The role of K⁺ channels in bile acid-independent bile flow (BAIF) was studied in the isolated and bile duct-cannulated perfused rat liver by changing the driving force on K⁺ and by using a variety of K⁺ channel blockers. Bile flow rate, effluent perfusate K⁺ content, and portal pressure were measured. Increase in perfusate K⁺ 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 K⁺ equilibrium potential and hence K⁺ channel activity. To investigate this further, the effects of compounds established as K⁺ channel blockers in liver or other tissues were surveyed. Ba²⁺ (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 K⁺ 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 K⁺ channel blocker, Ba²⁺ caused a net K⁺ uptake. Conversely, TEA did not affect basal K⁺ 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 K⁺ channel blockers Ba²⁺ and TEA occurs by significantly different mechanisms. Whereas the Ba²⁺ response implicates K⁺ channel activity as a significant driving force in BAIF, TEA-sensitive K⁺ channels are not present or are not involved in bile formation.

hepatocyte; bile acid independent; basolateral; tetraethylammonium

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