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Cl(-)-dependent secretory mechanisms in isolated rat bile duct epithelial units.

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Liver Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520-8019, USA.


Cholangiocytes absorb and secrete fluid, modifying primary canalicular bile. In several Cl(-)-secreting epithelia, Na(+)-K(+)-2Cl(-) cotransport is a basolateral Cl(-) uptake pathway facilitating apical Cl(-) secretion. To determine if cholangiocytes possess similar mechanisms independent of CO2/HCO, we assessed Cl(-)-dependent secretion in rat liver isolated polarized bile duct units (IBDUs) by using videomicroscopy. Without CO2/HCO, forskolin (FSK) stimulated secretion entirely dependent on Na(+) and Cl(-) and inhibited by Na(+)-K(+)-2Cl(-) inhibitor bumetanide. Carbonic anhydrase inhibitor ethoxyzolamide had no effect on FSK-stimulated secretion, indicating negligible endogenous CO2/HCO transport. In contrast, FSK-stimulated secretion was inhibited approximately 85% by K(+) channel inhibitor Ba(2+) and blocked completely by bumetanide plus Ba(2+). IBDU Na(+)-K(+)-2Cl(-) cotransport activity was assessed by recording intracellular pH during NH4Cl exposure. Bumetanide inhibited initial acidification rates due to NH entry in the presence and absence of CO2/HCO. In contrast, when stimulated by FSK, a 35% increase in Na(+)-K(+)-2Cl(-) cotransport activity occurred without CO2/HCO. These data suggest a cellular model of HCO-independent secretion in which Na(+)-K(+)-2Cl(-) cotransport maintains high intracellular Cl(-) concentration. Intracellular cAMP concentration increases activate basolateral K(+) conductance, raises apical Cl(-) permeability, and causes transcellular Cl(-) movement into the lumen. Polarized IBDU cholangiocytes are capable of vectorial Cl(-)-dependent fluid secretion independent of HCO. Bumetanide-sensitive Na(+)-K(+)-2Cl(-) cotransport, Cl(-)/HCO exchange, and Ba(2+)-sensitive K(+) channels are important components of stimulated fluid secretion in intrahepatic bile duct epithelium.

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