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Aggravation of left ventricular remodeling by a novel specific endothelin ET(A) antagonist EMD94246 in rats with
1II. Medizinische Klinik, Klinikum Mannheim der Universität Heidelberg, Germany.
Insights
Selective endothelin ET(A) receptor blockade did not improve outcomes after myocardial infarction in rats. Instead, it worsened left ventricular remodeling by promoting dilation in large infarct models.
Area of Science:
- Cardiovascular Research
- Pharmacology
- Experimental Medicine
Background:
- Endothelin receptor antagonists have shown promise in managing myocardial infarction.
- Previous studies indicated ET(A) antagonists reduce mortality and combined ET(A)+ET(B) antagonists prevent left ventricular dilatation.
Purpose of the Study:
- To investigate the long-term effects of selective endothelin ET(A) receptor blockade on left ventricular function and remodeling post-myocardial infarction.
- To test the hypothesis that ET(A) receptor blockade confers beneficial effects.
Main Methods:
- Rats underwent coronary artery ligation or sham operation.
- EMD94246, a selective ET(A) antagonist, or placebo was administered orally for eight weeks.
- Left ventricular hemodynamics and volume were assessed post-treatment.
Main Results:
- EMD94246 treatment did not impact mortality or hemodynamic parameters.
- Selective ET(A) antagonism significantly increased left ventricular volume in rats with large myocardial infarcts.
- The drug promoted chronic left ventricular dilatation.
Conclusions:
- Long-term blockade of the endothelin ET(A) receptor with EMD94246 did not provide beneficial effects.
- Selective ET(A) antagonism exacerbated left ventricular remodeling, leading to dilatation in a large myocardial infarction model.
Abstract:
An endothelin (ET(A)) antagonist reduced mortality and an ET(A) + ET(B) antagonist prevented left ventricular dilatation in rats with large myocardial infarction. This study tested the hypothesis that long-term blockade of the ET(A) receptor would have beneficial effects on left ventricular function and remodeling. Three hours after coronary artery ligation or sham operation in rats, EMD94246 (100 mg/kg/day, n=62) or placebo (n=62) was given by gavage. Eight weeks later, left ventricular hemodynamic measurements were performed and left ventricular volume determined with a double-lumen catheter after KCl-induced cardiac arrest. EMD94246 treatment had no effects on mortality or hemodynamic parameters. In rats with large infarcts, EMD94246 significantly increased left ventricular volume (2.5+/-0.1 vs. 2.2+/-0.1 ml/kg; p < 0.05). The nonpeptide ET(A)-selective antagonist EMD94246 promoted chronic left ventricular dilatation in rats with large myocardial infarction.