Cholestatic effects of the K1 channel blockers Ba21 and TEA occur through different pathways in the rat liver

Hill, Ceredwyn Elizabeth, and Jody Elisabeth Jacques. Cholestatic effects of the K1 channel blockers Ba21 and TEA occur through different pathways in the rat liver. Am. J. Physiol. 276 (Gastrointest. Liver Physiol. 39): G43– G48, 1999.—The role of K1 channels in bile acid-independent bile flow (BAIF) was studied in the isolated and bile ductcannulated perfused rat liver by changing the driving force on K1 and by using a variety of K1 channel blockers. Bile flow rate, effluent perfusate K1 content, and portal pressure were measured. Increase in perfusate K1 from 5.9 to 80 mM caused inhibition of bile flow that could be fitted to a Boltzmann distribution, indicating partial dependence of bile formation on the K1 equilibrium potential and hence K1 channel activity. To investigate this further, the effects of compounds established as K1 channel blockers in liver or other tissues were surveyed. Ba21 (1–5 mM) inhibited mean bile flow by 20%. Tetraethylammonium (TEA) inhibition of basal bile flow was biphasic with saturable (IC50 ,0.7 mM) and linear components. In contrast, infusion of the K1 channel blockers 4-aminopyridine (5 mM), cesium (2.5 mM), quinidine (0.1 mM), iberiotoxin (90 nM), or paxilline (100 nM) did not affect bile flow. As expected for a K1 channel blocker, Ba21 caused a net K1 uptake. Conversely, TEA did not affect basal K1 fluxes, although TEA-induced cholestasis was accompanied by a 26% decrease in biliary glutathione excretion. These results suggest that the partial cholestasis induced by the K1 channel blockers Ba21 and TEA occurs by significantly different mechanisms. Whereas the Ba21 response implicates K1 channel activity as a significant driving force in BAIF, TEAsensitive K1 channels are not present or are not involved in bile formation.