Effect of Endothelin Blockade on Early Cardiovascular Remodeling in the One-Clip-Two-Kidney Hypertension of the Rat

Abstract

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.