Bile salt independent flow during bile salt-induced choleresis and cholestasis in the rat: role of biliary thiol secretion.
Previous studies have shown that the generation of the so-called "bile salt-independent flow" (BSIF) may be partly dependent on the hepatic availability and rate of canalicular secretion of osmotically active substances such as glutathione (GSH) and derived thiols. This study examined the role of common bile salts (BS) on the BSIF formation under both choleretic and cholestatic conditions, and on the relationship of the BSIF to the biliary thiol secretion. Experiments were carried out in adult male Sprague-Dawley rats both in situ in the isolated perfused rat liver and in vivo. The effect of choleretic and cholestatic doses of BS on the biliary BS secretion rate (BSSR), BS-dependent flow (BSDF), and BSIF was evaluated. In the perfused rat liver, the infusion of low and physiological doses of taurocholic acid stimulated the biliary BSSR, BSDF, and BSIF. This was associated with increased biliary thiol secretion and thiol-dependent bile flow. In vivo administration of taurocholic acid, taurochenodeoxycholic acid or taurolithocholic acid in step-wise increasing doses leading to cholestasis showed that the onset of cholestasis was not accompanied by a significant decline in the BSSR or BSDF but rather by a marked inhibition of the apparent BSIE During cholestasis, the three BS produced a significant reduction of biliary thiol secretion, with a marked decrease in thiol-dependent bile flow sufficient to account for a major proportion of BSIF inhibition. This decline in thiol secretion occurred before the drop in biliary BS secretion and was more pronounced than the reduction in BS output. No change in hepatic thiol content was observed. Administration of free or glyco-conjugated BS also resulted in a significant decrease of BSIF during the cholestatic period, suggesting a common role for BSIF inhibition in BS-induced cholestasis. The changes in bile flow during BS-induced choleresis and cholestasis are mediated by changes in the portion of the BSIF regulated by the thiol secretion.