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Pharmacological characterisation of the interaction between glycopyrronium bromide and indacaterol fumarate in human isolated bronchi, small airways and bronchial epithelial cells
BACKGROUND: Nowadays, there is a considerable gap in knowledge concerning the mechanism(s) by which long-acting β(2)-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) interact to induce bronchodilation. This study aimed to characterise the pharmacological interaction between glycopyrro...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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BioMed Central
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4906998/ https://www.ncbi.nlm.nih.gov/pubmed/27296533 http://dx.doi.org/10.1186/s12931-016-0386-8 |
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author | Cazzola, Mario Calzetta, Luigino Puxeddu, Ermanno Ora, Josuel Facciolo, Francesco Rogliani, Paola Matera, Maria Gabriella |
author_facet | Cazzola, Mario Calzetta, Luigino Puxeddu, Ermanno Ora, Josuel Facciolo, Francesco Rogliani, Paola Matera, Maria Gabriella |
author_sort | Cazzola, Mario |
collection | PubMed |
description | BACKGROUND: Nowadays, there is a considerable gap in knowledge concerning the mechanism(s) by which long-acting β(2)-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) interact to induce bronchodilation. This study aimed to characterise the pharmacological interaction between glycopyrronium bromide and indacaterol fumarate and to identify the mechanism(s) leading to the bronchorelaxant effect of this interaction. METHODS: The effects of glycopyrronium plus indacaterol on the contractile tone of medium and small human isolated bronchi were evaluated, and acetylcholine and cAMP concentrations were quantified. The interaction was assessed by Bliss Independence approach. RESULTS: Glycopyrronium plus indacaterol synergistically inhibited the bronchial tone (medium bronchi, +32.51 % ± 7.86 %; small bronchi, +28.46 % ± 5.35 %; P < 0.05 vs. additive effect). The maximal effect was reached 140 min post-administration. A significant (P < 0.05) synergistic effect was observed during 9 h post-administration on the cholinergic tone, but not on the histaminergic contractility. Co-administration of glycopyrronium and indacaterol reduced the release of acetylcholine from the epithelium but not from bronchi, and enhanced cAMP levels in bronchi and epithelial cells (P < 0.05 vs. control), an effect that was inhibited by the selective KCa(++) channel blocker iberiotoxin. The role of cAMP-dependent pathway was confirmed by the synergistic effect elicited by the adenylate cyclase activator forskolin on glycopyrronium (P < 0.05 vs. additive effect), but not on indacaterol (P > 0.05 vs. additive effect), with regard of the bronchial relaxant response and cAMP increase. CONCLUSIONS: Glycopyrronium/indacaterol co-administration leads to a synergistic improvement of bronchodilation by increasing cAMP concentrations in both airway smooth muscle and bronchial epithelium, and by decreasing acetylcholine release from the epithelium. |
format | Online Article Text |
id | pubmed-4906998 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-49069982016-06-15 Pharmacological characterisation of the interaction between glycopyrronium bromide and indacaterol fumarate in human isolated bronchi, small airways and bronchial epithelial cells Cazzola, Mario Calzetta, Luigino Puxeddu, Ermanno Ora, Josuel Facciolo, Francesco Rogliani, Paola Matera, Maria Gabriella Respir Res Research BACKGROUND: Nowadays, there is a considerable gap in knowledge concerning the mechanism(s) by which long-acting β(2)-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) interact to induce bronchodilation. This study aimed to characterise the pharmacological interaction between glycopyrronium bromide and indacaterol fumarate and to identify the mechanism(s) leading to the bronchorelaxant effect of this interaction. METHODS: The effects of glycopyrronium plus indacaterol on the contractile tone of medium and small human isolated bronchi were evaluated, and acetylcholine and cAMP concentrations were quantified. The interaction was assessed by Bliss Independence approach. RESULTS: Glycopyrronium plus indacaterol synergistically inhibited the bronchial tone (medium bronchi, +32.51 % ± 7.86 %; small bronchi, +28.46 % ± 5.35 %; P < 0.05 vs. additive effect). The maximal effect was reached 140 min post-administration. A significant (P < 0.05) synergistic effect was observed during 9 h post-administration on the cholinergic tone, but not on the histaminergic contractility. Co-administration of glycopyrronium and indacaterol reduced the release of acetylcholine from the epithelium but not from bronchi, and enhanced cAMP levels in bronchi and epithelial cells (P < 0.05 vs. control), an effect that was inhibited by the selective KCa(++) channel blocker iberiotoxin. The role of cAMP-dependent pathway was confirmed by the synergistic effect elicited by the adenylate cyclase activator forskolin on glycopyrronium (P < 0.05 vs. additive effect), but not on indacaterol (P > 0.05 vs. additive effect), with regard of the bronchial relaxant response and cAMP increase. CONCLUSIONS: Glycopyrronium/indacaterol co-administration leads to a synergistic improvement of bronchodilation by increasing cAMP concentrations in both airway smooth muscle and bronchial epithelium, and by decreasing acetylcholine release from the epithelium. BioMed Central 2016-06-13 2016 /pmc/articles/PMC4906998/ /pubmed/27296533 http://dx.doi.org/10.1186/s12931-016-0386-8 Text en © The Author(s). 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Cazzola, Mario Calzetta, Luigino Puxeddu, Ermanno Ora, Josuel Facciolo, Francesco Rogliani, Paola Matera, Maria Gabriella Pharmacological characterisation of the interaction between glycopyrronium bromide and indacaterol fumarate in human isolated bronchi, small airways and bronchial epithelial cells |
title | Pharmacological characterisation of the interaction between glycopyrronium bromide and indacaterol fumarate in human isolated bronchi, small airways and bronchial epithelial cells |
title_full | Pharmacological characterisation of the interaction between glycopyrronium bromide and indacaterol fumarate in human isolated bronchi, small airways and bronchial epithelial cells |
title_fullStr | Pharmacological characterisation of the interaction between glycopyrronium bromide and indacaterol fumarate in human isolated bronchi, small airways and bronchial epithelial cells |
title_full_unstemmed | Pharmacological characterisation of the interaction between glycopyrronium bromide and indacaterol fumarate in human isolated bronchi, small airways and bronchial epithelial cells |
title_short | Pharmacological characterisation of the interaction between glycopyrronium bromide and indacaterol fumarate in human isolated bronchi, small airways and bronchial epithelial cells |
title_sort | pharmacological characterisation of the interaction between glycopyrronium bromide and indacaterol fumarate in human isolated bronchi, small airways and bronchial epithelial cells |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4906998/ https://www.ncbi.nlm.nih.gov/pubmed/27296533 http://dx.doi.org/10.1186/s12931-016-0386-8 |
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