title: Effects of aminoguanidine, an inhibitor of inducible nitric oxide synthase, on nitric oxide production and its metabolites in healthy control subjects, healthy smokers, and COPD patients.
abstract: BACKGROUND
  Nitric oxide (NO) is produced by resident and inflammatory cells in the respiratory tract by the enzyme NO synthase (NOS), which exists in three isoforms: neuronal NOS (nNOS), inducible NOS (iNOS), and endothelial NOS. NO production is increased in patients with COPD, and the production of NO under oxidative stress conditions generates reactive nitrogen species that may amplify the inflammatory response in COPD.
  
  
  METHODS
  To examine the role of increased NO in COPD, we administered a relatively selective iNOS inhibitor, aminoguanidine, by nebulization in a double-blind, placebo-controlled study in COPD patients, healthy smokers, and healthy nonsmoking subjects. We investigated whether aminoguanidine had any effect on exhaled NO produced in the central lung (flux of NO from the airways [Jno] and peripheral lungs (concentration of NO in peripheral lung [Calv], on NO metabolites (nitrite [NO(2)(-)]/nitrate [NO(3)(-)], peroxinitrite [ONOO(-)], nitrotyrosine), and on a marker of oxidative stress (8-isoprostane) in exhaled breath condensate (EBC) and in sputum.
  
  
  RESULTS
  Aminoguanidine administration resulted in a significant reduction in Jno compared with administration of the saline solution control in healthy subjects, smokers, and COPD patients. Calv in smokers and in COPD patients was not completely inhibited 1 h after aminoguanidine inhalation, in marked contrast to previous results in asthma. Moreover, ONOO(-) and NO(2)(-)/NO(3)(-) levels were also increased in EBC and in sputum of smokers and COPD and were not completely inhibited following aminoguanidine inhalation. 8-Isoprostane levels were also increased in smokers and in COPD patients but were not reduced after aminoguanidine inhalation.
  
  
  CONCLUSIONS
  These results suggest that the constitutive NOS isoform as well as iNOS might be involved in NO release and contribute to the high Calv and ONOO(-) production in patients with COPD.
  
  
  BACKGROUND
  Clinicaltrials.gov Identifier: NCT00180635.
authors: Section of Airway Disease, National Heart and Lung Institute, Imperial College, London, UK.
authors: Caterina
authors: C
authors: Brindicci
authors: Section of Airway Disease, National Heart and Lung Institute, Imperial College, London, UK.
authors: Kazuhiro
authors: K
authors: Ito
authors: Section of Airway Disease, National Heart and Lung Institute, Imperial College, London, UK.
authors: Olga
authors: O
authors: Torre
authors: Section of Airway Disease, National Heart and Lung Institute, Imperial College, London, UK.
authors: Peter J
authors: PJ
authors: Barnes
authors: Section of Airway Disease, National Heart and Lung Institute, Imperial College, London, UK. Electronic address: s.kharitonov@imperial.ac.uk.
authors: Sergei A
authors: SA
authors: Kharitonov
mesh_terms: D000280:Administration, Inhalation; D000368:Aged; D015415:Biomarkers / Q000032:analysis; D001985:Bronchial Provocation Tests; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D006146:Guanidines / Q000008:administration & dosage*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009330:Nebulizers and Vaporizers; D009569:Nitric Oxide / Q000096:biosynthesis*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors; D018384:Oxidative Stress / Q000502:physiology; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000378:metabolism; D012016:Reference Values; D012129:Respiratory Function Tests; D012907:Smoking / Q000188:drug therapy* / Q000378:metabolism; D013183:Sputum / Q000737:chemistry; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D006146:Guanidines; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C004479:pimagedine