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Dietary nitrate ameliorates pulmonary hypertension: cytoprotective role for endothelial nitric oxide synthase and xanthine oxidoreductase.

Baliga, RS, Milsom, AB, Ghosh, SM, Trinder, SL, Macallister, RJ, Ahluwalia, A and Hobbs, AJ (2012) Dietary nitrate ameliorates pulmonary hypertension: cytoprotective role for endothelial nitric oxide synthase and xanthine oxidoreductase. Circulation, 125 (23). pp. 2922-2932.

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Abstract

BACKGROUND: Pulmonary hypertension (PH) is a multifactorial disease characterized by increased pulmonary vascular resistance and right ventricular failure; morbidity and mortality remain unacceptably high. Loss of nitric oxide (NO) bioactivity is thought to contribute to the pathogenesis of PH, and agents that augment pulmonary NO signaling are clinically effective in the disease. Inorganic nitrate (NO(3)(-)) and nitrite (NO(2)(-)) elicit a reduction in systemic blood pressure in healthy individuals; this effect is underpinned by endogenous and sequential reduction to NO. Herein, we determined whether dietary nitrate and nitrite might be preferentially reduced to NO by the hypoxia associated with PH, and thereby offer a convenient, inexpensive method of supplementing NO functionality to reduce disease severity. METHODS AND RESULTS: Dietary nitrate reduced the right ventricular pressure and hypertrophy, and pulmonary vascular remodeling in wild-type mice exposed to 3 weeks of hypoxia; this beneficial activity was mirrored largely by dietary nitrite. The cytoprotective effects of dietary nitrate were associated with increased plasma and lung concentrations of nitrite and cGMP. The beneficial effects of dietary nitrate and nitrite were reduced in mice lacking endothelial NO synthase or treated with the xanthine oxidoreductase inhibitor allopurinol. CONCLUSIONS: These data demonstrate that dietary nitrate, and to a lesser extent dietary nitrite, elicit pulmonary dilatation, prevent pulmonary vascular remodeling, and reduce the right ventricular hypertrophy characteristic of PH. This favorable pharmacodynamic profile depends on endothelial NO synthase and xanthine oxidoreductase -catalyzed reduction of nitrite to NO. Exploitation of this mechanism (ie, dietary nitrate/nitrite supplementation) represents a viable, orally active therapy for PH.

Item Type: Article
Authors :
NameEmailORCID
Baliga, RSUNSPECIFIEDUNSPECIFIED
Milsom, ABUNSPECIFIEDUNSPECIFIED
Ghosh, SMUNSPECIFIEDUNSPECIFIED
Trinder, SLs.trinder@surrey.ac.ukUNSPECIFIED
Macallister, RJUNSPECIFIEDUNSPECIFIED
Ahluwalia, AUNSPECIFIEDUNSPECIFIED
Hobbs, AJUNSPECIFIEDUNSPECIFIED
Date : 12 June 2012
Identification Number : 10.1161/CIRCULATIONAHA.112.100586
Uncontrolled Keywords : Allopurinol, Animal Feed, Animals, Anoxia, Antibiotics, Antineoplastic, Bleomycin, Cyclic GMP, Disease Models, Animal, Enzyme Inhibitors, Hypertension, Pulmonary, Hypertrophy, Right Ventricular, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Nitrates, Nitric Oxide Synthase Type III, Nitrites, Pulmonary Circulation, Ventricular Pressure, Xanthine Dehydrogenase
Related URLs :
Depositing User : Symplectic Elements
Date Deposited : 17 May 2017 10:45
Last Modified : 17 May 2017 14:52
URI: http://epubs.surrey.ac.uk/id/eprint/829052

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