Ursodeoxycholic acid choleresis: relationship to biliary HCO-3 and effects of Na+-H+ exchange inhibitors.
We have recently shown that substitution of Li+ for perfusate Na+ eliminates the HCO3(-)-rich choleresis produced by ursodeoxycholic acid (UDCA) in isolated perfused rat liver and that the increase in bile flow produced by both UDCA and taurocholic acid is partially inhibited by 1 mM amiloride. Although these findings are consistent with a role for Na+-H+ exchange in the choleresis produced by these bile acids, both Li+ substitution and amiloride affect other cellular processes, including Na+-K+-ATPase activity. We have now further explored both the relationship between UDCA-stimulated bile flow and biliary HCO3- secretion and the possible role of Na+-H+ exchange in this process by comparing the effects of amiloride with two of its more potent and presumably more specific analogues, 5-(N,N-dimethyl)amiloride hydrochloride (DMA) and 5-(N-ethyl-N-isopropyl)amiloride (EIA). In the absence of inhibitor, UDCA increased biliary HCO3- concentration ([HCO3-]) up to an apparent maximum of 60-70 mM, and bile flow and biliary HCO3- output appeared to be linearly related over a sixfold range of bile flow rates. Amiloride, DMA, and EIA each produced a concentration-dependent inhibition of UDCA-stimulated bile flow and biliary HCO3- output with an apparent rank order potency (EIA greater than DMA greater than amiloride) similar to that reported for inhibition of Na+-H+ exchange in other systems. None of the inhibitors significantly altered biliary UDCA output or the relationship between UDCA-induced bile flow and either biliary [HCO3-] or biliary HCO3- output. Effects of these inhibitors did not appear attributable either to nonspecific toxicity, as reflected by hepatic release of lactate dehydrogenase or K+, or to inhibition of hepatic Na+-K+-ATPase, measured as Na+-dependent uptake of 86Rb. In contrast to their effects on UDCA choleresis, these inhibitors had little or no effect on basal bile flow, biliary [HCO3-], and biliary HCO3- output. These findings indicate that UDCA-induced but not basal bile formation is closely coupled to biliary HCO3- concentration and output, and they provide additional evidence that UDCA choleresis requires an intact Na+-H+ exchange mechanism.
Renner
E L
EL
Department of Medicine, University of California School of Medicine, San Francisco 94143.
Lake
J R
JR
Cragoe
E J
EJ
Van Dyke
R W
RW
Scharschmidt
B F
BF
D000584:Amiloride / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001639:Bicarbonates / Q000378:metabolism*; D001646:Bile / Q000201:enzymology / Q000378:metabolism* / Q000502:physiology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D002756:Cholagogues and Choleretics / Q000494:pharmacology*; D003840:Deoxycholic Acid / Q000031:analogs & derivatives*; D004305:Dose-Response Relationship, Drug; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D011188:Potassium / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D012413:Rubidium / Q000378:metabolism; D012964:Sodium / Q000494:pharmacology; D017923:Sodium-Hydrogen Exchangers; D014580:Ursodeoxycholic Acid / Q000378:metabolism / Q000494:pharmacology*
D001639:Bicarbonates; D002352:Carrier Proteins; D002756:Cholagogues and Choleretics; D017923:Sodium-Hydrogen Exchangers; D003840:Deoxycholic Acid; D014580:Ursodeoxycholic Acid; D000584:Amiloride; D012964:Sodium; D007770:L-Lactate Dehydrogenase; D012413:Rubidium; D011188:Potassium