Ursodeoxycholate-induced changes in hepatic Na+-H+ exchange and biliary HCO3- excretion.
Ursodeoxycholate (UDC)-induced HCO3- -rich choleresis may be due to activation of sinusoidal Na+-H+ exchange followed by an increase in intracellular pH (pHi) and HCO3- excretion via canalicular Cl- -HCO3- exchange. To test this hypothesis, we studied the effect of UDC and tauroursodeoxycholate (TUDC) on net H+ efflux from perfused rat livers and pHi in isolated hepatocytes in the presence and absence of amiloride. UDC-induced increases in biliary HCO3- concentration and excretion were inhibited by amiloride. However, these increases were temporally associated with an initial decline in H+ efflux and pHi followed by a gradual recovery toward base line. The initial decline in H+ efflux was associated with a rapid uptake of UDC. Amiloride inhibited only the recovery phases of H+ efflux and pHi. TUDC increased amiloride-sensitive H+ efflux without affecting biliary [HCO3-] and decreased pHi in the presence but not in the absence of amiloride. Amiloride decreased TUDC-induced choleresis and HCO3- excretion most likely by decreasing TUDC excretion. TUDC decreased biliary [Cl-] and increased hepatic O2 uptake more than UDC. We conclude that a rapid influx of UDC in the protonated form decreases pHi and net H+ efflux initially. The recovery phase is due to Na+-H+ exchange activated by decreased pHi and possibly by UDC and increased cellular respiration. TUDC indirectly stimulates Na+-H+ exchange most likely by increasing cellular respiration. UDC-induced HCO3- -rich choleresis, which is observed at a time when both net H+ efflux and pHi are less than control values, is unlikely to be due to a direct activation of Na+-H+ exchange.
Anwer
M S
MS
Department of Medicine, Tufts University School of Veterinary Medicine, North Grafton, Massachusetts 01536.
Hondalus
M K
MK
Atkinson
J M
JM
D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D001639:Bicarbonates / Q000378:metabolism*; D001659:Biliary Tract / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D003840:Deoxycholic Acid / Q000031:analogs & derivatives*; D006859:Hydrogen / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism / Q000493:pharmacokinetics; D051381:Rats; D017923:Sodium-Hydrogen Exchangers; D013657:Taurodeoxycholic Acid / Q000494:pharmacology; D014580:Ursodeoxycholic Acid / Q000378:metabolism / Q000494:pharmacology*
D001639:Bicarbonates; D002352:Carrier Proteins; D017923:Sodium-Hydrogen Exchangers; D003840:Deoxycholic Acid; D013657:Taurodeoxycholic Acid; D014580:Ursodeoxycholic Acid; D000584:Amiloride; D006859:Hydrogen; D010100:Oxygen