Author | Carvalho, Katharinne Ingrid Moraes | |
Author | Coutinho, Diego de Sá | |
Author | Joca, Humberto Cavalcante | |
Author | Miranda, Artur Santos | |
Author | Cruz, Jader dos Santos | |
Author | Silva, Emerson Teixeira | |
Author | Souza, Marcus Vinícius Nora | |
Author | Faria, Robson Xavier | |
Author | Silva, Patricia Machado Rodrigues e | |
Author | Costa, Jorge Carlos Santos | |
Author | Martins, Marco Aurélio | |
Access date | 2021-01-13T18:29:21Z | |
Available date | 2021-01-13T18:29:21Z | |
Document date | 2020 | |
Citation | CARVALHO, Katharine Ingrid Moraes et al. Anti-Bronchospasmodic Effect of JME-173, a Novel Mexiletine Analog Endowed With Highly Attenuated Anesthetic Activity. Frontiers in Pharmacology, v. 11, Article 1159, p. 1-12, July 2020. | pt_BR |
ISSN | 1663-9812 | pt_BR |
URI | https://www.arca.fiocruz.br/handle/icict/45670 | |
Language | eng | pt_BR |
Publisher | Frontiers Media | pt_BR |
Rights | open access | pt_BR |
Subject in Portuguese | Anestésico local | pt_BR |
Subject in Portuguese | Hiper-reatividade das vias aéreas | pt_BR |
Subject in Portuguese | Asma | pt_BR |
Subject in Portuguese | Broncodilatador | pt_BR |
Subject in Portuguese | Fronteiras anti-inflamatórias | pt_BR |
Title | Anti-Bronchospasmodic Effect of JME-173, a Novel Mexiletine Analog Endowed With Highly Attenuated Anesthetic Activity | pt_BR |
Type | Article | pt_BR |
DOI | 10.3389/fphar.2020.01159 | |
Abstract | Local anesthetics (LAs), such as lidocaine and mexiletine, inhibit bronchoconstriction in asthmatics, but adverse effects limit their use for this specific clinical application. In this study, we describe the anti-spasmodic properties of the mexiletine analog 2-(2- aminopropoxy)-3,5-dimethyl, 4-Br-benzene (JME-173), which was synthesized and screened for inducing reduced activity on Na+ channels. The effectiveness of JME-173 was assessed using rat tracheal rings, a GH3 cell line and mouse cardiomyocytes to access changes in smooth muscle contraction, and Na+, and Ca++ionic currents, respectively. Bronchospasm and airway hyper-reactivity (AHR) were studied using whole-body barometric plethysmography in A/J mice. We observed that the potency of JME-173 was 653-fold lower than mexiletine in inhibiting Na+ currents, but 12-fold higher in inhibiting L-type Ca++ currents. JME-173 was also more potent than mexiletine in inhibiting tracheal contraction by carbachol, allergen, extracellular Ca++, or sodium orthovanadate provocations. The effect of JME-173 on carbachol-induced tracheal contraction remained unaltered under conditions of de-epithelized rings, b2-receptor blockade or adenylate cyclase inhibition. When orally administered, JME-173 and theophylline inhibited methacholine-induced bronchospasm at time points of 1 and 3 h post-treatment, while only JME-173 remained active for at least 6 h. In addition, JME-173 also inhibited AHR in a mouse model of lipopolysaccharide (LPS)-induced lung inflammation. Thus, the mexiletine analog JME-173 shows highly attenuated activity on Na+ channels and optimized anti-spasmodic properties, in a mechanism that is at least in part mediated by regulation of Ca++ inflow toward the cytosol. Thus, JME-173 is a promising alternative for the treatment of clinical conditions marked by lifethreatening bronchoconstriction. | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Inflamação. Rio de Janeiro, RJ, Brasil. | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Inflamação. Rio de Janeiro, RJ, Brasil. | pt_BR |
Affilliation | Universidade Federal de Minas Gerais. Laboratório de Membranas Excitáveis e Biologia Cardiovascular. Belo Horizonte, MG, Brasil. | pt_BR |
Affilliation | Universidade Federal de Minas Gerais. Laboratório de Membranas Excitáveis e Biologia Cardiovascular. Belo Horizonte, MG, Brasil. | pt_BR |
Affilliation | Universidade Federal de Minas Gerais. Laboratório de Membranas Excitáveis e Biologia Cardiovascular. Belo Horizonte, MG, Brasil. | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Farmanguinhos. Rio de Janeiro, RJ, Brasil. | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Farmanguinhos. Rio de Janeiro, RJ, Brasil. | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Toxoplasmose e outras Protozoases. Rio de Janeiro, RJ, Brasil. | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Inflamação. Rio de Janeiro, RJ, Brasil. | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Farmanguinhos. Rio de Janeiro, RJ, Brasil. | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Inflamação. Rio de Janeiro, RJ, Brasil. | pt_BR |
Subject | Local anesthetic | pt_BR |
Subject | Airway hyper-reactivity | pt_BR |
Subject | Asthma | pt_BR |
Subject | Bronchodilator | pt_BR |
Subject | Anti-inflammatory Frontiers | pt_BR |