The gastrointestinal HCO(3)(-) secretion functions to limit the mucosal acid damage due to HCl secreted in the stomach or organic acids produced in the large intestine. We studied HCO(3)(-) secretion in the mouse large intestine with isolated tissues mounted in chambers by using pH stat method. Addition of Cl(-) to the mucosal side caused an increase in HCO(3)(-) secretion in the cecum and distal colon but had little, if any, effect in the proximal colon. In agreement with this, mucosal surface pH was higher in the cecum and distal colon than in the proximal colon. The Cl(-)-induced HCO(3)(-) secretion in the cecum was inhibited by 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB, mucosal addition), but not by DIDS (mucosal or serosal), acetazolamide, amiloride (serosal) or glibenclamide (mucosal). Removal of Na(+) or addition of propionate had hardly any effect on the Cl(-)-induced HCO(3)(-) secretion. These results suggest that a NPPB-sensitive, DIDS-resistant Cl(-)/ HCO(3)(-) exchanger is present in the apical membrane, and mediates Cl(-)-dependent HCO(3)(-) secretion. This process is probably mainly responsible for the formation of the high pH at the mucosal surface.