Mechanisms Underlying Erythrocyte and Endothelial Nitrite Reduction to Nitric Oxide in Hypoxia Role for Xanthine Oxidoreductase and Endothelial Nitric Oxide Synthase
Andrew J. Webb,Alexandra B. Milsom,Krishnaraj S. Rathod,Wai Lum Chu,Shehla Qureshi,Matthew J. Lovell,Florence Lecomte,David Perrett,Carmello Raimondo,Espeed Khoshbin,Zubair Ahmed,Rakesh Uppal,Nigel Benjamin,Adrian J. Hobbs,Amrita Ahluwalia +14 more
TLDR
It is demonstrated that conversion of nitrite to NO by blood vessels and RBCs was enhanced in the presence of the Xor substrate xanthine and attenuated by the XOR inhibitor allopurinol in acidic and hypoxic conditions only.Abstract:
Reduction of nitrite (NO(2)(-)) provides a major source of nitric oxide (NO) in the circulation, especially in hypoxemic conditions. Our previous studies suggest that xanthine oxidoreductase (XOR) is an important nitrite reductase in the heart and kidney. Herein, we have demonstrated that conversion of nitrite to NO by blood vessels and RBCs was enhanced in the presence of the XOR substrate xanthine (10 micromol/L) and attenuated by the XOR inhibitor allopurinol (100 micromol/L) in acidic and hypoxic conditions only. Whereas endothelial nitric oxide synthase (eNOS) inhibition had no effect on vascular nitrite reductase activity, in RBCs L-NAME, L-NMMA, and L-arginine inhibited nitrite-derived NO production by >50% (P<0.01) at pH 7.4 and 6.8 under hypoxic conditions. Western blot and immunohistochemical analysis of RBC membranes confirmed the presence of eNOS and abundant XOR on whole RBCs. Thus, XOR and eNOS are ideally situated on the membranes of RBCs and blood vessels to generate intravascular vasodilator NO from nitrite during ischemic episodes. In addition to the proposed role of deoxyhemoglobin, our findings suggest that the nitrite reductase activity within the circulation, under hypoxic conditions (at physiological pH), is mediated by eNOS; however, as acidosis develops, a substantial role for XOR becomes evident.read more
Citations
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Inorganic Nitrate Supplementation Lowers Blood Pressure in Humans Role for Nitrite-Derived NO
Vikas Kapil,Alexandra B. Milsom,M Okorie,Sheiva Maleki-Toyserkani,Farihah Akram,Farkhanda Rehman,S. Arghandawi,Vanessa Pearl,Nigel Benjamin,Stavros P. Loukogeorgakis,Raymond J. MacAllister,Adrian J. Hobbs,Andrew J. Webb,Amrita Ahluwalia +13 more
TL;DR: These findings demonstrate dose-dependent decreases in blood pressure and vasoprotection after inorganic nitrate ingestion in the form of either supplementation or by dietary elevation and intimate sex differences in nitrate processing involving the entero-salivary circulation are likely to be major contributing factors to the lower blood pressures and the Vasoprotective phenotype of premenopausal women.
Journal ArticleDOI
Nitrate and nitrite in biology, nutrition and therapeutics
Jon O. Lundberg,Mark T. Gladwin,Amrita Ahluwalia,Nigel Benjamin,Nathan S. Bryan,Anthony R. Butler,Pedro Cabrales,Angela Fago,Martin Feelisch,Peter C. Ford,Bruce A. Freeman,Michael P. Frenneaux,Joel M. Friedman,Malte Kelm,Christopher G. Kevil,Daniel B. Kim-Shapiro,Andrey V. Kozlov,Jack R. Lancaster,David J. Lefer,Kenneth E.L. McColl,Kenneth R. McCurry,Rakesh P. Patel,Joel Petersson,Tienush Rassaf,Valentin Reutov,George B. Richter-Addo,Alan N. Schechter,Sruti Shiva,Koichiro Tsuchiya,Ernst E. van Faassen,Andrew J. Webb,Brian S. Zuckerbraun,Jay L. Zweier,Eddie Weitzberg +33 more
TL;DR: The latest advances in the understanding of the biochemistry, physiology and therapeutics of nitrate, nitrite and NO were discussed during a recent 2-day meeting at the Nobel Forum, Karolinska Institutet in Stockholm.
Journal ArticleDOI
Nitric oxide signalling in cardiovascular health and disease
TL;DR: The updated paradigms on NOS regulation, NO interaction with reactive oxidant species in specific subcellular compartments, and downstream effects of NO in target cardiovascular tissues are summarized, while emphasizing the latest developments of molecular tools and biomarkers to modulate and monitor NO production and bioavailability.
Journal ArticleDOI
Nitrite as regulator of hypoxic signaling in mammalian physiology
Ernst E. van Faassen,Soheyl Bahrami,Martin Feelisch,Neil Hogg,Malte Kelm,Daniel B. Kim-Shapiro,Andrey V. Kozlov,Haitao Li,Jon O. Lundberg,Ron Mason,Hans Nohl,Tienush Rassaf,Alexandre Samouilov,Anny Slama-Schwok,Sruti Shiva,Anatoly F. Vanin,Eddie Weitzberg,Jay L. Zweier,Mark T. Gladwin +18 more
TL;DR: The mechanisms and properties of these various pathways and the role played by the local concentration of free oxygen in the affected tissue are discussed and additional direct signaling events not involving free nitric oxide are proposed.
Journal ArticleDOI
Vascular effects of dietary nitrate (as found in green leafy vegetables and beetroot) via the nitrate‐nitrite‐nitric oxide pathway
Satnam Lidder,Andrew J. Webb +1 more
TL;DR: The Nitrate 'Veg-Table' with 'Nitrate Units' is developed to achieve a nitrate intake that is likely to be sufficient to derive benefit, but also to minimize the risk of potential side effects from excessive ingestion, given the current available evidence.
References
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Journal ArticleDOI
Acute Blood Pressure Lowering, Vasoprotective, and Antiplatelet Properties of Dietary Nitrate via Bioconversion to Nitrite
Andrew J. Webb,Nakul Patel,Stavros P. Loukogeorgakis,M Okorie,Zainab Aboud,Shivani Misra,Rahim Rashid,Philip Miall,John E. Deanfield,Nigel Benjamin,Raymond J. MacAllister,Adrian J. Hobbs,Amrita Ahluwalia +12 more
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Journal ArticleDOI
Simulation of the diffusion and reaction of endogenously produced nitric oxide
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