Combined effects of AT(1) and ETA receptor antagonists, candesartan, and A-127722 in DOCA-salt hypertensive rats

Several recent studies have provided evidence that many of the hemodynamic and mitogenic actions of angiotensin II (Ang II) are mediated by endothelin -1 (ET-1). We hypothesized that Ang II and ET-1 act synergistically to prom ote a decline in renal function and the development of renal fibrosis in th e deoxycorticosterone acetate (DOCA)-salt model of malignant hypertension a nd renal dysfunction. Experiments were conducted to determine the effects o f ETA receptor antagonism (A-127722) and AT(1) receptor antagonism (candesa rtan cilexetil) on the development of renal fibrosis and the decline of ren al function. Surgery was conducted on male, Sprague-Dawley rats to remove t he right kidney and implant subcutaneously a time-release pellet containing DOCA. DOCA-treated rats were also given 0.9% NaCl to drink. After recovery from surgery, rats received one of four treatments via the drinking soluti on: (1) candesartan cilexetil (10 mg/kg/day), (2) A-127722 (10 mg/kg/day), (3) candesartan cilexetil plus A-127722, or (4) untreated controls. Over th e course of a 3-week treatment period, systolic arterial pressure in all gr oups were elevated. However, this increase was significantly attenuated in the group given combined A-127722 and candesartan, but not with candesartan alone. Creatinine clearance, used as a measure of GFR, was significantly h igher in rats treated with either or both drugs. Ar the end of the study, r enal medullary tissue was harvested for determination of TGF-beta and fibro nectin content (ELISA). TGF-beta levels were not reduced by either ETA AT(1 ), or combined ETA and AT(1) receptor blockade. Likewise, fibronectin conte nt was similar among groups. These studies indicate that combined ETA and A T(1) receptor blockade may produce some improvement on hemodynamics, but ha ve no effect on progression of renal damage in this non-renin-dependent mod el of hypertension. (C) 2001 Elsevier Science Inc. All rights reserved.