Trypsin inhibits a chloride independent pancreatic ductal bicarbonate secretion via protease-activated receptor 2

Background: Low doses of ethanol and bile acids stimulate pancreatic ductal bicarbonate secretion, whereas in high concentrations they will cause global inhibition of ion transport.

Aim: To investigate the effects of trypsin on pancreatic duct cells.

Methods: Pancreatic protease-activated receptor 2 (PAR2) expression was determined by immunohistochemistry. Intracellular pH (pHi) and Ca2+ concentration ([Ca2+]i) were measured on isolated intra/interlobular microperfused guinea pig pancreatic ducts by microfluorimetry.

Results: PAR2 expression was found on the luminal membrane of intralobular, but not on interlobular ducts. Luminal administration of trypsin or PAR2 activating peptide (AP) had no effect on pHi in HCO3–free solution, however in the presence of HCO3-, a marked pHi elevation was observed suggesting an inhibitory effect of a HCO3- efflux mechanism. Removal of extracellular Cl- did not diminish the level of alkalosis caused by trypsin or PAR2-AP. Trypsin and PAR2-AP, even at low concentrations, activated Ca2+ signaling from the basal and luminal membranes of duct cells. The soybean trypsin inhibitor or the Ca2+ chelator BAPTA-AM totally blocked the effect of trypsin on [Ca2+]i, whereas Ca2+-free external solution did not prevent this effect.

Conclusion: Our results suggest that the inhibition of pancreatic HCO3- secretion during the onset of acute pancreatitis may be mediated by the activation of PAR2.

This work was supported by OTKA, MTA and NKTH.