Combined Angiotensin and Endothelin Receptor Blockade Attenuates Adverse Cardiac Remodeling Post-Myocardial Infarction in the Rat: Possible Role of Transforming Growth Factor β₁

Myocardial infarction (MI) is associated with activation of the vasoconstrictor peptides, angiotensin II (AngII) and endothelin-1 (ET-1), which are thought to contribute to adverse cardiac remodeling and dysfunction. The present 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 of eight female Sprague-Dawley rats were randomized at 24 h post-LVMI to 1 week treatment with either vehicle, an ET_A/B receptor antagonist (bosentan), an AT₁ receptor antagonist (valsartan), or combined treatment. Vehicle-treated animals developed LV dysfunction with extensive accumulation of collagen type I and increased α₁(I) procollagen mRNA compared to sham controls. Whilst individual receptor blockade with either bosentan or valsartan reduced LVEDP towards sham control levels, there were no significant changes to myocardial collagen deposition in comparison to vehicle. In contrast, improved ventricular function by combined treatment was associated with reduced type I collagen deposition within left ventricular non-infarct regions, as well as reduced peptide distribution and cardiac gene expression of the profibrogenic peptide, transforming growth factor β₁ (TGFβ₁). These data demonstrate that combined AngII and ET receptor blockade has beneficial effects on myocardial fibrogenesis over individual treatments during adverse cardiac remodeling early post-MI.