GLUCAGON INDUCES BILIARY PROTEIN EXCRETION IN GUINEA-PIGS

This study was done to determine glucagon's effect on protein biliary excretion in anesthetized, bile duct-cannulated guinea pigs. Glucagon (1.4 nmol.min-1.kg-1) induced choleresis and increased protein biliary concentration from 0.12 +/- 0.04 to 0.20 +/- 0.6 mg/ml and protein ou tput from 22.8 +/- 3.8 to 54.5 +/- 16.1 mug.kg-1.min-1. Protein biliar y excretion increased during the first 10 min of glucagon infusion and progressively declined thereafter. Biochemical analysis of biliary pr otein revealed that the increase could be accounted for primarily by a n increase in the lysosomal enzymes acid phosphatase and beta-glucuron idase. Biliary excretion of the canalicular membrane enzymes 5'-nucleo tidase and alkaline phosphatase only modestly increased, whereas that of [C-14]sucrose, a marker of paracellular fluid transport, was unaffe cted. On the other hand, glucagon enhanced biliary entry of horseradis h peroxidase in a fashion similar to that observed with total endogeno us protein. These effects were mediated by the adenosine 3',5'-cyclic monophosphate (cAMP) system, since infusion of dibutyryl-cAMP at 0.5 m umol.kg-1.min-1 increased bile flow and biliary protein excretion in a time-dependent manner, as observed with glucagon. Glucagon's failure to sustain enhanced protein biliary output was not due to declining he patic concentrations of cAMP or to depletion of hepatocellular lysosom al enzymes. These studies provide evidence that glucagon stimulates bi liary excretion of protein in guinea pigs that can be accounted for by biliary discharge of enzymes originating from the canalicular membran e and, primarily, from the lysosomal compartment. Although the precise mechanism(s) underlying these effects remains to be elucidated, it is suggested that the increase in canalicular membrane enzyme excretion is due to glucagon's effect on exocytosis. The increase in lysosome bi liary entry is most likely expressive of the hormone stimulation of ly sosome fusion with the canalicular membrane and/or some other event in volved in the genesis and/or biliary excretion of these organelles.