Evidence for saturation of catechol-0-methyltransferase by low concentrations of noradrenaline in perfused lungs of rats

Bryan-Lluka L.J. (1995) Evidence for saturation of catechol-0-methyltransferase by low concentrations of noradrenaline in perfused lungs of rats. Naunyn-Schmiedeberg's Archives of Pharmacology, 351 4: 408-416. doi:10.1007/BF00169082


Author Bryan-Lluka L.J.
Title Evidence for saturation of catechol-0-methyltransferase by low concentrations of noradrenaline in perfused lungs of rats
Journal name Naunyn-Schmiedeberg's Archives of Pharmacology   Check publisher's open access policy
ISSN 0028-1298
Publication date 1995-01-01
Sub-type Article (original research)
DOI 10.1007/BF00169082
Volume 351
Issue 4
Start page 408
End page 416
Total pages 9
Publisher Springer-Verlag
Subject 3004 Pharmacology
Abstract Previous studies on the pulmonary removal and metabolism of catecholamines in rat lungs have shown that, when the lungs are perfused with a low concentration (1 nmol/1) of noradrenaline, the amine is metabolized by catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO), but is predominantly O-methylated, and the activities of COMT and MAO are 0.357 min-1 and 0.186 min-1, respectively. The aim of the present study was to examine the changes in the metabolic profile of noradrenaline in rat lungs over a range of concentrations, and to examine the kinetics of the pulmonary O-methylation of noradrenaline and adrenaline. In isolated lungs perfused with 3H-noradrenaline, there was a progressive decrease in the proportion of O-methylated metabolites and a corresponding increase in the proportion of deaminated metabolites, as the noradrenaline concentration in the perfusion solution was increased from 1 to 10 to 100 to 1000 nmol/l. Experiments designed to determine the rate of uptake of noradrenaline in lungs perfused with 1 nmol/l 3H-noradrenaline, under conditions of MAO inhibited, COMT inhibited and COMT and MAO inhibited, showed that the results were compatible with co-existence of COMT and MAO in the pulmonary endothelial cells. Hence, it appeared that the changing metabolic profile with amine concentration in the previous series of experiments was not due to saturation of noradrenaline uptake into cells that contained COMT but not MAO. Further experiments to examine the kinetics of O-methylation of noradrenaline and adrenaline (MAO inhibited) showed that the O-methylation of these amines in the lungs was predominantly saturable, with half-saturation occurring at concentrations (9.8 nmol/I and 19.4 nmol/l, respectively) that were two orders of magnitude lower than those required to half-saturate uptake1 of the amines. Saturation of O-methylation by these low concentrations of noradrenaline (1) provides the explanation for the change in the metabolic profile of noradrenaline described above and (ii) appears to occur because Vmax uptake ≫ Vmax COMT for the metabolizing system consisting of non-neuronal uptake1 + COMT in the lungs, as has been described previously for the system consisting of uptake2 + COMT in extraneuronal sites in rat heart. The results show that the metabolic profile of catecholamines in the pulmonary circulation will reflect that occurring at physiological levels only if studies are carried out with very low amine concentrations.
Keyword Catechol-O-methyltransferase
Kinetics
Monoamine oxidase
Noradrenaline
Rat lungs
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Unknown

Document type: Journal Article
Sub-type: Article (original research)
 
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