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      Inhibition of PDE5 Restores Depressed Baroreflex Sensitivity in Renovascular Hypertensive Rats

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          Abstract

          Renal artery stenosis is frequently associated with resistant hypertension, which is defined as failure to normalize blood pressure (BP) even when combined drugs are used. Inhibition of PDE5 by sildenafil has been shown to increase endothelial function and decrease blood pressure in experimental models. However, no available study evaluated the baroreflex sensitivity nor autonomic balance in renovascular hypertensive rats treated with sildenafil. In a translational medicine perspective, our hypothesis is that sildenafil could improve autonomic imbalance and baroreflex sensitivity, contributing to lower blood pressure. Renovascular hypertensive 2-kidney-1-clip (2K1C) and sham rats were treated with sildenafil (45 mg/Kg/day) during 7 days. At the end of treatment, BP and heart rate (HR) were recorded in conscious rats after a 24-h-recovery period. Spontaneous and drug-induced baroreflex sensitivity and autonomic tone were evaluated; in addition, lipid peroxidation was measured in plasma samples. Treatment was efficient in increasing both spontaneous and induced baroreflex sensitivity in treated hypertensive animals. Inhibition of PDE5 was also capable of ameliorating autonomic imbalance in 2K1C rats and decreasing systemic oxidative stress. Taken together, these beneficial effects resulted in significant reductions in BP without affecting HR. We suggest that sildenafil could be considered as a promising alternative to treat resistant hypertension.

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          Most cited references54

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          Angiotensin-converting enzyme 2, angiotensin-(1-7) and Mas: new players of the renin-angiotensin system.

          Angiotensin (Ang)-(1-7) is now recognized as a biologically active component of the renin-angiotensin system (RAS). Ang-(1-7) appears to play a central role in the RAS because it exerts a vast array of actions, many of them opposite to those attributed to the main effector peptide of the RAS, Ang II. The discovery of the Ang-converting enzyme (ACE) homolog ACE2 brought to light an important metabolic pathway responsible for Ang-(1-7) synthesis. This enzyme can form Ang-(1-7) from Ang II or less efficiently through hydrolysis of Ang I to Ang-(1-9) with subsequent Ang-(1-7) formation by ACE. In addition, it is now well established that the G protein-coupled receptor Mas is a functional binding site for Ang-(1-7). Thus, the axis formed by ACE2/Ang-(1-7)/Mas appears to represent an endogenous counterregulatory pathway within the RAS, the actions of which are in opposition to the vasoconstrictor/proliferative arm of the RAS consisting of ACE, Ang II, and AT(1) receptor. In this brief review, we will discuss recent findings related to the biological role of the ACE2/Ang-(1-7)/Mas arm in the cardiovascular and renal systems, as well as in metabolism. In addition, we will highlight the potential interactions of Ang-(1-7) and Mas with AT(1) and AT(2) receptors.
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            Reactive oxygen species, vascular oxidative stress, and redox signaling in hypertension: what is the clinical significance?

            Metabolism of oxygen by cells generates potentially deleterious reactive oxygen species (ROS). Under normal conditions the rate and magnitude of oxidant formation is balanced by the rate of oxidant elimination. However, an imbalance between prooxidants and antioxidants results in oxidative stress, which is the pathogenic outcome of oxidant overproduction that overwhelms the cellular antioxidant capacity. The kidney and vasculature are rich sources of NADPH oxidase-derived ROS, which under pathological conditions play an important role in renal dysfunction and vascular damage. Strong experimental evidence indicates that increased oxidative stress and associated oxidative damage are mediators of renovascular injury in cardiovascular pathologies. Increased production of superoxide anion and hydrogen peroxide, reduced nitric oxide synthesis, and decreased bioavailability of antioxidants have been demonstrated in experimental and human hypertension. These findings have evoked considerable interest because of the possibilities that therapies targeted against free radicals by decreasing ROS generation or by increasing nitric oxide availability and antioxidants may be useful in minimizing vascular injury and renal dysfunction and thereby prevent or regress hypertensive end-organ damage. This article highlights current developments in the field of ROS and hypertension, focusing specifically on the role of oxidative stress in hypertension-associated vascular damage. In addition, recent clinical trials investigating cardiovascular benefits of antioxidants are discussed, and some explanations for the rather disappointing results from these studies are addressed. Finally, important avenues for future research in the field of ROS, oxidative stress, and redox signaling in hypertension are considered.
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              The sympathetic nervous system alterations in human hypertension.

              Several articles have dealt with the importance and mechanisms of the sympathetic nervous system alterations in experimental animal models of hypertension. This review addresses the role of the sympathetic nervous system in the pathophysiology and therapy of human hypertension. We first discuss the strengths and limitations of various techniques for assessing the sympathetic nervous system in humans, with a focus on heart rate, plasma norepinephrine, microneurographic recording of sympathetic nerve traffic, and measurements of radiolabeled norepinephrine spillover. We then examine the evidence supporting the importance of neuroadrenergic factors as promoters and amplifiers of human hypertension. We expand on the role of the sympathetic nervous system in 2 increasingly common forms of secondary hypertension, namely hypertension associated with obesity and with renal disease. With this background, we examine interventions of sympathetic deactivation as a mode of antihypertensive treatment. Particular emphasis is given to the background and results of recent therapeutic approaches based on carotid baroreceptor stimulation and radiofrequency ablation of the renal nerves.
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                Author and article information

                Contributors
                URI : http://loop.frontiersin.org/people/215179/overview
                URI : http://loop.frontiersin.org/people/215195/overview
                URI : http://loop.frontiersin.org/people/82484/overview
                URI : http://loop.frontiersin.org/people/201872/overview
                Journal
                Front Physiol
                Front Physiol
                Front. Physiol.
                Frontiers in Physiology
                Frontiers Media S.A.
                1664-042X
                28 January 2016
                2016
                : 7
                : 15
                Affiliations
                [1] 1Centro de Biotecnologia, Universidade Federal da Paraíba Joao Pessoa, Brazil
                [2] 2Centro de Ciências Médicas, Universidade Federal da Paraíba Joao Pessoa, Brazil
                [3] 3Centro de Ciências da Saúde, Universidade Federal da Paraíba Joao Pessoa, Brazil
                Author notes

                Edited by: Debra I. Diz, Wake Forest University School of Medicine, USA

                Reviewed by: Patrick J. Mueller, Wayne State University, USA; Abdel Abdel-Rahman, East Carolina University Brody School of Medicine, USA

                *Correspondence: Camille de Moura Balarini camille.balarini@ 123456gmail.com

                This article was submitted to Integrative Physiology, a section of the journal Frontiers in Physiology

                Article
                10.3389/fphys.2016.00015
                4729906
                26858657
                0f017b07-d669-456e-a122-df125275bc5a
                Copyright © 2016 Cavalcanti, Alves, Oliveira, Cruz, França-Silva, Braga and Balarini.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 02 August 2015
                : 11 January 2016
                Page count
                Figures: 4, Tables: 3, Equations: 0, References: 57, Pages: 9, Words: 7284
                Funding
                Funded by: Conselho Nacional de Desenvolvimento Científico e Tecnológico 10.13039/501100003593
                Funded by: Coordenação de Aperfeiçoamento de Pessoal de Nível Superior 10.13039/501100002322
                Categories
                Physiology
                Original Research

                Anatomy & Physiology
                resistant hypertension,sildenafil,baroreflex,nitric oxide,angiotensin-ii
                Anatomy & Physiology
                resistant hypertension, sildenafil, baroreflex, nitric oxide, angiotensin-ii

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