Bucindolol attenuates the vascular remodeling of pulmonary arteries by modulating the expression of the endothelin-1 A receptor in rats with pulmonary arterial hypertension

• Published in: Biomedicine & pharmacotherapy 2018-03, Vol.99, p.704-714
• Main Authors: de Lima-Seolin, Bruna Gazzi, Hennemann, Matheus Mittmann, Fernandes, Rafael Oliveira, Colombo, Rafael, Bonetto, Jéssica Hellen Poletto, Teixeira, Rayane Brinck, Khaper, Neelam, Godoy, Alessandra Eifler Guerra, Litvin, Isnard Elman, Sander da Rosa Araujo, Alex, Schenkel, Paulo Cavalheiro, Belló-Klein, Adriane
• Format: Article
• Language: English
• Subjects: Adrenergic beta-Antagonists - pharmacology; Adrenergic receptor blocker; Animals; Bucindolol; Disease Models, Animal; Echocardiography; Endothelin-1 receptor; Hypertension, Pulmonary - drug therapy; Hypertension, Pulmonary - physiopathology; Male; Monocrotaline; Monocrotaline - toxicity; Nitric oxide synthase; Nitric Oxide Synthase Type III; Oxidative Stress - drug effects; Propanolamines - pharmacology; Pulmonary Artery - drug effects; Pulmonary Artery - metabolism; Rats; Rats, Wistar; Receptor, Endothelin A - drug effects; Receptor, Endothelin A - metabolism; Receptor, Endothelin B - drug effects; Receptor, Endothelin B - metabolism; Vascular Remodeling - drug effects
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2018.01.127

The aim of this study was to investigate the role of the ß-adrenergic blocker bucindolol on endothelial dysfunction and pulmonary vascular remodeling in rats with pulmonary arterial hypertension (PAH). Male Wistar rats were divided into four groups: control, monocrotaline (MCT), control + bucindolol and monocrotaline + bucindolol (MCT + BCD). PAH was induced by an injection of monocrotaline (60 mg/kg i.p.). After two weeks, the animals were treated for seven days with bucindolol (2 mg/kg/day i.p.) or vehicle. Echocardiography was performed upon treatment completion to analyze pulmonary vascular resistance (PVR) and right ventricle (RV) myocardial performance index. Lungs were collected for oxidative stress and western blot analysis, and the pulmonary artery was analyzed for histological and immunohistochemical parameters. The MCT + BCD group showed a decrease (32%) in the protein expression of endothelin-1 type A receptor (ETAR) and in the ratio of ETA/endothelin-1 type B receptor (ETBR) (62%) as compared to the MCT group. Bucindolol treatment did not alter oxidative stress, as determined by lipid peroxidation analysis and antioxidant enzyme activities and expression, endothelial nitric oxide synthase immunocontent and decreased nitrotyrosine levels. Moreover, bucindolol improved vascular remodeling of the pulmonary artery in the MCT + BCD group by decreasing (21%) PVR and increasing RV workload in relation to MCT.