Investigação da atividade espasmolítica de uma série de derivados do lapachol em íleo de cobaia: um estudo comparativo
Autor(a) principal: | |
---|---|
Data de Publicação: | 2014 |
Tipo de documento: | Dissertação |
Idioma: | por |
Título da fonte: | Biblioteca Digital de Teses e Dissertações da UFPB |
Texto Completo: | https://repositorio.ufpb.br/jspui/handle/123456789/11164 |
Resumo: | The naphthoquinones are substances of great interest, since they have a variety of biological activities. Belonging to this group, there is lapachol, an isolated naphthoquinone species of Tabebuia spp., popularly known as "ipê". Many pharmacological activities, such as spasmolytic, are related to lapachol and its natural or synthetic derivatives. Researchers have turned their attention to this molecule in order to create compounds with therapeutic potential. From this perspective it was decided to investigate the spasmolytic effect of a new series of lapachol derivatives (UFRPE 15, UFRPE 17, UFRPE 31, UFRPE 114, UFRPE 115 e UFRPE 116) and norlapachol (UFRPE 106, UFRPE 107, UFRPE 111, UFRPE 112, UFRPE 113 e UFRPE 117) in the isolated guinea pig ileum, as well as investigate the mechanism of action of the compound which show a better efficacy. In the pharmacological screening, the lapachol derivatives showed low efficacy in inhibiting the phasic contractions induced by carbachol (CCh) and histamine. Only UFRPE 115 inhibited the phasic contractions induced by histamine in a concentration-dependent manner. However, derivatives from norlapachol were more promising, since all of them inhibited the phasic contractions induced by CCh and histamine in a concentration-dependent manner, where UFRPE 107, UFRPE 112 and UFRPE 117 compounds showed a better potency and efficacy. The spasmolytic effect of these has been reported in the ileum pre-contracted with KCl, CCh or histamine, and it was noted that these three derivatives relaxed guinea pig ileum in a concentrationdependent manner, and in special the UFRPE 117 showed the highest relative potency, thus, it was selected to study its mechanism of action. Once UFRPE 117 inhibited histamine-induced contractions and relaxed the ileum pre-contracted by the same agonist, we evaluated the involvement of histamine receptors in this effect. UFRPE 117 inhibited the cumulative curves to histamine, shifting them to right and in a nonparallel manner with Emax reduction, suggesting a noncompetitive antagonism pseudo irreversible type. Since the spasmolytic potency of this compound was reduced when the ileum was pre-contracted with 40 mM KCl, we investigated the involvement of K + channels using 5 mM CsCl, a non-selective blocker of these channels, where its relaxing power was attenuated by approximately 12 folds in the presence of this blocker, suggesting the involvement of K+ channels in spasmolytic action UFRPE 117. To assess which of K+ subtypes channels were involved in this effect, we used 10-5 M glibenclamide, a KATP blocker, whose did not alter the relaxing potency of UFRPE 117, discarding the involvement of these channels. However, in the presence of 100 nM apamin, a selective blocker of SKCa and 1 mM TEA+, a selective blocker of BKCa, The UFRPE 117 relaxant potency was attenuated around 4 to 5 folds, respectively, confirming the involvement of SKCa and BKCa. Thus, the mechanism of spasmolytic action of the synthetic derivative of norlapachol, UFRPE 117, involves activation/positive modulation of SKCa and BKCa, which would lead to a hyperpolarization of the membrane, indirect blocking Cav, reduction of [Ca2+]c and consequent relaxation of this organ. |
id |
UFPB_f7ea867ae4cf84050f4198116239088f |
---|---|
oai_identifier_str |
oai:repositorio.ufpb.br:123456789/11164 |
network_acronym_str |
UFPB |
network_name_str |
Biblioteca Digital de Teses e Dissertações da UFPB |
repository_id_str |
|
spelling |
Investigação da atividade espasmolítica de uma série de derivados do lapachol em íleo de cobaia: um estudo comparativoDerivados do lapacholNaftoquinonaCanais de potássioAção espasmolíticaÍleo de cobaiaLapachol derivativesNaftoquinonePotassium channelsSpasmolytic actionGuinea pig ileumCNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIAThe naphthoquinones are substances of great interest, since they have a variety of biological activities. Belonging to this group, there is lapachol, an isolated naphthoquinone species of Tabebuia spp., popularly known as "ipê". Many pharmacological activities, such as spasmolytic, are related to lapachol and its natural or synthetic derivatives. Researchers have turned their attention to this molecule in order to create compounds with therapeutic potential. From this perspective it was decided to investigate the spasmolytic effect of a new series of lapachol derivatives (UFRPE 15, UFRPE 17, UFRPE 31, UFRPE 114, UFRPE 115 e UFRPE 116) and norlapachol (UFRPE 106, UFRPE 107, UFRPE 111, UFRPE 112, UFRPE 113 e UFRPE 117) in the isolated guinea pig ileum, as well as investigate the mechanism of action of the compound which show a better efficacy. In the pharmacological screening, the lapachol derivatives showed low efficacy in inhibiting the phasic contractions induced by carbachol (CCh) and histamine. Only UFRPE 115 inhibited the phasic contractions induced by histamine in a concentration-dependent manner. However, derivatives from norlapachol were more promising, since all of them inhibited the phasic contractions induced by CCh and histamine in a concentration-dependent manner, where UFRPE 107, UFRPE 112 and UFRPE 117 compounds showed a better potency and efficacy. The spasmolytic effect of these has been reported in the ileum pre-contracted with KCl, CCh or histamine, and it was noted that these three derivatives relaxed guinea pig ileum in a concentrationdependent manner, and in special the UFRPE 117 showed the highest relative potency, thus, it was selected to study its mechanism of action. Once UFRPE 117 inhibited histamine-induced contractions and relaxed the ileum pre-contracted by the same agonist, we evaluated the involvement of histamine receptors in this effect. UFRPE 117 inhibited the cumulative curves to histamine, shifting them to right and in a nonparallel manner with Emax reduction, suggesting a noncompetitive antagonism pseudo irreversible type. Since the spasmolytic potency of this compound was reduced when the ileum was pre-contracted with 40 mM KCl, we investigated the involvement of K + channels using 5 mM CsCl, a non-selective blocker of these channels, where its relaxing power was attenuated by approximately 12 folds in the presence of this blocker, suggesting the involvement of K+ channels in spasmolytic action UFRPE 117. To assess which of K+ subtypes channels were involved in this effect, we used 10-5 M glibenclamide, a KATP blocker, whose did not alter the relaxing potency of UFRPE 117, discarding the involvement of these channels. However, in the presence of 100 nM apamin, a selective blocker of SKCa and 1 mM TEA+, a selective blocker of BKCa, The UFRPE 117 relaxant potency was attenuated around 4 to 5 folds, respectively, confirming the involvement of SKCa and BKCa. Thus, the mechanism of spasmolytic action of the synthetic derivative of norlapachol, UFRPE 117, involves activation/positive modulation of SKCa and BKCa, which would lead to a hyperpolarization of the membrane, indirect blocking Cav, reduction of [Ca2+]c and consequent relaxation of this organ.Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPqAs naftoquinonas são substâncias de grande interesse, pois apresentam uma variedade de atividades biológicas. Pertencente a esse grupo, destaca-se o lapachol, uma naftoquinona isolada de espécies de Tabebuia spp., conhecidas popularmente como “ipês”. Uma vez que muitas atividades farmacológicas, como a espasmolítica, são relacionadas ao lapachol e aos seus derivados naturais ou sintéticos, pesquisadores tem voltado sua atenção para esta molécula a fim de criar compostos com potencial terapêutico. Nessa perspectiva decidiu-se investigar um possível efeito espasmolítico de uma nova série de derivados do lapachol (UFRPE 15, UFRPE 17, UFRPE 31, UFRPE 114, UFRPE 115 e UFRPE 116) e do norlapachol (UFRPE 106, UFRPE 107, UFRPE 111, UFRPE 112, UFRPE 113 e UFRPE 117) em íleo isolado de cobaia, bem como investigar o mecanismo de ação do composto que apresentar uma maior eficácia. Na triagem farmacológica, os compostos derivados do lapachol apresentaram uma baixa eficácia farmacológica em inibir as contrações fásicas induzidas por carbacol e por histamina, apenas o composto UFRPE 115 inibiu as contrações fásicas induzidas por histamina de maneira dependente de concentração. Entretanto, os derivados do norlapachol mostraram-se mais promissores, uma vez que todos inibiram as contrações fásicas induzidas por carbacol e por histamina de maneira dependente de concentração, onde os compostos UFRPE 107, UFRPE 112 e UFRPE 117 apresentaram uma maior potência e eficácia relativas. O efeito relaxante destes foi avaliado no íleo précontraído com KCl, CCh ou histamina, e observou-se que estes 3 derivados relaxaram o íleo de cobaia de maneira dependente de concentração, sendo o derivado UFRPE 117 o que apresentou maior potência relativa, assim foi selecionado para o estudo do seu mecanismo de ação. Uma vez que UFRPE 117 inibiu as contrações induzidas por histamina, bem como relaxou o íleo pré-contraído pelo mesmo agonista, avaliou-se a participação dos receptores histaminérgicos nesse efeito. UFRPE 117 inibiu as curvas cumulativas à histamina, desviando-as para direita, de maneira não paralela e com redução do Emax, sugerindo um antagonismo do tipo não competitivo pseudo irreversível. Como a potência relaxante deste composto foi reduzida quando o íleo era pré-contraído com 40 mM de KCl, investigou-se a participação dos canais de K+ utilizando 5 mM de CsCl, um bloqueador não seletivo destes canais, onde a sua potência relaxante foi atenuada em cerca de 12 vezes na presença desse bloqueador, sugerindo a participação dos canais de K+ na ação espasmolítica de UFRPE 117. Para avaliar quais os subtipos de canais de K+ estariam envolvidos nesse efeito, utilizou-se 10-5 M de glibenclamida, um bloqueador dos KATP que não alterou a potência relaxante de UFRPE 117, descartando a participação desses canais. Entretanto na presença de 100 nM de apamina um bloqueador seletivos dos SKCa, e 1 mM de TEA+, um bloqueador seletivo dos BKCa a potência relaxante de UFRPE 117 foi atenuada em cerca de 4 e 5 vezes respectivamente, confirmando a participação destes subtipos de canais de K+. Assim o mecanismo de ação espasmolítica do derivado sintético do norlapachol, UFRPE 117 envolve a ativação/modulação positiva dos SKCa e BKCa, o que levaria a uma hiperpolarização de membrana, bloqueio indireto dos Cav, redução da [Ca2+]c e consequente relaxamento desse órgão.Universidade Federal da ParaíbaBrasilFarmacologiaPrograma de Pós-Graduação em Produtos Naturais e Sintéticos BioativosUFPBda Silva, Bagnólia Araújohttp://lattes.cnpq.br/2569484428391315Cavalcante, Fabiana de AndradeSilva, Ana Caroline de Lima2018-08-07T17:10:03Z2018-08-072018-08-07T17:10:03Z2014-02-27info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesishttps://repositorio.ufpb.br/jspui/handle/123456789/11164porinfo:eu-repo/semantics/openAccessreponame:Biblioteca Digital de Teses e Dissertações da UFPBinstname:Universidade Federal da Paraíba (UFPB)instacron:UFPB2018-09-06T00:30:58Zoai:repositorio.ufpb.br:123456789/11164Biblioteca Digital de Teses e Dissertaçõeshttps://repositorio.ufpb.br/PUBhttp://tede.biblioteca.ufpb.br:8080/oai/requestdiretoria@ufpb.br|| diretoria@ufpb.bropendoar:2018-09-06T00:30:58Biblioteca Digital de Teses e Dissertações da UFPB - Universidade Federal da Paraíba (UFPB)false |
dc.title.none.fl_str_mv |
Investigação da atividade espasmolítica de uma série de derivados do lapachol em íleo de cobaia: um estudo comparativo |
title |
Investigação da atividade espasmolítica de uma série de derivados do lapachol em íleo de cobaia: um estudo comparativo |
spellingShingle |
Investigação da atividade espasmolítica de uma série de derivados do lapachol em íleo de cobaia: um estudo comparativo Silva, Ana Caroline de Lima Derivados do lapachol Naftoquinona Canais de potássio Ação espasmolítica Íleo de cobaia Lapachol derivatives Naftoquinone Potassium channels Spasmolytic action Guinea pig ileum CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
title_short |
Investigação da atividade espasmolítica de uma série de derivados do lapachol em íleo de cobaia: um estudo comparativo |
title_full |
Investigação da atividade espasmolítica de uma série de derivados do lapachol em íleo de cobaia: um estudo comparativo |
title_fullStr |
Investigação da atividade espasmolítica de uma série de derivados do lapachol em íleo de cobaia: um estudo comparativo |
title_full_unstemmed |
Investigação da atividade espasmolítica de uma série de derivados do lapachol em íleo de cobaia: um estudo comparativo |
title_sort |
Investigação da atividade espasmolítica de uma série de derivados do lapachol em íleo de cobaia: um estudo comparativo |
author |
Silva, Ana Caroline de Lima |
author_facet |
Silva, Ana Caroline de Lima |
author_role |
author |
dc.contributor.none.fl_str_mv |
da Silva, Bagnólia Araújo http://lattes.cnpq.br/2569484428391315 Cavalcante, Fabiana de Andrade |
dc.contributor.author.fl_str_mv |
Silva, Ana Caroline de Lima |
dc.subject.por.fl_str_mv |
Derivados do lapachol Naftoquinona Canais de potássio Ação espasmolítica Íleo de cobaia Lapachol derivatives Naftoquinone Potassium channels Spasmolytic action Guinea pig ileum CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
topic |
Derivados do lapachol Naftoquinona Canais de potássio Ação espasmolítica Íleo de cobaia Lapachol derivatives Naftoquinone Potassium channels Spasmolytic action Guinea pig ileum CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
description |
The naphthoquinones are substances of great interest, since they have a variety of biological activities. Belonging to this group, there is lapachol, an isolated naphthoquinone species of Tabebuia spp., popularly known as "ipê". Many pharmacological activities, such as spasmolytic, are related to lapachol and its natural or synthetic derivatives. Researchers have turned their attention to this molecule in order to create compounds with therapeutic potential. From this perspective it was decided to investigate the spasmolytic effect of a new series of lapachol derivatives (UFRPE 15, UFRPE 17, UFRPE 31, UFRPE 114, UFRPE 115 e UFRPE 116) and norlapachol (UFRPE 106, UFRPE 107, UFRPE 111, UFRPE 112, UFRPE 113 e UFRPE 117) in the isolated guinea pig ileum, as well as investigate the mechanism of action of the compound which show a better efficacy. In the pharmacological screening, the lapachol derivatives showed low efficacy in inhibiting the phasic contractions induced by carbachol (CCh) and histamine. Only UFRPE 115 inhibited the phasic contractions induced by histamine in a concentration-dependent manner. However, derivatives from norlapachol were more promising, since all of them inhibited the phasic contractions induced by CCh and histamine in a concentration-dependent manner, where UFRPE 107, UFRPE 112 and UFRPE 117 compounds showed a better potency and efficacy. The spasmolytic effect of these has been reported in the ileum pre-contracted with KCl, CCh or histamine, and it was noted that these three derivatives relaxed guinea pig ileum in a concentrationdependent manner, and in special the UFRPE 117 showed the highest relative potency, thus, it was selected to study its mechanism of action. Once UFRPE 117 inhibited histamine-induced contractions and relaxed the ileum pre-contracted by the same agonist, we evaluated the involvement of histamine receptors in this effect. UFRPE 117 inhibited the cumulative curves to histamine, shifting them to right and in a nonparallel manner with Emax reduction, suggesting a noncompetitive antagonism pseudo irreversible type. Since the spasmolytic potency of this compound was reduced when the ileum was pre-contracted with 40 mM KCl, we investigated the involvement of K + channels using 5 mM CsCl, a non-selective blocker of these channels, where its relaxing power was attenuated by approximately 12 folds in the presence of this blocker, suggesting the involvement of K+ channels in spasmolytic action UFRPE 117. To assess which of K+ subtypes channels were involved in this effect, we used 10-5 M glibenclamide, a KATP blocker, whose did not alter the relaxing potency of UFRPE 117, discarding the involvement of these channels. However, in the presence of 100 nM apamin, a selective blocker of SKCa and 1 mM TEA+, a selective blocker of BKCa, The UFRPE 117 relaxant potency was attenuated around 4 to 5 folds, respectively, confirming the involvement of SKCa and BKCa. Thus, the mechanism of spasmolytic action of the synthetic derivative of norlapachol, UFRPE 117, involves activation/positive modulation of SKCa and BKCa, which would lead to a hyperpolarization of the membrane, indirect blocking Cav, reduction of [Ca2+]c and consequent relaxation of this organ. |
publishDate |
2014 |
dc.date.none.fl_str_mv |
2014-02-27 2018-08-07T17:10:03Z 2018-08-07 2018-08-07T17:10:03Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/masterThesis |
format |
masterThesis |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
https://repositorio.ufpb.br/jspui/handle/123456789/11164 |
url |
https://repositorio.ufpb.br/jspui/handle/123456789/11164 |
dc.language.iso.fl_str_mv |
por |
language |
por |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.publisher.none.fl_str_mv |
Universidade Federal da Paraíba Brasil Farmacologia Programa de Pós-Graduação em Produtos Naturais e Sintéticos Bioativos UFPB |
publisher.none.fl_str_mv |
Universidade Federal da Paraíba Brasil Farmacologia Programa de Pós-Graduação em Produtos Naturais e Sintéticos Bioativos UFPB |
dc.source.none.fl_str_mv |
reponame:Biblioteca Digital de Teses e Dissertações da UFPB instname:Universidade Federal da Paraíba (UFPB) instacron:UFPB |
instname_str |
Universidade Federal da Paraíba (UFPB) |
instacron_str |
UFPB |
institution |
UFPB |
reponame_str |
Biblioteca Digital de Teses e Dissertações da UFPB |
collection |
Biblioteca Digital de Teses e Dissertações da UFPB |
repository.name.fl_str_mv |
Biblioteca Digital de Teses e Dissertações da UFPB - Universidade Federal da Paraíba (UFPB) |
repository.mail.fl_str_mv |
diretoria@ufpb.br|| diretoria@ufpb.br |
_version_ |
1801842930596446208 |