Combined angiotensin and endothelin receptor blockade attenuates adverse cardiac remodeling post-myocardial infarction in the rat: Possible role of transforming growth factor beta(1)

Myocardial infarction (MI) is associated with activation of the vasoconstri ctor peptides, angiotensin II (AngII) and endothelin (ET-1). Which are thou ght to contribute to adverse cardiac remodeling and dysfunction. The presen t study sought to determine whether combined AngII and ET receptor blockade improves cardiac remodeling over individual treatments in an experimental model of left ventricular myocardial infarction (LVMI) in the rat. Groups o f eight female Sprague-Dawley rats were randomized at 24 h post-LVMI to 1 w eek treatment with either vehicle. an ETA,B receptor antagonist (bosentan). an AT(1) receptor antagonist (valsartan). or combined treatment. vehicle-t reated animals developed LV dysfunction with extensive accumulation of coll agen type I and increased alpha (1)(I) procollagen mRNA compared to sham co ntrols. Whilst individual receptor blockade with either bosentan or valsart an reduced LVEUP towards sham control levels, there were no significant cha nges to myocardial collagen deposition in comparison to vehicle. In contras t. improved ventricular function by combined treatment was associated with reduced type I collagen deposition within left ventricular non-infarct regi ons, as well as reduced peptide distribution and cardiac gene expression of the profibrogenic peptide, transforming growth factor B, (TGF beta (1)). T hese data demonstrate that combined AngII and ET receptor blockade has bene ficial effects on myocardial fibrogenesis or er individual treatments durin g adverse cardiac remodeling early post-MI. (C) 2001 Academic Press.