Effects of calmodulin antagonists on secretion of bile and bile acid

In the isolated perfused rat liver, the effects of calmodulin (CaM) antagonists, chlorpromazine (CPZ), trifluoperazine (TFP), W-7 and W-5, on secretion of bile and bile acid were compared. Without addition of taurocholic acid to the perfusate, TFP (200 microM or higher), CPZ (200 microM) and W-7 (400 microM) decreased the bile flow transiently. In contrast, W-5 did not decrease the bile flow. Taking into consideration the binding of TFP and CPZ to bovine serum albumin in the perfusate, they diminished the bile flow by inhibiting CaM function. This was also supported by the difference between the effects of W-7 and W-5. These findings suggested that CaM was involved in the secretion of bile. Under the constant infusion of taurocholic acid into the perfusate, CaM antagonists decreased the secretion of bile acid. However this might be due to the inhibition of bile acid uptake, because these agents inhibited the uptake into isolated rat hepatocytes. The concentrations required for inhibition of the uptake were near to those which decreased the viability, suggesting that the inhibition was due to their non-specific cytotoxic effect. Future studies must be carried out to determine whether CaM is involved in the secretion of bile acid.