Efeitos da testosterona sobre a reatividade vascular de ratos hipertensos

Detalhes bibliográficos
Autor(a) principal: Gonçalves, Leticia Tinoco
Data de Publicação: 2023
Tipo de documento: Tese
Idioma: por
Título da fonte: Repositório Institucional da Universidade Federal do Espírito Santo (riUfes)
Texto Completo: http://repositorio.ufes.br/handle/10/16766
Resumo: The abusive use of testosterone is considered a global public health problem, with several side effects. In the cardiovascular system, its effects are still controversial, ranging from protective to deleterious actions. Because testosterone is a hormone that can be converted to 17 β-estradiol and dihydrotestosterone (DHT), part of the effects found with supraphysiological doses can be attributed to its metabolites. Therefore, we investigated the hypothesis that a supraphysiological dose of testosterone impairs the endothelium-dependent vasodilation of mesenteric resistance arteries, as well as its repercussions on oxidative stress (OS) and blood pressure (BP). We also evaluated the participation of 17 β-estradiol and DHT in the responses found. We used Spontaneously Hypertensive Rats (SHR), aged 8 to 10 weeks, divided into 5 groups: intact (SHAM), orchiectomized (ORX), intact testosterone-treated (TTO; 3 mg/Kg/day/s.c.), intact treated with testosterone and anastrozole [aromatase enzyme inhibitor (TTO+ANA; 0.1 mg/Kg/day)] and intact treated with testosterone and finasteride [5α-reductase enzyme inhibitor (TTO+FIN; 5 mg/Kg/day)] for 4 weeks. BP was assessed by tail cuff plethysmography. We performed concentration-response curves to acetylcholine (ACh, 0.1 nM - 10 µM) in mesenteric arteries using a wire myograph, in the absence and presence of pharmacological inhibitors. Also testosterone, 17 β-estradiol and dihydrotestosterone concentrations were evaluated. Vascular detection of superoxide anion (O2 •- ) and endothelium ultrastructure were analyzed by DHE and scanning electron microscopy (SEM), respectively. Data were expressed as mean ± standard error of the mean, and analyzed by Student's t-test or one-way or two-way ANOVA, followed by Tukey's post hoc test (p < 0.05). Orchiectomy reduced levels of testosterone, 17 β-estradiol and dihydrotestosterone, impaired ACh vasodilation, increased OS, altered endothelial morphology without altering BP. Testosterone treatment did not impair ACh vasodilation compared to the SHAM group, however it altered the endothelial pathways of relaxation, with lesser participation of NO and greater participation of prostanoids, possibly derived from COX-1. In addition, in the TTO group, the participation of EDH was greater compared to SHAM, indicating that EETs, H2O2 and K+ channels contributed to this vasodilator response. In the TTO+ANA group, the reduction in 17 β-estradiol levels did not impair ACh vasodilation, however, it decreased the participation of nitric oxide, prostanoids and increased EDH, and increased O2•- levels with alteration of endothelial morphology. TTO+FIN showed impairment in the vasodilator response to ACh, with an increased participation of NO and a lower participation of prostanoids. Regarding EDH, with a decrease in dihydrotestosterone, there was no increase in the participation of EETs, H2O2 and K+ channels compared to TTO. DHT seems to contribute to the decrease of NO and estrogen seems to stimulate the action of the NO pathway and prostanoids. In estrogen reduction, testosterone maintains endothelial vasodilation by greater stimulation of EDH, with more action of EETs, H2O2 and K+ channels, with greater formation of O2 •- . These results may contribute to the elucidation of the modulating role of testosterone on endothelial function, even in treatment with a supraphysiological dose, in addition to showing the importance of the presence of estrogen for the cardiovascular system in situations of endothelial dysfunction.
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spelling Santos, Roger Lyrio doshttps://orcid.org/0000-0003-3399-3523http://lattes.cnpq.br/1122196233280741Gonçalves, Leticia Tinocohttps://orcid.org/0000-0003-2202-8541http://lattes.cnpq.br/0836713525136907Ceravolo, Graziela Scaliantihttps://orcid.org/0000-0001-7558-6294http://lattes.cnpq.br/0517142252318597Padilha, Alessandra Simaohttps://orcid.org/0000-0002-9585-1347http://lattes.cnpq.br/7658998034219799Bonaventura, Daniellahttps://orcid.org/0000-0001-5253-4918http://lattes.cnpq.br/9290907947235226Santos, Leonardo doshttp://lattes.cnpq.br/41320870013626232024-05-30T01:41:29Z2024-05-30T01:41:29Z2023-02-15The abusive use of testosterone is considered a global public health problem, with several side effects. In the cardiovascular system, its effects are still controversial, ranging from protective to deleterious actions. Because testosterone is a hormone that can be converted to 17 β-estradiol and dihydrotestosterone (DHT), part of the effects found with supraphysiological doses can be attributed to its metabolites. Therefore, we investigated the hypothesis that a supraphysiological dose of testosterone impairs the endothelium-dependent vasodilation of mesenteric resistance arteries, as well as its repercussions on oxidative stress (OS) and blood pressure (BP). We also evaluated the participation of 17 β-estradiol and DHT in the responses found. We used Spontaneously Hypertensive Rats (SHR), aged 8 to 10 weeks, divided into 5 groups: intact (SHAM), orchiectomized (ORX), intact testosterone-treated (TTO; 3 mg/Kg/day/s.c.), intact treated with testosterone and anastrozole [aromatase enzyme inhibitor (TTO+ANA; 0.1 mg/Kg/day)] and intact treated with testosterone and finasteride [5α-reductase enzyme inhibitor (TTO+FIN; 5 mg/Kg/day)] for 4 weeks. BP was assessed by tail cuff plethysmography. We performed concentration-response curves to acetylcholine (ACh, 0.1 nM - 10 µM) in mesenteric arteries using a wire myograph, in the absence and presence of pharmacological inhibitors. Also testosterone, 17 β-estradiol and dihydrotestosterone concentrations were evaluated. Vascular detection of superoxide anion (O2 •- ) and endothelium ultrastructure were analyzed by DHE and scanning electron microscopy (SEM), respectively. Data were expressed as mean ± standard error of the mean, and analyzed by Student's t-test or one-way or two-way ANOVA, followed by Tukey's post hoc test (p < 0.05). Orchiectomy reduced levels of testosterone, 17 β-estradiol and dihydrotestosterone, impaired ACh vasodilation, increased OS, altered endothelial morphology without altering BP. Testosterone treatment did not impair ACh vasodilation compared to the SHAM group, however it altered the endothelial pathways of relaxation, with lesser participation of NO and greater participation of prostanoids, possibly derived from COX-1. In addition, in the TTO group, the participation of EDH was greater compared to SHAM, indicating that EETs, H2O2 and K+ channels contributed to this vasodilator response. In the TTO+ANA group, the reduction in 17 β-estradiol levels did not impair ACh vasodilation, however, it decreased the participation of nitric oxide, prostanoids and increased EDH, and increased O2•- levels with alteration of endothelial morphology. TTO+FIN showed impairment in the vasodilator response to ACh, with an increased participation of NO and a lower participation of prostanoids. Regarding EDH, with a decrease in dihydrotestosterone, there was no increase in the participation of EETs, H2O2 and K+ channels compared to TTO. DHT seems to contribute to the decrease of NO and estrogen seems to stimulate the action of the NO pathway and prostanoids. In estrogen reduction, testosterone maintains endothelial vasodilation by greater stimulation of EDH, with more action of EETs, H2O2 and K+ channels, with greater formation of O2 •- . These results may contribute to the elucidation of the modulating role of testosterone on endothelial function, even in treatment with a supraphysiological dose, in addition to showing the importance of the presence of estrogen for the cardiovascular system in situations of endothelial dysfunction.O uso abusivo da testosterona é considerado um problema de saúde pública global, apresentando diversos efeitos adversos. No sistema cardiovascular, seus efeitos ainda são controversos, variando de ações protetoras a deletérias. Como a testosterona é um hormônio que pode ser convertido a 17 β-estradiol e a dihidrotestosterona (DHT), parte dos efeitos encontrados com dose suprafisiológica pode ser atribuído aos seus metabólitos. Por isso, investigamos a hipótese de que dose suprafisiológica de testosterona promova prejuízo na vasodilatação dependente do endotélio de artérias mesentéricas de resistência, bem como suas repercussões sobre o estresse oxidativo e pressão arterial (PA). Avaliamos também a participação de 17 β-estradiol e DHT nas respostas encontradas. Utilizamos ratos espontaneamente hipertensos (SHR, Spontaneously hipertensive rats), com 8 a 10 semanas de idade, distribuídos em 5 grupos: intactos (SHAM), orquiectomizados (ORX), intactos tratados com testosterona (TTO; 3 mg/Kg/dia/s.c.), intactos tratados com testosterona e anastrozol [inibidor da enzima aromatase (TTO+ANA; 0,1 mg/Kg/dia)] e intactos tratados com testosterona e finasterida [inibidor da enzima 5α-redutase (TTO+FIN; 5 mg/Kg/dia)] por 4 semanas. A PA foi avaliada por pletismografia de cauda. Realizamos curvas concentração-resposta à acetilcolina (ACh, 0,1 nM - 10 µM) em artérias mesentéricas em miógrafo de arame, na ausência e presença de inibidores farmacológicos. As concentrações de testosterona, 17 β-estradiol e dihidrotestosterona foram avaliadas. A presença de espécies reativas de oxigênio e a ultraestrutura do endotélio foram analisadas por fluorescência emitida ao dihidroetídio (DHE) e microscopia eletrônica de varredura (MEV), respectivamente. Dados foram expressos como média ± EPM, e analisados por teste t Student ou ANOVA uma ou duas vias, seguida pelo post hoc de Tukey (p<0,05). A orquiectomia reduziu as concentrações sanguíneas de testosterona, 17 β-estradiol e dihidrotestosterona, prejudicou a vasodilatação à ACh, aumentou o EO, alterou a morfologia endotelial sem alterar a PA. O tratamento com testosterona não prejudicou a vasodilatação à ACh comparada ao grupo SHAM, contudo alterou as vias endoteliais de relaxamento, com menor participação do NO e maior dos prostanoides, possivelmente derivados da COX-1. Além disso, no grupo TTO maior foi a participação da hiperpolarização dependente do endotélio (EDH) comparado ao SHAM, indicando que os EETs, H2O2 e canais para K+ contribuíram para essa resposta vasodilatadora. No grupo TTO+ANA, a redução dos níveis de 17 β-estradiol não prejudicou a vasodilatação à ACh contudo, diminuiu a participação do óxido nítrico e prostanoides, e aumentou a EDH e os níveis de O2 •- , com alteração da morfologia endotelial. O TTO+FIN apresentou prejuízo na resposta vasodilatadora à ACh, com uma participação aumentada do NO e menor dos prostanoides. Em relação a EDH, com diminuição da dihidrotestosterona, não houve aumento na participação dos EETs, H2O2 e dos canais para K+ comparado ao TTO. A DHT parece contribuir para a diminuição do NO e o estrogênio parece estimular a ação da via do NO e dos prostanoides. Na redução de estrogênio, a testosterona manteve a vasodilatação endotelial por maior estímulo a EDH, com mais ação dos EETs, H2O2 e dos canais para K+ , com maior formação de O2 •- . Estes resultados podem contribuir para elucidação do papel modulador da testosterona sobre a função endotelial, mesmo em tratamento com dose suprafisiológica, além de mostrar a importância da presença do estrogênio para o sistema cardiovascular em situações de disfunção endotelial.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Texthttp://repositorio.ufes.br/handle/10/16766porUniversidade Federal do Espírito SantoDoutorado em Ciências FisiológicasPrograma de Pós-Graduação em Ciências FisiológicasUFESBRCentro de Ciências da Saúdesubject.br-rjbnFisiologiaHormônios sexuais masculinosEstrogênioDihidrotestosteronaAnastrozolFinasteridaEfeitos da testosterona sobre a reatividade vascular de ratos hipertensostitle.alternativeinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da Universidade Federal do Espírito Santo (riUfes)instname:Universidade Federal do Espírito Santo (UFES)instacron:UFESORIGINALTese Leticia Tinoco Gonçalves - Letícia Tinoco Gonçalves.pdfapplication/pdf3145185http://repositorio.ufes.br/bitstreams/84eda7b1-1f30-4a4c-a8ce-e2f186d80902/downloadb3d983c319f6ff1df9b6859891bcff8aMD5110/167662024-09-17 08:17:12.159oai:repositorio.ufes.br:10/16766http://repositorio.ufes.brRepositório InstitucionalPUBhttp://repositorio.ufes.br/oai/requestopendoar:21082024-10-15T17:54:03.661052Repositório Institucional da Universidade Federal do Espírito Santo (riUfes) - Universidade Federal do Espírito Santo (UFES)false
dc.title.none.fl_str_mv Efeitos da testosterona sobre a reatividade vascular de ratos hipertensos
dc.title.alternative.none.fl_str_mv title.alternative
title Efeitos da testosterona sobre a reatividade vascular de ratos hipertensos
spellingShingle Efeitos da testosterona sobre a reatividade vascular de ratos hipertensos
Gonçalves, Leticia Tinoco
Fisiologia
Hormônios sexuais masculinos
Estrogênio
Dihidrotestosterona
Anastrozol
Finasterida
subject.br-rjbn
title_short Efeitos da testosterona sobre a reatividade vascular de ratos hipertensos
title_full Efeitos da testosterona sobre a reatividade vascular de ratos hipertensos
title_fullStr Efeitos da testosterona sobre a reatividade vascular de ratos hipertensos
title_full_unstemmed Efeitos da testosterona sobre a reatividade vascular de ratos hipertensos
title_sort Efeitos da testosterona sobre a reatividade vascular de ratos hipertensos
author Gonçalves, Leticia Tinoco
author_facet Gonçalves, Leticia Tinoco
author_role author
dc.contributor.authorID.none.fl_str_mv https://orcid.org/0000-0003-2202-8541
dc.contributor.authorLattes.none.fl_str_mv http://lattes.cnpq.br/0836713525136907
dc.contributor.advisor1.fl_str_mv Santos, Roger Lyrio dos
dc.contributor.advisor1ID.fl_str_mv https://orcid.org/0000-0003-3399-3523
dc.contributor.advisor1Lattes.fl_str_mv http://lattes.cnpq.br/1122196233280741
dc.contributor.author.fl_str_mv Gonçalves, Leticia Tinoco
dc.contributor.referee1.fl_str_mv Ceravolo, Graziela Scalianti
dc.contributor.referee1ID.fl_str_mv https://orcid.org/0000-0001-7558-6294
dc.contributor.referee1Lattes.fl_str_mv http://lattes.cnpq.br/0517142252318597
dc.contributor.referee2.fl_str_mv Padilha, Alessandra Simao
dc.contributor.referee2ID.fl_str_mv https://orcid.org/0000-0002-9585-1347
dc.contributor.referee2Lattes.fl_str_mv http://lattes.cnpq.br/7658998034219799
dc.contributor.referee3.fl_str_mv Bonaventura, Daniella
dc.contributor.referee3ID.fl_str_mv https://orcid.org/0000-0001-5253-4918
dc.contributor.referee3Lattes.fl_str_mv http://lattes.cnpq.br/9290907947235226
dc.contributor.referee4.fl_str_mv Santos, Leonardo dos
dc.contributor.referee4Lattes.fl_str_mv http://lattes.cnpq.br/4132087001362623
contributor_str_mv Santos, Roger Lyrio dos
Ceravolo, Graziela Scalianti
Padilha, Alessandra Simao
Bonaventura, Daniella
Santos, Leonardo dos
dc.subject.cnpq.fl_str_mv Fisiologia
topic Fisiologia
Hormônios sexuais masculinos
Estrogênio
Dihidrotestosterona
Anastrozol
Finasterida
subject.br-rjbn
dc.subject.por.fl_str_mv Hormônios sexuais masculinos
Estrogênio
Dihidrotestosterona
Anastrozol
Finasterida
dc.subject.br-rjbn.none.fl_str_mv subject.br-rjbn
description The abusive use of testosterone is considered a global public health problem, with several side effects. In the cardiovascular system, its effects are still controversial, ranging from protective to deleterious actions. Because testosterone is a hormone that can be converted to 17 β-estradiol and dihydrotestosterone (DHT), part of the effects found with supraphysiological doses can be attributed to its metabolites. Therefore, we investigated the hypothesis that a supraphysiological dose of testosterone impairs the endothelium-dependent vasodilation of mesenteric resistance arteries, as well as its repercussions on oxidative stress (OS) and blood pressure (BP). We also evaluated the participation of 17 β-estradiol and DHT in the responses found. We used Spontaneously Hypertensive Rats (SHR), aged 8 to 10 weeks, divided into 5 groups: intact (SHAM), orchiectomized (ORX), intact testosterone-treated (TTO; 3 mg/Kg/day/s.c.), intact treated with testosterone and anastrozole [aromatase enzyme inhibitor (TTO+ANA; 0.1 mg/Kg/day)] and intact treated with testosterone and finasteride [5α-reductase enzyme inhibitor (TTO+FIN; 5 mg/Kg/day)] for 4 weeks. BP was assessed by tail cuff plethysmography. We performed concentration-response curves to acetylcholine (ACh, 0.1 nM - 10 µM) in mesenteric arteries using a wire myograph, in the absence and presence of pharmacological inhibitors. Also testosterone, 17 β-estradiol and dihydrotestosterone concentrations were evaluated. Vascular detection of superoxide anion (O2 •- ) and endothelium ultrastructure were analyzed by DHE and scanning electron microscopy (SEM), respectively. Data were expressed as mean ± standard error of the mean, and analyzed by Student's t-test or one-way or two-way ANOVA, followed by Tukey's post hoc test (p < 0.05). Orchiectomy reduced levels of testosterone, 17 β-estradiol and dihydrotestosterone, impaired ACh vasodilation, increased OS, altered endothelial morphology without altering BP. Testosterone treatment did not impair ACh vasodilation compared to the SHAM group, however it altered the endothelial pathways of relaxation, with lesser participation of NO and greater participation of prostanoids, possibly derived from COX-1. In addition, in the TTO group, the participation of EDH was greater compared to SHAM, indicating that EETs, H2O2 and K+ channels contributed to this vasodilator response. In the TTO+ANA group, the reduction in 17 β-estradiol levels did not impair ACh vasodilation, however, it decreased the participation of nitric oxide, prostanoids and increased EDH, and increased O2•- levels with alteration of endothelial morphology. TTO+FIN showed impairment in the vasodilator response to ACh, with an increased participation of NO and a lower participation of prostanoids. Regarding EDH, with a decrease in dihydrotestosterone, there was no increase in the participation of EETs, H2O2 and K+ channels compared to TTO. DHT seems to contribute to the decrease of NO and estrogen seems to stimulate the action of the NO pathway and prostanoids. In estrogen reduction, testosterone maintains endothelial vasodilation by greater stimulation of EDH, with more action of EETs, H2O2 and K+ channels, with greater formation of O2 •- . These results may contribute to the elucidation of the modulating role of testosterone on endothelial function, even in treatment with a supraphysiological dose, in addition to showing the importance of the presence of estrogen for the cardiovascular system in situations of endothelial dysfunction.
publishDate 2023
dc.date.issued.fl_str_mv 2023-02-15
dc.date.accessioned.fl_str_mv 2024-05-30T01:41:29Z
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dc.publisher.none.fl_str_mv Universidade Federal do Espírito Santo
Doutorado em Ciências Fisiológicas
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dc.publisher.department.fl_str_mv Centro de Ciências da Saúde
publisher.none.fl_str_mv Universidade Federal do Espírito Santo
Doutorado em Ciências Fisiológicas
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