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 (pHi) 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 (pHu)], which was lower in Krebs-Ringer bicarbonate than in N-2-hydroxyethylpiperazine-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 pHi 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 pHi during the UDCA infusion (0.5-1 mM) by a secondary activation of the Na(+)-H+ exchanger (amiloride inhibition of pHi recovery; n = 4), and pHi overshot basal levels by 0.1-0.2 pHu 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 pHi in BDE cells as a weak acid.
Alvaro
D
D
Department of Internal Medicine, Yale University, School of Medicine, New Haven, Connecticut 06510.
Mennone
A
A
Boyer
J L
JL
D000643:Ammonium Chloride / Q000494:pharmacology; D000818:Animals; D017920:Antiporters / Q000378:metabolism; D001652:Bile Ducts / Q000166:cytology / Q000378:metabolism*; D027963:Chloride-Bicarbonate Antiporters; D002712:Chlorides / Q000378:metabolism; D019826:Cholic Acid; D002793:Cholic Acids / Q000494:pharmacology; D004847:Epithelial Cells; D004848:Epithelium / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D007425:Intracellular Membranes / Q000378:metabolism*; D051381:Rats; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology; D014580:Ursodeoxycholic Acid / Q000494:pharmacology*
D017920:Antiporters; D027963:Chloride-Bicarbonate Antiporters; D002712:Chlorides; D002793:Cholic Acids; D017923:Sodium-Hydrogen Exchangers; D000643:Ammonium Chloride; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine; D014580:Ursodeoxycholic Acid; D019826:Cholic Acid