trandolapril and Hypertension--Renovascular

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.. 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.. 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.. 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.

Topics: Animals; Aorta; Blood Pressure; Coronary Vessels; Endomyocardial Fibrosis; Endothelin A Receptor Antagonists; Hypertension, Renovascular; Hypertrophy, Left Ventricular; Indoles; Male; Mesenteric Arteries; Phenylpropionates; Pyrimidines; Rats; Rats, Sprague-Dawley

A chymase-dependent angiotensin II-forming pathway is present in human vascular tissues; however, the role, if it plays any, of chymase in the pathogenesis of hypertension is not known. When investigating the role of chymase, it is important to recognize marked differences in vascular angiotensin II-forming systems among species. We found recently that hamsters, like humans, possess the dual angiotensin II-forming system.. To analyze the potential involvement of angiotensin converting enzyme and chymase in the pathogenesis of hypertension, and to further characterize the efficiency of angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists for the treatment of hypertension.. The mean arterial pressure in the two-kidney, one clip hamster model had increased significantly 2 weeks after clipping (acute stage), reached a peak after 4 weeks, and was sustained at the high level until 32 weeks after clipping (chronic stage). Plasma renin activity increased markedly during the acute stage, but returned to the normal level during the chronic stage. Vascular angiotensin converting enzyme activity during 4-32 weeks after clipping was significantly higher than that in the control hamsters. By contrast, vascular chymase was not activated throughout the experimental period. Administrations of an angiotensin converting enzyme inhibitor, trandolapril, and an angiotensin II receptor antagonist, CV-11974, equally lowered the mean arterial pressure during the acute and chronic stages.. Vascular angiotensin converting enzyme plays a predominant role in the maintenance of two-kidney, one clip hypertension in hamsters, which, like humans, possess a dual system of formation of angiotensin II. Vascular chymase was not involved in the pathogenesis of two-kidney, one clip hypertension in the hamster.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Aorta; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Chymases; Cricetinae; Humans; Hypertension, Renovascular; Indoles; Male; Peptidyl-Dipeptidase A; Renin; Serine Endopeptidases; Tetrazoles

The effects of the angiotensin-converting enzyme inhibitor trandolapril were studied using a Goldblatt (two-kidney, one-clip) rat model of renovascular hypertension after 4 weeks of oral treatment at 0.3 or 1 mg/kg/day. The effects of trandolapril on blood pressure and on cardiac and vascular hypertrophy were analyzed in comparison with the control group. Trandolapril produced a rapid, dose-dependent decrease in blood pressure, which plateaued after 2 weeks of treatment. Complete normalization of blood pressure was observed at a daily dose of 1 mg/kg. Dose-dependent inhibition of cardiac hypertrophy was also observed, heart:body weight ratio being decreased by 17 and 30% at 0.3 and 1 mg/kg, respectively, leading to a normalization of this parameter at the higher dose compared with normotensive controls. Similarly, trandolapril produced a marked decrease in vascular wall hypertrophy in both the mesenteric artery and the aorta. Indeed, complete normalization of media thickness was observed, compared with the normotensive control group, at 1 mg/kg of trandolapril. These results show that short-term treatment with trandolapril can induce complete regression of cardiac and vascular hypertrophy, which is associated with the development of renal hypertension.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Vessels; Cardiomegaly; Hypertension, Renovascular; Hypertrophy; Indoles; Male; Rats; Rats, Wistar