Avaliação dos efeitos do tratamento com sildenafil na hipertensão induzida por infusão de angiotensina II
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Data
2018-11-09
Autores
Moreira, Ananda Tissianel Dias
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Universidade Federal do Espírito Santo
Resumo
Angiotensin II (Ang II) is responsible for multiple actions in the organism, being considered an effector peptide of several of physiological and physiopathological actions in the Renin-Angiotensin-Aldosterone (RAA) system. This endogenous peptide shows an important role in development of arterial hypertension (AH), since it is capable to promote deleterious effects target organs of AH, such as morphofunctional changes in arteries and heart. This study aimed to test the hypothesis that an inhibitor of phosphodiesterase 5 (PDE5), sildenafil, can reducing the damage caused by the increase of Ang II. Therefore, we evaluated the effects of the treatment on blood pressure (BP), cardiac hypertrophy, Ang II plasma levels, morphofunctional changes of the arteries of conductance and resistance, and the systemic and vascular cells oxidative stress. Male mice wild-type C57BL/6 were divided into the following groups: Normotensive (control) and hypertensive animals. Mice were induced to hypertension by Ang II infusion (1000 ng/kg/min, for 4 Weeks). Thereafter, we treated the groups with Sildenafil (40 mg/kg/day) or water for the last two weeks. Temporal analysis of systolic BP (SBP) was performed throughout the experimental period (prior to infusion and 7, 14, 21 and 28 days after the infusion of Ang II). At the end of the treatment the animals were anesthetized and the blood was collected for the plasma quantification of Ang II and the heart was removed to verify the cardiac hypertrophy. Mesenteric arterial bed (MAB) and thoracic aorta were removed for analyses of vascular function, morphology and oxidative stress. We found that, after 4 weeks, the hypertensive animals showed an increase of SBP (186 ± 3 mmHg), of plasma levels of Ang II (53 ± 2.4 pg/mL) and the index of cardiac hypertrophy (0.09 ± 0.003 mg/mm). The treatment with sildenafil was able to reduce the SBP in 23 mmHg and the Ang II plasma levels and cardiac hypertrophy showed a decreasing of 30% and 32%, respectively. Vascular function analyses revealed an increased contractile response in hypertensive animals (Rmax: 70%) in both vessels of the study, presenting reactivity norepinephrine in MAB and phenylephrine in aortic rings. The treatment with sildenafil was capable to restore the endothelial function, reducing the reactivity to sympathomimetics drugs. Part of these effects are mainly caused by the increasing the nitric oxide (NO) and the decreasing of reactive oxygen species (ROS) and prostanoids vasoconstrictors. In addition to the morphofunctional changes, Ang II induced the vascular hypertrophy and promoted alteration in the endothelial surface. Treatment with sildenafil promoted 12 important morphological changes, such as reduction of the cross-sectional area and a restructuring of the endothelial cells. Superoxide anion, peroxynitrite and hydroxyl radical analyses revealed that Ang II increase in these ROS and the treatment with sildenafil was able to reduce oxidative stress. Taken together, our results demonstrate that sildenafil decreased the deleterious effects of Ang II on the resistance and conductance vessels, mainly by promoting a balance between ROS/NO/Prostanoids vasoconstrictors and vasodilators. This study represents an advance in the beneficial effects of sildenafil. The data present herein may be useful for new clinical studies for cardiovascular diseases treatment associated with intense activation of RAA system and for the hypertension resistant treatment.
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Palavras-chave
Hypertension , Angiotensin II , Endothelial dysfunction , Sildenafil , Oxidative stress , Hipertensão , Angiotensina II , Disfunção endotelial , Sildenafil e estresse oxidativo
Citação
MOREIRA, Tissianel Dias.
Avaliação dos efeitos do tratamento do coldenafil na hipertensão induzida por infusão de angiotensina II.2018.Tese (Doutorado em Ciências Fisiológicas) - Universidade Federal do Espírito Santo, Centro de Ciências da Saúde, Vitória, 2018.