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1 Merck Sharp & Dohme-Cardiovascular Research Center, 2 Institute for Surgical Research, and 3 Department of Medicine B, Rikshospitalet, University of Oslo, N-0027 Oslo, Norway
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 · day1,
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.
endothelin; hypertrophy; ischemic heart failure
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