Current Pharmaceutical Biotechnology                 Send Orders for Reprints to reprints@benthamscience.ae Current Pharmaceutical Biotechnology, 2018, 19, 483-494 483 RESEARCH ARTICLE Beneficial Morphofunctional Changes Promoted by Sildenafil in Resis- tance Vessels in the Angiotensin II-Induced Hypertension Model Ananda T. Dias 1 , Marcos A.S. Leal 1 , Tadeu C. Zanardo 2 , Gisele M. Alves 3 , Marcella L. Porto 4 , Breno V. Nogueira 2 , Agata L. Gava 1 , Bianca P. Campagnaro 3 , Thiago M.C. Pereira 3,4 , Silvana S. Meyrelles 1 , Manuel Campos-Toimil 5 and Elisardo C. Vasquez 1,3* 1 Laboratory of Translational Physiology, Health Sciences Center, Federal University of Espirito Santo, Vitoria, Brazil; 2 Departm Morphological Sciences, Health Sciences Center, Federal University of Espirito Santo, Vitoria, ES, Brazil; 3 Pharmaceutical Sciences Graduate Program, Vila Velha University, Vila Velha, ES, Brazil; 4 Federal Institute of Edu- cation, Science and Technology, Vila Velha, ES, Brazil; 5 Group of Research in Pharmacology of Chronic Diseases (CDPHARMA), Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), University of Santiago de Compostela, 15782, Santiago de Compostela, Spain A R T I C L E H I S T O R Y Received: April 20, 2018 Revised: June 12, 2018 Accepted: June 18, 2018 DOI: 10.2174/1389201019666180625094704 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 respon- siveness 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 ves- sels. 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 cardiovascu- lar diseases related to activation of the renin-angiotensin system. Keywords: Angiotensin, sildenafil, phosphodiesterase, ROS, nitric oxide, NADPH oxidase. 1. INTRODUCTION The number of people suffering from arterial hyperten- sion has grown markedly and currently encompasses ap- proximately 50% of the elderly population [1]. This pathol- ogy is a major risk factor for and a key driver of cardiovas- cular disease (CVD) and is a leading cause of preventable deaths in developed nations worldwide [2]. If this condition continues, the annual number of deaths from CVD which *Address correspondence to this author at the Pharmaceutical Sciences Graduate Program, Vila Velha University (UVV), Av Comissario Jose Dantas de Melo 21, Boa Vista, CEP 29102-920, Vila Velha City, ES, Brazil; Tel: 55-27-3421-2001; E-mail: evasquez@terra.com.br reached 17.5 million in 2012, is estimated to reach 22.2 mil- lion by 2030 [3]. Current knowledge highlights the importance of the mul- titarget angiotensin II (Ang II) peptide in the development and progression of hypertension [4-6]. It is well known that sustained activation of the renin-Ang II system results in exaggerated vasoconstriction [7], vascular smooth muscle cell proliferation [8, 9], cardiac and vascular hypertrophy [10, 11], inflammation and extracellular matrix degradation, and exacerbates the neural sympathetic activity of the heart and resistance vessels [4, 12]. Moreover, Ang II worsens the reactive oxygen species (ROS)/nitric oxide (NO) imbalance, 1873-4316/18 $58.00+.00 © 2018 Bentham Science Publishers