Contents lists available at ScienceDirect Life Sciences journal homepage: www.elsevier.com/locate/lifescie Chronic administration of sildenafil improves endothelial function in spontaneously hypertensive rats by decreasing COX-2 expression and oxidative stress José Jairo Teixeira-da-Silva a , Hicla Stefany Nunes-Moreira a , Cristina Oliveira Silva b , Saad Lahlou c , Fabio Naro d , Fabiano Elias Xavier a , Glória Pinto Duarte a, ⁎ a Departamento de Fisiologia e Farmacologia, Centro de Biociências, Universidade Federal de Pernambuco, Recife 50670-901, PE, Brazil b Núcleo de Nutrição, Centro Acadêmico de Vitória, Universidade Federal de Pernambuco, Recife 55608-680, PE, Brazil c Departamento de Fisiologia e Farmacologia, Faculdade de Medicina, Universidade Federal do Ceará, Fortaleza 60430-270, CE, Brazil d Dipartimento di Scienze Anatomiche, Istologiche, Medico-legali e dell‘Apparato Locomotore, Università di Roma - Sapienza, Rome 00161, Italy ARTICLE INFO Keywords: Endothelial dysfunction Hypertension Phosphodiesterase Sildenafil Vasorelaxation ABSTRACT Aims: Spontaneously hypertensive rats (SHR) exhibit impaired endothelial vasodilation and enhanced vaso- constriction. The phosphodiesterase 5 (PDE5) inhibitor sildenafil (Sild) potentiates the nitric oxide (NO)- mediated effects exerting antioxidative and anti-inflammatory actions. In the present study, we hypothesized that Sild could improve endothelial function in SHR. Materials and methods: Male rats were treated daily for 60 days by oral gavage with Sild (45 mg/kg) before the onset of the hypertensive state (pre-hypertensive protocol). The aortic relaxation to acetylcholine (ACh), sodium nitroprusside (SNP) and the phenylephrine (Phe)-induced contraction was evaluated in SHR. Protein expression of eNOS, p-eNOS, caveolin, COX-1, COX-2, ERK and p-ERK was measured by Western blot. Key findings: Resting blood pressure was not modified by Sild administration. Treatment with Sild did not alter the relaxation response to SNP but improved the ACh-induced relaxation and reduced Phe-induced contraction in aortic rings from SHR. This protective effect of Sild could be attributed to reduced superoxide anions (O 2 - ) generation, cyclooxygenase type 2 (COX-2) protein downregulation and increased NO bioavailability. Significance: Sild improves endothelial function in SHR aorta without affecting resting blood pressure values. These results indicate that PDE5 inhibition has a potential role in the improvement of vascular function and could be an adjuvant in the treatment of essential hypertension. 1. Introduction Hypertension is commonly associated with structural and functional vascular abnormalities. These include increase in arterial stiffness, wall to lumen ratio, vasoconstrictor responses and endothelial dysfunction [1], which themselves are associated with highest cardiovascular risk. Endothelial dysfunction results from impairment of nitric oxide (NO) bioavailability. In hypertension, NO deficiency is a multifactorial pro- cess involving the decrease of NO production and the increase of NO degradation by reactive oxygen species (ROS) [2]. The intracellular effects of NO are mediated by generation of cyclic 3′5′-guanosine monophosphate (cGMP) and its increased breakdown is associated with the development of endothelial dysfunction [3]. Phosphodiesterase 5 (PDE5) is one of the responsible factors for selective degradation of cGMP levels in various tissues. Its activity modulates the intensity and duration of cGMP mediated intracellular signal [4,5]. Increased activity of cGMP-hydrolyzing PDE5 is associated with arterial hypertension [6,7]. At vascular level, PDE5 inhibitors potentiate the NO-mediated ef- fects by increasing cGMP levels leading to activation of protein kinase G (PKG) [3,4,7]. In addition to its vasodilatory effect related to increased cGMP/PKG signaling, sildenafil (Sild) presents antioxidative and anti- genotoxic activity [8], increases the number and function of endothelial progenitor cells [9] and decreases lipid deposition in conductance ar- teries [8]. In a recent study, Leal et al. [10] demonstrated that chronic Sild administration to atherosclerotic (apoE -/- ) mice decreases pro- inflammatory cytokines and O 2 – production and antagonizing the vas- cular dysfunction induced by COX-derived thromboxane A 2 (TxA 2 ). The https://doi.org/10.1016/j.lfs.2019.03.074 Received 5 January 2019; Received in revised form 20 March 2019; Accepted 29 March 2019 ⁎ Corresponding author at: Universidade Federal de Pernambuco, Centro de Biociências, Departamento de Fisiologia e Farmacologia, Avenida Prof. Moraes Rêgo, Cidade Universitária, 50670-901 Recife, Brazil. E-mail address: duarteg@ufpe.br (G.P. Duarte). Life Sciences 225 (2019) 29–38 Available online 30 March 2019 0024-3205/ © 2019 Published by Elsevier Inc. T