Hardcastle J, Hardcastle P T, Chapman J, Taylor C J
Department of Biomedical Science, University of Sheffield, UK.
J Pharm Pharmacol. 2001 May;53(5):711-9. doi: 10.1211/0022357011775839.
Bile acids cause secretion throughout the intestinal tract and this process contributes to maintaining the fluidity of intestinal contents. In cystic fibrosis (CF) defective intestinal secretion can lead to excessive dehydration of the luminal contents and the development of clinical symptoms. This study was designed to investigate bile acid-induced secretion in mouse ileum and to determine whether this process was defective in CF. Taurocholic acid-induced secretion was monitored as a rise in short-circuit current (SCC) in ileal sheets from normal (Swiss MF1) and transgenic CF mice. Taurocholic acid increased the SCC in both intact and stripped ileal sheets from Swiss MF1 mice. This effect was due to a stimulation of electrogenic Cl- secretion as it was inhibited by Cl(-)-free conditions, serosal furosemide (frusemide), mucosal diphenylamine-2-carboxylic acid (DPC) and increased serosal K+ concentration, without being affected by reduced mucosal Na+ concentration. Taurocholic acid-induced secretion was inhibited by tetrodotoxin, indicating the involvement of a neural pathway, but this did not include capsaicin-sensitive afferent neurons or muscarinic cholinoreceptors. Mucosal mast cells also contributed to the response. Responses in tissues from transgenic wild-type mice were similar to those obtained with Swiss MF1 animals, but ilea from CF mice exhibited a lower basal SCC with significantly reduced secretory responses to acetylcholine and taurocholic acid. We concluded that taurocholic acid induces ileal secretion by a mechanism that entails activation of enteric nerves and degranulation of mucosal mast cells. Impaired bile acid-induced secretion in CF may contribute to luminal dehydration.
胆汁酸可引起整个肠道的分泌，这一过程有助于维持肠内容物的流动性。在囊性纤维化（CF）中，肠道分泌功能缺陷可导致肠腔内容物过度脱水并引发临床症状。本研究旨在调查胆汁酸诱导的小鼠回肠分泌情况，并确定这一过程在CF中是否存在缺陷。通过监测正常（瑞士MF1）和转基因CF小鼠回肠片短路电流（SCC）的升高来检测牛磺胆酸诱导的分泌。牛磺胆酸可增加瑞士MF1小鼠完整和剥离回肠片的SCC。这种作用是由于对电中性Cl⁻分泌的刺激，因为它在无Cl⁻条件、浆膜侧使用速尿、黏膜侧使用二苯胺-2-羧酸（DPC）以及增加浆膜侧K⁺浓度时受到抑制，而不受黏膜侧Na⁺浓度降低的影响。牛磺胆酸诱导的分泌受到河豚毒素的抑制，表明涉及神经通路，但这不包括辣椒素敏感的传入神经元或毒蕈碱型胆碱能受体。黏膜肥大细胞也参与了这一反应。转基因野生型小鼠组织的反应与瑞士MF1动物相似，但CF小鼠的回肠基础SCC较低，对乙酰胆碱和牛磺胆酸的分泌反应明显降低。我们得出结论，牛磺胆酸通过一种需要激活肠神经和黏膜肥大细胞脱颗粒的机制诱导回肠分泌。CF中胆汁酸诱导的分泌受损可能导致肠腔脱水。
