Papaverine inhibits bile acid excretion in isolated perfused rat liver

We investigated the effects of papaverine on bile acid excretion into bile in the presence of infusions of taurocholic acid, tauroursodeoxycholic acid, taurochenodeoxycholic acid and taurodehydrocholic acid in a single‐pass, isolated perfused rat liver model. Although continuous infusion of papaverine (1.6 μmol/min) did not reduce bile acid excretion in the presence of low‐dose (1.0 μmol/min) infusions of taurocholic acid or tauroursodeoxycholic acid, papaverine significantly inhibited biliary excretion of bile acids in the presence of low‐dose taurochenodeoxycholic acid (‐50%) and high‐dose (3.0 μmol/min) taurocholic acid (‐54%), tauroursodeoxycholic acid (‐37%) and taurodehydrocholic acid (‐31%). During continuous infusion of taurocholic acid (3 μmol/min), a 15‐min infusion of papaverine (3.2 μmol/min) reduced bile acid excretion significantly; however, total uptake of bile acid was slightly decreased by the papaverine infusion. Bile acid excretion increased over the baseline value after the papaverine infusion was stopped and then returned to baseline. These results suggest that papaverine does not affect the uptake phase of bile acids at the sinusoidal membrane but may affect the intracellular transport phase or the excretory phase at the bile canalicular membrane. When taurocholic acid was infused at a constant rate of 3 μmol/min for 20 min without papaverine and then stopped, bile acid excretion decreased gradually and was nearly zero by 52 min. Cumulative bile acid excretion in the 52 min after the end of the infusion reached 3.3 ± 0.2 μmol/gm liver and represented the storage capacity of the liver. When taurocholic acid was coinfused with papaverine at a constant rate of 3.0 μmol/min for 20 min and both infusions were stopped simultaneously, storage capacity of the liver increased significantly, from 3.3 ± 0.2 to 4.0 ± 0.2 μmol/gm liver. Taurocholic acid coinfused with papaverine at a constant rate of 3.0 μmol/min for 20 min. Then taurocholic acid infusion was stopped while the papaverine infusion was continued throughout the experiment. In this experiment, the storage capacity of the liver was reduced significantly, from 3.3 ± 0.2 to 2.2 ± 0.3 μmol/gm liver. and it was revealed that papaverine reduced vasopressin‐induced increase in cytosolic Ca2+ with isolated hepatocytes. Our results show that papaverine inhibited the biliary excretion of bile acids without affecting the uptake phase of bile acid and suggest that the microtubule‐dependent vesicl