Molecular mechanisms of chronic pancreatitis : Ethanol-induced dysfunction of ion channels

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1. To investigate the secretory mechanism of HCO_3^-, across the luminal membrane of pancreatic duct cell we have measured intracellular concentrations of HCO_3^- ([HCO_3^-]_i) and of Cl^- ([Cl^-]_i) in microperfused interlobular duct segments isolated from guinea-pig pancreas. When the HCO_3^- concentration in the lumen was raised to 125 mM (24 mM Cl^-) under cAMP stimulation, pH_i did not increase above 7.2 ([HCO_3^-]_i = 〜 20 mM), indicating that luminal Cl^--HCO_3^- exchange was inhibited. Under the same condition, [Cl^-]_i was kept very low at 〜7 mM, which would tend to favor HCO_3^-' secretion via a luminal anion conductance.2. 5-hydroxytryptamine (5-HT, serotonin) at 0. 1μM strongly inhibited fluid secretion in isolated ducts via 5-HT_3 receptor. The action is mediated by the inhibition of basolateral HCO_3^- accumulation via Na^+-HCO_3^- cotransport. 5-HT released from pancreatic ductal enterochromaffin cells may regulate fluid secretion in a paracrine fashion.3. RT-PCR analysis and immunohistochemistry of isolated ducts revealed the expression of AQP1 in duct cells. The osmotic water permeability of the ductal epithelium was reduced by 80-90% with either basolateral or luminal application of HgCl_2. AQP1 of the known water channels appears to be the main water pathway in pancreatic ductal epithelium.4. Although ethanol abuse is the most common cause of acute and chronic pancreatitis, the mechanism by which ethanol causes the disease is not well understood. Ethanol at 1 mM, the concentration observed after an occasional social drinking, significantly augmented the maximal rate of fluid secretion and induced a transient increase in intracellular Ca^<2+> concentration in ducts stimulated with secretin or dibutyryl cAMP. When the flow of pancreatic juice is disturbed by protein plug or stones, fluid hypersecretion induced by ethanol would elevate the intraductal pressure in the proximal part of the duct, leading to edema formation or pancreatitis.