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...
| Main Author: | SILVA, José Jairo Teixeira da |
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| Other Authors: | DUARTE, Glória Isolina Boente Pinto |
| Format: | doctoralThesis |
| Language: | por |
| Published: |
Universidade Federal de Pernambuco
2020
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| Subjects: | |
| Online Access: |
https://repositorio.ufpe.br/handle/123456789/36896 |
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| Summary: |
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. |
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