title: Dietary nitrate ameliorates pulmonary hypertension: cytoprotective role for endothelial nitric oxide synthase and xanthine oxidoreductase.
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.
  
  
  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.affiliation: William Harvey Research Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, United Kingdom.   a.j.hobbs@qmul.ac.uk.
authors.forename: Reshma S
authors.initials: RS
authors.lastname: Baliga
authors.forename: Alexandra B
authors.initials: AB
authors.lastname: Milsom
authors.forename: Suborno M
authors.initials: SM
authors.lastname: Ghosh
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Trinder
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Macallister
authors.forename: Amrita
authors.initials: A
authors.lastname: Ahluwalia
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Hobbs
mesh_terms: D000493:Allopurinol / Q000494:pharmacology; D000821:Animal Feed; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D001761:Bleomycin / Q000633:toxicity; D006152:Cyclic GMP / Q000097:blood; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism*; D017380:Hypertrophy, Right Ventricular / Q000188:drug therapy / Q000378:metabolism; D000860:Hypoxia / Q000378:metabolism / Q000517:prevention & control; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009566:Nitrates / Q000097:blood / Q000494:pharmacology* / Q000652:urine; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism*; D009573:Nitrites / Q000097:blood / Q000494:pharmacology / Q000652:urine; D011652:Pulmonary Circulation / Q000187:drug effects / Q000502:physiology; D017725:Ventricular Pressure / Q000187:drug effects / Q000502:physiology; D014968:Xanthine Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000903:Antibiotics, Antineoplastic; D004791:Enzyme Inhibitors; D009566:Nitrates; D009573:Nitrites; D001761:Bleomycin; D000493:Allopurinol; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D014968:Xanthine Dehydrogenase; D006152:Cyclic GMP