Background Acute pancreatitis is among the few inflammatory diseases for which no specific pharmacological treatment is available. It has previously been shown that bile acids alter pancreatic ductal secretion and these effects are probably involved in the pathogenesis of bile-induced pancreatitis.
Objective To understand the mechanism responsible for bile-induced hypersecretion and, in particular, to identify the molecular target for bile acids in native pancreatic duct epithelial cells (PDECs).
Methods Patch clamp recordings and spectrofluorimetry were used to measure whole cell currents and rates of HCO3− secretion, respectively, from isolated guinea pig pancreatic ducts. Expression of ion channels and receptors was investigated by immunohistochemistry/immunofluorescence of intact pancreatic tissue.
Results Exposing PDECs to chenodeoxycholate (CDC, 100 μM) reversibly increased whole cell K+ currents and hyperpolarised cell membrane potential. Bile acid-stimulated K+ currents were inhibited by Ba2+ (2 mM), iberiotoxin (100 nM), and suppressed by strong intracellular Ca2+ buffering. Luminally applied iberiotoxin also blocked CDC-stimulated HCO3− secretion from microperfused ducts; however, the inhibitor did not influence the stimulatory effect of secretin, carbachol or luminally applied ATP. The specific large-conductance Ca2+-activated potassium (BK) channel activator, NS11021, induced a similar increase in HCO3− secretion to CDC. Immunohistochemical analysis showed strong BK channel protein expression on the apical membrane of PDECs, while the G-protein-coupled bile acid receptor-1 was not detected in PDECs, but was present in acinar cells.
Conclusion It was shown for the first time that BK channels (i) are expressed at the apical membrane of guinea pig PDECs; (ii) have a crucial role in regulating HCO3− secretion and (iii) are also essential for the bile acid-induced hypersecretion and, therefore, underlie the response of the pancreas to this noxious agent.
- bile acids
- BK channels
- bicarbonate secretion
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Funding Hungarian Scientific Research Fund to VV, ZR and PH (PD78087, K78311 and NNF 78851), a Bolyai Postdoctoral Fellowship to PH and ZR (00334/08/5 and 00174/10/5), a Royal Society International Joint Project Grant (HAS and the Royal Society) to PH and MAG, and National Development Agency (NDA) grants (TAMOP-4.2.2-08/1/2008-0002 and 00134.2.1.B-09/1/KONV).
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed.