prostaglandin-d2 and Cholestasis

Bile secretion has been reported to be regulated by circulating hormones and by autonomic liver nerves. In the in situ perfused rat liver, prostaglandins reduce bile flow and bile acid secretion. The aim of this study was to investigate the regulation of bile secretion by prostaglandins in the in vivo situation. The bile duct and portal vein of anaesthetised Wistar rats were cannulated by polyethylene tubes. Bile flow was determined gravimetrically. Bile acids were quantified by the 3-alpha-hydroxy-steroid-dehydrogenase method and by high-pressure-liquid-chromatography (HPLC) separation. Administration of 1 microM prostaglandin F2 alpha into the portal vein over 5 minutes reduced bile flow from 1.57 microliter/min.g liver to 0.95 microliter/min.g liver and bile acids secretion from 148 to 81 nmol/100g/min. The administration of different doses (0.1 microM, 1 microM, 10 microM) of prostaglandin F2 alpha reduced hepatic bile secretion in a dose-dependent manner. Similar effects were observed after infusion of prostaglandin D2. However, the ratio of the bile acids (alpha-tauromuricholic acid), beta-tauromuricholic acid, taurocholic acid, taurochenodeoxycholic acid, and taurodeoxycholic acid) was unchanged by prostaglandin F2 alpha. In conclusion, infusion of prostaglandin F2 alpha into the portal vein results in a reduction of bile flow and bile acid secretion in a dose-dependent manner. These results suggest that the effect is linked to canicular bile secretion.

Topics: Animals; Bile; Bile Acids and Salts; Cholestasis; Dinoprost; Infusions, Intravenous; Kinetics; Male; Portal Vein; Prostaglandin D2; Rats; Rats, Wistar

Chlorpromazine (10 mumol/L) causes a marked increase in portal pressure in perfused rat liver. Simultaneously, oxygen consumption, hepatic clearance of taurocholate and bile flow are diminished. These effects are prevented by the cyclooxygenase inhibitors indomethacin (15 mumol/L), acetylsalicylate (3 mmol/L) or ibuprofen (200 mumol/L). On addition of chlorpromazine the liver releases increased amounts of prostaglandin D2; this increase does not occur in the presence of indomethacin. At higher concentrations of chlorpromazine (100 mumol/L) the inhibition of taurocholate clearance and bile flow is accompanied by only a moderate increase of portal pressure, and indomethacin is without effect. At this high concentration, substantial cell damage, as indicated by the release of lactate dehydrogenase, is present. We conclude that arachidonic acid-derived metabolites, notably prostanoids, are involved in the inhibition of bile flow and of taurocholate clearance observed at low concentrations of chlorpromazine. The data suggest that changes in the microcirculation are responsible for the impairment of the liver functions. At higher concentrations of chlorpromazine the cell toxicity of the drug becomes prominent.

Topics: Animals; Bile; Blood Pressure; Chlorpromazine; Cholestasis; Cyclooxygenase Inhibitors; Indomethacin; L-Lactate Dehydrogenase; Liver; Male; Oxygen Consumption; Perfusion; Portal System; Prostaglandin D2; Rats; Rats, Inbred Strains; Taurocholic Acid