Inhibition of phosphodiesterase 5 restores endothelial function in renovascular hypertension

Background: the clipping of an artery supplying one of the two kidneys (2K1C) activates the renin-angiotensin (Ang) system (RAS), resulting in hypertension and endothelial dysfunction. Recently, we demonstrated the intrarenal beneficial effects of sildenafil on the high levels of Ang II and reactive oxygen species (ROS) and on high blood pressure (BP) in 2K1C mice. Thus, in the present study, we tested the hypothesis that sildenafil improves endothelial function in hypertensive 2K1C mice by improving the NO/ROS balance.Methods: 2K1C hypertension was induced in C57BL/6 mice. Two weeks later, they were treated with sildenafil (40 mg/kg/day, via oral) or vehicle for 2 weeks and compared with sham mice. At the end of the treatment, the levels of plasma and intrarenal Ang peptides were measured. Endothelial function and ROS production were assessed in mesenteric arterial bed (MAB).Results: the 2K1C mice exhibited normal plasma levels of Ang I, II and 1-7, whereas the intrarenal Ang I and II were increased (similar to 35% and similar to 140%) compared with the Sham mice. Sildenafil normalized the intrarenal Ang I and II and increased the plasma (similar to 45%) and intrarenal (+15%) Ang 1-7. the 2K1C mice exhibited endothelial dysfunction, primarily due to increased ROS and decreased NO productions by endothelial cells, which were ameliorated by treatment with sildenafil.Conclusion: These data suggest that the effects of sildenafil on endothelial dysfunction in 2K1C mice may be due to interaction with RAS and restoring NO/ROS balance in the endothelial cells from MAB. Thus, sildenafil is a promising candidate drug for the treatment of hypertension accompanied by endothelial dysfunction and kidney disease.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)State Agency for the Development of Science and Technology (FAPES/Universal)Univ Fed Espirito Santo, Hlth Sci Ctr, Lab Translat Physiol, Vitoria, ES, BrazilEmescam Sch Hlth Sci, Vitoria, ES, BrazilUniversidade Federal de São Paulo, Dept Med, Div Nephrol, São Paulo, BrazilUniv Fed Espirito Santo, Hlth Sci Ctr, Pharmaceut Sci Grad Program, Vitoria, ES, BrazilUniv Fed Paraiba, Hlth Sci Ctr, Dept Physiol & Pathol, BR-58059900 Joao Pessoa, PB, BrazilUVV, Pharmaceut Sci Grad Program, Vila Velha, ES, BrazilFed Inst Educ Sci & Technol IFES, Vila Velha, ES, BrazilUniversidade Federal de São Paulo, Dept Med, Div Nephrol, São Paulo, BrazilCNPq: 302582/2011-8CNPq: 476525/2012-8CNPq: 305188/2012-7CNPq: 473177/2013-7State Agency for the Development of Science and Technology (FAPES/Universal): 012/2011State Agency for the Development of Science and Technology (FAPES/Universal): 54498465CNPq: 012/2009Web of Scienc

Sildenafil ameliorates oxidative stress and DNA damage in the stenotic kidneys in mice with renovascular hypertension

Background: Oxidative stress and DNA damage have been implicated in the pathogenesis of renovascular hypertension induced by renal artery stenosis in the two-kidney, one-clip (2K1C) Goldblatt model. Considering our previous report indicating that the chronic blockade of phosphodiesterase 5 with sildenafil (Viagra (R)) has marked beneficial effects on oxidative stress and DNA damage, we tested the hypothesis that sildenafil could also protect the stenotic kidneys of 2K1C hypertensive mice against oxidative stress and genotoxicity.Methods: the experiments were performed with C57BL6 mice subjected to renovascular hypertension by left renal artery clipping. Two weeks after clipping, the mice were treated with sildenafil (40 mg/kg/ day for 2 weeks, 2K1C-sildenafil group) or the vehicle (2K1C). These mice were compared with control mice not subjected to renal artery clipping (Sham). After hemodynamic measurements, the stenotic kidneys were assessed using flow cytometry to evaluate cell viability and the comet assay to evaluate DNA damage. Measurements of intracellular superoxide anions and hydrogen peroxide levels as well as nitric oxide bioavailability were also obtained.Results: Sildenafil treatment significantly reduced mean arterial pressure (15%), heart rate (8%), intrarenal angiotensin II (50%) and renal atrophy (36%). in addition, it caused a remarkable decrease of reactive oxygen species production. On the other hand, sildenafil increased nitric oxide levels relative to those in the nontreated 2K1C mice. Sildenafil treatment also significantly reduced the high level of kidney DNA damage that is a characteristic of renovascular hypertensive mice.Conclusions: Our data reveal that sildenafil has a protective effect on the stenotic kidneys of 2K1C mice, suggesting a new use of phosphodiesterase 5 inhibitors for protection against the DNA damage observed in the hypoperfused kidneys of individuals with renovascular hypertension. Further translational research is necessary to delineate the mechanisms involved in the prevention of renal stenosis in the clinical setting.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)State Agency for the Development of Science and Technology (FAPES)Univ Fed Espirito Santo, Hlth Sci Ctr, Lab Translat Physiol, Vitoria, ES, BrazilUniv Fed Paraiba, Hlth Sci Ctr, Dept Physiol & Pathol, BR-58059900 Joao Pessoa, Paraiba, BrazilUniversidade Federal de São Paulo, Dept Med, Div Nephrol, São Paulo, BrazilUniv Vila Velha, Pharmaceut Sci Grad Program, Vila Velha, ES, BrazilFed Inst Educ Sci & Technol IFES, Vila Velha, ES, BrazilUniversidade Federal de São Paulo, Dept Med, Div Nephrol, São Paulo, BrazilCNPq: 302582/2011-8CNPq: 476525/2012-8CNPq: 305188/2012-7CNPq: 473177/2013-7State Agency for the Development of Science and Technology (FAPES): 54498465CNPq: 012/2009Web of Scienc

The International Natural Product Sciences Taskforce (INPST) and the power of Twitter networking exemplified through #INPST hashtag analysis

Background: The development of digital technologies and the evolution of open innovation approaches have enabled the creation of diverse virtual organizations and enterprises coordinating their activities primarily online. The open innovation platform titled "International Natural Product Sciences Taskforce" (INPST) was established in 2018, to bring together in collaborative environment individuals and organizations interested in natural product scientific research, and to empower their interactions by using digital communication tools. Methods: In this work, we present a general overview of INPST activities and showcase the specific use of Twitter as a powerful networking tool that was used to host a one-week "2021 INPST Twitter Networking Event" (spanning from 31st May 2021 to 6th June 2021) based on the application of the Twitter hashtag #INPST. Results and Conclusion: The use of this hashtag during the networking event period was analyzed with Symplur Signals (https://www.symplur.com/), revealing a total of 6,036 tweets, shared by 686 users, which generated a total of 65,004,773 impressions (views of the respective tweets). This networking event's achieved high visibility and participation rate showcases a convincing example of how this social media platform can be used as a highly effective tool to host virtual Twitter-based international biomedical research events

Pendidikan Multikultular di Indonesia: Urgensi sebagai Resolusi Konflik

This research focuses on a pluralistic Indonesian nation that has ethnic, racial, social, semantic and cultural diversity, conflicts often arise in this country, a multicultural approach as conflict resolution, with this multicultural education can change people's perspectives, and live a pluralistic life, maintain integration nation and identity instead of creating conflict between groups, the purpose of the research is to know in detail about multicultural education in depth, secondly to examine in detail multiculturalism as conflict resolution, especially in Indonesia, thirdly to understand the urgency of multicultural education in Indonesia, the method used by researchers is library study method, library research, library study, data analysis. In using this method, researchers get a lot of information and data from various sources such as books, journals, etc. Data analysis method is used to answer all the existing problems. The results of this study indicate that multiculturalism is very important to maintain the integrity, strength, unity and progress of the country and the world

Sildenafil (Viagra®) Prevents Cox-1/ TXA2 Pathway-Mediated Vascular Hypercontractility in ApoE-/- Mice

Background/Aims: The atherosclerotic apolipoprotein E-deficient (apoE-/-) mouse exhibits impaired vasodilation and enhanced vasoconstriction responsiveness. The objectives of this study were: a) to determine the relative contribution of cyclooxygenases (Cox-1 and Cox-2), thromboxane A2 (TXA2) and endothelin-1 (ET-1) to enhancing vascular hyperresponsiveness in this model of atherosclerosis and b) to investigate the beneficial effects of the phosphodiesterase 5 inhibitor sildenafil on this endothelial dysfunction. Methods: Adult male apoE-/- mice were treated with sildenafil (40 mg/kg/day, for 3 weeks) and compared with non-treated ApoE-/- and wild-type mice. The beneficial effects of sildenafil on vascular contractile response to phenylephrine (PE) in aortic rings were evaluated before and after incubation with Cox-1 (SC-560) or Cox-2 (NS-398) inhibitors or the TP antagonist SQ-29548, and on contractile responsiveness to ET-1. Results: ApoE-/- mice exhibited enhanced vasoconstriction to PE (Rmax ∼35%, p<0.01), which was prevented by treatment with sildenafil. The enhanced PE-induced contractions were abolished by both Cox-1 inhibition and TP antagonist, but were not modified by Cox-2 inhibition. Aortic rings from ApoE-/- mice also exhibited enhanced contractions to ET-1 (Rmax ∼30%, p<0.01), which were attenuated in sildenafil-treated ApoE-/- mice. In addition, we observed augmented levels of vascular proinflammatory cytokines in ApoE-/- mice, which were partially corrected by treatment with sildenafil (IL-6, IL-10/IL-6 ratio and MCP-1). Conclusion: The present data show that the Cox-1/TXA2 pathway prevails over the Cox-2 isoform in the mediation of vascular hypercontractility observed in apoE-/-mice. The results also show a beneficial effect of sildenafil on this endothelial dysfunction and on the proinflammatory cytokines in atherosclerotic animals, opening new perspectives for the treatment of other endothelium-related cardiovascular abnormalities