Beta1-adrenoceptor antagonist, metoprolol attenuates cardiac myocyte Ca2+ handling dysfunction in rats with pulmonary artery hypertension.
J Mol Cell Cardiol
; 120: 74-83, 2018 07.
Article
em En
| MEDLINE
| ID: mdl-29807024
ABSTRACT
Right heart failure is the major cause of death in Pulmonary Artery Hypertension (PAH) patients but is not a current, specific therapeutic target. Pre-clinical studies have shown that adrenoceptor blockade can improve cardiac function but the mechanisms of action within right ventricular (RV) myocytes are unknown. We tested whether the ß1-adrenoceptor blocker metoprolol could improve RV myocyte function in an animal model of PAH, by attenuating adverse excitation-contraction coupling remodeling. PAH with RV failure was induced in rats by monocrotaline injection. When PAH was established, animals were given 10â¯mg/kg/day metoprolol (MCTâ¯+â¯BB) or vehicle (MCT). The median time to the onset of heart failure signs was delayed from 23â¯days (MCT), to 31â¯days (MCTâ¯+â¯BB). At 23⯱â¯1â¯days post-injection, MCTâ¯+â¯BB showed improved in vivo cardiac function, measured by echocardiography. RV hypertrophy was reduced despite persistent elevated afterload. RV myocyte contractility during field stimulation was improved at higher pacing frequencies in MCTâ¯+â¯BB. Preserved t-tubule structure, more uniform evoked Ca2+ release, increased SERCA2a expression and faster ventricular repolarization (measured in vivo by telemetry) may account for the improved contractile function. Sarcoplasmic reticulum Ca2+ overload was prevented in MCTâ¯+â¯BB myocytes resulting in fewer spontaneous Ca2+ waves, with a lower pro-arrhythmic potential. Our novel finding of attenuation of defects in excitation contraction coupling by ß1-adrenoceptor blockade with delays in the onset of HF, identifies the RV as a promising therapeutic target in PAH. Moreover, our data suggest existing therapies for left ventricular failure may also be beneficial in PAH induced RV failure.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Artéria Pulmonar
/
Cálcio
/
Disfunção Ventricular Direita
/
Miócitos Cardíacos
/
Antagonistas de Receptores Adrenérgicos beta 1
/
Hipertensão Pulmonar
/
Metoprolol
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
J Mol Cell Cardiol
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Reino Unido