SOMATOSTATIN INHIBITS SECRETIN-INDUCED DUCTAL HYPERCHOLERESIS AND EXOCYTOSIS BY CHOLANGIOCYTES

Previous work from our laboratory has implicated hormone-induced plasma membrane movement (i.e., endo- and exocytosis) in water and electrolyte transport by the epithelial cells that line the ducts in the liver (i.e., cholangiocytes). To further explore the cellular mechanisms regulating ductal bile secretion, we infused somatostatin and/or secretin intravenously into rats 2 wk after either bile duct ligation (BDL), a procedure that induces selective proliferation of cholangiocytes, or sham surgery and measured bile flow and biliary constituents. We also determined the effect of somatostatin on basal and secretin-induced exocytosis by purified cholangiocytes isolated from rat liver after BDL. Finally, we studied the expression of the somatostatin receptor gene by both ribonuclease (RNase) protection and nuclear run-on assays using cDNA encoding for two subtypes of the somatostatin receptor gene (i.e., SSTR(1) and SSTR(2)). In vivo, somatostatin infusion caused a dose-dependent bicarbonate-poor decrease (57% maximal decrease below baseline; P < 0.05) in bile flow in BDL but not in sham-operated rats; in contrast, secretin caused a dose-dependent bicarbonate-rich choleresis (228% maximal increase above baseline; P < 0.05) in BDL but not in sham-operated rats. Simultaneous or prior infusion of somatostatin inhibited the secretin-induced hypercholeresis in BDL rats. In vitro, somatostatin had no effect on basal exocytosis by cholangiocytes isolated from BDL rats; however, somatostatin inhibited (88% maximal inhibition; P < 0.05) secretin-induced exocytosis by cholangiocytes in a dose-dependent fashion. In addition, somatostatin inhibited secretin-induced increases in levels of adenosine 3',5'-cyclic monophosphate (cAMP) in cholangiocytes isolated from BDL rats. By RNase protection assays, SSTR(2) (but not SSTR1) mRNA was detected in normal liver exclusively in cholangiocytes; after BDL, SSTR(2) mRNA expression increased similar to 20-fold per cholangiocyte compared with normal rats. Synthesis of SSTR(2) mRNA, as assessed by nuclear run-on assays, increased to a similar extent in individual cholangiocytes after BDL. Our data suggest that somatostatin interacts directly with receptors located in liver exclusively on cholangiocytes and, in concert with secretin, regulates ductal bile secretion in BDL rat liver via alterations in cAMP-dependent exocytosis.