EFFECT OF URSODEOXYCHOLIC ACID ON INTRACELLULAR PH REGULATION IN ISOLATED RAT BILE-DUCT EPITHELIAL-CELLS

To determine if ursodeoxycholic acid (UDCA) induces a HCO3--rich hypercholeresis by stimulating HCO3- secretion from bile duct epithelial (BDE) cells, we studied the effect of UDCA, sodium tauroursodeoxycholate (TUDCA), and cholic acid on intracellular pH (pH(i)) regulation and HCO3- excretion in BDE cells isolated from normal rat liver. Exposure of BDE cells to UDCA (0.5-1.5 mM) produced a dose-dependent initial acidification [from -0.05 to -0.16 pH units (pH(u))], which was lower in Krebs-Ringer bicarbonate than in N-2-hydroxyethyl-piperazine-N'-2-ethanesulfonic acid (HEPES), because of the higher cell-buffering power in the presence of HCO3-. In contrast, TUDCA (1 mM) had no effect on pH, in either media. BDE acidification induced by UDCA (1.5 mM) in KRB was not inhibited by Cl- depletion excluding activation of Cl--HCO3- exchange. Most BDE cells spontaneously recovered their basal pH(i) during the UDCA infusion (0.5-1 mM) by a secondary activation of the Na+-H+ exchanger (amiloride inhibition of pH(i) recovery; n = 4), and pH(i) overshot basal levels by 0.1-0.2 pH(u) after UDCA withdrawal. The activity of Cl--HCO3- exchange (Cl- removal/readmission maneuver) as well as the activities of Na+-H- exchange and Na+-HCO3- symport (NH4Cl acid load in HEPES and KRB, respectively) were unaffected by UDCA (0.5 mM) compared with controls. Cholic acid (1.5 mM), which does not produce a hypercholeresis, also acidified BDE cells in KRB media. These studies indicate that UDCA does not stimulate HCO3- excretion from isolated rat BDE cells but modifies pH(i) in BDE cells as a weak acid.