O-methylation and decarboxylation of α-methyldopa in brain and spinal cord: Depletion of S-adenosylmethionine and accumulation of metabolites in catecholaminergic neurones

Lo, C.-M.; Kwok, M.; Wurtman, Richard J.

doi:10.1016/0028-3908(76)90116-7

Cited by 10 publications

(9 citation statements)

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“…The next day, the supernatant fluids were adjusted to pH 2.0 and passed over 4.5-cm columns of Dowex 50W-X4 (Carlson and Waldeck, 1964;Lo et al, 1976). The columns were washed with 10 ml of 0.1 M citrate-phosphate buffer (pH 2.5); then 10 ml of water, and buffer and water were discarded.…”

Section: -0-methylated Methyldopa Metaboutes/zavisca Et Almentioning

confidence: 99%

“…We were interested particularly in spinal cord levels, since it is possible that AMD or OMMD may act at descending monoaminergic synapses (Chalmers and Wurtman, 1971;Lo et al, 1976). Relatively high doses of OMMD (50 and 100 mg/kg) were used to obtain readily measurable antihypertensive responses and tissue levels of OMMD (and, if present, AMD).…”

Section: Ommd Levels and Blood Pressure Change After Different Doses mentioning

confidence: 99%

“…Considerable evidence supports the view that the active agent is o-methyl-norepinephrine (AMNE), the decarboxylated and /?-hydroxylated product of AMD. However, the exact nature of the active agent and the mechanism by which it affects blood pressure remain obscure.Previous experiments in our laboratory (Lo et al, 1976) demonstrated a dose-related accumulation of O-methylated metabolites in the brains and spinal cords of mice given isotopically labeled AMD. These O-methylated metabolites seem to be produced or stored in catecholaminergic (CA) neurons, since their accumulation is prevented by destruction of CA nerve terminals with 6-hydroxy-dopamine (Lo et al, 1976).…”

mentioning

confidence: 99%

“…Previous experiments in our laboratory (Lo et al, 1976) demonstrated a dose-related accumulation of O-methylated metabolites in the brains and spinal cords of mice given isotopically labeled AMD. These O-methylated metabolites seem to be produced or stored in catecholaminergic (CA) neurons, since their accumulation is prevented by destruction of CA nerve terminals with 6-hydroxy-dopamine (Lo et al, 1976).…”

mentioning

confidence: 99%

“…These O-methylated metabolites seem to be produced or stored in catecholaminergic (CA) neurons, since their accumulation is prevented by destruction of CA nerve terminals with 6-hydroxy-dopamine (Lo et al, 1976). Repeated administration of isotopically labeled AMD to mice was associated with a considerable increase in levels of some of these 3-O-methylated metabolites in brains and spinal cords.…”

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confidence: 99%

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Mechanism of action of methyldopa in the rat. Role of 3-O-methylated metabolites.

Zavisca¹,

Breau²,

Wurtman³

1979

Circulation Research

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SUMMARYWe studied the effect of 3-O-methyl-methyldopa (OMMD), the 3-O-methylated metabolite of the antihypertensive drug methyldopa (a-methyldopa, AMD), on blood pressure in the spontaneously hypertensive rat. OMMD lowered blood pressure in a dose-related manner when given orally or intraperitoneally. Its action lasted longer than that of AMD, and daily oral administration produced a cumulative fall in blood pressure. Oral and intraperitoneal OMMD produced similar reductions of blood pressure and similar tissue OMMD levels. After intraperitoneal injection of different doses, levels of OMMD measured in brain, spinal cord, and plasma correlated with the magnitude of the antihypertensive effect. No AMD was detected in tissues after either route of administration, which suggests that the antihypertensive effect was not based on demethylation of OMMD to AMD. Peripheral inhibition of the enzyme, aromatic amino acid decarboxylase (AAAD), failed to suppress OMMD's effect on blood pressure; in contrast, central inhibition of AAAD did decrease OMMD's antihypertensive effect. These observations suggest that 3-O-methylated metabolites may participate in the antihypertensive effect of AMD. Ore Res 45: 684-690, 1979 AN AMINE metabolite acting in the central nervous system (CNS) mediates the antihypertensive effect of methyldopa (a-methyldopa, "Aldomet," AMD), a widely used antihypertensive drug (Dollery and Bulpitt, 1975;Henning, 1975;Van Zwieten, 1973). Considerable evidence supports the view that the active agent is o-methyl-norepinephrine (AMNE), the decarboxylated and /?-hydroxylated product of AMD. However, the exact nature of the active agent and the mechanism by which it affects blood pressure remain obscure.Previous experiments in our laboratory (Lo et al., 1976) demonstrated a dose-related accumulation of O-methylated metabolites in the brains and spinal cords of mice given isotopically labeled AMD. These O-methylated metabolites seem to be produced or stored in catecholaminergic (CA) neurons, since their accumulation is prevented by destruction of CA nerve terminals with 6-hydroxy-dopamine (Lo et al., 1976). Repeated administration of isotopically labeled AMD to mice was associated with a considerable increase in levels of some of these 3-O-methylated metabolites in brains and spinal cords. This evidence raises the possibility that O-methylated metabolites might participate in AMD's antihypertensive effects, especially when multiple doses are given.Other evidence also supports the possibility that O-methylated metabolites might be involved. Prescott et al. (1966) observed that hypertensive patients taking AMD for 1 month have a 40% increase in the percentage excreted as 3-O-methyl-methyldopa (OMMD), compared with amounts excreted after a single dose. These authors also noted a direct linear correlation between the antihypertensive effect of AMD and the 24-hour urinary excretion of OMMD in chronically treated patients. These results suggest that the O-methylation of AMD can be induced and might assume therapeutic ...

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Section: -0-methylated Methyldopa Metaboutes/zavisca Et Almentioning

confidence: 99%

Section: Ommd Levels and Blood Pressure Change After Different Doses mentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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