Avaliação do relaxamento vascular induzido por um novo derivado pirazólico protótipo a fármaco (LQFM 021), possível inibidor de fosfodiesterase
Autor(a) principal: | |
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Data de Publicação: | 2012 |
Tipo de documento: | Dissertação |
Idioma: | por |
Título da fonte: | Repositório Institucional da UFG |
dARK ID: | ark:/38995/0013000000g6z |
Texto Completo: | http://repositorio.bc.ufg.br/tede/handle/tde/2110 |
Resumo: | The inhibition of phosphodiesterases (PDEs) increases intracellular levels of cyclic nucleotides 3 ': 5'-cyclic adenosine monophosphate (cAMP) and 3 ': 5'-cyclic guanosine monophosphate (cGMP), which has many physiological and biochemical effects, especially in cardiovascular system. The objective of this study was to analyze the pharmacological effects of a new compound derived from pyrazole, LQFM 021, which was indicated by molecular modeling studies as a possible inhibitor of PDE-3. For this purpose, aortas were isolated of rats and mounted in organ baths for isometric tension recording of the relaxing effect of LQFM 021, in preparations pre-contracted with phenylephrine. We analyzed the involvement of the vascular endothelium, soluble guanylate cyclase (sGC) and adenylate cyclase (AC), the role of K+ channels and Ca2+, besides the contribution of Ca2+ uptake by the sarcoplasmic reticulum. As a result, was demonstrated that the LQFM 021 induces vascular relaxation (Emax: 54.9 ± 6.0%), being this relaxation potentiated by endothelium (Emax: 88.1 ± 2.1%). The inhibition of AC with MDL-12.330A (10 μM) or of the sGC with ODQ (1 μM) reduced the relaxation of 88.1 ± 2.1%, to 48.35 ± 3.01% and 19.95 ± 2.32%, respectively. The pre-contraction with KCl 45 mM or treatment of preparations with TEA (5 mM), reduced almost completely the relaxing effect of the compound. Inhibition of Ca2+ / ATPase reticular with CPA (10 mM) reduced the relaxation stimulated by 021 LQFM approximately 66.5%. Concentration-response curve contractile induced by phenylephrine (0.1 nM to 1 μM) or by CaCl2 (0-3 mM, zero-calcium + phenylephrine) were reduced by pretreatment of preparations with LQFM 021 (EC50). In conclusion, this study showed that the new synthetic derivative of pyrazole LQFM 021 is a potential inhibitor of PDE-3 and has vasorelaxant activity. The endothelium potentiates the relaxation stimulated by the compound. The route of sGC and AC are involved in the mechanism of action of LQFM 021. Was also evidenced by participation from sarcoplasmatic reticulum, well as the flow of K+ and Ca2+ through the cell membrane. |
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ROCHA, Matheus Lavorentihttp://lattes.cnpq.br/7459866708740096http://lattes.cnpq.br/1364582990248485MARTINS, Daniella Ramos2014-07-29T16:11:50Z2012-05-032012-02-28MARTINS, Daniella Ramos. Synthesis, vasodilator activity and toxicity of new derivative pirazólico (LQFM 021), a possible inhibitor of phosphodiesterase. 2012. 64 f. Dissertação (Mestrado em Ciências da Saúde - Farmácia) - Universidade Federal de Goiás, Goiânia, 2012.http://repositorio.bc.ufg.br/tede/handle/tde/2110ark:/38995/0013000000g6zThe inhibition of phosphodiesterases (PDEs) increases intracellular levels of cyclic nucleotides 3 ': 5'-cyclic adenosine monophosphate (cAMP) and 3 ': 5'-cyclic guanosine monophosphate (cGMP), which has many physiological and biochemical effects, especially in cardiovascular system. The objective of this study was to analyze the pharmacological effects of a new compound derived from pyrazole, LQFM 021, which was indicated by molecular modeling studies as a possible inhibitor of PDE-3. For this purpose, aortas were isolated of rats and mounted in organ baths for isometric tension recording of the relaxing effect of LQFM 021, in preparations pre-contracted with phenylephrine. We analyzed the involvement of the vascular endothelium, soluble guanylate cyclase (sGC) and adenylate cyclase (AC), the role of K+ channels and Ca2+, besides the contribution of Ca2+ uptake by the sarcoplasmic reticulum. As a result, was demonstrated that the LQFM 021 induces vascular relaxation (Emax: 54.9 ± 6.0%), being this relaxation potentiated by endothelium (Emax: 88.1 ± 2.1%). The inhibition of AC with MDL-12.330A (10 μM) or of the sGC with ODQ (1 μM) reduced the relaxation of 88.1 ± 2.1%, to 48.35 ± 3.01% and 19.95 ± 2.32%, respectively. The pre-contraction with KCl 45 mM or treatment of preparations with TEA (5 mM), reduced almost completely the relaxing effect of the compound. Inhibition of Ca2+ / ATPase reticular with CPA (10 mM) reduced the relaxation stimulated by 021 LQFM approximately 66.5%. Concentration-response curve contractile induced by phenylephrine (0.1 nM to 1 μM) or by CaCl2 (0-3 mM, zero-calcium + phenylephrine) were reduced by pretreatment of preparations with LQFM 021 (EC50). In conclusion, this study showed that the new synthetic derivative of pyrazole LQFM 021 is a potential inhibitor of PDE-3 and has vasorelaxant activity. The endothelium potentiates the relaxation stimulated by the compound. The route of sGC and AC are involved in the mechanism of action of LQFM 021. Was also evidenced by participation from sarcoplasmatic reticulum, well as the flow of K+ and Ca2+ through the cell membrane.A inibição das fosfodiesterases (PDEs) aumenta os níveis intracelulares de nucleotídeos cíclicos 3' : 5'-monofosfato cíclico de adenosina (AMPc) e 3' : 5'-monofosfato cíclico de guanosina (GMPc), os quais tem muitos efeitos fisiológicos e bioquímicos, sobretudo no sistema cardiovascular. O objetivo deste estudo foi analisar os efeitos farmacológicos de um novo composto derivado do pirazol, LQFM 021, o qual foi apontado por estudos de modelagem molecular como possível inibidor de PDE-3. Para tanto, artérias aortas de ratos foram isoladas e montadas em banhos de órgão para registro da tensão isométrica do efeito relaxante do LQFM 021, em preparações pré-contraídas com fenilefrina. Foi analisada a participação do endotélio vascular, da guanilato ciclase solúvel (GCs) e da adenilato ciclase (AC), o papel dos canais de K+ e de Ca2+, além da contribuição da captação de Ca2+ pelo retículo sarcoplasmático. Como resultado, foi demonstrado que o LQFM 021 induz relaxamento vascular (Emax: 54.9 ± 6.0%), sendo este relaxamento potencializado pelo endotélio (Emax:88.1 ± 2.1%). A inibição da AC com MDL-12.330A (10 μM) ou da GCs com ODQ (1 μM), reduziram o relaxamento de 88,1 ± 2,1%, para 48,35 ± 3,01% e 19,95 ± 2,32%, respectivamente. A pré-contração com KCl 45 mM ou o tratamento das preparações com TEA (5 mM), reduziram quase que por completo o efeito relaxante do composto. A inibição da Ca2+/ATPase reticular com CPA (10 μM), reduziu o relaxamento estimulado pelo LQFM 021 em aproximadamente 66,5%. Curva concentração-resposta contrátil induzida pela fenilefrina (0,1 nM a 1 μM) ou pelo CaCl2 (0 a 3 mM, em meio zero-cálcio + fenilefrina) foram reduzidas pelo pré-tratamento das preparações com LQFM 021 (EC50). Em conclusão, este estudo mostrou que o novo derivado sintético de pirazol LQFM 021 é um possível inibidor de PDE-3 e possui atividade vasorelaxante. O endotélio participa e potencializa o relaxamento estimulado pelo composto. A via da GCs e AC estão envolvidas no mecanismo de ação do LQFM 021. Também foi evidenciada a participação do retículo sarcoplasmático, bem como o fluxo de K+ e de Ca2+ através da membrana celular.Made available in DSpace on 2014-07-29T16:11:50Z (GMT). No. of bitstreams: 1 Dissertacao DAniella Ramos Martins.pdf: 914272 bytes, checksum: 038f97a7fcd95721aab346f4a3bd0587 (MD5) Previous issue date: 2012-02-28application/pdfhttp://repositorio.bc.ufg.br/TEDE/retrieve/4842/Dissertacao%20DAniella%20Ramos%20Martins.pdf.jpgporUniversidade Federal de GoiásMestrado em Ciências FarmacêuticasUFGBRCiências da Saúde - FarmáciaFosfodiesterasesrelaxamentoaortaAMPcGMPcphosphodiesteraserelaxationaorticcAMPcGMPCNPQ::CIENCIAS DA SAUDE::FARMACIAAvaliação do relaxamento vascular induzido por um novo derivado pirazólico protótipo a fármaco (LQFM 021), possível inibidor de fosfodiesteraseSynthesis, vasodilator activity and toxicity of new derivative pirazólico (LQFM 021), a possible inhibitor of phosphodiesteraseinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da UFGinstname:Universidade Federal de Goiás (UFG)instacron:UFGORIGINALDissertacao DAniella Ramos Martins.pdfapplication/pdf914272http://repositorio.bc.ufg.br/tede/bitstreams/b8d8cb9d-caa7-4133-9904-3c3f83438a47/download038f97a7fcd95721aab346f4a3bd0587MD51THUMBNAILDissertacao DAniella Ramos Martins.pdf.jpgDissertacao DAniella Ramos Martins.pdf.jpgGenerated Thumbnailimage/jpeg2104http://repositorio.bc.ufg.br/tede/bitstreams/1b4667c1-f5dd-4931-9fda-91e88206bfc1/downloadc4715912a635b5fbde63d2a9b070733fMD52tde/21102014-07-30 03:17:00.749open.accessoai:repositorio.bc.ufg.br:tde/2110http://repositorio.bc.ufg.br/tedeRepositório InstitucionalPUBhttp://repositorio.bc.ufg.br/oai/requesttasesdissertacoes.bc@ufg.bropendoar:2014-07-30T06:17Repositório Institucional da UFG - Universidade Federal de Goiás (UFG)false |
dc.title.por.fl_str_mv |
Avaliação do relaxamento vascular induzido por um novo derivado pirazólico protótipo a fármaco (LQFM 021), possível inibidor de fosfodiesterase |
dc.title.alternative.eng.fl_str_mv |
Synthesis, vasodilator activity and toxicity of new derivative pirazólico (LQFM 021), a possible inhibitor of phosphodiesterase |
title |
Avaliação do relaxamento vascular induzido por um novo derivado pirazólico protótipo a fármaco (LQFM 021), possível inibidor de fosfodiesterase |
spellingShingle |
Avaliação do relaxamento vascular induzido por um novo derivado pirazólico protótipo a fármaco (LQFM 021), possível inibidor de fosfodiesterase MARTINS, Daniella Ramos Fosfodiesterases relaxamento aorta AMPc GMPc phosphodiesterase relaxation aortic cAMP cGMP CNPQ::CIENCIAS DA SAUDE::FARMACIA |
title_short |
Avaliação do relaxamento vascular induzido por um novo derivado pirazólico protótipo a fármaco (LQFM 021), possível inibidor de fosfodiesterase |
title_full |
Avaliação do relaxamento vascular induzido por um novo derivado pirazólico protótipo a fármaco (LQFM 021), possível inibidor de fosfodiesterase |
title_fullStr |
Avaliação do relaxamento vascular induzido por um novo derivado pirazólico protótipo a fármaco (LQFM 021), possível inibidor de fosfodiesterase |
title_full_unstemmed |
Avaliação do relaxamento vascular induzido por um novo derivado pirazólico protótipo a fármaco (LQFM 021), possível inibidor de fosfodiesterase |
title_sort |
Avaliação do relaxamento vascular induzido por um novo derivado pirazólico protótipo a fármaco (LQFM 021), possível inibidor de fosfodiesterase |
author |
MARTINS, Daniella Ramos |
author_facet |
MARTINS, Daniella Ramos |
author_role |
author |
dc.contributor.advisor1.fl_str_mv |
ROCHA, Matheus Lavorenti |
dc.contributor.advisor1Lattes.fl_str_mv |
http://lattes.cnpq.br/7459866708740096 |
dc.contributor.authorLattes.fl_str_mv |
http://lattes.cnpq.br/1364582990248485 |
dc.contributor.author.fl_str_mv |
MARTINS, Daniella Ramos |
contributor_str_mv |
ROCHA, Matheus Lavorenti |
dc.subject.por.fl_str_mv |
Fosfodiesterases relaxamento aorta AMPc GMPc |
topic |
Fosfodiesterases relaxamento aorta AMPc GMPc phosphodiesterase relaxation aortic cAMP cGMP CNPQ::CIENCIAS DA SAUDE::FARMACIA |
dc.subject.eng.fl_str_mv |
phosphodiesterase relaxation aortic cAMP cGMP |
dc.subject.cnpq.fl_str_mv |
CNPQ::CIENCIAS DA SAUDE::FARMACIA |
description |
The inhibition of phosphodiesterases (PDEs) increases intracellular levels of cyclic nucleotides 3 ': 5'-cyclic adenosine monophosphate (cAMP) and 3 ': 5'-cyclic guanosine monophosphate (cGMP), which has many physiological and biochemical effects, especially in cardiovascular system. The objective of this study was to analyze the pharmacological effects of a new compound derived from pyrazole, LQFM 021, which was indicated by molecular modeling studies as a possible inhibitor of PDE-3. For this purpose, aortas were isolated of rats and mounted in organ baths for isometric tension recording of the relaxing effect of LQFM 021, in preparations pre-contracted with phenylephrine. We analyzed the involvement of the vascular endothelium, soluble guanylate cyclase (sGC) and adenylate cyclase (AC), the role of K+ channels and Ca2+, besides the contribution of Ca2+ uptake by the sarcoplasmic reticulum. As a result, was demonstrated that the LQFM 021 induces vascular relaxation (Emax: 54.9 ± 6.0%), being this relaxation potentiated by endothelium (Emax: 88.1 ± 2.1%). The inhibition of AC with MDL-12.330A (10 μM) or of the sGC with ODQ (1 μM) reduced the relaxation of 88.1 ± 2.1%, to 48.35 ± 3.01% and 19.95 ± 2.32%, respectively. The pre-contraction with KCl 45 mM or treatment of preparations with TEA (5 mM), reduced almost completely the relaxing effect of the compound. Inhibition of Ca2+ / ATPase reticular with CPA (10 mM) reduced the relaxation stimulated by 021 LQFM approximately 66.5%. Concentration-response curve contractile induced by phenylephrine (0.1 nM to 1 μM) or by CaCl2 (0-3 mM, zero-calcium + phenylephrine) were reduced by pretreatment of preparations with LQFM 021 (EC50). In conclusion, this study showed that the new synthetic derivative of pyrazole LQFM 021 is a potential inhibitor of PDE-3 and has vasorelaxant activity. The endothelium potentiates the relaxation stimulated by the compound. The route of sGC and AC are involved in the mechanism of action of LQFM 021. Was also evidenced by participation from sarcoplasmatic reticulum, well as the flow of K+ and Ca2+ through the cell membrane. |
publishDate |
2012 |
dc.date.available.fl_str_mv |
2012-05-03 |
dc.date.issued.fl_str_mv |
2012-02-28 |
dc.date.accessioned.fl_str_mv |
2014-07-29T16:11:50Z |
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info:eu-repo/semantics/masterThesis |
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dc.identifier.citation.fl_str_mv |
MARTINS, Daniella Ramos. Synthesis, vasodilator activity and toxicity of new derivative pirazólico (LQFM 021), a possible inhibitor of phosphodiesterase. 2012. 64 f. Dissertação (Mestrado em Ciências da Saúde - Farmácia) - Universidade Federal de Goiás, Goiânia, 2012. |
dc.identifier.uri.fl_str_mv |
http://repositorio.bc.ufg.br/tede/handle/tde/2110 |
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ark:/38995/0013000000g6z |
identifier_str_mv |
MARTINS, Daniella Ramos. Synthesis, vasodilator activity and toxicity of new derivative pirazólico (LQFM 021), a possible inhibitor of phosphodiesterase. 2012. 64 f. Dissertação (Mestrado em Ciências da Saúde - Farmácia) - Universidade Federal de Goiás, Goiânia, 2012. ark:/38995/0013000000g6z |
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http://repositorio.bc.ufg.br/tede/handle/tde/2110 |
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Universidade Federal de Goiás |
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Mestrado em Ciências Farmacêuticas |
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UFG |
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BR |
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Ciências da Saúde - Farmácia |
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Universidade Federal de Goiás |
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