Abstract
Angiotensin II is a key player in the pathogenesis of renovascular hypertension, a condition associated with endothelial dysfunction. We investigated aliskiren (ALSK) and L-arginine treatment both alone and in combination on blood pressure (BP), and vascular reactivity in aortic rings. Hypertension was induced in 40 male Wistar rats by clipping the left renal artery. Animals were divided into Sham, 2-kidney, 1-clip (2K1C) hypertension, 2K1C+ALSK (ALSK), 2K1C+L-arginine (L-arg), and 2K1C+ALSK+L-arginine (ALSK+L-arg) treatment groups. For 4 weeks, BP was monitored and endothelium-dependent and independent vasoconstriction and relaxation were assessed in aortic rings. ALSK+L-arg reduced BP and the contractile response to phenylephrine and improved acetylcholine relaxation. Endothelium removal and incubation with N-nitro-L-arginine methyl ester (L-NAME) increased the response to phenylephrine in all groups, but the effect was greater in the ALSK+L-arg group. Losartan reduced the contractile response in all groups, apocynin reduced the contractile response in the 2K1C, ALSK and ALSK+L-arg groups, and incubation with superoxide dismutase reduced the phenylephrine response in the 2K1C and ALSK groups. eNOS expression increased in the 2K1C and L-arg groups, and iNOS was increased significantly only in the 2K1C group compared with other groups. AT1 expression increased in the 2K1C compared with the Sham, ALSK and ALSK+L-arg groups, AT2 expression increased in the ALSK+L-arg group compared with the Sham and L-arg groups, and gp91phox decreased in the ALSK+L-arg group compared with the 2K1C and ALSK groups. In conclusion, combined ALSK+L-arg was effective in reducing BP and preventing endothelial dysfunction in aortic rings of 2K1C hypertensive rats. The responsible mechanisms appear to be related to the modulation of the local renin-angiotensin system, which is associated with a reduction in endothelial oxidative stress.
Highlights
Hypertension is manifested by increased arterial pressure and by complex structural and functional alterations of its target organs
Losartan reduced the contractile response in all groups, apocynin reduced the contractile response in the 2K1C, ALSK and ALSK+L-arg groups, and incubation with superoxide dismutase reduced the phenylephrine response in the 2K1C and ALSK groups. endothelial nitric oxide synthase (eNOS) expression increased in the 2K1C and L-arg groups, and inducible nitric oxide synthase (iNOS) was increased significantly only in the 2K1C group compared with other groups
The present study demonstrated the effects of a 21-day treatment with ALSK and L-arginine, alone or in combination, on blood pressure and vascular reactivity to phenylephrine in rats with renovascular hypertension
Summary
Hypertension is manifested by increased arterial pressure and by complex structural and functional alterations of its target organs. Long-term hypertension often results in left ventricular hypertrophy, which is considered a risk factor for coronary heart disease [1], and causes structural alterations of the vascular wall characterized by endothelial dysfunction, extracellular matrix deposition, medial layer thickening due to hypertrophy/hyperplasia, and migration of vascular smooth muscle cells (VSMCs) [2]. Kidney ischemia results in an increase of plasma renin activity and the consequent increase in angiotensinogen concentration leads to a persistent rise in blood pressure [2,3]. This hypertension model is associated with increased angiotensin II levels, and this peptide produces mitogenic effects, which are critically involved in the development of the structural and functional vascular changes caused by hypertension [4]. Previous studies have reported that angiotensin II stimulates the production of ROS such as superoxide through the activation of membrane-bound nicotinamide adenine dinucleotide www.bjournal.com.br (NADH) or nicotinamide adenine dinucleotide phosphate (NADPH) oxidase [6]
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Schedule a callMore From: Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas
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