THE INFLUENCE OF GLUCAGON ON THE HEPATIC TRANSPORT OF TAUROCHOLATE INISOLATED-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 dilu tion method were employed. The hepatic availability at steady-state wa s 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 av ailability was decreased from 0.04 to 0.02 with a stepwise increase in glucagon concentration. Thirty min after the infusion of glucagon (30 0 nM), [H-3]TCA and [C-14]inulin were injected in a bolus state into t he 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 stead y-state experiments. In the control experiment, the influx clearance ( PS(inf)) was 20 times higher than the efflux clearance (PS(eff)). Gluc agon (300 nM) in the perfusate enhanced PS(inf) by 50% of the control, whereas sequestration clearance (CL(seq)) and the biliary excretion r ate constant remained unchanged. PS(eff) was stimulated to 2 times the control, but still remained much smaller than CL(seq). Based on the c omparison of PS(inf), PS(eff) and CL(seq), the rate-determining proces s of TCA hepatic elimination was the influx process in both the presen ce and absence of glucagon. Taken together, the enhancement of the inf lux process was responsible for the decrease in TCA hepatic availabili ty caused by glucagon. Glucagon also enhanced the bile flow rate, but did not alter the biliary excretion rate of TCA, suggesting that gluca gon might stimulate the bile acid independent bile flow.