Communication via gap junctions modulates bile secretion in the isolated perfused rat liver

Background & Aims: Bile secretion is regulated in part by adenosine 3',5'-cyclic monophosphate (cAMP) and cytosolic Ca2+ (Ca-i(2+)). Hormone receptors that link to these second messengers are not uniformly distributed across the hepatic lobule, but both cAMP and Ca-i(2+) cross gap junctions, so we tested whether gap junctional communication plays a role in changes in bile flow induced by the activation of these receptors, Methods: cAMP levels in isolated perfused rat livers were increased by using glucagon, because glucagon receptors are predominantly on pericentral hepatocytes, or by using dibutyryl cAMP, which acts on hepatocytes throughout the hepatic lobule, Ca-i(2+) concentration was increased by using vasopressin, because V-1a receptors are most heavily expressed on pericentral hepatocytes, or by using 2,5-di(tert-butyl)-1,4-benzo-hydroquinone (t-BuBHQ), which increases the Ca-i(2+) concentration in hepatocytes throughout the hepatic lobule. We used 18 alpha-glycyrrhetinic acid (alpha GA) to block gap junction conductance, which was assessed by fluorescence recovery after photobleaching. Results: alpha GA blocked fluorescence recovery after photobleaching without altering the basal rate of bile flow, Glucagon and dibutyryl cAMP increased bile flow; alpha GA blocked the glucagon-induced increase but not that induced by dibutyryl cAMP, Vasopressin and t-BuBHQ decreased bile flow; alpha GA exacerbated the decrease induced by vasopressin but not by t-BuBHQ, Conclusions: Glucagon and vasopressin modulate bile flow in a manner that depends in part on gap junctional communication, even though the two hormones activate second messengers with opposing effects on bile flow. The organization of second messenger signals across the hepatic lobule may be an important component of hormonal regulation of bile secretion.