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Original Research: COPD |

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

Caterina Brindicci, MD, PhD; Kazuhiro Ito, PhD; Olga Torre, MD; Peter J. Barnes, DM, DSc; Sergei A. Kharitonov, MD, PhD
Author and Funding Information

*From the Section of Airway Disease, National Heart and Lung Institute, Imperial College, London, UK.

Correspondence to: Sergei A. Kharitonov, MD, PhD, Section of Airway Disease, National Heart and Lung Institute, Imperial College London, Dovehouse St, London SW3 6LY, UK; e-mail: s.kharitonov@imperial.ac.uk


Financial support was provided by the National Heart and Lung Institute, Imperial College, London, UK.

The authors declare no conflicts of interest related to this study.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).


Chest. 2009;135(2):353-367. doi:10.1378/chest.08-0964
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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 [NO2]/nitrate [NO3], 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 NO2/NO3 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.

Trial registration:  Clinicaltrials.gov Identifier: NCT00180635.

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