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Role of phosphodiesterase 5 in cardiovascular pathophysiology in spontaneously hypertensive rats

The aim of this study was to investigate the impact of chronic phosphodiesterase type 5A inhibition (PDE5Ai) by sildenafil in different stages of development in a model of essential hypertension. For this purpose, male spontaneously hypertensive rats (SHRs) were chronically treated with PDE5A inhibi...

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Main Author: SILVA, José Jairo Teixeira da
Other Authors: DUARTE, Glória Isolina Boente Pinto
Format: doctoralThesis
Language: por
Published: Universidade Federal de Pernambuco 2020
Subjects:
Hipertensão
Fosfodiesterase 5
Sildenafil
Online Access: https://repositorio.ufpe.br/handle/123456789/36896
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spelling ir-123456789-368962020-03-10T05:12:01Z Role of phosphodiesterase 5 in cardiovascular pathophysiology in spontaneously hypertensive rats SILVA, José Jairo Teixeira da DUARTE, Glória Isolina Boente Pinto NARO, Fabio http://lattes.cnpq.br/6187868944378162 http://lattes.cnpq.br/8679257801282290 Hipertensão Fosfodiesterase 5 Sildenafil The aim of this study was to investigate the impact of chronic phosphodiesterase type 5A inhibition (PDE5Ai) by sildenafil in different stages of development in a model of essential hypertension. For this purpose, male spontaneously hypertensive rats (SHRs) were chronically treated with PDE5A inhibitor sildenafil (45mg/kg/60days) during the advance of hypertension in young SHRs (pre-hypertensive protocol, 4 until 12 weeks-old rats). The impact of sildenafil treatment on established hypertension in adult SHRs (hypertensive protocol, 16 until 24 weeks-old rats) was also evaluated. In the pre-hypertensive protocol, chronic PDE5Ai promotes a significant increase in acetylcholine-induced relaxation without altering the relaxation evoked by sodium nitroprusside in conductance arteries. By contrast, in the same preparations, it promotes a reduction in contractile response induced by phenylephrine in conductance arteries from SHRs. Sildenafil improvement of vascular function during the development of hypertension since it decreased oxidative stress, a mechanism dependent of cyclooxygenase type 2 (COX-2) and mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK1/2) in aortic tissues. Resting blood pressure, vascular remodeling and the reactivity of resistance arteries were not modified after sildenafil treatment. In hypertensive protocol, chronic inhibition of PDE5A counteracts sympathetic signaling in hearts from SHRs treated with sildenafil, probably by blunting systolic β-adrenergic receptor (β-AR) stimulation in hypertensive hearts. Still, at 6 months of age analysis of cross-sectional area of cardiac myocytes demonstrated a significant reduction of myocytes area in SHR-Sild group compared to the area of cardiomyocytes from untreated rats, suggesting an antihypertrophic effect related to PDE5Ai. Furthermore, chronic sildenafil administration not only contributes with the reduction of left ventricle cardiac reactive oxygen species (ROS) production but also significantly increased of superoxide dismutase activity (SOD), without significant effects on catalase (CAT) activity. In SHRs, sildenafil treatment resulted in downregulation of beta-myosin heavy chain (β-MHC), transforming factor GATA binding protein 4 (GATA4) and nuclear factor of activated T-cells (NFATc3) protein expression which are markers of cardiac hypertrophy, and promotes downregulation of and transforming growth factor β (TGF-β) protein expression, a marker of fibrosis. On the other hand, atrial natriuretic peptide (ANP) protein expression was upregulated in SHR-Sild group suggesting a mechanism related with cardioprotection. Thus, in hypertensive protocol we reported the first direct evidence that sildenafil blunts cardiac contractility and heart rate (HR) after β-adrenergic stimulation in SHR-Sild group, as well as attenuates cardiac oxidative stress and cardiac hypertrophy secondary to hypertension. Both, vascular function improvement and antihypertrophic effect in our model, are involved with the decrease of oxidative stress after sildenafil administration. Taken together, these finds demonstrates a potential role of PDE5Ai as an adjunct therapy in hypertension. CAPES O objetivo desse estudo foi investigar os efeitos da inibição crônica da fosfodiesterase 5 (PDE5Ai) na hipertensão essencial. Para isto, foram utilizados ratos espontaneamente hipertensos (SHRs) cronicamente tratados com sildenafil (45mg/kg/60dias), um inibidor da PDE5A, durante o desenvolvimento da hipertensão em SHRs jovens (protocolo pré-hipertensivo, 4 semanas até 12 semanas de idade). O impacto da inibição crônica da PDE5A também foi avaliado em SHRs adultos, momento no qual a pressão arterial se encontrava bem estabelecida nesse modelo (protocolo hipertensivo, 16 semanas até 22 semanas de idade). Aos 3 meses, o tratamento com sildenafil promoveu um aumento significativo do relaxamento vascular induzido pela acetilcolina, sem alterações significativas no relaxamento vascular induzido pelo nitroprussiato de sódio. Ademais, a PDE5Ai induziu uma redução da resposta contrátil à fenilefrina na aorta do grupo SHR-Sild. O tratamento crônico com sildenafil resultou em melhora da função vascular durante o desenvolvimento da hipertensão, uma vez que reduziu o estresse oxidativo tecidual, por modular a via da ciclooxigenase do tipo 2 e modular a ativação de proteínas quinases reguladas por mitógeno (MAP)/quinases reguladas por sinal extracelular (ERK1/2) na aorta. Pressão arterial, frequência cardíaca, remodelamento vascular e reatividade de vasos de resistência não foram modificados pelo tratamento com o sildenafil. Aos 6 meses de idade, no protocolo hipertensivo, a PDE5Ai atenuou a resposta à estimulação simpática no coração de animais tratados com sildenafil quando comparados com os animais não tratados. A área de secção transversa dos cardiomiócitos dos animais do grupo SHR-Sild foi reduzida quando comparada aos animais tratados com o veículo, sugerindo um efeito anti-hipertrófico associado a inibição da PDE5A. O tratamento não apenas atenuou a hipertrofia ventricular esquerda, mas também contribuiu com a redução da produção cardíaca de espécies reativas de oxigênio, e promoveu aumento significativo da atividade da superóxido dismutase, sem alterações na atividade da catalase. Neste protocolo experimental, a PDE5Ai resultou em menor expressão proteica da miosina de cadeia pesada (β-MHC), do fator de transcrição GATA4 e do fator nuclear de células T ativadas (NFATc3), marcadores clássicos de hipertrofia cardíaca. Além disso, promoveu diminuição da expressão proteica do fator transformador de crescimento beta (TGF-β), o qual é diretamente relacionado a fibrose tecidual. Foi observado um aumento significativo da expressão proteica do peptídeo natriurético atrial (ANP) no tecido cardíaco, o qual foi associado a cardioproteção. Em ambos os protocolos experimentais, a melhora da função vascular e os efeitos anti-hipertróficos associados a inibição da PDE5A pelo sildenafil estão relacionados com a diminuição do estresse oxidativo tecidual, o que demonstra uma nova possibilidade terapêutica na utilização do sildenafil no tratamento da hipertensão arterial. 2020-03-09T19:46:21Z 2020-03-09T19:46:21Z 2019-12-18 doctoralThesis SILVA, José Jairo Teixeira da. Role of phosphodiesterase 5 in cardiovascular pathophysiology in spontaneously hypertensive rats. 2019. Tese (Doutorado em Bioquímica e fisiologia) – Universidade Federal de Pernambuco, Recife, 2019. https://repositorio.ufpe.br/handle/123456789/36896 por embargoedAccess Attribution-NonCommercial-NoDerivs 3.0 Brazil http://creativecommons.org/licenses/by-nc-nd/3.0/br/ application/pdf Universidade Federal de Pernambuco UFPE Brasil Programa de Pos Graduacao em Bioquimica e Fisiologia
institution REPOSITORIO UFPE
collection REPOSITORIO UFPE
language por
topic Hipertensão
Fosfodiesterase 5
Sildenafil
spellingShingle Hipertensão
Fosfodiesterase 5
Sildenafil
SILVA, José Jairo Teixeira da
Role of phosphodiesterase 5 in cardiovascular pathophysiology in spontaneously hypertensive rats
description The aim of this study was to investigate the impact of chronic phosphodiesterase type 5A inhibition (PDE5Ai) by sildenafil in different stages of development in a model of essential hypertension. For this purpose, male spontaneously hypertensive rats (SHRs) were chronically treated with PDE5A inhibitor sildenafil (45mg/kg/60days) during the advance of hypertension in young SHRs (pre-hypertensive protocol, 4 until 12 weeks-old rats). The impact of sildenafil treatment on established hypertension in adult SHRs (hypertensive protocol, 16 until 24 weeks-old rats) was also evaluated. In the pre-hypertensive protocol, chronic PDE5Ai promotes a significant increase in acetylcholine-induced relaxation without altering the relaxation evoked by sodium nitroprusside in conductance arteries. By contrast, in the same preparations, it promotes a reduction in contractile response induced by phenylephrine in conductance arteries from SHRs. Sildenafil improvement of vascular function during the development of hypertension since it decreased oxidative stress, a mechanism dependent of cyclooxygenase type 2 (COX-2) and mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK1/2) in aortic tissues. Resting blood pressure, vascular remodeling and the reactivity of resistance arteries were not modified after sildenafil treatment. In hypertensive protocol, chronic inhibition of PDE5A counteracts sympathetic signaling in hearts from SHRs treated with sildenafil, probably by blunting systolic β-adrenergic receptor (β-AR) stimulation in hypertensive hearts. Still, at 6 months of age analysis of cross-sectional area of cardiac myocytes demonstrated a significant reduction of myocytes area in SHR-Sild group compared to the area of cardiomyocytes from untreated rats, suggesting an antihypertrophic effect related to PDE5Ai. Furthermore, chronic sildenafil administration not only contributes with the reduction of left ventricle cardiac reactive oxygen species (ROS) production but also significantly increased of superoxide dismutase activity (SOD), without significant effects on catalase (CAT) activity. In SHRs, sildenafil treatment resulted in downregulation of beta-myosin heavy chain (β-MHC), transforming factor GATA binding protein 4 (GATA4) and nuclear factor of activated T-cells (NFATc3) protein expression which are markers of cardiac hypertrophy, and promotes downregulation of and transforming growth factor β (TGF-β) protein expression, a marker of fibrosis. On the other hand, atrial natriuretic peptide (ANP) protein expression was upregulated in SHR-Sild group suggesting a mechanism related with cardioprotection. Thus, in hypertensive protocol we reported the first direct evidence that sildenafil blunts cardiac contractility and heart rate (HR) after β-adrenergic stimulation in SHR-Sild group, as well as attenuates cardiac oxidative stress and cardiac hypertrophy secondary to hypertension. Both, vascular function improvement and antihypertrophic effect in our model, are involved with the decrease of oxidative stress after sildenafil administration. Taken together, these finds demonstrates a potential role of PDE5Ai as an adjunct therapy in hypertension.
author2 DUARTE, Glória Isolina Boente Pinto
format doctoralThesis
author SILVA, José Jairo Teixeira da
author_sort SILVA, José Jairo Teixeira da
title Role of phosphodiesterase 5 in cardiovascular pathophysiology in spontaneously hypertensive rats
title_short Role of phosphodiesterase 5 in cardiovascular pathophysiology in spontaneously hypertensive rats
title_full Role of phosphodiesterase 5 in cardiovascular pathophysiology in spontaneously hypertensive rats
title_fullStr Role of phosphodiesterase 5 in cardiovascular pathophysiology in spontaneously hypertensive rats
title_full_unstemmed Role of phosphodiesterase 5 in cardiovascular pathophysiology in spontaneously hypertensive rats
title_sort role of phosphodiesterase 5 in cardiovascular pathophysiology in spontaneously hypertensive rats
publisher Universidade Federal de Pernambuco
publishDate 2020
url https://repositorio.ufpe.br/handle/123456789/36896
_version_ 1661517328806838272
score 13.657419

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