ET-receptor antagonism, myocardial gene expression, and ventricular remodeling during CHF in rats.
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.
Oie
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Merck Sharp & Dohme-Cardiovascular Research Center, Rikshospitalet, University of Oslo, N-0027 Oslo, Norway.
Bjønerheim
R
R
Grogaard
H K
HK
Kongshaug
H
H
Smiseth
O A
OA
Attramadal
H
H
D000808:Angiotensinogen / Q000235:genetics; D000818:Animals; D000077300:Bosentan; D003331:Coronary Vessels / Q000601:surgery; D065128:Endothelin Receptor Antagonists; D015870:Gene Expression / Q000187:drug effects; D006333:Heart Failure / Q000503:physiopathology*; D017379:Hypertrophy, Left Ventricular / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D008026:Ligation; D008297:Male; D009203:Myocardial Infarction / Q000150:complications / Q000473:pathology; D009206:Myocardium / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin / Q000235:genetics*; D013449:Sulfonamides / Q000494:pharmacology; D016277:Ventricular Function, Left / Q000187:drug effects
D065128:Endothelin Receptor Antagonists; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin; D013449:Sulfonamides; D000808:Angiotensinogen; D000077300:Bosentan