Regulation of the HCO_3^-channel, therapeutic research of chronic pancreatitis

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The interlobular duct cells of the guinea-pig pancreas secrete HCO_3^-across their luminal membrane into a HCO_3^--rich (125 mM) luminal fluid against a six-fold concentration gradient. Since HCO_3^-transport cannot be achieved by luminal Cl^-/HCO_3^-exchange under these conditions, we have investigated the possibility that it is mediated by an anion conductance. We have measured intracellular pH (HCO_3^-concentration, [HCO_3^-]_i) and Cl^-concentration ([CO^-]_i) by microfluorometry (using BCECF and MEQ) and the intracellular potential (Vm) by microelectrode of duct cells in luminally-microperfused, interlobular duct segments. When the lumen was perfused with a high HCO_3^-(24 mM CL^--125 mM HCO_3^-) solution (to simulate physiological condition in vivo) under cAMP stimulation, [HCO_3^-]_i was at 〜20 mM, [Cl^-]_i was as little as 〜7 mM, and V_m was 〜-60 mV. These results can be explained by a model in which the depolarizing effect of Cl^-efflux via CFTR across the luminal membrane is minimized by the depletion of intracellular Cl^-and offset by the hyperpolarizing effects of electrogenic Na^+-HCO_3^-cotransport (stoichiometry=1:2) at the basolateral membrane. The net effect is a luminally directed electrochemical potential gradient for HCO_3^-that is sustained during maximal stimulation. Our calculations indicate that the electrodiffusive efflux of HCO_3^-to the lumen via CFTR, driven by this gradient, would be sufficient to fully account for the observed secretory flux of HCO_3^-.