Pancreatic ductal bicarbonate secretion: Past, present and future

The pancreatic duct epithelium in the guinea-pig and many other species secretes HCO3- at concentrations approaching 150 mM. This cannot be explained by conventional models based upon HCO3- secretion via an anion exchanger at the luminal membrane because: 1) under these conditions, the Cl- and HCO3- concentration gradients would favour HCO3- reabsorption rather than secretion, and 2) the luminal anion exchanger appears to be inhibited by luminal HCO3- concentrations of 125 mM or more. There may, however, be a sufficiently large electrochemical gradient to drive HCO3- secretion across the luminal membrane via an anion conductance. In contrast to earlier studies on rat ducts, the membrane potential Em in guinea-pig duct cells does not depolarise appreciably upon stimulation with secretagogues but remains constant at about - 60 mV. Consequently, even with 125 mM or more HCO3- in the lumen and an estimated 20 mM in the cytoplasm, the electrochemical gradient for HCO3- will still favour secretion to the lumen. Under the same conditions, the intracellular Cl- concentration drops to very low levels (approximately 7 mM) presumably because, although Cl- may leave freely through the cystic fibrosis transmembrane conductance regulator (CFTR) channels in the luminal membrane, there is no major pathway for Cl- uptake across the basolateral membrane. Consequently a HCO3--rich secretion may arise as a result of the lack of competition from intracellular Cl- for efflux via the anion conductances at the luminal membrane. Whether CFTR, or another anion conductance, provides such a pathway for HCO3- remains to be seen.