Lenzen R, Alpini G, Tavoloni N
Department of Medicine, Heinrich-Heine-University, Dusseldorf, Federal Republic of Germany.
Am J Physiol. 1992 Oct;263(4 Pt 1):G527-32. doi: 10.1152/ajpgi.1992.263.4.G527.
Although convincing evidence has been obtained to support a ductular origin of secretin choleresis, the precise mechanism of the choleretic effect of the hormone is poorly understood. The present studies were carried out to 1) further clarify the anatomic site at which secretin stimulates bile flow and 2) establish the signal transduction system underlying this effect. To this end, parenchymal and nonparenchymal liver cells, the latter enriched in bile duct cells, were isolated from rats with ductular cell hyperplasia, and the effect of secretin on intracellular formation of both adenosine 3',5'-cyclic monophosphate (cAMP) and inositol phosphates (IPs) was compared with that observed with glucagon and [Tyr10,13,Phe22,Trp25]secretin (SG-secretin). In the pancreas, secretin stimulates both messenger systems, while SG-secretin activates only the cAMP cascade. In isolated hepatocytes, both secretin and SG-secretin failed to increase formation of cAMP and IPs, which were instead activated by glucagon. In isolated bile duct cells, secretin induced formation of both cAMP and IPs, while SG-secretin stimulated solely the cAMP system, as in the pancreas. Glucagon did not stimulate either messenger system in this cell preparation. In vivo, both secretin and SG-secretin stimulated a bicarbonate-rich fluid in rats with bile ductular cell hyperplasia and in normal guinea pigs, which was demonstrated to originate at the distal biliary epithelium. These findings support the existing view that glucagon stimulates canalicular bile flow, while secretin increases secretory activity at the bile ductules and/or ducts. More importantly, they indicate that stimulation of ductular secretory activity by secretin is mediated by the cAMP system and does not involve the IP signal transduction pathway.
尽管已经获得了令人信服的证据来支持促胰液素胆汁分泌来自胆小管，但该激素利胆作用的确切机制仍知之甚少。本研究旨在：1）进一步阐明促胰液素刺激胆汁流动的解剖部位；2）确定这种作用背后的信号转导系统。为此，从患有胆小管细胞增生的大鼠中分离出实质肝细胞和非实质肝细胞（后者富含胆管细胞），并将促胰液素对细胞内3',5'-环磷酸腺苷（cAMP）和肌醇磷酸（IPs）形成的影响与胰高血糖素和[酪氨酸10,13,苯丙氨酸22,色氨酸25]促胰液素（SG-促胰液素）的作用进行比较。在胰腺中，促胰液素刺激这两种信使系统，而SG-促胰液素仅激活cAMP级联反应。在分离的肝细胞中，促胰液素和SG-促胰液素均未能增加cAMP和IPs的形成，而胰高血糖素可激活它们。在分离的胆管细胞中，促胰液素诱导cAMP和IPs的形成，而SG-促胰液素仅刺激cAMP系统，与胰腺中的情况相同。胰高血糖素在这种细胞制剂中不刺激任何一种信使系统。在体内，促胰液素和SG-促胰液素均刺激患有胆小管细胞增生的大鼠和正常豚鼠分泌富含碳酸氢盐的液体，这被证明起源于远端胆管上皮。这些发现支持了现有的观点，即胰高血糖素刺激胆小管胆汁流动，而促胰液素增加胆小管和/或胆管的分泌活性。更重要的是，它们表明促胰液素对胆小管分泌活性的刺激是由cAMP系统介导的，不涉及IP信号转导途径。
