Rodríguez Myrian R, Sabbatini María Eugenia, Santella Gisela, Vescina Cristina, Vatta Marcelo S, Bianciotti Liliana G
Cátedras de Fisiopatología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956, Piso 5 (1113AAD) Buenos Aires, Argentina.
Regul Pept. 2006 Jul 15;135(1-2):54-62. doi: 10.1016/j.regpep.2006.04.001. Epub 2006 May 19.
The role of Endothelin-1 (ET-1) in the central nervous system is not fully understood yet although several studies strongly support its neuromodulatory role. A high density of endothelin receptors is present in the dorsal vagal complex that is the major site for the regulation of the digestive function. Therefore in the present study we sought to establish the role of ET-1 in the central regulation of bile secretion in the rat. Intracerebroventricular ET-1 injection exhibited opposite behaviors on spontaneous bile secretion according to the dose administered. Lower doses of ET-1 (1 fM) increased bile flow and bicarbonate excretion whereas higher doses (1 nM) decreased bile flow and bile acid output. Both the choleretic and the cholestatic effects of ET-1 were abolished in animals pretreated with icv BQ-610 (selective ETA antagonist) but not with BQ-788 (selective ETB antagonist). In addition, truncal vagotomy but not adrenergic blockade abolished ET-1 effects on bile secretion. Brain nitric oxide was not involved in ET-1 response since L-NAME pretreatment failed to affect ET-1 actions on the liver. Portal venous pressure was increased by centrally administered ET-1 being the magnitude of the increase similar with low and high doses of the peptide. These results show that centrally applied ET-1 modified different bile flow fractions independent of hemodynamic changes. Lower doses of ET-1 increased bile acid independent flow whereas higher doses decreased bile acid dependent flow. Vagal pathways through the activation of apparently distinct ETA receptors mediated the cholestatic as well as the choleretic effects induced by ET-1. Present findings show that ET-1 participates in the central regulation of bile secretion in the rat and give further insights into the complexity of brain-liver interaction.
尽管多项研究有力地支持内皮素 -1（ET-1）的神经调节作用，但其在中枢神经系统中的作用尚未完全明确。背迷走神经复合体中存在高密度的内皮素受体，该复合体是调节消化功能的主要部位。因此，在本研究中，我们试图确定ET-1在大鼠胆汁分泌中枢调节中的作用。根据注射剂量的不同，脑室内注射ET-1对自发性胆汁分泌表现出相反的作用。较低剂量的ET-1（1 fM）可增加胆汁流量和碳酸氢盐排泄，而较高剂量（1 nM）则会降低胆汁流量和胆汁酸输出。用脑室注射BQ-610（选择性ETA拮抗剂）预处理的动物，ET-1的利胆和胆汁淤积作用均被消除，但用BQ-788（选择性ETB拮抗剂）预处理则无此效果。此外，切断迷走神经干可消除ET-1对胆汁分泌的影响，而肾上腺素能阻断则不能。脑一氧化氮不参与ET-1反应，因为L-NAME预处理未能影响ET-1对肝脏的作用。中枢给予ET-1可增加门静脉压力，低剂量和高剂量肽引起的压力升高幅度相似。这些结果表明，中枢应用ET-1可改变不同的胆汁流量分数，且与血流动力学变化无关。较低剂量的ET-1增加胆汁酸非依赖性流量，而较高剂量则降低胆汁酸依赖性流量。ET-1诱导的胆汁淤积和利胆作用是通过激活明显不同的ETA受体的迷走神经通路介导的。目前的研究结果表明，ET-1参与大鼠胆汁分泌的中枢调节，并进一步揭示了脑-肝相互作用的复杂性。
