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Effects of aminoguanidine, an inhibitor of inducible nitric oxide synthase, on nitric oxide production and its metabolites in healthy controls, healthy smokers and COPD patients

Section of Airway Disease, National Heart and Lung Institute, Imperial College, London, United Kingdom

s.kharitonov{at}imperial.ac.uk

Abstract

BackgroundNitric oxide (NO) is produced by resident and inflammatory cells in the respiratory tract by the enzyme NO synthase (NOS), which NOS exists in three isoforms: neuronal NOS (nNOS), inducible NOS (iNOS) and endothelial NOS (eNOS). 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.

MethodsTo examine the role of increased NO in COPD, we administered a relatively selective iNOS inhibitor, aminoguanidine (AG), by nebulization in a double-blind, placebo-controlled study in COPD patients, healthy smokers and healthy non-smoking subjects. We investigated whether AG had any effect on exhaled NO produced in the central (J_NO) and peripheral lungs (C_alv), on NO metabolities (nitrite/nitrate, peroxinitrite, nitrotyrosine) and on a marker of oxidative stress (8-isoprostane) in exhaled breath condensate (EBC) and in sputum.

ResultsAG administration resulted in a significant reduction in J_NO compared with administration of the saline solution control in healthy subjects, smokers and COPD patients. C_alv in smokers and in COPD patients was not completely inhibited one hour after AG inhalation, in marked contrast to previous results in asthma. Moreover, peroxynitrite, nitrite/nitrate levels were also increased in EBC and in sputum of smokers and COPD and were not completely inhibited following AG inhalation. 8-isoprostane levels were also increased in smokers and in COPD patients but were not reduced after AG inhalation.

ConclusionsThese results suggest that cNOS isoform as well as iNOS might be involved in NO release and contribute to the high C_alv and peroxynitrite production in COPD.

Key Words: nitric oxide • nitric oxide synthase inhibitor • peripheral inflammation • nitric oxide metabolites • nitrosative stress