THE FATE OF [H-3] (-)-NORADRENALINE IN THE PERFUSED-RAT-LIVER

1 Hepatic removal and metabolism as well as biliary excretion of norad renaline were studied. Rat livers were perfused in situ for 60 min wit h Krebs-Henseleit buffer at 37 degrees C containing 2 nM [H-3]-(-)-nor adrenaline. [H-3]-noradrenaline and its [H-3]-metabolites were determi ned in liver, venous effluent and bile. 2 Removal of [H-3]-noradrenali ne by the liver, calculated as the sum of total radioactivity in the l iver at the end of perfusion plus total radioactivity in the bile form ed during perfusion plus [H-3]-metabolites in the venous effluent form ed during perfusion, was 40.2 +/- 6.9 pmol g(-1) h(-1). This removal c orresponded to about 25% of the amount of [H-3]-noradrenaline offered to the liver. 3 A proportion of the [H-3]-noradrenaline (86.8%) taken up by the Liver was metabolized, 13.2% remained unmetabolized in the l iver and 0.019% was excreted unmetabolized into the bile. The most abu ndant metabolites were those present in the [H-3]-OMDA fraction (72.5% ), followed by [H-3]-NMN (15.8%), [H-3]-DOPEG (6.1%) and [H-3]-DOMA (5 .6%). Some of these metabolites (66.6%) were recovered from the venous effluent, 32.7% from the Liver and only 1.3% from the bile. The amoun t of [H-3]-noradrenaline present in the liver at the end of the perfus ion produced a tissue:perfusion medium ratio of 2.6. 4 Simultaneous in hibition of monoamine oxidase and catechol-O-methyl transferase With p argyline (75 mg kg(-1), i.p., 3 h before) and tolcapone (1 mu M), resp ectively, markedly reduced the formation of [H-3]-NMN, [H-3]-DOPEG and [H-3]-DOMA, but did not affect the hepatic removal of [H-3]-noradrena line, the content of [H-3]-noradrenaline in the liver, the formation o f [H-3]-OMDA or the excretion of [H-3]-noradrenaline and its [H-3]-met abolites into the bile. 5 Treatment with an uptake(2) blocker, cortico sterone (40 mu M), did not change the hepatic removal and metabolism o f [H-3]-noradrenaline or the biliary excretion of [H-3]-noradrenaline and its [H-3]-metabolites. 6 These findings indicate that the perfused rat Liver efficiently removed and metabolized [H-3]-noradrenaline, bo th monoamine oxidase and catechol-O-methyl transferase being involved in the metabolism of this amine. The apparent lack of effect of monoam ine oxidase and catechol-O-methyl transferase inhibition on the format ion of [H-3]-OMDA may be due to the presence, especially in the liver, of conjugated metabolites of [H-3]-noradrenaline in the [H-3]-OMDA fr action. These results also show that uptake(2) does not seem to be inv olved in the hepatic uptake of [H-3]-noradrenaline, confirming previou s findings. Finally, the results indicate that the rat Liver perfused with Krebs-Henseleit buffer is not a suitable experimental model for s tudies on the biliary excretion of catecholamines.