EFEITO DO SILDENAFIL SOBRE ALTERAÇÕES VASCULARES E DANO TECIDUAL INDUZIDOS PELO CHOQUE SÉPTICO

Detalhes bibliográficos
Autor(a) principal: Silvério, Vanessa Kovalski
Data de Publicação: 2015
Tipo de documento: Dissertação
Idioma: por
Título da fonte: Biblioteca Digital de Teses e Dissertações da UEPG
Texto Completo: http://tede2.uepg.br/jspui/handle/prefix/98
Resumo: Septic shock, which is triggered by microbial products, is mainly characterized by an inadequate tissue perfusion caused by a decreased in blood pressure, vascular damage, hyporeactivity to vasoconstrictors and disseminated intravascular coagulation, which can lead to multiple organ dysfunction and death. Nitric oxide (NO) is an important player in the pathogenesis of sepsis and septic shock, having both protective and deleterious effects. Trials of nonselective NOS inhibitors have shown increased mean arterial pressure, but also increased pulmonary artery pressure and reduced cardiac output. Thus, despite the intense research, there was no clinical progress so far. Perhaps this is due to lack of compression of NO signaling pathways. There is a knowledge gap on the role of the NO-guanylate cyclase- guanosine 3 ', 5'-cyclic monophosphate (cGMP) pathway during the early stages of sepsis. Most work has studied the role of cGMP by inhibiting the enzyme responsible for its production (guanylate cyclase), however, in this work we chose to try the increased cGMP levels by inhibiting an enzyme responsible for their degradation, phosphodiesterase 5 (PDE5). In the early stages of shock occurs an intense release of vasoconstrictors agents, which can lead to ischemia damage. In this scenario, cGMP could play a key role counterbalancing these agents and preventing tissue damage. Sildenafil, a type-5 cGMP phosphodiesterase inhibitor, increase GMP at smooth muscle cells and promotes vasodilation .Thus, the purpose of this study was to investigate the effect of treatment with sildenafil in the early stages of sepsis. Male Wistar rats were divided into 2 groups of 16 animals each and submitted to either Cecal Ligation and Puncture (CLP) or the sham procedure. Eight hours after the procedure, the CLP and sham groups were randomly assigned to receive sildenafil (10 mg/kg orally) or vehicle. Twenty-four hours after the CLP or sham procedure, the mean arterial blood pressure, systolic and diastolic blood pressure and vascular reactivity to phenylephrine were evaluated. Additionally, blood samples were collected for measurement of nitric oxide (nitrate and nitrite), urea, creatinine, AST, ALT, lactate and CK.; hematological analyzes were also performed. Statistical significance was analyzed by two-way ANOVA followed by post hoc Bonferroni. The results shows that the CLP was able to reproduce the main characteristics of humans sepsis like as, systemic inflamation, hypotension, reduced response to vasoconstrictors, hypoxia and tissue damage. Interestingly, treatment with sildenafil improved and the organ hypoperfusion at early stages of sepsis reducing organ injury. Thus, phosphodiesterase inhibition may be a useful therapeutic strategy if administered at the proper window of opportunity.
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spelling Fernandes, DanielCPF:02503226922http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4765512H0Vellosa, José Carlos RebuglioCPF:21919065830http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4774388H9Paludo, KatiaCPF:03372434927http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4799913J2Silva, MárcioCPF:88295524968http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4701017A5CPF:05956786965http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4270948A8Silvério, Vanessa Kovalski2017-07-21T14:13:07Z2016-11-242017-07-21T14:13:07Z2015-02-26SILVÉRIO, Vanessa Kovalski. EFEITO DO SILDENAFIL SOBRE ALTERAÇÕES VASCULARES E DANO TECIDUAL INDUZIDOS PELO CHOQUE SÉPTICO. 2015. 58 f. Dissertação (Mestrado em Farmacos, Medicamentos e Biociências Aplicadas à Farmácia) - UNIVERSIDADE ESTADUAL DE PONTA GROSSA, Ponta Grossa, 2015.http://tede2.uepg.br/jspui/handle/prefix/98Septic shock, which is triggered by microbial products, is mainly characterized by an inadequate tissue perfusion caused by a decreased in blood pressure, vascular damage, hyporeactivity to vasoconstrictors and disseminated intravascular coagulation, which can lead to multiple organ dysfunction and death. Nitric oxide (NO) is an important player in the pathogenesis of sepsis and septic shock, having both protective and deleterious effects. Trials of nonselective NOS inhibitors have shown increased mean arterial pressure, but also increased pulmonary artery pressure and reduced cardiac output. Thus, despite the intense research, there was no clinical progress so far. Perhaps this is due to lack of compression of NO signaling pathways. There is a knowledge gap on the role of the NO-guanylate cyclase- guanosine 3 ', 5'-cyclic monophosphate (cGMP) pathway during the early stages of sepsis. Most work has studied the role of cGMP by inhibiting the enzyme responsible for its production (guanylate cyclase), however, in this work we chose to try the increased cGMP levels by inhibiting an enzyme responsible for their degradation, phosphodiesterase 5 (PDE5). In the early stages of shock occurs an intense release of vasoconstrictors agents, which can lead to ischemia damage. In this scenario, cGMP could play a key role counterbalancing these agents and preventing tissue damage. Sildenafil, a type-5 cGMP phosphodiesterase inhibitor, increase GMP at smooth muscle cells and promotes vasodilation .Thus, the purpose of this study was to investigate the effect of treatment with sildenafil in the early stages of sepsis. Male Wistar rats were divided into 2 groups of 16 animals each and submitted to either Cecal Ligation and Puncture (CLP) or the sham procedure. Eight hours after the procedure, the CLP and sham groups were randomly assigned to receive sildenafil (10 mg/kg orally) or vehicle. Twenty-four hours after the CLP or sham procedure, the mean arterial blood pressure, systolic and diastolic blood pressure and vascular reactivity to phenylephrine were evaluated. Additionally, blood samples were collected for measurement of nitric oxide (nitrate and nitrite), urea, creatinine, AST, ALT, lactate and CK.; hematological analyzes were also performed. Statistical significance was analyzed by two-way ANOVA followed by post hoc Bonferroni. The results shows that the CLP was able to reproduce the main characteristics of humans sepsis like as, systemic inflamation, hypotension, reduced response to vasoconstrictors, hypoxia and tissue damage. Interestingly, treatment with sildenafil improved and the organ hypoperfusion at early stages of sepsis reducing organ injury. Thus, phosphodiesterase inhibition may be a useful therapeutic strategy if administered at the proper window of opportunity.O choque séptico, que é desencadeado por produtos microbianos, é caracterizado principalmente por uma perfusão tecidual inadequada causada pela diminuição da pressão arterial, lesão vascular, hiporreatividade a vasoconstritores e coagulação intravascular disseminada, o que pode levar à disfunção de múltiplos órgãos e morte. O óxido nítrico (NO) tem um importante papel na patogênese da sepse e choque séptico, tendo efeitos tanto protetores como deletérios. Ensaios clínicos com inibidores não seletivos da NOS (óxido nítrico sintase) motraram melhora nos níveis da pressão arterial média, porém houve também um aumento da pressão da artéria pulmonar e redução do débito cardíaco. Assim, apesar da investigação intensa, não houve progressos clínicos até agora. Talvez isso se deve à falta de compreensão do NO e suas vias de sinalização. Há por exemplo uma lacuna sobre o papel da enzima guanilato ciclase solúvel e do segundo mensageiro guanosina 3',5'- monofosfato cíclico (cGMP) durante os momentos iniciais da sepse. A maioria dos trabalhos tem estudado o papel do cGMP através da inibição da enzima responsável pela sua produção (guanilato ciclase), porém, neste trabalho optamos por tentar o aumento dos níveis de cGMP através da inibição de uma enzima responsável pela sua degradação, a fosfodiesterase 5 (PDE5). Nos primeiros estágios de choque ocorre uma intensa liberação de agentes vasoconstritores, o que pode levar a danos por isquemia. Neste cenário, o cGMP pode desempenhar um papel chave para contrabalançar esses agentes e impedir danos nos tecidos. O sildenafil, um inibidor de fosfodiesterase do tipo 5, aumenta cGMP em células do músculo liso promovendo vasodilatação. Assim, o propósito do presente estudo foi investigar o efeito do tratamento com sildenafil nas fases iniciais da sepse. Ratos Wistar machos foram divididos em 2 grupos de 16 animais cada e submetidos ao procedimento CLP (Cecal Ligation and Puncture) ou à falsa cirurgia (sham). Oito horas após o procedimento, os grupos CLP e sham foram aleatoriamente divididos para receber sildenafil (10 mg / kg por via oral) ou veículo. Vinte e quatro horas após o procedimento CLP ou sham, a pressão arterial média, sistólica e diastólica e reatividade vascular à fenilefrina foram avaliadas. Além disso, amostras de sangue foram coletadas para a dosagem de óxido nítrico (nitrato e nitrito), uréia, creatinina, AST, ALT, lactato e CK; análises hematológicas também foram realizadas. A significância estatística foi analisada por ANOVA de duas vias seguida de post hoc Bonferroni. Os resultados mostram que o modelo CLP foi capaz de reproduzir as principais características da sepse como inflamação sistêmica, hipotensão, redução da resposta ao vasoconstritores, hipóxia e dano tecidual. Interessantemente, o tratamento com sildenafil melhorou a hipoperfusão em estágios iniciais de sepse reduzindo a lesão de órgãos. Sendo assim, inibidores das fosfodiasterases, como o sildenafil, podem ser ferramentas terapêuticas úteis para o tratamento da sepse, desde que administrados na correta janela de oportunidade.Made available in DSpace on 2017-07-21T14:13:07Z (GMT). No. of bitstreams: 1 Vanessa Kovalski Silverio.pdf: 1423306 bytes, checksum: 68729da0a75b158004d6a33911081b96 (MD5) Previous issue date: 2015-02-26Coordenação de Aperfeiçoamento de Pessoal de Nível Superiorapplication/pdfporUNIVERSIDADE ESTADUAL DE PONTA GROSSAPrograma de Pós Graduação Ciências FarmacêuticasUEPGBRFarmacos, Medicamentos e Biociências Aplicadas à Farmáciasepseóxido nítricocGMPSildenafilsepsisnitric oxidecGMPSildenafilCNPQ::CIENCIAS DA SAUDE::FARMACIAEFEITO DO SILDENAFIL SOBRE ALTERAÇÕES VASCULARES E DANO TECIDUAL INDUZIDOS PELO CHOQUE SÉPTICOinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisinfo:eu-repo/semantics/openAccessreponame:Biblioteca Digital de Teses e Dissertações da UEPGinstname:Universidade Estadual de Ponta Grossa (UEPG)instacron:UEPGORIGINALVanessa Kovalski Silverio.pdfapplication/pdf1423306http://tede2.uepg.br/jspui/bitstream/prefix/98/1/Vanessa%20Kovalski%20Silverio.pdf68729da0a75b158004d6a33911081b96MD51prefix/982017-07-21 11:13:07.022oai:tede2.uepg.br:prefix/98Biblioteca Digital de Teses e Dissertaçõeshttps://tede2.uepg.br/jspui/PUBhttp://tede2.uepg.br/oai/requestbicen@uepg.br||mv_fidelis@yahoo.com.bropendoar:2017-07-21T14:13:07Biblioteca Digital de Teses e Dissertações da UEPG - Universidade Estadual de Ponta Grossa (UEPG)false
dc.title.por.fl_str_mv EFEITO DO SILDENAFIL SOBRE ALTERAÇÕES VASCULARES E DANO TECIDUAL INDUZIDOS PELO CHOQUE SÉPTICO
title EFEITO DO SILDENAFIL SOBRE ALTERAÇÕES VASCULARES E DANO TECIDUAL INDUZIDOS PELO CHOQUE SÉPTICO
spellingShingle EFEITO DO SILDENAFIL SOBRE ALTERAÇÕES VASCULARES E DANO TECIDUAL INDUZIDOS PELO CHOQUE SÉPTICO
Silvério, Vanessa Kovalski
sepse
óxido nítrico
cGMP
Sildenafil
sepsis
nitric oxide
cGMP
Sildenafil
CNPQ::CIENCIAS DA SAUDE::FARMACIA
title_short EFEITO DO SILDENAFIL SOBRE ALTERAÇÕES VASCULARES E DANO TECIDUAL INDUZIDOS PELO CHOQUE SÉPTICO
title_full EFEITO DO SILDENAFIL SOBRE ALTERAÇÕES VASCULARES E DANO TECIDUAL INDUZIDOS PELO CHOQUE SÉPTICO
title_fullStr EFEITO DO SILDENAFIL SOBRE ALTERAÇÕES VASCULARES E DANO TECIDUAL INDUZIDOS PELO CHOQUE SÉPTICO
title_full_unstemmed EFEITO DO SILDENAFIL SOBRE ALTERAÇÕES VASCULARES E DANO TECIDUAL INDUZIDOS PELO CHOQUE SÉPTICO
title_sort EFEITO DO SILDENAFIL SOBRE ALTERAÇÕES VASCULARES E DANO TECIDUAL INDUZIDOS PELO CHOQUE SÉPTICO
author Silvério, Vanessa Kovalski
author_facet Silvério, Vanessa Kovalski
author_role author
dc.contributor.advisor1.fl_str_mv Fernandes, Daniel
dc.contributor.advisor1ID.fl_str_mv CPF:02503226922
dc.contributor.advisor1Lattes.fl_str_mv http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4765512H0
dc.contributor.advisor-co1.fl_str_mv Vellosa, José Carlos Rebuglio
dc.contributor.advisor-co1ID.fl_str_mv CPF:21919065830
dc.contributor.advisor-co1Lattes.fl_str_mv http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4774388H9
dc.contributor.referee1.fl_str_mv Paludo, Katia
dc.contributor.referee1ID.fl_str_mv CPF:03372434927
dc.contributor.referee1Lattes.fl_str_mv http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4799913J2
dc.contributor.referee2.fl_str_mv Silva, Márcio
dc.contributor.referee2ID.fl_str_mv CPF:88295524968
dc.contributor.referee2Lattes.fl_str_mv http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4701017A5
dc.contributor.authorID.fl_str_mv CPF:05956786965
dc.contributor.authorLattes.fl_str_mv http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4270948A8
dc.contributor.author.fl_str_mv Silvério, Vanessa Kovalski
contributor_str_mv Fernandes, Daniel
Vellosa, José Carlos Rebuglio
Paludo, Katia
Silva, Márcio
dc.subject.por.fl_str_mv sepse
óxido nítrico
cGMP
Sildenafil
topic sepse
óxido nítrico
cGMP
Sildenafil
sepsis
nitric oxide
cGMP
Sildenafil
CNPQ::CIENCIAS DA SAUDE::FARMACIA
dc.subject.eng.fl_str_mv sepsis
nitric oxide
cGMP
Sildenafil
dc.subject.cnpq.fl_str_mv CNPQ::CIENCIAS DA SAUDE::FARMACIA
description Septic shock, which is triggered by microbial products, is mainly characterized by an inadequate tissue perfusion caused by a decreased in blood pressure, vascular damage, hyporeactivity to vasoconstrictors and disseminated intravascular coagulation, which can lead to multiple organ dysfunction and death. Nitric oxide (NO) is an important player in the pathogenesis of sepsis and septic shock, having both protective and deleterious effects. Trials of nonselective NOS inhibitors have shown increased mean arterial pressure, but also increased pulmonary artery pressure and reduced cardiac output. Thus, despite the intense research, there was no clinical progress so far. Perhaps this is due to lack of compression of NO signaling pathways. There is a knowledge gap on the role of the NO-guanylate cyclase- guanosine 3 ', 5'-cyclic monophosphate (cGMP) pathway during the early stages of sepsis. Most work has studied the role of cGMP by inhibiting the enzyme responsible for its production (guanylate cyclase), however, in this work we chose to try the increased cGMP levels by inhibiting an enzyme responsible for their degradation, phosphodiesterase 5 (PDE5). In the early stages of shock occurs an intense release of vasoconstrictors agents, which can lead to ischemia damage. In this scenario, cGMP could play a key role counterbalancing these agents and preventing tissue damage. Sildenafil, a type-5 cGMP phosphodiesterase inhibitor, increase GMP at smooth muscle cells and promotes vasodilation .Thus, the purpose of this study was to investigate the effect of treatment with sildenafil in the early stages of sepsis. Male Wistar rats were divided into 2 groups of 16 animals each and submitted to either Cecal Ligation and Puncture (CLP) or the sham procedure. Eight hours after the procedure, the CLP and sham groups were randomly assigned to receive sildenafil (10 mg/kg orally) or vehicle. Twenty-four hours after the CLP or sham procedure, the mean arterial blood pressure, systolic and diastolic blood pressure and vascular reactivity to phenylephrine were evaluated. Additionally, blood samples were collected for measurement of nitric oxide (nitrate and nitrite), urea, creatinine, AST, ALT, lactate and CK.; hematological analyzes were also performed. Statistical significance was analyzed by two-way ANOVA followed by post hoc Bonferroni. The results shows that the CLP was able to reproduce the main characteristics of humans sepsis like as, systemic inflamation, hypotension, reduced response to vasoconstrictors, hypoxia and tissue damage. Interestingly, treatment with sildenafil improved and the organ hypoperfusion at early stages of sepsis reducing organ injury. Thus, phosphodiesterase inhibition may be a useful therapeutic strategy if administered at the proper window of opportunity.
publishDate 2015
dc.date.issued.fl_str_mv 2015-02-26
dc.date.available.fl_str_mv 2016-11-24
2017-07-21T14:13:07Z
dc.date.accessioned.fl_str_mv 2017-07-21T14:13:07Z
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dc.identifier.citation.fl_str_mv SILVÉRIO, Vanessa Kovalski. EFEITO DO SILDENAFIL SOBRE ALTERAÇÕES VASCULARES E DANO TECIDUAL INDUZIDOS PELO CHOQUE SÉPTICO. 2015. 58 f. Dissertação (Mestrado em Farmacos, Medicamentos e Biociências Aplicadas à Farmácia) - UNIVERSIDADE ESTADUAL DE PONTA GROSSA, Ponta Grossa, 2015.
dc.identifier.uri.fl_str_mv http://tede2.uepg.br/jspui/handle/prefix/98
identifier_str_mv SILVÉRIO, Vanessa Kovalski. EFEITO DO SILDENAFIL SOBRE ALTERAÇÕES VASCULARES E DANO TECIDUAL INDUZIDOS PELO CHOQUE SÉPTICO. 2015. 58 f. Dissertação (Mestrado em Farmacos, Medicamentos e Biociências Aplicadas à Farmácia) - UNIVERSIDADE ESTADUAL DE PONTA GROSSA, Ponta Grossa, 2015.
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dc.publisher.department.fl_str_mv Farmacos, Medicamentos e Biociências Aplicadas à Farmácia
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