Abstract
Asthma is a disease characterized by chronic inflammation and hyper responsiveness of airways. We aimed to assess the relaxant potential of phosphodiesterase-4 (PDE4) inhibitors N-sulfonilhidrazonic derivatives on non-asthmatic and asthmatic guinea pig trachea. Firstly, guinea pigs were sensitized and challenged with ovalbumin, and then morphological, and contractile changes were evaluated resulting from asthma, followed by evaluation of relaxant effect of derivatives on guinea pig trachea and the cAMP levels measurement by ELISA. It has been evidenced hypertrophy of airway smooth muscle, inflammatory infiltrate, and vascular abnormalities. Moreover, only sensitized tracheal rings were responsive to OVA. Contractile response to histamine, but not to carbachol, was greater in sensitized animals, however the relaxant response to aminophylline and isoprenaline were the same in non-asthmatics and asthmatics. N-sulfonilhidrazonic derivatives presented equipotent relaxant action independent of epithelium, with exception of LASSBio-1850 that presented a low efficacy (< 50%) and LASSBio-1847 with a 4-fold higher potency on asthmatics. LASSBio-1847 relaxant curve was impaired in the presence of propranolol and potentiated by isoprenaline in both groups. Furthermore, relaxation was potentiated 54- and 4-fold by forskolin in non-asthmatics and asthmatics, respectively. Likewise, LASSBio-1847 potentiated relaxant curve of aminophylline 147- and 4-fold in both groups. The PKA inhibitor H-89 impaired the relaxant potency of the derivative. Finally, LASSBio-1847 increased tracheal intracellular cAMP levels similarly to rolipram, selective PDE4 inhibitor, in both animals. LASSBio-1847 showed to be promising to relax guinea pig trachea from non-sensitized and sensitized guinea pigs by activation of β2-adrenergic receptors/AC/cAMP pathway.
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Acknowledgements
The authors thank José Crispim Duarte and Luís C. Silva for providing technical assistance, and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) for financial support.
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This work was supported by National Council for Scientific and Technological Development (CNPq). IRRM, LHCV, and LHACS received additional research support for doctoral scholarship, and BAC received research support from CNPq (Grant number 476692/2012-1).
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All authors contributed to the study conception and design. IRRM was the main executor, and obtained, analyzed, and discussed all data. MMM, MCCS, FRQ, LHACS, IKCN, PMS and LML participated in the acquisition and analysis of data. LHCV and LHACS also participated in the writing, review, and editing of the article. BAS was the advisor of the work. All authors read and approved the manuscript. The authors declare that all data were generated in-house and that no paper mill was used.
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All experiments were previously approved by the Ethics Committee on Animal Use of UFPB (protocol CEUA/UFPB 0610/11). The procedures adopted to reduce the pain and suffering of animals were carried out in accordance with the Ethical guidelines for investigation of experimental pain in conscious animals (Zimmermann 1983) and the Guidelines for the ethical use of animals in applied etiology studies (Sherwin et al. 2003). Also, the authors followed the ARRIVE Guidelines for Reporting Animal Research (Kilkenny et al. 2010). To adapting to the 3Rs Principle, measures were adopted to choose the appropriate animal model and plan the number of animals and their maximum reuse for different experimental protocols. Furthermore, other measures adopted included: Adoption of adequate accommodation, environment, food, and environmental control according to their biology; and carrying out appropriate management for the species, which was carried out only by people properly trained for this purpose.
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Martins, I.R.R., de Melo Medeiros, M., Vasconcelos, L.H.C. et al. New phosphodiesterase-4 inhibitors present airways relaxant activity in a guinea pig acute asthma model. Naunyn-Schmiedeberg's Arch Pharmacol 397, 4419–4434 (2024). https://doi.org/10.1007/s00210-023-02905-8
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DOI: https://doi.org/10.1007/s00210-023-02905-8