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ET-receptor antagonism, myocardial gene expression, and ventricular remodeling during CHF in rats
E Oie1, R Bjønerheim, H K Grogaard
1Merck Sharp & Dohme-Cardiovascular Research Center, Rikshospitalet, University of Oslo, N-0027 Oslo, Norway.
Insights
Endothelin-1 receptor antagonism with bosentan reduced left ventricular dilation in heart failure rats. However, it did not alter the compensatory hypertrophic response, suggesting ET-1 is not crucial for early myocardial hypertrophy in heart failure.
Area of Science:
- Cardiology
- Pharmacology
- Molecular Biology
Background:
- Elevated myocardial and plasma endothelin-1 (ET-1) are observed in congestive heart failure (CHF).
- The specific role of endogenous ET-1 in CHF progression is not fully understood.
Purpose of the Study:
- To investigate myocardial gene expression and left ventricular (LV) remodeling during chronic ET-receptor antagonism in CHF rats.
- To correlate these changes with the effects of ET-receptor blockade.
Main Methods:
- Rats with myocardial infarction underwent treatment with bosentan (ET-receptor antagonist) or vehicle for 15 days.
- Echocardiography, pressure-volume analysis, and gene expression (preproET-1 mRNA) were assessed.
- Histological analysis of cardiomyocyte size and ventricular weight ratios were performed.
Main Results:
- Bosentan attenuated LV dilatation and improved systolic and diastolic pressures and fractional shortening.
- Myocardial preproET-1 mRNA and fetal gene program expression increased in CHF rats, unaffected by bosentan.
- Hypertrophic responses, including cardiomyocyte size and RV/body weight ratio, were sustained, with normalized relative wall thickness.
Conclusions:
- ET-receptor antagonism with bosentan mitigates LV remodeling and improves cardiac function in early post-infarction heart failure.
- ET-1 does not appear to be a critical mediator of myocardial hypertrophy during this phase.
- The study highlights the beneficial effects of bosentan on LV remodeling independent of its impact on hypertrophy mechanisms.
Abstract:
Both myocardial and plasma endothelin-1 (ET-1) are elevated in congestive heart failure (CHF). However, the role played by endogenous ET-1 in the progression of CHF remains unknown. The aim of the present study was to investigate and correlate myocardial gene expression programs and left ventricular (LV) remodeling during chronic ET-receptor antagonism in CHF rats. After ligation of the left coronary artery, rats were randomized to oral treatment with a nonselective ET-receptor antagonist (bosentan, 100 mg . kg-1 . day-1, n = 11) or vehicle (saline, n = 13) for 15 days, starting 24 h after induction of myocardial infarction. Bosentan substantially attenuated LV dilatation during postinfarction failure as evaluated by echocardiography. Furthermore, bosentan decreased LV systolic and end-diastolic pressures and increased fractional shortening. Myocardial expression of preproET-1 mRNA and a fetal gene program characteristic of myocardial hypertrophy were increased in the CHF rats and were not affected by bosentan. Consistently, right ventricular-to-body weight ratios, diameters of cardiomyocytes, and echocardiographic analysis demonstrated a sustained hypertrophic response and a normalized relative wall thickness after intervention with bosentan. Thus the modest reduction of preload and afterload provided by bosentan substantially attenuates LV dilatation, causing improved pressure-volume relationships. However, the compensatory hypertrophic response was not altered by ET-receptor antagonism. Therefore, ET-1 does not appear to play a crucial role in the mechanisms of myocardial hypertrophy during the early phase of postinfarction failure.