Cholestasis and changes of portal pressure caused by chlorpromazine in the perfused rat liver.
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.
Akerboom
T
T
Institut für Physiologische Chemie I, Universität Düsseldorf, Federal Republic of Germany.
Schneider
I
I
vom Dahl
S
S
Sies
H
H
D000818:Animals; D001646:Bile / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects; D002746:Chlorpromazine / Q000494:pharmacology*; D002779:Cholestasis / Q000139:chemically induced* / Q000503:physiopathology; D016861:Cyclooxygenase Inhibitors; D007213:Indomethacin / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D010101:Oxygen Consumption / Q000187:drug effects; D010477:Perfusion; D011168:Portal System / Q000187:drug effects*; D015230:Prostaglandin D2 / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013656:Taurocholic Acid / Q000378:metabolism
D016861:Cyclooxygenase Inhibitors; D013656:Taurocholic Acid; D007770:L-Lactate Dehydrogenase; D015230:Prostaglandin D2; D002746:Chlorpromazine; D007213:Indomethacin