AMEZINIUM AND DEBRISOQUINE ARE SUBSTRATES OF UPTAKE, AND POTENT INHIBITORS OF MONOAMINE-OXIDASE IN PERFUSED LUNGS OF RATS

Previous studies have resulted in the classification of amezinium as a selective inhibitor of neuronal monoamine oxidase (MAO), because it i s a much more potent MAO inhibitor in intact tissues, in which it is a ccumulated in noradrenergic neurones by uptake,, than in tissue homoge nates. Tn the present study, the effects of amezinium on the deaminati on of noradrenaline were investigated in intact lungs of rats, since t he pulmonary endothelial cells are a site where the catecholamine tran sporter is non-neuronal uptake(1). In addition, another drug that is b oth a substrate of uptake(1) and a MAO inhibitor, debrisoquine, was in vestigated in the study. The first aim of the study was to show whethe r amezinium and debrisoquine are substrates of uptake, in rat lungs. A fter loading of isolated perfused lungs with H-3-noradrenaline (MAO an d catechol-O-methyltransferase (COMT) inhibited), the efflux of H-3-no radrenaline was measured for 30 min. When 1 mu mol/l amezinium or 15 m u mol/l debrisoquine was added for the last 15 min of efflux, there wa s a rapid and marked increase in the fractional rate of loss of H-3-no radrenaline, which was reduced by about 70% when 1 mu mol/l desipramin e was present throughout the efflux period. These results showed that both drugs were substrates for uptake(1) in rat lungs. In lungs perfus ed with 1 nmol/l H-3-noradrenaline (COMT inhibited), 10, 30 and 300 nm ol/l amezinium caused 58%, 76% and 74% inhibition of noradrenaline dea mination, respectively. and 30, 300 and 3000 nmol/l debrisoquine cause d 56%, 89% and 96% inhibition of noradrenaline deamination, respective ly. When MAO-B was also inhibited, 10 nmol/l amezinium caused 84% inhi bition of the deamination of noradrenaline by MAO-A in the lungs. In c ontrast, in hearts perfused with 10 nmol/l H-3-noradrenaline under con ditions where the amine was accumulated by uptake(2) (COMT, uptake(1) and vesicular transport inhibited), 10 nmol/l amezinium had no effect and 300 nmol/l amezinium caused only 36% inhibition of deamination of noradrenaline. The results when considered with previous reports in th e literature show that amezinium is about 1000 times more potent and d ebrisoquine is about 20 times more potent for MAO inhibition in rat lu ngs than in tissue homogenates, and the reason for their high potencie s in the intact lungs is transport and accumulation of the drugs in th e pulmonary endothelial cells by uptake(1). Amezinium is much less pot ent as a MAO inhibitor in cells with the uptake(2) transporter, such a s the myocardial cells of the heart. The results also confirmed previo us reports that amezinium is highly selective for MAO-A.