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Beneficial Morphofunctional Changes Promoted by Sildenafil in Resistance Vessels in the Angiotensin II-Induced Hypertension Model

[ Vol. 19 , Issue. 6 ]

Author(s):

Ananda T. Dias, Marcos A. S. Leal, Tadeu C. Zanardo, Gisele M. Alves, Marcella L. Porto, Breno V. Nogueira, Agata L. Gava, Bianca P. Campagnaro, Thiago M. C. Pereira, Silvana S. Meyrelles, Manuel Campos-Toimil and Elisardo C. Vasquez*   Pages 483 - 494 ( 12 )

Abstract:


Background: By acting on multiple targets and promoting diverse actions, angiotensin II (Ang II) plays a pivotal role in vascular function. Recent studies suggested that phosphodiesterase-5 (PDE-5) inhibitors exhibit therapeutic effects in cardiovascular diseases. Here, the effects of sildenafil on vascular disturbances were analyzed in a mouse model of Ang II-induced hypertension.

Methods and Results: Male C57BL/6 mice were used as untreated animals (control) or infused with Ang II (1000 ηg/kg/min) for 28 days and treated with sildenafil (40 mg/kg/min) or vehicle (Ang II) during the last two weeks. After 4 weeks, the Ang II animals exhibited a high systolic blood pressure (186±3 mmHg vs. 127±3 mmHg for control mice), which was attenuated by sildenafil (163±7 mmHg). The mesenteric vessels from the Ang II animals revealed damage to the endothelial layer, an increase in the cross-section area (1.9-fold) and vascular cell production of peroxynitrite (512±13 a.u.), which was ameliorated in the Ang II-Sil group (1.2-fold and 400±17 a.u.). Analysis of the vascular responsiveness showed an increased contractility response to norepinephrine in Ang II animals (Rmax: 70%), which was abolished by sildenafil through increased nitric oxide (NO) bioavailability and decreased reactive oxygen species (ROS) and vasoconstrictor prostanoids.

Conclusion: Sildenafil attenuates the morphofunctional deleterious effects of Ang II on resistance vessels. The benefits of sildenafil seem to occur through restoring the balance of ROS/NO/eicosanoids. Therefore, this study opened new avenues for further clinical targeting of the treatment of cardiovascular diseases related to activation of the renin-angiotensin system.

Keywords:

Angiotensin, sildenafil, phosphodiesterase, ROS, nitric oxide, NADPH oxidase.

Affiliation:

Laboratory of Translational Physiology, Health Sciences Center, Federal University of Espirito Santo, Vitoria, Laboratory of Translational Physiology, Health Sciences Center, Federal University of Espirito Santo, Vitoria, Dept. Morphological Sciences, Health Sciences Center, Federal University of Espirito Santo, Vitoria, ES, Pharmaceutical Sciences Graduate Program, Vila Velha University, Vila Velha, ES, Federal Institute of Education, Science and Technology, Vila Velha, ES, Dept. Morphological Sciences, Health Sciences Center, Federal University of Espirito Santo, Vitoria, ES, Laboratory of Translational Physiology, Health Sciences Center, Federal University of Espirito Santo, Vitoria, Pharmaceutical Sciences Graduate Program, Vila Velha University, Vila Velha, ES, Pharmaceutical Sciences Graduate Program, Vila Velha University, Vila Velha, ES, Laboratory of Translational Physiology, Health Sciences Center, Federal University of Espirito Santo, Vitoria, Group of Research in Pharmacology of Chronic Diseases (CDPHARMA), Center for Research in Molecular[EV1] Medicine and Chronic Diseases (CIMUS), University of Santiago de Compostela, 15782, Santiago de Compostela, Laboratory of Translational Physiology, Health Sciences Center, Federal University of Espirito Santo, Vitoria



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