Long-term effects of selective and nonselective endothelin receptor antagonists in mice with heart failure

Abstract

Background: The ETA and ETB receptors mediate vasoconstriction, aldosterone release, and fibrosis. However, the role of ETB receptors is still controversial because those expressed on endothelial cells also stimulate vasodilatation and may oppose the actions of the ETA receptor. Plasma levels of endothelin-1 (ET-1) are increased in heart failure (HF) and are associated with myocardial dysfunction. The relative efficacy of selective and nonselective ET antagonists in the treatment of HF is unclear. We hypothesized that blockade of ETA receptors may improve cardiac function and prevent left ventricular remodeling in mice with HF, and these effects may be mediated in part by activation of ETB. Methods and Results: A mouse model of chronic HF induced by myocardial infarction (MI) was used. Seven days after MI, mice were divided into vehicle, ETA-ant, or ETA/B-ant groups and treated for 23 weeks. Cardiac function, LV dimensions, and hemodynamics were evaluated in conscious mice before MI and during treatment. Histologic analysis of the heart and liver was performed at the end of the study. HF significantly decreased EF and increased LV dimensions, interstitial collagen fraction (ICF) and myocyte cross-sectional area (MCSA). Both ETA-ant and ETA/B-ant slightly increased EF but had no significant effect on LV dimensions, hypertrophy, or ICF. Both treatments decreased MCSA; however, this was only significant in the ETA/B-ant group. Conclusions: Both selective and nonselective ET-ant have similar slight effects on cardiac function and remodeling. This suggests that (1) ETB receptors do not mediate the beneficial cardiac effects of ETA-ant and (2) blockade of the ET system alone may not provide significant cardioprotection, at least in mice with HF induced by MI.