Abstract-In deoxycorticosterone acetate (DOCA)-salt hypertension, the endothelin-1 system is activated and plays a role in cardiac fibrosis. Remodeling of extracellular matrix (ECM) may lead to interstitial fibrosis, which may contribute to heart failure. Imbalance in synthesis and degradation of the ECM by matrix metalloproteinases (MMPs) as well as inflammation may play a role in matrix protein deposition and cardiac remodeling in hypertension. We measured expression of the extracellular matrix protein fibronectin, the activity of the gelatinases MMP-2 and MMP-9, the proinflammatory transcription factor NFB, and the adhesion molecules, vascular cell adhesion molecule (VCAM)-1 and platelet-endothelial cell adhesion molecule (PECAM)-1 in hearts of DOCA-salt hypertensive (DS) rats treated or not with the endothelin ET A antagonist BMS 182874 (BMS). Unilaterally nephrectomized rats (UniNx) were compared with DS rats treated or not with BMS 40 mg/kg/d. Fibronectin deposition was detectable at the first week, and remained elevated thereafter. This increase was abrogated by administration of the ET A antagonist. Enzymatic activity of gelatinases was increased (PϽ0.01) in DS compared with control during the first and second week. BMS blocked the increase of MMP-2 and MMP-9 activity at week 1 (PϽ0.05); MMP activity remained lower than in DS at week 2. NF-B binding activity in DS was higher (PϽ0.05) than it was in controls during the second week, and was reduced by BMS. The adhesion molecules VCAM-1 and PECAM-1, and the antiapoptotic molecule xIAP were upregulated in the left ventricle of the heart of DS rats and downregulated in the rats treated with the ET A antagonist. In conclusion, cardiac extracellular remodeling in rats with endothelin-dependent hypertension was associated with increased fibronectin, MMP activity, and upregulation of inflammatory mediators, all of which were reduced by ET A antagonism. A number of studies have demonstrated that there is an endothelin (ET)-dependent component in blood pressure elevation and in vascular, cardiac, and renal complications in mineralocorticoid hypertension, including that in the deoxycorticosterone acetate (DOCA)-salt hypertensive rat. [1][2][3][4][5] We previously showed that collagen deposition was dramatically increased in the left ventricle of DOCA-salt rats. 3 Although development of left ventricular hypertrophy was unaffected by treatment with the ET A -selective endothelin receptor antagonist A-127722, cardiac collagen deposition was significantly reduced. Collagen deposition was associated with increased transforming growth factor (TGF)␤ 1 expression, a well-known profibrotic factor, which was also abrogated by the ET A antagonist. Collagen deposition is not the only mechanism involved in remodeling of the heart in hypertension and under the action of hormones such as ET-1, angiotensin II, and aldosterone. Matrix metalloproteinase (MMP) expression is increased in the heart in experimental animals and in patients with heart failure. 6,7 Indeed, MMPs have a majo...

The present report provides preliminary evidence in favour of a direct action of the hormone on vascular smooth muscle via a specific EpoR.

ET(A) receptor-mediated collagen deposition in hearts of DOCA-salt rats results from increased procollagen synthesis associated with an initial increment in expression of TGF-beta(1). These results support the hypothesis of a role for endothelin-1 in cardiac collagen deposition in mineralocorticoid hypertension, which may have pathophysiological and pharmacological implications in hypertensive heart disease.

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