THE CONTRIBUTION BY MONOAMINE-OXIDASE AND CATECHOL-O-METHYLTRANSFERASE TO THE TOTAL-BODY AND PULMONARY PLASMA-CLEARANCE OF CATECHOLAMINES

To study the effects of inhibition of catechol-O-methyltransferase (CO MT) and monoamine oxidase (MAO) on the removal of circulating catechol amines, anaesthetized rabbits were infused for 120 min with H-3-labell ed noradrenaline, adrenaline and dopamine. Total-body plasma clearance s (Cl-tot) and pulmonary fractional extractions (ER(p)) of the infused amines and the cardiac output of plasma (COp) were determined under s teady-state conditions at the end of each of two consecutive 60-min tr eatment periods. MAO and COMT were inhibited by treatment with pargyli ne (40 mg/kg) and tolcapone (3 mg/kg followed by 1.5 mg/kg given every 30 min), respectively. Two groups of animals were studied. Group I in volved animals treated with tolcapone throughout and given pargyline a t the beginning of the second treatment period. In group II, pargyline was given at the beginning of the first, and the treatment with tolca pone was started at the beginning of the second treatment period. As p revious experiments had shown that COMT inhibition alone is without an y effect on Cl-tot of the three catecholamines considered here, the re sults obtained in the first treatment period of group I can be taken t o reflect control results. At the end of the first treatment period, C l-tot of noradrenaline, adrenaline and dopamine (expressed as a percen tage of COp) was 88%, 85% and 142%, respectively, in group I (COMT inh ibition) and 67%, 77% and 115%, respectively, in group II (MAO inhibit ion; P < 0.05 for the group difference regarding Cl-tot of noradrenali ne and dopamine). MAO inhibition on top of COMT inhibition (group I) l owered Cl-tot of noradrenaline, adrenaline and dopamine by 23%, 12% an d 26%, respectively, and COMT inhibition on top of MAO inhibition (gro up II) reduced Cl-tot of these catecholamines by 13%, 20% and 17%, res pectively. At the end of the first treatment period, the pulmonary pla sma clearance (Cl-p = ER(p) x COp) of noradrenaline and dopamine was 1 3 and 25 ml kg(-1) min(-1), respectively, in group I and 12 and 28 ml kg(-1) min(-1), respectively, in group II. Cl-p of adrenaline did not differ from zero in either group. Cl-p of noradrenaline and dopamine w as reduced by 74% and 70%, respectively, when both enzymes were inhibi ted in group I and by 70% and 67%, respectively, when both enzymes wer e inhibited in group II. Hence, inhibition of either MAO or COMT alone had little, if any, effect on the removal of noradrenaline, adrenalin e and dopamine on passage through the systemic and pulmonary circulati on. Combined inhibition of both MAO and COMT was highly effective in r educing the pulmonary clearance of noradrenaline and dopamine, but pro duced only minor decreases in the total-body clearance of all three ca techolamines.