Document Detail


Dietary nitrate ameliorates pulmonary hypertension: cytoprotective role for endothelial nitric oxide synthase and xanthine oxidoreductase.
MedLine Citation:
PMID:  22572914     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Reshma S Baliga; Alexandra B Milsom; Suborno M Ghosh; Sarah L Trinder; Raymond J Macallister; Amrita Ahluwalia; Adrian J Hobbs
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-05-09
Journal Detail:
Title:  Circulation     Volume:  125     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2012 Jun 
Date Detail:
Created Date:  2012-06-12     Completed Date:  2012-08-23     Revised Date:  2013-06-25    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2922-32     Citation Subset:  AIM; IM    
Affiliation:
William Harvey Research Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, United Kingdom. a.j.hobbs@qmul.ac.uk.
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MeSH Terms
Descriptor/Qualifier:
Allopurinol / pharmacology
Animal Feed
Animals
Anoxia / metabolism,  prevention & control
Antibiotics, Antineoplastic / toxicity
Bleomycin / toxicity
Cyclic GMP / blood
Disease Models, Animal
Enzyme Inhibitors / pharmacology
Hypertension, Pulmonary / chemically induced,  drug therapy*,  metabolism*
Hypertrophy, Right Ventricular / drug therapy,  metabolism
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Nitrates / blood,  pharmacology*,  urine
Nitric Oxide Synthase Type III / genetics,  metabolism*
Nitrites / blood,  pharmacology,  urine
Pulmonary Circulation / drug effects,  physiology
Ventricular Pressure / drug effects,  physiology
Xanthine Dehydrogenase / antagonists & inhibitors,  metabolism*
Grant Support
ID/Acronym/Agency:
084449//Wellcome Trust; //Wellcome Trust
Chemical
Reg. No./Substance:
0/Antibiotics, Antineoplastic; 0/Enzyme Inhibitors; 0/Nitrates; 0/Nitrites; 11056-06-7/Bleomycin; 315-30-0/Allopurinol; 7665-99-8/Cyclic GMP; EC 1.14.13.39/Nitric Oxide Synthase Type III; EC 1.14.13.39/Nos3 protein, mouse; EC 1.17.1.4/Xanthine Dehydrogenase
Comments/Corrections
Comment In:
Circulation. 2012 Dec 11;126(24):e348   [PMID:  23230319 ]
Circulation. 2012 Jun 12;125(23):2824-6   [PMID:  22572912 ]
Circulation. 2013 Jan 15;127(2):e275   [PMID:  23319817 ]

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