Chronic treatment with nebivolol attenuates large arteries hypertrophy in renovascular hypertension 2-kidneys 1-clip.

Author(s)

Carla Speroni Ceron

• Document type: Doctoral Thesis
• Press: Ribeirão Preto.
• Institution: Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC)
• Defense date: 2012-11-21

Examining board members

Jose Eduardo Tanus dos Santos; Wilson Nadruz Junior; Andre Schmidt; Cristina Antoniali Silva; Carlos Renato Tirapelli

• Advisor: Jose Eduardo Tanus dos Santos

Abstract

Hypertension is a serious clinical condition with structural changes in the cardiovascular system. Beta-adrenoreceptor antagonists are used in hypertension therapy. Nebivolol is a third-generation selective 1-adrenoreceptor antagonist that stimulates endothelial cell NO production and prevents vascular NAD(P)H oxidase activation. Metoprolol is a second-generation selective 1-adrenoreceptor antagonist, without vasodilatory effect. The matrix metalloproteinases (MMPs), especially MMP-2, participate actively in the vascular remodeling process, and are activated by reactive oxygen species (ROS). There are increases in ROS, of MMPs, and vascular remodeling in hypertension. Because of these, it´s possible that nebivolol prevent MMP increases and vascular remodeling associated with hypertension beyond its 1-receptorblocking properties. First, structural aortic changes in the development of two-kidney, one-clip hypertension (2K-1C) were evaluated. Sham or 2K1C hypertensive rats were studied after 2, 4, 6, and 10 weeks of hypertension. Systolic blood pressure (SBP) was monitored weekly. Morphometry of structural changes in the aortic wall was studied in hematoxylin/eosin, orcein and picrosirius red sections. Aortic NAD(P)H activity and superoxide production was evaluated. Aortic gelatinolytic activity was determined by in situ zymography, and MMP-2, MMP-14, and tissue inhibitor of MMPs (TIMP)-2 levels were determined by gelatin zymography, immunofluorescence and immunohistochemistry. Six weeks after surgery, hypertensive and sham rats were treated with metoprolol (20 mg/kg/ day) or nebivolol (10 mg/kg/day), for four weeks, in the second-protocol. Systolic blood pressure (SBP) was monitored weekly Aortic structural were studied in hematoxylin/eosin sections. NAD(P)H oxidase activity and ROS and nitrotyrosine production were evaluated. MMPs levels and activity were determined by zymography and in situ zymography. In the temporal study, 2K-1C hypertension was associated with increased aortic collagen and elastin content in the early phase of hypertension, which was associated with vascular hypertrophy, increased vascular MMPs levels, and increased gelatinolytic activity, possibly as a result of increased vascular NAD(P)H oxidase activity and oxidative stress. In the second-protocol, similar reductions in SBP were found with both metoprolol and nebivolol treatments. However, only Nebi reversed aortic hypertrophy, the increases in aortic NAD(P)H oxidase activity, in aortic ROS levels, in nitrotyrosine staining, in aortic MMP-2 levels and in aortic MMP activity. These results indicate that vascular remodeling of renovascular hypertension is an early process associated with increases in MMPs activities, enhanced matrix deposition and oxidative stress, and that treatment with Nebi attenuate the oxidative stress and the vascular remodeling associated with 2K-1C hypertension. (AU)

• FAPESP's process: 09/15663-0 - Effect of different beta-blockers in the vascular alterations of renovascular hypertension
• Grantee: Carla Speroni Ceron
• Support Opportunities: Scholarships in Brazil - Doctorate