Effect of bile acids on ion conductances in guinea pig pancreatic duct cells

Background: Exposure of the pancreas to bile acids is considered to be one of the possible causes of acute pancreatitis. However, little information is available about the effects of bile acids on intact pancreatic ducts. Our group has shown that luminal chenodeoxycholate (CDC) at a low dose (0.1mM) stimulated HCO3- secretion in intact pancreatic ducts (Venglovecz et al Gut 2008). Our aim was to investigate whether CDC could also regulate ion channels in ductal cells.

Methods: We have used the patch clamp technique to measure whole cell currents. Single guinea pig pancreatic duct cells were prepared by a combination of enzymatic treatment and mechanical disruption of intact pancreatic ducts.

Results: Using a KCl-rich pipette solution, exposure of pancreatic duct cells to CDC (0.1 mM) reversibly increased whole cell currents by 3-fold in 75% of recordings (15/20 cells), and hyperpolarised membrane potential by ˜ 18 mV. Resting and CDC-activated currents showed marked outward rectification, and were moderately voltage-dependent. CDC-induced currents were inhibited by external barium (2 mM, n=6), as well as by the selective high conductance K+-channel blocker, iberiotoxin (100 nM, n=7). Bile acid-induced activation was abolished when cytosolic Ca2+ buffering was increased with 5 mM EGTA (ethylene glycol tetraacetic acid), and was only moderately reduced by removal of bath Ca2+.

Conclusion: Together these results provide strong evidence that low doses of CDC selectively activate iberiotoxin-sensitive K+-channels through an increase in cytosolic Ca2+ concentration, primarily from internal stores. Activation of a K+ conductance would hyperpolarise membrane potential and thereby increase the electrochemical driving force for HCO3- secretion through electrogenic apical anion exchangers. Supported by OTKA, MTA and a Royal Society International Project Grant.