To elucidate mechanisms of glucagon-induced bicarbonaterich choleresis, we investigated the effect of glucagon on ion transport processes involved in the regulation of intracellular pH (pH1) in isolated rat hepatocyte couplets. It was found that glucagon (200 nM), without influencing resting pH1, significantly stimulates the Cl-/HCO3 exchange activity.The effect of glucagon was associated with a sevenfold increase in cAMP levels in rat hepatocytes. The activity of the Cl-/HCO3-exchanger was also stimulated by DBcAMP + forskolin. The effect of glucagon on the Cl-/HCO3 exchange was individually blocked by two specific and selective inhibitors of protein kinase A, uM) and H-89 (30 ,uM), the latter having no influence on the glucagon-induced cAMP accumulation in isolated rat hepatocytes. The Cl -channel blocker, NPPB (10 pmM), showed no effect on either the basal or the glucagon-stimulated Cl-/ HCO3 exchange. In contrast, the protein kinase C agonist, PMA (10 jpM), completely blocked the glucagon stimulation of the C1-/HCO3 exchange; however, this effect was achieved through a significant inhibition of the glucagonstimulated cAMP accumulation in rat hepatocytes. Colchicine pretreatment inhibited the basal as well as the glucagon-stimulated Cl-/HCO3 exchange activity. The Na+/H+ exchanger was unaffected by glucagon either at basal pH1 or at acid pH, values. In contrast, glucagon, at basal pH1, stimulated the Na+-HCO-symport. The main findings of this study indicate that glucagon, through the cAMP-dependent protein kinase A pathway, stimulates the activity of the Cl-/HCO3 exchanger in isolated rat hepatocyte couplets, a mechanism which could account for the in vivo induced bicarbonate-rich choleresis. (J. Clin. Invest. 1995.

Summary Parenteral nutrition is often associated with hepatobiliary complications. Hepatic steatosis, intrahepatic cholestasis and biliary sludge are the most frequent. Cholestasis predominates in infants, steatosis in adults, and biliary sludge in both. Other less frequent complications are steatohepatitis and gallstones. All hepatobiliary complications are more likely to occur after extended periods of total parenteral nutrition, and are prevented by the concomitant consumption of nutrients by the enteral route. The pathogenic causes are multiple and only partially known. They include lack of gastrointestinal stimuli for biliary secretion and gall‐bladder motility, abnormalities in bile acid metabolism, the presence of sepsis, and the potentially unfavourable effects of individual components in the total parenteral nutrition formulae, including an excess of calories. Each potential mechanism and its clinical relevance is discussed in this review.

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