Summary

Heart failure is a critical clinical state, which is a consequence of progressive cardiac impairment. The deterioration of the cardiac function is a result of different mechanisms including humoral activation. Among these activated systems, the endothelins (ET) and hormones from renin-angiotensin-aldosterone system (RAAS), as the case for angiotensin II (AngII) and aldosterone (Aldo), have an important role in the ventricular remodeling. Moreover, either effector hormone of the RAAS evokes increased expression of ET by cultured fibroblasts and chronic RAAS activation is associated with elevated circulating ET. To address the relative importance of ET in evoking ventricular fibrosis in hyperaldosterone states this study was undertaken. This included: uninephrectomized rats on high salt diet receiving Aldo (0.75mg/h) by subcutaneous osmotic minipump for 6 wks; and intact rats receiving AngII (75 ng/min) by minipump for 2 wks. Subgroups of each model were treated with bosentan (Bos), a combined ETA and ETB receptor antagonist. Each were compared to age/sex matched untreated controls. Collagen accumulation within perivascular space of intramyocardial coronary arteries and contiguous interstitial space (reactive fibrosis), and the number of microscopic scars (reparative fibrosis) were identified by videomorphometry while total ventricular fibrosis was assessed by hydroxyproline concentration. Compared with untreated controls: a) rats receiving AngII or Aldo were found to have morphologic evidence of augmented perivascular/interstitial collagen accumulation and scarring of both right and left ventricles (p<0.05) and increased (p<0.0001) hydroxyproline concentration; b) in response to co-administration of Bos the animals had attenuated reactive fibrosis (p<0.05); however, the number of scars and increased hydroxyproline concentration were not altered compared to either treatment group. Thus, in these rat models of primary and secondary hyperaldosteronism the RAAS has been confirmed as an important agent in promoting ventricular remodeling. It was also demonstrated the ET contribution to the development of perivascular/interstitial fibrosis of the right and left ventricles. In this scenario the cardioprotective effects of Bos was demonstrated.