We studied the determinants of maximum bile acid secretory rate (SRm) in the rat. The choledochocaval fistula rat model manifested a bile acid secretory rate far in excess of the SRm previously reported for taurocholate in this species. We studied the ability of various bile acid solutions to maintain the high secretion rate in this model. Whole-rat bile, but not taurocholate in 2% albumin nor rat bile with bile acid content over 90% taurocholate, maintained secretion rate. We concluded that the mixture of bile acids in rat bile was the most important determinant of the high secretion rate and that the high rate was not due to a peculiarity of the model itself nor to the infusion of biliary lipids together with bile acids. Conventional determination of the SRm in the bile fistula rat confirmed this impression, with the least toxic bile acids manifesting the highest SRm. During infusion of taurocholate beyond the SRm, bile flow and bile acid secretion rate fell. This was accompanied only by scattered focal necrosis of single liver cells or of small aggregates of cells and not by any diffuse subcellular morphological change. We believe the maximum bile acid secretory rate is determined by toxicity of a specific bile acid for the secretory mechanism rather than by a limitation in transport receptor number as is usual with substances manifesting classical transport maxima. The high SRm of the 7 beta-hydroxy bile acid, ursodeoxycholic acid, is probably related to its very low toxicity. The high SRm in the choledochocaval fistula rat is probably related to the presence of 7 beta-hydroxy muricholic acids in the bile of this species.
Hepatic transport of 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) was studied in isolated perfused rat livers and in isolated rat hepatocytes to determine if DIDS-induced decrease in biliary HCO3- excretion is due to a DIDS-HCO3- exchange and/or due to inhibition of Cl(-)-HCO3- exchange. In isolated perfused rat livers, DIDS reversibly decreased biliary HCO3- concentration and excretion. The changes in biliary HCO3- concentration were inversely related to biliary DIDS concentration. DIDS was concentrated in bile, indicating active hepatic transport. Replacement of perfusate HCO3- with equimolar dimethyloxazolidinedione (DMO) or tricine decreased biliary excretion, but not hepatic uptake, of DIDS. Biliary excretion of DIDS was also associated with a decrease in bile pH, and this decrease in pH was greater in the presence of HCO3-. HCO3-, but not DMO or tricine, stimulated DIDS efflux from preloaded hepatocytes. DIDS efflux was also temperature dependent and increased with increasing extracellular pH. Collectively, these results are consistent with the presence of a DIDS-HCO3- (OH-) exchange mechanism at the canalicular membrane. HCO3(-)-dependent Cl- uptake in hepatocytes was competitively inhibited by DIDS (Ki = 0.24 mM), confirming the presence of DIDS-inhibitable Cl(-)-HCO3- exchange. However, the ability of DIDS to decrease biliary HCO3- excretion persisted when perfusate Cl- was replaced by isethionate. Moreover, biliary HCO3- concentration returned to base line despite the presence of 2-6 mM DIDS in bile. Thus it seems unlikely that the inhibition of Cl(-)-HCO3- exchange by DIDS is a major mechanism of inhibition of HCO3- excretion. We, therefore, conclude that a DIDS-HCO3- (OH-) exchange at the canalicular membrane is the most likely explanation for the observed decrease in biliary HCO3- excretion.
We perfused isolated rat livers with Krebs-Ringer buffer, with no recirculation. Bile flow virtually stopped during 30 min of anoxia and resumed following reoxygenation to reach a plateau of 44% of the control level. When taurodehydrocholic acid (TDHC, 50 nmol/ min/g liver) was administered during reoxygenation, bile flow increased three-fold (16.1 ± 1.3 to 45.3 ± 6.3 µl/g liver). The increase in bile output with TDHC was 27.8 µl/g liver, which was 89% of the control output. Bile acid output during this period was 1.4 µmol/g liver, which was 93% of the control level. Addition of allopurinol (50 nmol/min/g liver) without TDHC increased bile flow significantly (16.1 ± 1.3 to 21.3 ± 1.2 µl/g liver), but the change was not significant when allopurinol and TDHC were given. The addition of allopurinol also reduced the cumulative release of lactate dehydrogenase from the liver during the reoxygenation period, but had no effect on hepatic adenosine triphosphate levels. Our data suggest that the bile acid-independent bile flow is sensitive to reoxygenation injury following anoxia whereas bile acid output and bile acid-dependent bile flow are resistant.
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