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PubMed1993

Differential role of brain ascending noradrenergic bundles in the circulatory effects of alpha-methyldopa and clonidine.

We examined the contribution of the ascending noradrenergic (NA) projections to the circulatory effects of intracisternal (i.c.) administration of clonidine and alpha-methyldopa (alpha-MD) in conscious rabbits. We compared the effects of combined dorsal and ventral NA fibre bundle lesions with those of individual bundle lesions. Local microinjection of 6-hydroxydopamine (6-OHDA) bilaterally into both NA fibre bundles in the midbrain produced marked reduction in norepinephrine (NE) after 4 weeks in all forebrain regions examined, but dopamine concentrations generally were not affected. The decreases in mean arterial pressure (MAP) and heart rate (HR) to i.c. injections of clonidine in animals with forebrain NE depletion were similar to those observed in vehicle-injected animals. In contrast, the normal decrease in HR produced by alpha-MD was abolished in rabbits with lesions of both the dorsal and ventral NA bundle (8% of control) and markedly reduced in rabbits with lesions of only the ventral bundle (33% of control). Lesions of the dorsal bundle alone produced a modest attenuation of bradycardia (62% of control). The effects of the lesions were not observed in sinoaortically denervated (SAD) rabbits, suggesting that the main component of the bradycardia affected was baroreflex vagal facilitation. The effects on the hypotension produced by alpha-MD were only slight.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic Fibers↗
PubMedDate not supplied

Changes in plasma and extracellular fluid volume during long-term treatment with alpha-methyldopa in 11 thiazide-treated patients with essential hypertension.

In eleven patients with essential hypertension, plasma volume (T-1824) (PV), extracellular fluid volume (82Br-distribution space) (ECFV), blood pressure (BP) and the ratio plasma to interstitial fluid volume (PV/IF) have been determined three times before treatment, after more than two months of thiazide treatment and after three and six months of combined thiazide-alpha-methyldopa (AMD) therapy. During combined treatment, PV/IF showed a significant increase, whereas PV and ECFV did not change significantly. Compared to values during thiazide therapy, PV and PV/IF increased, whereas ECFV was unchanged. BP was reduced significantly after thiazide treatment and showed a further significant fall when AMD was added. Based on the results and a review of the literature, it is concluded that AMD acts by interfering with the normal sympathetic activity, thereby producing a reduced venomotor tone and increased venous capacity. The concomitant reduced venous return of blood to the heart is suggested to contribute to the antihypertensive effect of AMD by means of a decreased cardiac output.

Aged↗
PubMed1978

Adverse reactions with methyldopa--a decade's reports.

During 1966-75 the Swedish Adverse Drug Reaction Committee received some 300 reports of reactions to methyldopa. As the Swedish rules for reporting adverse reactions emphasize the importance of severe and unexpected reactions, the relative incidence of various adverse effects differs greatly from what would be found in an intensive study. The three most commonly reported reactions are fever, hemolysis and hepatic effects. Two-thirds of these patients were women. The median age of the groups differed, from 57 years (hepatic effects) to 69 years (hemolysis). The clinical picture of the different reactions was consistent, in the main, with what has been described previously. Between 70 and 85% of the patients in these groups were admitted to hospital because of the adverse reaction.

Adult↗
PubMed1982

alpha-Methyldopa, alpha-methyldopamine an alpha-methylnoradrenaline: substrates for the thermolabile form of human platelet phenol sulphotransferase.

1 Sulphate conjugation catalyzed by phenol sulphotransferase (PST) is an important pathway in the catabolism of alpha-methyldopa (MD). Variations in PST activity in an easily obtained tissue such as the human platelet might reflect individual differences in the sulphate conjugation of MD in other organs and tissues. There are at least two forms of human platelet PST, a thermolabile form for which dopamine is a substrate and a thermostable form for which low concentrations of phenol can serve as a substrate. 2 MD, alpha-methyldopamine (MDA) and alpha-methylnoradrenaline (MNA) were tested as substrates for human platelet PST. All three were substrates for the thermolabile form of the enzyme and none were substrates for the thermostable form of PST. Apparent Michaelis-Menten (Km) values for MD, MDA and MNA were 5.5, 0.014 and 0.28 mM, respectively. Apparent Km values for 3'-phosphoadenosine-5'-phosphosulphate, the sulphate donor for the reaction, were 0.08, 0.13 and 0.10 microM, respectively, for the three catechol substrates. The pH optima for the reaction were 7.5 for MD and 6.5 for both MDA and MNA. 3 When platelet homogenates from 20 individual subjects were tested, there were significant correlations between PST activities measured with dopamine and those measured with MD, MDA and MNA (r = 0.54, 0.98 and 0.93, P less than 0.02, less than 0.001, and less than 0.001, respectively), but not between activities measured with low concentrations of phenol and those measured with MD, MDA and MNA (r = 0.021, 0.045 and 0.046, respectively). There results were also compatible with the conclusion that MD, MDA and MNA were substrates for the thermolabile form of platelet PST. 4 These observations will make it possible to test the hypothesis that variations in the activity of the thermolabile form of platelet PST may reflect individual differences in the sulphate conjugation of MD, MDA and MNA.

Arylsulfotransferase↗
PubMed1984

Walking capacity of patients with intermittent claudication during chronic antihypertensive treatment with metoprolol and methyldopa.

In a placebo-controlled double-blind crossover trial, the effect of a 3-week course of treatment with metoprolol (100-200 mg daily) and methyldopa (500-1000 mg daily) on walking capacity on a treadmill with increasing work load was studied in 14 hypertensive patients with intermittent claudication. The walking capacity was not affected by the antihypertensive treatment.

Adult↗
PubMed1988

alpha-Methyldopa produces mydriasis in the rat by stimulation of CNS alpha 2-adrenoceptors.

1. The effects of i.v. administration of alpha-methyldopa (MD) on rat pupil diameter were investigated. All experiments were carried out in rats in which vagosympathetic nerve trunks were sectioned bilaterally at the cervical level. 2. In anaesthetized rats MD produced a marked dose-related increase in pupil diameter. The onset of pupillary response to MD was gradual and reached maximal levels 2-3 h after administration. 3. Pretreatment with alpha 2-adrenoceptor antagonists yohimbine (1.5 mg kg-1, i.v.) or idazoxan (0.5 mg kg-1, i.v.) blocked the pupillary response to MD. In contrast, the alpha 1-antagonists prazosin (1.0 mg kg-1, i.v.) and phenoxybenzamine (1.5 mg kg-1, i.v.) did not significantly alter the pupillary effects of MD. 4. Selective enzymatic blockade with 3-hydroxy-benzyl-hydrazine (NSD-1015; 25 mg kg-1, i.p.), a dopa-decarboxylase inhibitor, as well as bis (4-methyl-homopiperazinyl-thiocarbonyl) disulphide (FLA-63, 5.0 mg kg-1, i.p.), a dopamine-beta-hydroxylase inhibitor, prevented the mydriatic effect of MD. 5. The above findings support the hypothesis that MD produces a clonidine-like CNS mydriasis in the rat. This effect appears to be mediated primarily by the MD metabolite, alpha-methylnoradrenaline. 6. These results indicate that MD produces mydriasis in the rat by a CNS action. The mydriatic action of MD appears to be produced by its metabolite alpha-methylnoradrenaline which in turn stimulates CNS postsynaptic alpha 2-adrenoceptors.

Adrenergic alpha-Antagonists↗
PubMed1982

The absorption and excretion of methyldopa ingested concomitantly with amino acids or food rich in protein.

Absorption and urinary excretion of 2-14C-L-alpha-methyldopa (alpha MD) were investigated in 5 healthy human volunteers. The drug was administered alone, with a mixture of amino acids and with a meal consisting of roast beef. The radioactivity in plasma and urine was not decreased significantly by either treatment, and it was concluded that the overall absorption of the drug was virtually unchanged. The amount of unconjugated alpha MD in plasma and urine, however, was significantly decreased following administration of the drug with roast beef. As the acid labile conjugates of alpha MD were practically unchanged an increased biotransformation to other metabolites owing to the protein rich meal was suggested more probable than competition between alpha MD and amino acids in the specific transport systems.

Adult↗
PubMed1981

Blood pressure reduction in elderly: a randomised controlled trial of methyldopa.

A total of 123 out of 549 elderly residents of local authority welfare homes in Nottinghamshire were found at screening to have a standing or lying diastolic blood pressure of 100 mm Hg or more. These 123 subjects were randomly allocated to simple observation or to treatment with methyldopa. The cumulative mortality was similar in the observed and treated groups and in the normotensive group from which the subjects had been separated. Thus moderate hypertension, whether treated or not, was not a major risk predictor in the elderly population studied.

Aged↗
PubMed1984

Effect of alpha-methyldopa on alpha-noradrenergic receptor binding sites in the mouse brain.

alpha-Methyldopa (alpha-MD) was administered intraperitoneally into adult male mice and its effect on alpha 1- and alpha 2-noradrenergic receptor binding sites in the brain was investigated, using [3H]WB-4101 and [3H]clonidine, respectively. A single injection of 50-200 mg/kg alpha-MD abolished the high affinity binding to alpha 2-receptor sites and only the low affinity binding was observed with lower Bmax values. A significant effect of alpha-MD on alpha 1-receptor sites was not detected even after repeated injections (200 mg/kg/day X 3). Pretreatment with fusaric acid or diethyldithiocarbamate (inhibitors of dopamine-beta-hydroxylase) exerted no influence on the actions of alpha-MD on alpha 2-receptor sites, whereas NSD-1055 (an inhibitor of dopa decarboxylase) inhibited the effects of alpha-MD. It is concluded, therefore, that alpha-methyldopamine, a decarboxylated metabolite of alpha-MD, may be responsible for the reducing effect of alpha-MD on alpha 2-receptor sites.

Animals↗
PubMed1975

Ultrastructural mapping of methyldopa and anti-D IgG erythrocyte antigen receptors.

The ultrastructural distribution pattern and site density of alpha-methyldopa immunoglobin G (alpha-MD IgG) on the red cell membrane was observed and compared with that of anti-D IgG, with ferritin-conjugated rabbit anti-human IgG and [125I]anti-D. alpha-MD IgG binds to all common types of human red cells, both Rho (D) positive and negative, to give a random, aperiodic distribution pattern grossly indistinguishable from the red cell D receptor site pattern. alpha-MD IgG inhibits the binding of [125I]anti-D to D-positive red cells when the reaction is controlled with respect to total reaction volume, ionic strength, and the appropriate concentrations of the two IgG reactants. To determine if a alpha-MD IgG binds to the D-antigen receptor, D-positive red cells were sensitized with alpha-MD and [125I]anti-D IgG spearately and with both IgG preparations. The cell-bound radioactivity served to identify what proportion of the total ferritin-labeled IgG sites were due to anti-D. With nonsaturating concentrations of anti-D the number of IgG sites observed was equal to the sum of the sites found when the red cell was sensitized separately with alpha-MD and anti-D IgG. With saturating concentrations of anti-D there was a reduction in the expected number of IgG sites, indicating that alpha-MD IgG was excluded from binding. There was no comparable interaction of alpha-MD IgG and anti-D IgG when D-negative red cells were used. The results obtained indicate that alpha-MD IgG does not bind to the D antigen. The interaction between alpha-MD IgG and anti-D IgG for binding sites on the red cell membrane may be due to the close physical proximity of the two receptors, so as to produce steric hindrance in binding of the two IgG preparations when both are present. The alpha-MD IgG receptor appears to be a part of the Rh antigen complex that occurs in both D-positive and D-negative red cells and probably contains receptors for other types of warm-antibody immune hemolytic anemias.

Adult↗
PubMed1979

Multicentre general practitioner assessment of 'Tenormin' and methyldopa.

A large scale study in general practice was set up to investigate the effects of transferring hypertensive patients from treatment with usually less than 1 g daily of methyldopa to atenolol ('Tenormin') 100 mg daily. The results demonstrate an improvement in blood pressure control with atenolol treatment and a reduction in the incidence of side-effects. The simple dosage regime, combined with proven effectiveness and a relative lack of side-effects makes atenolol a useful treatment for the hypertensive patient.

Adult↗
PubMed1985

Effects of clonidine, alpha-methyldopa and hydralazine on met-enkephalinergic neurons in cerebral nuclei of spontaneously hypertensive rats.

Immunocytofluorescent and microautoradiographic methods were applied to measure met-enkephalin-like immunoreactivity (MELI) and ME receptor binding (MERB) levels in cerebral nuclei of serial brain slices from SHR which received clonidine, alpha-methyldopa and hydralazine at equivalent hypotensive doses. All three drugs increased both MELI and MERB levels in the caudal part of the n. tractus solitarii and its functionally related dorsomedullary nuclei and decreased them in the n. accumbens septi, in accordance with the correspondent change in glucose utilization rates in these nuclei as reported previously. Both CNS-active agents (not hydralazine) also increased MELI and MERB levels in the n. intercalatus and substantia grisea centralis, and they decreased them in the n. ventromedialis hypothalami. Differences in both CNS-active agents were minor. Vasodilative hydralazine alone decreased these levels both in the n. reticularis medialis and n. tegmenti ventralis, and it increased them slightly in the area lateralis hypothalami. The present studies indicate that ME neurons of these dorsomedullary and supramedullary nuclei may act as direct as well as homeostatic controls of blood pressure.

Animals↗
PubMed1990

Double blind comparative trial of Abana and methyldopa for monotherapy of hypertension in Indian patients.

Abana is a herbomineral medicinal preparation with a property of down-regulation of beta-adrenergic receptors. A double-blind, parallel group study was conducted in 43 Indian men and women suffering from hypertension to evaluate the antihypertensive effect of Abana and compare it with that of methyldopa (M-DOPA). Twenty-one patients received 800 mg tds of Abana and 22 patients received 250 mg tds of M-DOPA for 4 weeks. Blood pressure and pulse rate were recorded at weekly intervals. Relevant clinical and biochemical investigations were carried out before and after treatment. In patients treated with Abana, there was a significant fall both in systolic B.P. (from 167 +/- 3.73 to 145 +/- 6.11 mmHg) and in diastolic B.P. (from 110 +/- 1.86 to 91 +/- 3.04 mmHg) at the end of 4 weeks. Similarly in patients treated with M-DOPA, systolic blood pressure was significantly reduced from 165 +/- 4.92 to 146 +/- 4.9 mmHg and diastolic blood pressure was reduced from 106 +/- 2.74 to 96 +/- 2.67 mmHg after 4 weeks. The onset of antihypertensive effect was earlier and there was a higher percentage of responders (80%) in the Abana-treated group. None of the patients had clinically or biochemically significant side-effects. The results of this study suggest that therapy with Abana proved highly effective in hypertensive patients.

Adult↗
PubMed1989

Limitation of the alpha-methylnorepinephrine hypothesis in the hypotensive effect of alpha-methyldopa.

To test the hypothesis that alpha-methylnorepinephrine (MNE) is the principal active metabolite involved in the hypotensive action of alpha-methyldopa (MD), we determined the relationship between MD's depressor response and tissue levels of MD metabolites in critical sites. After administration of 250 mg/kg MD intraperitoneally to Sprague-Dawley rats (300 +/- 50 g), we studied both heart (left ventricle) and brainstem MD, MNE and endogenous NE levels using HPLC with electrochemical detection. We also measured systolic blood pressure before and during MD (25-250 mg/kg i.p.) treatment using the tail-cuff method. Our results indicate that: (1) peak MD hypotensive response was dose-dependent. (2) Central NE concentration was maximally reduced by 2 hours whereas peripheral NE was maximally reduced by 18 hours. The maximal hypotensive effect was closer to the central peak distribution of MNE than MD. (3) The MD concentrations and NE concentrations in brainstem and heart showed counterclockwise hysteresis while MNE showed clockwise hysteresis. Furthermore, the area of MNE hysteresis in brainstem was larger than that of NE. We conclude that MD's depressor effect can not be completely explained by the assumption that MNE is the sole active metabolite; alternate metabolites or mechanisms would appear to be operative.

Animals↗