Cholestatic effects of the K+ channel blockers Ba2+ and TEA occur through different pathways in the rat liver.
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 approximately 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.
Hill
C E
CE
Department of Physiology and the Gastrointestinal Diseases Research Unit, Queen's University, Kingston, Ontario, Canada K7L 5G2.
Jacques
J E
JE
D000818:Animals; D001464:Barium / Q000494:pharmacology; D001646:Bile / Q000187:drug effects / Q000502:physiology; D002779:Cholestasis / Q000139:chemically induced* / Q000503:physiopathology*; D004058:Diffusion; D005978:Glutathione / Q000652:urine; D066298:In Vitro Techniques; D008099:Liver / Q000503:physiopathology*; D008297:Male; D011188:Potassium / Q000037:antagonists & inhibitors / Q000378:metabolism; D026902:Potassium Channel Blockers; D051381:Rats; D017207:Rats, Sprague-Dawley; D019789:Tetraethylammonium / Q000494:pharmacology
D026902:Potassium Channel Blockers; D001464:Barium; D019789:Tetraethylammonium; D005978:Glutathione; D011188:Potassium