The ß3 Adrenergic Receptor Agonist BRL37344 Exacerbates Atrial Structural Remodeling Through iNOS Uncoupling in Canine Models of Atrial Fibrillation.
Cell Physiol Biochem
; 38(2): 514-30, 2016.
Article
em En
| MEDLINE
| ID: mdl-26828873
ABSTRACT
BACKGROUND/AIMS:
The role of the ß3-adrenergic receptor (ß3-AR) agonist BRL37344 in atrial fibrillation (AF) structural remodeling and the underlying mechanisms as a therapeutic target were investigated.METHODS:
Four groups of dogs were evaluated sham, pacing, ß3-AR agonist BRL37344 (ß3-AGO), and ß3-AR antagonist L748337 (ß3-ANT) groups. Dogs in the pacing, ß3-AGO and ß3-ANT groups were subjected to rapid atrial pacing for four weeks. Atrial structure and function, AF inducibility and duration, atrial myocyte apoptosis and interstitial fibrosis were assessed. Atrial superoxide anions were evaluated by fluorescence microscopy and colorimetric assays. Cardiac nitrate+nitrite levels were used to assess nitric oxide (NO) production. Protein and mRNA expression of ß3-AR, neuronal NO synthase (nNOS), inducible NO synthase (iNOS), endothelial NO synthase (eNOS) and guanosine triphosphate cyclohydrolase-1 (GCH-1) as well as tetrahydrobiopterin (BH4) levels were measured.RESULTS:
ß3-AR was up-regulated in AF. Stimulation of ß3-AR significantly increased atrial myocyte apoptosis, fibrosis and atrial dilatation, resulting in increased AF induction and prolonged duration. These effects were attenuated by ß3-ANT. Moreover, ß3-AGO reduced BH4 and NO production and increased superoxide production, which was inhibited by the specific iNOS inhibitor, 1400w ß3-AGO also increased iNOS but decreased eNOS and had no effect on nNOS expression in AF.CONCLUSIONS:
ß3-AR stimulation resulted in atrial structural remodeling by increasing iNOS uncoupling and related oxidative stress. ß3-AR up-regulation and iNOS uncoupling might be underlying AF therapeutic targets.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fibrilação Atrial
/
Receptores Adrenérgicos beta 3
/
Óxido Nítrico Sintase Tipo II
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Remodelamento Atrial
/
Átrios do Coração
Limite:
Animals
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article