Effect of endothelin blockade on early cardiovascular remodeling in the one-clip-two-kidney hypertension of the rat

Background: In models of hypertension and of renal failure, pharmacological blockade of the ET(A) receptor has been shown to cause some inconsistent lowering of blood pressure (BP) and lesser left ventricular hypertrophy (LVH). The effects of ET(A) receptor blockade (ET(A)-RB) on vascular remodeling and their potential relation to BP lowering, have not been clarified.

Design: The experimental study in male Sprague-Dawley rats was designed to compare four experimental groups: (1) sham-operated controls (sham); (2) untreated rats with one-clip-two-kidney (1C-2K) renovascular hypertension; (3) 1C-2K rats treated with the ACE inhibitor (ACE-i) trandolapril (0.3 mg/kg b.w./day), and (4) 1C-2K rats treated with the ET(A)-RB LU-135252 (50 mg/kg b.w./day). BP was measured weekly by tail plethysmography. After 3 weeks, animals were sacrificed and cardiac, aortic and mesenteric artery morphology was evaluated using morphometric and stereological techniques.

Results: Systolic BP was significantly higher in 1C-2K rats compared to sham. BP was not significantly affected by ET(A)-RB, but was significantly lowered by the ACE-i. Despite no significant change in BP, ET(A)-RB treatment led to a significantly less volume density of the cardiac interstitium (sham 1.40 +/- 0.18, 1C-2K 2.66 +/- 0.56, 1C-2K + ACE-i 1.88 +/- 0.38, 1C-2K + ET(A)-RB 2.15 +/- 0.37%). In contrast, ET(A)-RB had no significant effect on left ventricular/body weight ratio (sham 2.85 +/- 0.26, 1C-2K 2.96 +/- 0.33, 1C-2K + ACE-i 2.54 +/- 0.22 and 1C-2K + ET(A)-RB 3.15 +/- 0.44 mg/g) or on wall thickness of intramyocardial arteries.

Conclusions: The ET(A)-RB LU-135252 ameliorated the development of myocardial fibrosis in a short-term hyperreninemic normal salt model of experimental hypertension nearly as effectively as an ACE-i. This effect of LU-135252 is independent of systemic BP. In contrast to findings in other models, ET(A) receptor blockade had no significant effect on LVH or vascular remodeling. Only the ACE-i but not the ET(A)-RB prevented structural changes of small intramyocardial arteries and of the aorta.