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Master's Dissertation
DOI
10.11606/D.17.2009.tde-30082013-140134
Document
Author
Full name
Carla Speroni Ceron
Institute/School/College
Knowledge Area
Date of Defense
Published
Ribeirão Preto, 2009
Supervisor
Committee
Santos, Jose Eduardo Tanus dos (President)
Bendhack, Lusiane Maria
Nobre, Fernando
Title in Portuguese
Efeitos da espironolactona e da hidroclorotiazida sobre o estresse oxidativo e sobre a metaloproteinase-2 da matriz extracelular na hipertensão renovascular
Keywords in Portuguese
espironolactona
hidroclorotiazida
hipertensão renovascular
metaloproteinases
Abstract in Portuguese
O aumento do estresse oxidativo e da atividade das metaloproteinases contribui para as alterações vasculares estruturais e funcionais presentes na hipertensão renovascular. O objetivo desse trabalho foi verificar se o tratamento com espironolactona, hidroclorotiazida, ou ambas as drogas modificam as alterações presentes no modelo dois-rins, um-clipe de hipertensão renovascular na pressão arterial, incluindo-se remodelamento da aorta, alterações de reatividade vascular, estresse oxidativo e níveis e atividade da metaloproteinase-2 da matriz extracelular (MMP-2). Animais controles operados ou ratos submetidos à estenose da artéria renal foram tratados com o veículo, espironolactona (25 mg.kg-1dia-1), hidroclorotiazida (20 mg.kg-1dia-1), ou a combinação dos dois medicamentos para oito semanas. A pressão arterial sistólica foi monitorada semanalmente por pleitismografia de cauda. Anéis de aorta foram isolados para avaliar o relaxamento vascular dependente e independente do endotélio. A análise morfométrica da parede da aorta foi realizada em coloração de hematoxilina/eosina. Foram avaliados a produção do ânion superóxido na aorta pela -nicotinamida adenina dinucleotídeo fosfato oxidase vascular, a peroxidação lipídica plasmática, medida como substâncias reativas ao ácido tiobarbitúrico, os níveis e atividade de MMP-2 determinados por zimografia em gel e fluorimetria em extrato de aorta, imuno-histoquímica e zimografia situ. O tratamento com espironolactona, hidroclorotiazida, ou a combinação das drogas atenuou a hipertensão arterial, reverteu a disfunção endotelial, atenuou o remodelamento vascular da aorta, assim como o aumento no estresse oxidativo, e reduziu os níveis e a atividade da MMP-2 induzidos pela hipertensão. Estes resultados sugerem que a espironolactona e hidroclorotiazida, isoladamente ou em combinação, produzem efeitos antioxidantes e diminuem o aumento da atividade da MMP-2, melhorando assim a disfunção vascular e remodelamento encontrados nesse modelo de hipertensão renovascular.
Title in English
Effects of spironolactone and hydrochlorothiazide on oxidative stress and the extracellular matrix metalloproteinase-2 levels in the renovascular hypertension.
Keywords in English
hydrochlorothiazide
metalloproteinases
renovascular hypertension
spironolactone
Abstract in English
Increased oxidative stress and upregulation of matrix metalloproteinases may cause structural and functional vascular changes in renovascular hypertension. The aim of this work was to examine whether the treatment with spironolactone, hydrochlorothiazide, or both drugs modify two-kidney,one clip hypertensioninduced changes in arterial blood pressure, aortic remodeling, vascular reactivity, oxidative stress, and MMPs levels/activity. Sham operated or hypertensive rats were treated with vehicle, spironolactone (25 mg.kg-1day-1), hydrochlorothiazide (20 mg.kg-1day-1), or the combination of the two drugs for eight weeks. Systolic blood pressure was monitored weekly by tail-cuff plethysmography. Aortic rings were isolated to assess endothelium dependent and independent relaxations. Morphometry of the aortic wall was carried out in hematoxylin/eosin sections. Aortic nicotinamide adenine dinucleotide phosphate oxidase activity and superoxide production was evaluated. Formation of reactive oxygen species was measured in plasma as thiobarbituric acid reactive substances. Aortic metalloproteinase-2 levels and activity were determined by gelatin and in situ zymography, fluorimetry, and immunohistochemistry. Treatment with spironolactone, hydrochlorothiazide, or the combination attenuated two-kidney, one-clip induced hypertension and reversed the endothelial dysfunction, reversed the vascular aortic remodeling, attenuated hypertension-induced increases in oxidative stress, and reduced metalloproteinase-2 levels/activity induced by hypertension. These findings suggest that spironolactone or hydrochlorothiazide, alone or combined, produce antioxidant effects and decrease renovascular hypertension-induced MMP-2 upregulation, thus improving the vascular dysfunction and remodeling found in this model of hypertension.
 
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Publishing Date
2014-01-30
 
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