J., Hobbs, A. J., & Ahluwalia, A.
- Affiliations
- Queen Mary University of London (GB)
- From the William Harvey Research Institute, Barts and The London Medical School, Queen Mary University of London, London, United Kingdom (S.M.G., V.K., I.F.-C., K.J.B., V.P., A.B.M., R.K., S.M-T., M.Y., M.J.C., A.J.H., A.A.); IBSAL-Departamento de Fisiología y Farmacología, Universidad de Salamanca, Spain (I.F.-C.); University of Exeter Medical School, Exeter, United Kingdom (N.B.); and Clinical Pharmacology, King’s College London, London, United Kingdom (A.J.W.).
- ORCID
- Venue
- Hypertension
- Published
- 2013-05
- Volume
- 61
- Issue
- 5
- Pages
- 1091-1102
- ISSN
- 0194-911X (ISSN-L)
- 1524-4563
- OpenAlex
- W2100756743
- Cited by
- 218
- References
- 61
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 16 · 2023: 14 · 2022: 15 · 2021: 13 · 2020: 14 · 2019: 15 · 2018: 16 · 2017: 17 · 2016: 23 · 2015: 26 · 2014: 25 · 2013: 13
- FWCI
- 20.14
- Type
- journal article
- Language
- en
- Open access
- green
- kclpure.kcl.ac.uk
- Licence
- other-oa
- Locations
- Hypertension (publishedVersion)
- PubMed (publishedVersion)
- Research Portal (King's College London) (publishedVersion, other-oa)
- Funders
- National Institute for Health and Care Research (NF-SI-0512-10113)
- British Heart Foundation (SP/08/006/25110, SP08006)
- National Institutes of Health
- Medical Research Council (MR/K006584/1)
- Topics
- Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Blood Pressure and Hypertension Studies
- Keywords
- nitrite, nitrate supplementation, xanthine oxidoreductase, nitrite reductase, erythrocytes, vasodilation, blood pressure reduction, pulse wave velocity, allopurinol, spontaneously hypertensive rats, nitric oxide
- MeSH terms
- Allopurinol, Animals, Blood Pressure, Disease Models, Animal, Dose-Response Relationship, Drug, Enzyme Inhibitors, Erythrocytes, Female, Humans, Hypertension, Male, Middle Aged, Nitrites, Rats, Inbred SHR, Rats, Inbred WKY, Vasodilation, Xanthine Dehydrogenase, Signal Transduction, Cross-Over Studies, Rats, Translational Research, Biomedical
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