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.

Remodelação miocárdica na sobrecarga crônica de pressão ou de volume no coração de ratos

“…Myocardial interstitial fi brosis was observed in the RVH group in accordance with previous results from our laboratory 8 and other researchers 17,18 . This component of cardiac remodeling would be the result of both humoral fi broblast stimulation leading increased collagen synthesis 17,19,20 and cellular necrosis 21 .…”

Treatment with nebivolol combined with physical training promotes improvements in the cardiovascular responses of hypertensive rats

“…Thus, beta-blocker treatment does seem to directly interfere with the amount of connective tissue in the heart, not only by reducing sympathetic activity but also by reducing the release of renin, plasma renin concentration, and thus the expression of cardiac angiotensin II (Varagic et al 2012). The increased myocardial fibrosis observed for the HS group relative to other groups was also observed in other studies that used other models of hypertension (Matsubara et al , 2006Hocher et al 1999;Saam et al 2003). The literature shows that mechanisms involved in cardiac remodeling in hypertensive animals include the stimulation of fibroblasts for collagen synthesis in response to various humoral factors (Challah et al 1995;Nicoletti et al 1996;Hocher et al 1999) and cell necrosis .…”

Disruptions and detours in the myocardial matrix highway and heart failure

“…Increased synthesis and release of endothelin-1 exacerbates LV pump dysfunction in several cardiovascular diseases [74]. Moreover, endothelin-1 exposure can induce changes in fibrillar collagen synthesis and degradation pathways [75,76]. Sampling of the interstitial fluid through the microdialysis technique has demonstrated that compartmentalization of endothelin-1, similar to angiotensin II, occurs in vivo [77].…”