Effects of neutral amino acids on the antihypertensive action of methyldopa in spontaneously hypertensive rats

Zavisca, Frank; Wurtman, Richard J.

doi:10.1111/j.2042-7158.1978.tb13158.x

Cited by 9 publications

(3 citation statements)

References 16 publications

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“…1-4). The effective dose range, 50-200 mg/kg, is similar to that observed for another amino acid, methyldopa, used widely in the treatment of hypertension (12).…”

Section: Discussionmentioning

confidence: 52%

Tyrosine administration reduces blood pressure and enhances brain norepinephrine release in spontaneously hypertensive rats.

Sved¹,

Fernstrom²,

Wurtman³

1979

Proc. Natl. Acad. Sci. U.S.A.

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145

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Administration of L-tyrosine to normotensive or spontaneously hypertensive rats reduces blood pressure. The effect is maximal within 2 hr of injection. In spontaneously hypertensive rats, a dose of 50 mg/kg, intraperitoneally, reduces blood pressure by about 12 mm Hg (1 mm Hg = 1.33 X 102 pascals); a dose of 200 mg/kg produces the maximal effect, a reduction of about 40 mm Hg. Tryptophan injection (225 mg/kg) also lowers blood pressure in spontaneously hypertensive rats, but only by about half as much as an equivalent dose of tyrosine.Other amino acids tested (leucine, isoleucine, valine, alanine, arginine, and aspartate) do not affect blood pressure. Tyrosine injection appears to reduce blood pressure via an action within the central nervous system, since the effect can be blocked by co-administering other large neutral amino acids that reduce tyrosine's uptake into the brain. That tyrosine's antihypertensive action is mediated by an acceleration in norepinephrine or epinephrine release within the central nervous system is suggested by the concurrent increase that its injection produces in brain levels of methoxyhydroxyphenylethylglycol sulfate. Norepinephrine (NE) and possibly epinephrine release by nerve terminals in the mammalian central nervous system (CNS) modifies blood pressure. Depending on the locus, NE release can either increase or decrease blood pressure (1, 2). In the brain stem, stimulation of a-adrenergic receptors lowers blood pressure. The antihypertensive action of several drugs (e.g., clonidine and methyldopa) has been attributed to their ability to stimulate these brain-stem receptors (1). Epinephrine-containing neurons are also present in brain-stem regions involved in blood pressure regulation (3, 4). Thus, they may release their transmitter onto these same a receptors and thereby influence blood pressure.The synthesis and release of NE (or possibly epinephrine) in the rat brain are influenced by the availability of the precursor amino acid, tyrosine. Thus, tyrosine administration, which raises brain tyrosine levels, stimulates dopa accumulation in rats pretreated with R04-4602 (an inhibitor of aromatic L-aminoacid decarboxylase); the injection of other large neutral amino acids, which lowers brain tyrosine levels, diminishes dopa formation (5-7). Tyrosine injection also increases brain levels of methoxyhydroxyphenylethylglycol sulfate ref. 8), indicating that NE and epinephrine release might be enhanced by precursor administration. If stimulation of central a receptors can lower blood pressure and if tyrosine administration does enhance the release of NE (or perhaps epinephrine) from CNS nerve terminals, then tyrosine injection might also lower blood pressure. The studies described below have tested this hypothesis. (10) after isolation of the metabolite on QAE-Sephadex columns. Serum and brain tyrosine levels were also estimated fluorimetrically by the method of Waalkes and Udenfriend (11). Amino acids (L-form, free base; obtained from standard commercial suppliers), dissolve...

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“…1-4). The effective dose range, 50-200 mg/kg, is similar to that observed for another amino acid, methyldopa, used widely in the treatment of hypertension (12).…”

Section: Discussionmentioning

confidence: 52%

Tyrosine administration reduces blood pressure and enhances brain norepinephrine release in spontaneously hypertensive rats.

Sved¹,

Fernstrom²,

Wurtman³

1979

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

145

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“…The lowest dose tested (10 mg/kg) produced a small but insignificant effect; higher doses produced significant effects, with maximal falls in blood pressure occurring at 100 mg/kg. The effect of this dose was about half the maximal effect of AMD (Zavisca and Wurtman, 1978).…”

Section: Ommd Dose-response Curvementioning

confidence: 84%

“…In contrast, AMD had little effect at 2 hours, a peak effect at 4-5 hours, and no significant effect at 8 hours. The peak antihypertensive effect of OMMD is approximately half that of a similar dose of AMD (Zavisca and Wurtman, 1978) administered i.p.…”

Section: Ommd Time Coursementioning

confidence: 95%

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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4 Aromatic Amino Acids in the Brain

Cansev¹,

Wurtman²

2007

Handbook of Neurochemistry and Molecular Neurobiology

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Effects of neutral amino acids on the antihypertensive action of methyldopa in spontaneously hypertensive rats

Cited by 9 publications

References 16 publications

Tyrosine administration reduces blood pressure and enhances brain norepinephrine release in spontaneously hypertensive rats.

Tyrosine administration reduces blood pressure and enhances brain norepinephrine release in spontaneously hypertensive rats.

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

4 Aromatic Amino Acids in the Brain

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