Abstract
To study the effects of inhibition of catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO) on the removal of circulating catecholamines, anaesthetized rabbits were infused for 120 min with 3H-labelled noradrenaline, adrenaline and dopamine. Total-body plasma clearances (Cltot) and pulmonary fractional extractions (ERP) of the infused amines and the cardiac output of plasma (COP) were determined under steady-state conditions at the end of each of two consecutive 60-min treatment periods. MAO and COMT were inhibited by treatment with pargyline (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 involved animals treated with tolcapone throughout and given pargyline at the beginning of the second treatment period. In group II, pargyline was given at the beginning of the first, and the treatment with tolcapone was started at the beginning of the second treatment period. As previous experiments had shown that COMT inhibition alone is without any effect on Cltot, of the three catecholamines considered here, the results obtained in the first treatment period of group I can be taken to reflect control results.
At the end of the first treatment period, Cltot of noradrenaline, adrenaline and dopamine (expressed as a percentage of COP) was 88%, 85% and 142%, respectively, in group I (COMT inhibition) and 67%, 77% and 115%, respectively, in group II (MAO inhibition; P < 0.05 for the group difference regarding Cltot of noradrenaline and dopamine). MAO inhibition on top of COMT inhibition (group I) lowered Cltot of noradrenaline, adrenaline and dopamine by 23%, 12% and 26%, respectively, and COMT inhibition on top of MAO inhibition (group II) reduced Cltot of these catecholamines by 13%, 20% and 17%, respectively. At the end of the first treatment period, the pulmonary plasma clearance (Clp = ERP x COP) of noradrenaline and dopamine was 13 and 25 ml kg−1 min −, respectively, in group I and 12 and 28 ml kg−1 min−, respectively, in group II. ClP of adrenaline did not differ from zero in either group. ClP of noradrenaline and dopamine was reduced by 74% and 70%, respectively, when both enzymes were inhibited in group I and by 70% and 67%, respectively, when both enzymes were inhibited in group II.
Hence, inhibition of either MAO or COMT alone had little, if any, effect on the removal of noradrenaline, adrenaline and dopamine on passage through the systemic and pulmonary circulation. Combined inhibition of both MAO and COMT was highly effective in reducing the pulmonary clearance of noradrenaline and dopamine, but produced only minor decreases in the total-body clearance of all three catecholamines.
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References
Axelrod J (1966) Methylation reactions in the formation and metabolism of catecholamines and other biogenic amines. Pharmacol Rev 18:95–113
Brown MJ, Davies DS, Dollery CT (1979) Quantitative analysis of noradrenaline clearance. Br J Pharmacol 67:452P-453P
Brown MJ, Lhoste FJM, Zamboulis C, Ind PW, Jenner DA, Dollery CT (1982) Estimation of sympathetic activity in essential hypertension. Clin Pharmacol Ther 31:16–22
Bryan-Lluka LJ, Westwood NN, O'Donnell SR (1992) Vascular uptake of catecholamines in perfused lungs of the rat occurs by the same process as uptake, in noradrenergic neurones. Naunyn-Schmiedeberg's Arch Pharmacol 345:319–326
Cassis L, Ludwig J, Grohmann M, Trendelenburg U (1986) The effect of partial inhibition of monoamine oxidase on the steady-state rate of deamination of 3H-catecholamines in two metabolizing systems. Naunyn-Schmiedeberg's Arch Pharmacol 333:253–261
Eisenhofer G (1994) Plasma normetanephrine for examination of extraneuronal uptake and metabolism of noradrenaline in rats. Naunyn-Schmiedeberg's Arch Pharmacol 349:259–269
Eisenhofer G, Goldstein DS, Ropchak TG, Nguyen HQ, Keiser HR, Kopin IJ (1988) Source and physiological significance of plasma 3,4-dihydroxyphenylglycol and 3-methoxy-4-hydroxyphenylglycol. J Auton Nerv Syst 24:1–14
Esler M (1982) Assessment of sympathetic nervous function in humans from noradrenaline plasma kinetics. Clin Sci (colch) 62:247–254
Finberg JPM, Kopin IJ (1986) Chronic clorgyline treatment enhances release of norepinephrine following sympathetic stimulation in the rat. Naunyn-Schmiedeberg's Arch Pharmacol 332: 236–242
Friedgen B, Halbrügge T, Graefe K-H (1993a) Plasma clearances and extractions of four catecholamines in the anesthetized rabbit: the role of amine removal by blood cells. J Cardiovasc Pharmacol 21:21–28
Friedgen B, Halbrügge T, Graefe K-H (1993b) The part played by catechol-O-methyltransferase in the plasma kinetics of 3,4-dihydroxyphenylglycol and 3,4-dihydroxyphenylalanine in the anesthetized rabbit. Naunyn-Schmiedeberg's Arch Pharmacol 347:155–161
Friedgen B, Halbrügge T, Graefe K-H (1994) Roles of uptake, and catechol-O-methyltransferase in removal of circulating catecholamines in the rabbit. Am J Physiol 267:E814-E821
Fuentes JA, Neff NH (1977) Inhibition by pargyline of cardiovascular amine oxidase activity. Biochem Pharmacol 26:2107–2112
Gillis CN, Iwasawa Y (1972) Technique for measurement of norepinephrine and 5-hydroxytryptamine uptake by rabbit lung. J Appl Physiol 33:404–408
Gillis CN, Roth JA (1976) Pulmonary disposition of circulating vasoactive hormones. Biochem Pharmacol 25:2547–2553
Gillis CN, Roth JA (1977) The fate of biogenic monoamines in perfused rabbit lung. Br J Pharmacol 59:585–590
Graefe K-H (1981) The disposition of 3H-(-)noradrenaline in the perfused cat and rabbit heart. Naunyn-Schmiedeberg's Arch Pharmacol 318:71–82
Graefe K-H, Bönisch H (1988) The transport of amines across the axonal membranes of noradrenergic and dopaminergic neurones. In: Trendelenburg U, Weiner N (eds) Catecholamines I (Handbook of experimental pharmacology, vol 90/I) Springer, Berlin Heidelberg New York, PP 193–245
Graefe K-H, Bönisch H, Trendelenburg U (1971) Time-dependent changes in neuronal net uptake of noradrenaline after pretreatment with pargyline and/or reserpine. Naunyn-Schmiedeberg's Arch Pharmacol 271:1–28
Grohmann M (1987) The activity of the neuronal and extraneuronal catecholamine-metabolizing enzymes of the perfused rat heart. Naunyn-Schmiedeberg's Arch Pharmacol 336:139–147
Halbrügge T, Gerhardt T, Ludwig J, Heidbreder E, Graefe K-H (1988a) Assay of catecholamines and dihydroxyphenylethyleneglycol in human plasma and its application in orthostasis and mental stress. Life Sci 43:19–26
Halbrügge T, Ungell A-L, Wölfel R, Graefe K-H (1988b) Total body, systemic and pulmonary clearance and fractional extraction of unlabelled and differently 3H-labelled noradrenaline in the anaesthetized rabbit. Naunyn-Schmiedeberg's Arch Pharmacol 338:361–367
Halbrügge T, Lütsch K, Thyen A, Graefe K-H (1991) Role of nitric oxide formation in the regulation of haemodynamics and the release of noradrenaline and adrenaline. Naunyn-Schmiedeberg's Arch Pharmacol 344:720–727
Halbrügge T, Friedgen B, Ludwig J, Graefe K-H (1993) Effect of catechol-O-methyltransferase inhibition on the plasma clearance of noradrenaline and the formation of 3,4-dihydroxyphenylglycol in the rabbit. Naunyn-Schmiedeberg's Arch Pharmacol 347:162–170
Iversen LL (1967) The uptake and storage of noradrenaline in sympathetic nerves. Cambridge University Press, Cambridge
Kopin IJ (1972) Metabolic degradation of catecholamines. The relative importance of different pathways under physiological conditions and after administration of drugs. In: Blaschko H., Muscholl E (eds) Catecholamines (Handbook of experimental pharmacology, vol 23) Springer, Berlin Heidelberg New York, pp 270–282
Kopin IJ (1985) Catecholamine metabolism: basic aspects and clinical significance. Pharmacol Rev 37:333–364
Majewski H, Hedler L, Starke K (1982) The noradrenaline release rate in the anaesthetized rabbit: facilitation by adrenaline. Naunyn-Schmiedeberg's Arch Pharmacol 321:20–27
Neff NH, Yang HYT (1974) Another look at the monoamine oxidases and the MAO inhibitor drugs. Life Sci 14:2061–2074
Ratge D, Kohse KP, Steegmüller U, Wisser H (1991) Distribution of free and conjugated catecholamines between plasma, platelets and erythrocytes: different effects of intravenous and oral catecholamine administration. J Pharmacol Exp Ther 257:232–257
Roth JA, Gillis CN (1975) Multiple forms of amine oxidase in perfused rabbit lung. J Pharmacol Exp Ther 194:537–544
Rowland M, Tozer TN (1989) Clinical pharmacokinetics: concepts and applications. Lea and Febiger, Philadelphia, p 152
Trendelenburg U (1988) The extraneuronal uptake and metabolism of catecholamines. In: Trendelenburg U, Weiner N (eds) Catecholamines I (Handbook of experimental pharmacology, vol 90/I) Springer, Berlin Heidelberg New York, pp 279–319
Trendelenburg U (1990) The interaction of transport mechanisms and intracellular enzymes in metabolizing systems. J Neural Transm [Suppl] 32:3–18
Zürcher G, Keller HH, Kettler R, Borgulya J, Bonetti EP, Eigenmann R, Da Prada M (1990) Ro 40–7592, a novel, very potent and orally active inhibitor of catechol-O-methyltransferase: a pharmacological study in rats. Adv Neural 53:497–503
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Friedgen, B., Wölfel, R. & Graefe, KH. The contribution by monoamine oxidase and catechol-O-methyltransferase to the total-body and pulmonary plasma clearance of catecholamines. Naunyn-Schmiedeberg's Arch Pharmacol 353, 193–199 (1996). https://doi.org/10.1007/BF00168757
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DOI: https://doi.org/10.1007/BF00168757