A kinetic investigation of the pulmonary metabolism of dopamine in rats shows marked differences compared with noradrenaline

Abstract

The aim of this study was to investigate the deamination of dopamine in the intact pulmonary circulation of isolated lungs of the rat. The first part of the study showed that dopamine is not converted to noradrenaline by dopamine-beta-hydroxylase (DBH) when dopamine is perfused through isolated lung preparations with monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) inhibited. Hence, it was not necessary to inhibit DBH in subsequent experiments. The metabolite profile for deamination of dopamine in the lungs was examined by determining whether MAO and semicarbazide-sensitive amine oxidases (SSAO) contribute to the deamination of dopamine (and noradrenaline), and by determining the activity of MAO (kMAO) for the metabolism of dopamine. Lungs were perfused with 1 nmol/l 3H-dopamine or 3H-noradrenaline with COMT inhibited and, in experiments to determine the contribution of SSAO to deamination, with MAO inhibited. Inhibition of MAO reduced the deamination of dopamine and noradrenaline by 99.8% and 98.6%, respectively, indicating that MAO, and not SSAO, was responsible for deamination of the catecholamines in the lungs. The kMAO value for deamination of dopamine was 3.89 min-1. Further experiments were carried out to determine the contributions of MAO-A and MAO-B to the deamination of dopamine in lungs perfused with 1 nmol/l 3H-dopamine and 100 nmol/l lazabemide or 300 nmol/l Ro41-1049, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Amezinium and debrisoquine are substrates of uptake1 and potent inhibitors of monoamine oxidase in perfused lungs of rats

“…Tables 1 and 3 show that, with increasing concentrations of each of the drugs, the T/MNA values increased due to accumulation of noradrenaline in the cells when MAO was inhibited (see below), but the values reached a maximum and then decreased with further increases in the amezinium or debrisoquine concentrations. The maximal T/MNA values reached for both drugs were markedly less than the values of about 70 achieved in experiments in which both MAO and COMT were maximally inhibited by drugs that do not interact with the uptakel transporter (Scarcella and Bryan-Lluka 1995). The marked decrease in T/MNA occurred when the amezinium concentration was increased from 30 to 300 nmol/1, which are, respectively, below and above its IC50 value of 68 nmol/1 for inhibition of uptake1 in rat lungs .…”