Envolvimento de canais para potássio e de nucleotídios cíclicos no mecanismo de ação tocolítico do ácido 8(17),12E,14-labdatrieno-18-óico (labdano-302) em útero isolado de rata.

• Autor(a) principal: Travassos, Rafael de Almeida
• Data de Publicação: 2010
• 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/tede/6852
• topic: Labdano-302; Ação tocolítica; Canais para potássio; Nucleotídios cíclicos; Útero de rata; Labdane-302; Tocolytic action; Potassium channels; Cyclic nucleotides; Rat uterus; CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA

8(17),12E,14-labdatrien-18 oic acid (labdane-302), is a diterpene isolated from the stem bark of Xylopia langsdorfiana A. St.-Hil. & Tul. In a preliminary study, Ribeiro (2003) demonstrated that labdane-302 inhibited in an equipotent manner the phasic contractions induced by carbachol or oxytocin in rat uterus. The aim of the present study was to investigate the spasmolytic action mechanism of labdane-302 in that organ. Isometric and isotonic contractions were monitored and the parameters of relative potency and efficacy were determined from cumulative concentration-response curves. Labdane-302 inhibited the cumulative concentration-response curves to carbachol (pD´2 = 3.4 ± 0.1; r2 = 0.9 ± 0.05) and oxytocin (pD´2 = 3.8 ± 0.2; r2 = 0.9 ± 0.04) these were shifted to the right, in a non-parallel manner (Schild plot slope = 0.15 ± 0.04 and 1.13 ± 0.1 respectively), with reduction of the maximal effect (Emax), suggesting a noncompetitive antagonism. Labdane-302 was not effective in relaxing the uterus pre-contracted by 60 mM KCl (Emax = 9.75 ± 0.07%),on the other hand, relaxed in a significant and concentration dependent manner the rat uterus pre-contracted by oxytocin (pD2 = 4,3 ± 0,06), suggesting a possible involvement of the K+ channels in the spasmolytic effect caused by labdane-302. Because K+ channels play a major role in the regulation of membrane potential and modulation of CaV, we decided to investigate the participation of K+ channels in the spasmolytic action of labdane-302. The relaxant potency of labdane-302 (pD2 = 4.3 ± 0.06) was decreased about 16 times in the presence of CsCl (pD2 = 3.1 ± 0.06), a non-selective K+channels blocker, suggesting a possible involvement of the K+ channels in the tocolytic effect of the labdane-302. In order to verify which subtypes of K+ channels could be involved we used selectives blockers of these channels. The observation that 4-aminopyridine, a selective blocker of voltage-gated K+ channels (Kv), and that glibenclamide, a selective blocker of the ATP-sensitive K+ channels (KATP) did not change the relaxant effect of labdane-302 suggests that KV and KATP are not involved in its action mechanism. However, the log concentration-response curve induced by labdane-302 was shifted to the right in the presence of apamine (pD2 = 3.8 ± 0.03), a selective blocker of the small-conductance calcium-activated K+ channels (SKCa) and TEA+ 1 mM (pD2 = 3.6 ± 0.04), a selective blocker of the large conductance clacium-activated K+ channels (BKca). The involvement of BKCa was confirmed using a specific blocker of that channels iberiotoxin (IbTx) (pD2 = 3.8 ± 0.06) , suggesting the involvement of SKCa and BKCa in the tocolytic action mechanism induced by labdane-302 on uterus rat. The aminophylline a nonselective inhibitor of phosphodiesterases (PDE) potentiated (pD2 = 7.8 ± 0.1) in about 320 times the relaxation produced by labdane-302 in rat uterus. The results suggest that effect of labdane-302 on uterus rat, involves the activation of the SKCa e BKCa, which modulate indirectly the CaV, leading to a decrease the [Ca2+]c , and cyclic nucleotides like cAMP and cGMP may be involved in this tocolytic action