Mechanism of inhibition of hepatic bile acid uptake by amiloride and 4,4'-diisothiocyano-2,2'-disulfonic stilbene (DIDS).
The mechanisms by which amiloride and 4,4'-diisothiocyano-2,2'-disulfonic stilbene (DIDS) inhibit hepatic uptake of cholate and taurocholate (TC) were investigated in isolated rat hepatocytes. Amiloride inhibited Na(+)-dependent uptake of cholate and TC only when hepatocytes were preincubated with amiloride, indicating an indirect effect of amiloride. Time-dependent studies showed that the inhibition of bile acid uptake was associated with a parallel increase in intracellular Na+ concentration ([Na+]i). Although amiloride decreased intracellular pH, this decrease preceded amiloride-induced inhibition of bile acid uptake and increase in [Na+]i. Amiloride inhibited bile acid uptake, decreased membrane potential, and increased [Na+]i with comparable concentration dependency. DIDS inhibited Na(+)-dependent uptake of cholate and TC non-competitively. Neither DIDS nor amiloride inhibited Na(+)-independent uptake of cholate and TC. These results indicate that amiloride inhibits Na(+)-dependent cholate and TC uptake by decreasing the transmembrane Na(+)-gradient, and further support the hypothesis that two different transporters may be involved in hepatic bile acid uptake by Na(+)-dependent and Na(+)-independent mechanisms.[1]References
- Mechanism of inhibition of hepatic bile acid uptake by amiloride and 4,4'-diisothiocyano-2,2'-disulfonic stilbene (DIDS). Anwer, M.S., Branson, A.U., Atkinson, J.M. Biochem. Pharmacol. (1991) [Pubmed]
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