The fate of [3H]-(-)-noradrenaline in the perfused rat liver.
1. Hepatic removal and metabolism as well as biliary excretion of noradrenaline were studied. Rat livers were perfused in situ for 60 min with Krebs-Henseleit buffer at 37 degrees C containing 2 nM [3H]-(-)-noradrenaline. [3H]-noradrenaline and its [3H]-metabolites were determined in liver, venous effluent and bile. 2. Removal of [3H]-noradrenaline by the liver, calculated as the sum of total radioactivity in the liver at the end of perfusion plus total radioactivity in the bile formed during perfusion plus [3H]-metabolites in the venous effluent formed during perfusion, was 40.2 +/- 6.9 pmol g-1 h-1. This removal corresponded to about 25% of the amount of [3H]-noradrenaline offered to the liver. 3. A proportion of the [3H]-noradrenaline (86.8%) taken up by the liver was metabolized, 13.2% remained unmetabolized in the liver and 0.019% was excreted unmetabolized into the bile. The most abundant metabolites were those present in the [3H]-OMDA fraction (72.5%), followed by [3H]-NMN (15.8%), [3H]-DOPEG (6.1%) and [3H]-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 amount of [3H]-noradrenaline present in the liver at the end of the perfusion produced a tissue:perfusion medium ratio of 2.6. 4. Simultaneous inhibition of monoamine oxidase and catechol-O-methyl transferase with pargyline (75 mg kg-1, i.p., 3 h before) and tolcapone (1 microM), respectively, markedly reduced the formation of [3H]-NMN, [3H]-DOPEG and [3H]-DOMA, but did not affect the hepatic removal of [3H]-noradrenaline, the content of [3H]-noradrenaline in the liver, the formation of [3H]-OMDA or the excretion of [3H]-noradrenaline and its [3H]-metabolites into the bile. 5. Treatment with an uptake2 blocker, corticosterone (40 microM), did not change the hepatic removal and metabolism of [3H]-noradrenaline or the biliary excretion of [3H]-noradrenaline and its [3H]-metabolites. 6. These findings indicate that the perfused rat liver efficiently removed and metabolized [3H]-noradrenaline, both monoamine oxidase and catechol-O-methyl transferase being involved in the metabolism of this amine. The apparent lack of effect of monoamine oxidase and catechol-O-methyl transferase inhibition on the formation of [3H]-OMDA may be due to the presence, especially in the liver, of conjugated metabolites of [3H]-noradrenaline in the [3H]-OMDA fraction. These results also show that uptake2 does not seem to be involved in the hepatic uptake of [3H]-noradrenaline, confirming previous findings. Finally, the results indicate that the rat liver perfused with Krebs-Henseleit buffer is not a suitable experimental model for studies on the biliary excretion of catecholamines.
Martel
F
F
Faculty of Medicine, Institute of Pharmacology and Therapeutics, Porto, Portugal.
Azevedo
I
I
D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000818:Animals; D001577:Benzophenones / Q000494:pharmacology; D065098:Catechol O-Methyltransferase Inhibitors; D003345:Corticosterone / Q000494:pharmacology; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism*; D008297:Male; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D009596:Nitrophenols; D009638:Norepinephrine / Q000378:metabolism*; D010293:Pargyline / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D000077867:Tolcapone; D014316:Tritium
D018759:Adrenergic Uptake Inhibitors; D001577:Benzophenones; D065098:Catechol O-Methyltransferase Inhibitors; D008996:Monoamine Oxidase Inhibitors; D009596:Nitrophenols; D014316:Tritium; D010293:Pargyline; D000077867:Tolcapone; D003345:Corticosterone; D009638:Norepinephrine