Long-term effects of selective and nonselective endothelin receptor antagonists in mice with heart failure.
BACKGROUND
The ET(A) and ET(B) receptors mediate vasoconstriction, aldosterone release, and fibrosis. However, the role of ET(B) receptors is still controversial because those expressed on endothelial cells also stimulate vasodilatation and may oppose the actions of the ET(A) 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 ET(A) 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 ET(B).


RESULTS
A mouse model of chronic HF induced by myocardial infarction (MI) was used. Seven days after MI, mice were divided into vehicle, ET(A)-ant, or ET(A/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 ET(A)-ant and ET(A/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 ET(A/B)-ant group.


CONCLUSIONS
Both selective and nonselective ET-ant have similar slight effects on cardiac function and remodeling. This suggests that (1) ET(B) receptors do not mediate the beneficial cardiac effects of ET(A)-ant and (2) blockade of the ET system alone may not provide significant cardioprotection, at least in mice with HF induced by MI.
Cavasin
Maria A
MA
Hypertension and Vascular Research Division, Henry Ford Health System, Detroit, Michigan 48202, USA.
Carretero
Oscar A
OA
Yang
Fang
F
Oja-Tebbe
Nancy
N
Peng
Hongmei
H
Yang
Xiao-Ping
XP
D000818:Animals; D006332:Cardiomegaly / Q000150:complications / Q000188:drug therapy; D004195:Disease Models, Animal; D065128:Endothelin Receptor Antagonists; D005260:Female; D006333:Heart Failure / Q000150:complications / Q000188:drug therapy* / Q000401:mortality; D006439:Hemodynamics / Q000187:drug effects; D008099:Liver / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008955:Models, Cardiovascular; D009203:Myocardial Infarction / Q000150:complications / Q000188:drug therapy; D017466:Receptors, Endothelin / Q000627:therapeutic use*; D013318:Stroke Volume / Q000187:drug effects; D016019:Survival Analysis; D013997:Time Factors; D016896:Treatment Outcome; D016277:Ventricular Function, Left / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects
D065128:Endothelin Receptor Antagonists; D017466:Receptors, Endothelin