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 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.
authors.affiliation: William Harvey Research Institute, Barts and The London Medical School, Queen Mary University of London, London, United Kingdom.
authors.forename: Suborno M
authors.initials: SM
authors.lastname: Ghosh
authors.forename: Vikas
authors.initials: V
authors.lastname: Kapil
authors.forename: Isabel
authors.initials: I
authors.lastname: Fuentes-Calvo
authors.forename: Kristen J
authors.initials: KJ
authors.lastname: Bubb
authors.forename: Vanessa
authors.initials: V
authors.lastname: Pearl
authors.forename: Alexandra B
authors.initials: AB
authors.lastname: Milsom
authors.forename: Rayomand
authors.initials: R
authors.lastname: Khambata
authors.forename: Sheiva
authors.initials: S
authors.lastname: Maleki-Toyserkani
authors.forename: Mubeen
authors.initials: M
authors.lastname: Yousuf
authors.forename: Nigel
authors.initials: N
authors.lastname: Benjamin
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Webb
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Caulfield
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Hobbs
authors.forename: Amrita
authors.initials: A
authors.lastname: Ahluwalia
mesh_terms: D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D018592:Cross-Over Studies; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004912:Erythrocytes / Q000201:enzymology*; D005260:Female; D006801:Humans; D006973:Hypertension / Q000097:blood / Q000188:drug therapy / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D009573:Nitrites / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D015398:Signal Transduction / Q000502:physiology; D057170:Translational Research, Biomedical; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology*; D014968:Xanthine Dehydrogenase / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000502:physiology*
chemical_list: D004791:Enzyme Inhibitors; D009573:Nitrites; D000493:Allopurinol; D014968:Xanthine Dehydrogenase