Summary
Longitudinal strips were prepared from human uterine arteries obtained at hysterectomy. The artery had a low content of noradrenaline and dopamine, contrasting with a high content of the deaminated catechols, dihydroxyphenylglycol (DOPEG) and dihydroxymandelic acid (DOMA), which together represented 98% of endogenous catechols.
When incubated with 3H-noradrenaline (0.1 μmol/l), the uterine artery removed, accumulated and metabolized noradrenaline. Deaminated metabolites predominated, DOMA being the most abundant metabolite.
Cocaine markedly reduced the accumulation of 3H-noradrenaline and abolished 3H-DOPEG formation, but did not change 3H-DOMA. Selective monoamine oxidase (MAO) inhibitors (clorgyline, selegiline and 2-amino ethyl carboxamide derivatives) caused a marked decrease in the amounts of 3H-DOPEG, 3H-DOMA and 3H-O-methylated and deaminated metabolites (OMDA) formed by the tissue and an increase in 3H-normetanephrine (NMN) formation. Inhibition of catechol-O-methyltransferase suppressed NMN formation and reduced that of OMDA; hydrocortisone slightly depressed the formation of DOMA and OMDA.
Homogenates of the uterine artery deaminated 3H-5-HT, 14C-phenylethylamine and 3H-tyramine; inhibition curves of the deamination of 3H-tyramine by clorgyline and selegiline were compatible with the presence of both MOA A and MOA B.
Exposure of the strips to 6-hydroxydopamine (1.5 mmol/l for 20 min; 3 exposure periods followed by washout periods of 15,15 and 30 min) resulted in complete and selective chemical denervation of the arterial tissue. This chemical denervation had effects which were similar to those of cocaine. The 2-amino ethyl carboxamide derivatives markedly reduced the formation of deaminated metabolites by the denervated strips.
The semicarbazide-sensitive amine oxidase inhibitor semicarbazide reduced the formation of 3H-DOMA and 3H-DOPEG in intact strips, but was devoid of action in the denervated ones.
It is concluded that, in the human uterine artery, deamination predominates over O-methylation and that extraneuronal deamination, leading to the formation of DOMA (and of OMDA) plays a major role in the metabolism even of low concentrations of exogenous noradrenaline.
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Abbreviations
- COMT:
-
Catechol O-methyltransferase
- DOMA:
-
dihydroxymandelic acid
- DOPEG:
-
dihydroxyphenylglycol
- HPLC-ED:
-
high pressure liquid chromatography with electrochemical detection
- 5-HT:
-
5-hydroxytryptamine
- MAO:
-
monoamine oxidase
- NMN:
-
normetanephrine
- 6-OHDA:
-
6-hydroxydopamine
- OMDA:
-
O-methylated and deaminated metabolites of noradrenaline (3-methoxy-4-hydroxyphenylglycol and 3-methoxy-4-hydroxymandelic acid)
- Ro 01-2812:
-
3,5-dinitropyrocatechol
- Ro-19-6327:
-
N-(2-aminoethyl)-5-chloro-2-pyridine carboxamide hydrochloride
- Ro 41-1049:
-
N-(2-aminoethyl)-5-(mfluorophenyl)-4-thiazole carboxamide hydrochloride
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Supported by Instituto Nacional de Investigação Científica (INIC, FmP1) and Junta Nacional de Investigação Científica e Tecnológica (JNICT). Fatima Martel is a PhD student with a grant from JNICT
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Branco, D., Caramona, M., Martel, F. et al. Predominance of oxidative deamination in the metabolism of exogenous noradrenaline by the normal and chemically denervated human uterine artery. Naunyn-Schmiedeberg's Arch Pharmacol 346, 286–293 (1992). https://doi.org/10.1007/BF00173541
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DOI: https://doi.org/10.1007/BF00173541