Enhanced vasodilator activity of nitrite in hypertension: critical role for erythrocytic xanthine oxidoreductase and translational potential

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

doi:10.1161/HYPERTENSIONAHA.111.00933

Enhanced vasodilator activity of nitrite in hypertension: critical role for erythrocytic xanthine oxidoreductase and translational potential

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

Queen Mary University of London

Research output: Contribution to journal › Article › peer-review

186 Citations (Scopus)

Abstract

Elevation of circulating nitrite (NO2−) 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.

Original language	English
Pages (from-to)	1091-1102
Number of pages	12
Journal	Hypertension
Volume	61
Issue number	5
DOIs	https://doi.org/10.1161/HYPERTENSIONAHA.111.00933
Publication status	Published - May 2013

Keywords

Allopurinol
Animals
Blood Pressure
Cross-Over Studies
Disease Models, Animal
Dose-Response Relationship, Drug
Enzyme Inhibitors
Erythrocytes
Female
Humans
Hypertension
Male
Middle Aged
Nitrites
Rats
Rats, Inbred SHR
Rats, Inbred WKY
Signal Transduction
Translational Medical Research
Vasodilation
Xanthine Dehydrogenase

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10.1161/HYPERTENSIONAHA.111.00933

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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. (2013). Enhanced vasodilator activity of nitrite in hypertension: critical role for erythrocytic xanthine oxidoreductase and translational potential. Hypertension, 61(5), 1091-1102. https://doi.org/10.1161/HYPERTENSIONAHA.111.00933

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title = "Enhanced vasodilator activity of nitrite in hypertension: critical role for erythrocytic xanthine oxidoreductase and translational potential",

abstract = "Elevation of circulating nitrite (NO2−) 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 na{\"i}ve 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.",

keywords = "Allopurinol, Animals, Blood Pressure, Cross-Over Studies, Disease Models, Animal, Dose-Response Relationship, Drug, Enzyme Inhibitors, Erythrocytes, Female, Humans, Hypertension, Male, Middle Aged, Nitrites, Rats, Rats, Inbred SHR, Rats, Inbred WKY, Signal Transduction, Translational Medical Research, Vasodilation, Xanthine Dehydrogenase",

author = "Ghosh, {Suborno M} and Vikas Kapil and Isabel Fuentes-Calvo and Bubb, {Kristen J} and Vanessa Pearl and Milsom, {Alexandra B} and Rayomand Khambata and Sheiva Maleki-Toyserkani and Mubeen Yousuf and Nigel Benjamin and Webb, {Andrew J} and Caulfield, {Mark J} and Hobbs, {Adrian J} and Amrita Ahluwalia",

year = "2013",

month = may,

doi = "10.1161/HYPERTENSIONAHA.111.00933",

language = "English",

volume = "61",

pages = "1091--1102",

journal = "Hypertension",

issn = "0194-911X",

publisher = "American Heart Association, Inc.",

number = "5",

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Ghosh, SM, Kapil, V, Fuentes-Calvo, I, Bubb, KJ, Pearl, V, Milsom, AB, Khambata, R, Maleki-Toyserkani, S, Yousuf, M, Benjamin, N, Webb, AJ, Caulfield, MJ, Hobbs, AJ & Ahluwalia, A 2013, 'Enhanced vasodilator activity of nitrite in hypertension: critical role for erythrocytic xanthine oxidoreductase and translational potential', Hypertension, vol. 61, no. 5, pp. 1091-1102. https://doi.org/10.1161/HYPERTENSIONAHA.111.00933

TY - JOUR

T1 - Enhanced vasodilator activity of nitrite in hypertension

T2 - critical role for erythrocytic xanthine oxidoreductase and translational potential

AU - Ghosh, Suborno M

AU - Kapil, Vikas

AU - Fuentes-Calvo, Isabel

AU - Bubb, Kristen J

AU - Pearl, Vanessa

AU - Milsom, Alexandra B

AU - Khambata, Rayomand

AU - Maleki-Toyserkani, Sheiva

AU - Yousuf, Mubeen

AU - Benjamin, Nigel

AU - Webb, Andrew J

AU - Caulfield, Mark J

AU - Hobbs, Adrian J

AU - Ahluwalia, Amrita

PY - 2013/5

Y1 - 2013/5

N2 - Elevation of circulating nitrite (NO2−) 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.

AB - Elevation of circulating nitrite (NO2−) 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.

KW - Allopurinol

KW - Animals

KW - Blood Pressure

KW - Cross-Over Studies

KW - Disease Models, Animal

KW - Dose-Response Relationship, Drug

KW - Enzyme Inhibitors

KW - Erythrocytes

KW - Female

KW - Humans

KW - Hypertension

KW - Male

KW - Middle Aged

KW - Nitrites

KW - Rats

KW - Rats, Inbred SHR

KW - Rats, Inbred WKY

KW - Signal Transduction

KW - Translational Medical Research

KW - Vasodilation

KW - Xanthine Dehydrogenase

U2 - 10.1161/HYPERTENSIONAHA.111.00933

DO - 10.1161/HYPERTENSIONAHA.111.00933

M3 - Article

C2 - 23589565

SN - 0194-911X

VL - 61

SP - 1091

EP - 1102

JO - Hypertension

JF - Hypertension

IS - 5

ER -

Enhanced vasodilator activity of nitrite in hypertension: critical role for erythrocytic xanthine oxidoreductase and translational potential

Abstract

Keywords

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