Gastrin inhibits secretin-induced ductal secretion by interaction with specific receptors on rat cholangiocytes

Abstract

We assessed the effect of gastrin on ductal secretion in normal and bile duct-ligated (BDL) rats. The effect of gastrin on ductal secretion was examined in the presence of proglumide, a specific antagonist for gastrin receptor (GR). We isolated pure cholangiocytes from normal and BDL rats and assessed gastrin effects on secretin receptor (SR) gene expression and intracellular adenosine 3′,5′-cyclic monophosphate (cAMP) levels. We examined the presence of GR mRNA in cholangiocytes by reverse transcription polymerase chain reaction (RT-PCR). In normal or BDL rats, gastrin produced no changes in spontaneous bile secretion. Simultaneous infusion of gastrin inhibited secretin-induced choleresis and bicarbonate output in BDL rats. In the presence of proglumide gastrin did not inhibit secretin-induced choleresis in BDL rats. Gastrin decreased in cholangiocytes from BDL rats 1) SR gene expression and 2) secretin-induced cAMP levels. With the use of RT-PCR, GR mRNA was detected in cholangiocytes. Similar to what is shown for secretin and somatostatin, we propose that the opposing effects of secretin and gastrin on cholangiocyte secretory activity regulate ductal secretion in rats.

Acute Carbon Tetrachloride Feeding Selectively Damages Large, But Not Small, Cholangiocytes From Normal Rat Liver

“…2,[5][6][7][8][9][10][11] For example, secretin enhances ductal secretory activity by interaction with specific receptors on cholangiocytes, 12 resulting in an increase in intracellular adenosine 3Ј,5Ј-monophosphate (cAMP) levels. [5][6][7]9,13,14 Increased cAMP levels induce the opening of Cl Ϫ channels and activation of the Cl Ϫ /HCO 3 Ϫ exchanger activity, which results in the secretin-induced bicarbonate-rich choleresis in vivo. [5][6][7]10,11,15 We have demonstrated that intrahepatic cholangiocytes are morphologically and functionally heterogeneous.…”

“…[5][6][7]9,13,14 Increased cAMP levels induce the opening of Cl Ϫ channels and activation of the Cl Ϫ /HCO 3 Ϫ exchanger activity, which results in the secretin-induced bicarbonate-rich choleresis in vivo. [5][6][7]10,11,15 We have demonstrated that intrahepatic cholangiocytes are morphologically and functionally heterogeneous. 1,8,9,14,16,17 Specifically, we have shown that purified subpopulations of cholangiocytes and intrahepatic bile duct units (IBDU), separated by size, are heterogeneous with respect to secretin receptor (SR) gene expression, secretin-stimulated cAMP synthesis, and secretin-induced anion transport.…”

“…Type I (typical) ductal hyperplasia is confined to the portal tract and is observed in rats after 70% partial hepatectomy, bile duct ligation (BDL), combined BDL/furan treatment, or ␣-naphthylisothiocyanate feeding. [5][6][7]10,11,22,23 In this type of ductal hyperplasia, cholangiocytes maintain phenotypes of normal cholangiocyte lineage. 6,7,11 Type II (atypical) ductal hyperplasia can be noticed in prolonged liver diseases such as primary biliary cirrhosis 2,19,20 and is characterized by a poorly defined network of biliary conduits extending from the portal tract into the liver parenchyma.…”

“…[5][6][7]10,11,22,23 In this type of ductal hyperplasia, cholangiocytes maintain phenotypes of normal cholangiocyte lineage. 6,7,11 Type II (atypical) ductal hyperplasia can be noticed in prolonged liver diseases such as primary biliary cirrhosis 2,19,20 and is characterized by a poorly defined network of biliary conduits extending from the portal tract into the liver parenchyma. Type III or ''oval'' cell hyperplasia is seen in the early phases of experimentally induced carcinogenesis in rat liver 2,22 and is characterized by disorganized proliferation of tubular structures consisting of ''oval'' cells into the liver parenchyma.…”

Physiology of Cholangiocytes

“…The inhibitory effect of gastrin on secretin-stimulated cholangiocyte secretion is mediated via activation of the cholecystokinin-B/gastrin receptors, followed by membrane translocation and activation of the Ca 2+ -dependent PKC and abolishment of secretin-stimulated cAMP synthesis (103,109). Gastrin also induces membrane translocation of PKC in Mz-ChA-1 cells (134).…”