Study of relationship between intracellular signal transduction system and bile secretion

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In isolated rat hepatocytes, addition of vasopressin causes the inositol trisphosphate formation and increase of intracellular Ca^<2+> concentration ([Ca^<2+>]c) in a dose dependent manner. In the experiments with perfused liver, infusion of vasopressin caused transient increase and prominent decrease in bile secretion, resulting in cholestasis. Flow of horseradish peroxidase (HRP) into the bile increased by the treatment with vasopressin in a dose dependent manner. These data indicate that increase of [Ca^<2+>]c induces cholestasis, but enhances vesicle transport in rat hepatocytes.Protein kinase A activation by the treatment with cAMP analog clearly enhanced vasopressin induced [Ca^<2+>]c increase in isolated hepatocytes. cAMP analog increased bile secretion in perfused liver. However, treatment with cAMP analog caused a marked enhancement in transient increase and the subsequent decrease of bile secretion. Addition of low concentration of vasopressin (10pM) does not affect [Ca^<2+>]c and bile secretion, but increase of [Ca^<2+>]c and decrease of bile secretion were observed by the treatment with cAMP analog, suggesting the close relationship between [Ca^<2+>]c increase and cholestasis. However, tauroursodeoxycholate (TUDCA) prevented the enhancement effect of cAMP analog on [Ca^<2+>]c increase and cholestasis. In addition, TUDCA inhibits the activation of protein kinase A by glucagon. These data indicate that TUDCA may act as a inhibitory agent of protein kinase A.