Study of relationship between intracellular signal transduction system and bile secretion

在分离的大鼠肝细胞中，加压素以剂量依赖的方式引起肌醇三磷酸的形成和细胞内钙离子浓度([Ca^&lt；2+&gt；c)的增加。在肝脏灌流实验中，血管加压素引起胆汁分泌的一过性增加和显著减少，导致胆汁淤积。加入加压素后，胆汁中辣根过氧化物酶(HRP)流量增加，且呈剂量依赖关系。上述结果表明，[Ca~(2+)]_(2+)和[Ca~(2+)]_(gt；)c的升高导致大鼠肝细胞[Ca~(2+)&lt；2+&gt；]c的淤积，但增强了小泡的转运；cAMP类似物对蛋白激酶A的激活明显增强了加压素诱导的[Ca~(2+)&t；]_c的升高。CAMP类似物可增加肝脏胆汁分泌。然而，cAMP类似物处理后，一过性胆汁分泌增加和随后的胆汁分泌减少明显增强。加入低浓度加压素(10 Pm)对[Ca^&lt；2+&gt；]c和胆汁分泌无明显影响，但cAMP类似物处理后[Ca^&lt；2+&gt；]c升高，胆汁分泌减少，提示[Ca^&lt；2+&gt；]c升高与胆汁淤积密切相关。而牛磺酸脱氧胆酸(TUDCA)可阻断cAMP类似物对[Ca~(2+)]_c升高和胆汁淤积的促进作用。此外，TUDCA还可抑制胰高血糖素对蛋白激酶A的激活。这些数据表明，TUDCA可能是蛋白激酶A的抑制剂。

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.