The influence of glucagon on the hepatic transport of taurocholate in isolated perfused rat liver: kinetic analysis by the multiple indicator dilution technique.
Glucagon has been demonstrated to stimulate the uptake of bile acid in isolated rat hepatocytes (Am. J. Physiol., 249, G427 (1985)). In the present study, we determined the influence of glucagon on the hepatic transport of a bile acid, taurocholate (TCA), in isolated rat livers. A single-pass perfusion and a rapid-injection, multiple indicator dilution method were employed. The hepatic availability at steady-state was 0.04. With the presence of glucagon in the perfusate (from 10(-9) to 10(-7) M), the bile flow rate was stimulated by 30%, while hepatic availability was decreased from 0.04 to 0.02 with a stepwise increase in glucagon concentration. Thirty min after the infusion of glucagon (300 nM), [3H]TCA and [14C]inulin were injected in a bolus state into the portal vein, and the outflow was collected at 1.0 s intervals over 30 s. Glucagon decreased the instantaneous hepatic availability by 50% compared to the control level, and was thus compatible with the steady-state experiments. In the control experiment, the influx clearance (PSinf) was 20 times higher than the efflux clearance (PSeff). Glucagon (300 nM) in the perfusate enhanced PSinf by 50% of the control, whereas sequestration clearance (CLseq) and the biliary excretion rate constant remained unchanged. PSeff was stimulated to 2 times the control, but still remained much smaller than CLseq. Based on the comparison of PSinf, PSeff and CLseq, the rate-determining process of TCA hepatic elimination was the influx process in both the presence and absence of glucagon. Taken together, the enhancement of the influx process was responsible for the decrease in TCA hepatic availability caused by glucagon.(ABSTRACT TRUNCATED AT 250 WORDS)
Miyauchi
S
S
Department of Biophysics and Physicochemistry, Faculty of Pharmaceutical Sciences, University of Hokkaido, Sapporo, Japan.
Sawada
Y
Y
Iga
T
T
Hanano
M
M
Sugiyama
Y
Y
D000818:Animals; D001646:Bile / Q000187:drug effects / Q000378:metabolism; D002417:Cattle; D005934:Glucagon / Q000494:pharmacology*; D066298:In Vitro Techniques; D007201:Indicator Dilution Techniques; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D010477:Perfusion; D051381:Rats; D013656:Taurocholic Acid / Q000378:metabolism*
D013656:Taurocholic Acid; D005934:Glucagon