ET-RECEPTOR ANTAGONISM, MYOCARDIAL GENE-EXPRESSION, AND VENTRICULAR REMODELING DURING CHF IN RATS

Both myocardial and plasma endothelin-1 (ET-1) are elevated in congest ive heart failure (CHF). However, the role played by endogenous ET-1 i n 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 antago nism in CHF rats. After ligation of the left coronary artery, rats wer e randomized to oral treatment with a nonselective ET-receptor antagon ist (bosentan, 100 mg.kg(-1).day(-1), n = 11) or vehicle (saline, n = 13) for 15 days, starting 24 h after induction of myocardial infarctio n. Bosentan substantially attenuated LV dilatation during postinfarcti on failure as evaluated by echocardiography. Furthermore, bosentan dec reased LV systolic and end-diastolic pressures and increased fractiona l shortening. Myocardial expression of preproET-1 mRNA and a fetal gen e program characteristic of myocardial hypertrophy were increased in t he CHF rats and were not affected by bosentan. Consistently, right ven tricular-to-body weight ratios, diameters of cardiomyocytes, and echoc ardiographic analysis demonstrated a sustained hypertrophic response a nd a normalized relative wall thickness after intervention with bosent an. Thus the modest reduction of preload and afterload provided by bos entan substantially attenuates LV dilatation, causing improved pressur e-volume relationships. However, the compensatory hypertrophic respons e was not altered by ET-receptor antagonism. Therefore, ET-1 does not appear to play a crucial role in the mechanisms of myocardial hypertro phy during the early phase of postinfarction failure.