Estudo do efeito relaxante de um novo composto doador de óxido nítrico em preparações de traquéias isoladas de ratos

• Ano de defesa: 2011
• Autor(a) principal: CASTRO, Patrícia Ferreira da Silva
• Orientador(a): ROCHA, Matheus Lavorenti
• Tipo de documento: Dissertação
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Federal de Goiás
• Programa de Pós-Graduação: Mestrado em Ciências Farmacêuticas
• Departamento: Ciências da Saúde - Farmácia
• País: BR
• Palavras-chave em Português: Óxido Nítrico; complexo nitrosilados de rutênio; traquéia; relaxamento; canais para potássio; guanilato ciclase solúvel
• Palavras-chave em Inglês: Nitric oxide; nitrosyl ruthenium complex; trachea; relaxation; K+ channels and guanylate cyclase
• Área do conhecimento CNPq: CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA
• Link de acesso: http://repositorio.bc.ufg.br/tede/handle/tde/2104

This study evaluated the mechanisms of relaxation of two nitric oxide (NO) donors, ruthenium complex [Ru(terpy)(bdq)NO+]3+ (Terpy) and sodium nitroprusside (SNP) in isolated trachea of rats. The isolated trachea was sectioned into rings and contracted with carbachol in an organ chamber. The relaxing effect of Terpy and SNP was evaluated at increasing concentrations from 10 nM to 100 μM. Thus, we verified the contribution of the different types of K+ channels, the importance of sGC/cGMP pathway, the inhibition of COX and PDEs, the influence of the extra and intracellular Ca2+ sources and the influence of the epithelium on the relaxing response. The synergism between NO-donor and β-adrenoceptor agonist terbutaline was also verified. Additionally, we have used confocal microscopy in order to analyze the effect of the donors on cytosolic Ca2+ concentration. We have verified that both compounds led to the relaxation of tracheal smooth muscle preparations in a dependent-concentration mode. However, the maximum effect (Emax) induced by Terpy was higher than the effect of SNP. However, the Terpy effects were significantly reduced by pre-contraction with 75 mM KCl. K+ channel blockers like the tetraethylammonium, glybenclamide, BaCl2 and 4-aminopyridine reduced the relaxation to Terpy, while iberiotoxin and apamin did not modify this response. SNP- induced relaxation was significantly reduced by pretreatment with ODQ (sGC inhibitor). On the IBMX (non-selective PDEs inhibitor) increased the relaxation only to SNP. The response to both NO-donors was not altered by indomethacin, thapsigargin (reticular Ca2+-ATPase inhibitor) or ruthenium red (a mitochondrial Ca2+ uniporter inhibitor). The epithelium removal reduced the relaxation only to SNP, and it had no effects on Terpy. In relation to synergic effect of the association of NO-donors and terbutaline, we did not observe any additive effect in the relaxation induced by terbutaline. Terpy was more effective than SNP in reducing the cytosolic Ca2+ concentration measured by confocal microscopy. In conclusion, these results have shown that Terpy induces airway smooth muscle relaxation by cGMP-independent mechanisms. It involves Ca2+ and K+ fluxes (mainly via Kv, Kir and KATP channels) across the membrane, and it is more effective in reducing cytosolic Ca2+ concentration and inducing relaxation in the rat trachea than the SNP. In relation to SNP, the most important relaxation pathway seems to be related to sGC/cGMP pathway and activation of Kir and SKCa channels.