Cited by 218Nitric Oxide and Endothelin EffectsCardiovascular Health and Disease PreventionBlood Pressure and Hypertension Studies

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Enhanced Vasodilator Activity of Nitrite in Hypertension: Critical Role for Erythrocytic Xanthine Oxidoreductase and Translational Potential

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Ghosh, Suborno M., Kapil, Vikas, Fuentes-Calvo, Isabel, Bubb, Kristen J., Pearl, Vanessa, Milsom, Alexandra B., Khambata, Rayomand, Maleki-Toyserkani, Sheiva, Yousuf, Mubeen, Benjamin, Nigel, Webb, Andrew J., Caulfield, Mark J., Hobbs, Adrian J., Ahluwalia, Amrita·2013·Hypertension

DOI 10.1161/hypertensionaha.111.00933

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Abstract

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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Background
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Background
Dietary nitrate improves muscle microvascular reactivity and lowers blood pressure at rest and during isometric exercise in untreated hypertensives
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BackgroundInfluential
Recent Advancements in Polymeric N-Nitrosamine-Based Nitric Oxide (NO) Donors and their Therapeutic Applications
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Gasotransmitters
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“It was shown that nitrite protects against ischemic renal injury and that nitrite in beetroot attenuates human hypertension.(67,68) Therefore, studying the effect of nitrite in preeclampsia would be of high value.”
Background
Nitric oxide and sickle cell disease—Is there a painful connection?
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BackgroundInfluential
Effects of sodium nitrite on renal function and blood pressure in hypertensive vs. healthy study participants
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“While we applied 5-day high-dose supplementation in healthy participants, the BP-reducing effect of NO3 was reported in hypertensives after a single dose of dietary NO3 ingestion [23,44].”
BackgroundMethod
Nitrite Reduces Ischemia-Induced Ventricular Arrhythmias by Attenuating Connexin 43 Dephosphorylation in Rats
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“Nonetheless, an impairment of vascular relaxations by NO-donating drugs [47,48] has been shown in spontaneously hypertensive rats in which vascular H2O2 production is elevated [49].”
Background
Vascular xanthine oxidoreductase contributes to the antihypertensive effects of sodium nitrite in L-NAME hypertension
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Background
The nitric oxide dependence of cutaneous microvascular function to independent and combined hypoxic cold exposure
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“We propose that further functional characterisation of XDH mutants may unveil why sUA has not universally translated as a marker of CVD.”
InfluentialSelf-citation
Mechanistic Insights into Inorganic Nitrite-Mediated Vasodilation of Isolated Aortic Rings under Oxidative/Hypertensive Conditions and S-Nitros(yl)ation of Proteins in Germ-Free Mice
Stamm, P., Kalinovic, S., Oelze, M. W., Steven, S., Czarnowski, A., Kvandová, M., Bayer, F., Reinhardt, C., Münzel, T. F., & Daiber, A. (2022) · Biomedicines · doi:10.3390/biomedicines10030730 · Cited by 7
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Bioactive Compounds and Biological Activities of Red Beetroot (Beta vulgaris L.)
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Design and progress of a factorial trial testing the effect of spironolactone and inorganic nitrate on arterial function in people at risk of or with type 2 diabetes
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“patients did show a reduction in PWV after beetroot juice ingestion [17].”
Self-citation
Renal Soluble Guanylate Cyclase Is Downregulated in Sunitinib‐Induced Hypertension
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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: Kapil, Vikas
Bubb, Kristen J.
Khambata, Rayomand
Caulfield, Mark J.
Hobbs, Adrian J.
Ahluwalia, Amrita
Venue: Hypertension
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 2013-05
Volume: 61
Issue: 5
Pages: 1091-1102
ISSN: 0194-911X (ISSN-L)
1524-4563
DOI: 10.1161/hypertensionaha.111.00933
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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Enhanced Vasodilator Activity of Nitrite in Hypertension: Critical Role for Erythrocytic Xanthine Oxidoreductase and Translational Potential

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