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PubMed1993

Effect of methyldopa and isradipine on fetal heart rate pattern assessed by computerized cardiotocography in human pregnancy.

OBJECTIVE: The effects of two antihypertensive drugs, methyldopa and isradipine, on fetal heart rate pattern were analyzed by computerized cardiotocography. STUDY DESIGN: The first part of the study was a prospective, randomized, controlled trial of 19 women with preeclampsia in the third trimester given 2.5 mg of oral slow-release isradipine twice a day or 250 mg of methyldopa three times a day. In a second part of the study 23 women with preeclampsia in the third trimester given 5 mg of oral slow-release isradipine twice a day were compared with 23 matched controls without medication. Main outcome measures were maternal blood pressure and mean baseline fetal heart rate, fetal movements, number of accelerations, periods of high and low baseline variability, and mean baseline heart rate variability. RESULTS: Compared with the pretreatment value, the mean arterial blood pressure decreased significantly in all drug treatment groups. Fetal heart rate characteristics were not significantly changed during drug treatment or bed rest. CONCLUSION: The various features of the fetal heart rate pattern evaluated by computerized methods were not influenced by treatment with methyldopa or isradipine.

Adolescent↗
PubMed1995

Methyldopa hepatotoxicity in pregnancy: a case report.

A case of hepatotoxicity in a multiparous Native woman, who was begun on a regimen of methyldopa for control of chronic hypertension, is described. The patient was first seen for clinical evidence of hepatotoxicity approximately 3 weeks after initiation of treatment. At presentation the aspartate aminotransferase level was 1800 IU/L and alanine amniotransferase was 2415 IU/L. There was also a significant prolongation of clotting time, which required therapy. Resolution of symptoms occurred after cessation of the medication. Although methyldopa is considered to have a wide margin of safety in the treatment of chronic hypertension in pregnancy, potentially serious adverse effects can occur. It is important to monitor serum aminotransferase levels after initiation of methyldopa therapy.

Adult↗
PubMed1991

Activation of the microsomal glutathione S-transferase by metabolites of alpha-methyldopa.

Rat liver microsomes contain a membrane-bound GSH S-transferase (GSH-tr), an enzyme that is involved in the detoxication of xenobiotics. Also located on rat liver microsomes is the cytochrome P450 system, an enzyme complex that catalyzes the conversion of several xenobiotics into reactive intermediates. In this study, it was demonstrated that reactive products from alpha-methyldopa formed by the cytochrome P450 system are able to stimulate microsomal GSH-tr. Also, products formed from alpha-methyldopa that are generated by H2O2-horseradish peroxidase and tyrosinase are able to stimulate the activity of microsomal GSH-tr. GSH was able to prevent the activation of microsomal GSH-tr. Our results indicate that the ortho-quinone or semi-ortho-quinone radical of alpha-methyldopa is responsible for the stimulation of microsomal GSH-tr, probably via arylation of the free sulfhydryl group of microsomal GSH-tr. This conclusion was supported by the observation that 4-methyl-ortho-quinone itself was able to stimulate microsomal GSH-tr via sulfhydryl arylation. Our results are in conformity with the hypothesis that reactive products formed by the cytochrome P450 complex are able to stimulate microsomal GSH-tr and possibly in this way enhance their detoxication.

Animals↗
PubMed1989

Participation of opiate receptors located in the nucleus tractus solitarii in the hypotension induced by alpha-methyldopa.

The local administration of the opiate receptor antagonist, naltrexone, into the nucleus tractus solitarii (NTS) inhibited the hypotension induced by systemically injected alpha-methyldopa in conscious rats. In addition, the local injection into the NTS of a beta-endorphin antiserum but not of antisera against [Met5]enkephalin and dynorphin A(1-13) prevented the alpha-methyldopa-induced hypotension. These results suggest a role of opiate receptors in the NTS, or in a closely located medullary site, in the centrally mediated hypotension induced by alpha-methyldopa.

Animals↗
PubMed1985

The effects of phenobarbital, atropine, L-alpha-methyldopa, and DL-propranolol on dieldrin-induced hyperglycemia in the adult rat.

The hyperglycemic response of adult male Wistar rats given dieldrin (63 mg/kg, po) and either phenobarbital (40 mg/kg, ip), atropine (4 mg/kg, sc), L-alpha-methyldopa (200 mg/kg, ip), or DL-propranolol (8 mg/kg, sc) was studied. The hyperglycemia was maximal (73% above control values) 2 hr after exposure to dieldrin alone. Phenobarbital reduced the hyperglycemia by 41% and abolished dieldrin-induced convulsions. It also prevented the increases that dieldrin causes in hepatic phosphoenolpyruvate carboxykinase (PEPCK) activity. These results suggest that the dieldrin-induced hyperglycemia is mediated via the CNS. Atropine prevented the hyperglycemia for 2 hr and delayed the attainment of maximal glucose concentrations for another 2 hr. However, additional atropine 4, 8, 12, and 18 hr after the dieldrin had no effect. Atropine also increased (125%) the time to the onset of dieldrin-induced convulsions. It did not alter hepatic PEPCK activity. L-alpha-Methyldopa decreased (24%) the hyperglycemic response in the first 2 hr after dieldrin treatment. It caused similar reductions in blood glucose when given during the peak hyperglycemic response. L-alpha-Methyldopa also reduced (49%) the dieldrin-effected increase in hepatic PEPCK activity. DL-Propranolol did not alter the effects of dieldrin. Thus these data suggest that the dieldrin-induced hyperglycemia is mediated by the CNS, primarily via enhanced cholinergic activity and secondarily by increased alpha-adrenergic activity. It is suggested that the pancreas responds to the cholinergic outflow by increasing the secretion of glucagon while simultaneously responding to the alpha-adrenergic outflow by decreasing insulin secretion.

Administration, Oral↗
PubMed1986

Reproductive toxicology of methyldopa in male F344/N rats.

Methyldopa, a widely used antihypertensive drug, was administered to male Fischer 344/N rats by gavage 5 days/week for 65 days at dosages of 0, 50, 100, 200, or 400 mg/kg. Decreased body weight was seen in treated animals. After mating to untreated female Fischer 344/N rats on days 57-61, the male rats were necropsied (days 65-67) and reproductive toxicity was measured by sperm count, sperm motility, organ weights, hormone levels and histologic evaluation of the testis. Decreased fertility was seen in males dosed with 200 or 400 mg/kg methyldopa. Decreases were also seen in sperm count, sperm motility, apparent number of late spermatids, and plasma testosterone levels in males in the 200 and 400 mg/kg groups. This alternation of reproductive function in male rats was found to be reversible after a 13-week recovery period without dosing. The marked decrease in circulating testosterone levels following methyldopa treatment at 200 or 400 mg/kg may have contributed to the reproductive toxicity of this drug.

Animals↗
PubMed1993

Effects of methyldopa on uteroplacental and fetal hemodynamics in pregnancy-induced hypertension.

OBJECTIVE: Our purpose was to study the effect of methyldopa on uteroplacental and fetal hemodynamics in women with pregnancy-induced hypertension. STUDY DESIGN: A prospective study of Doppler ultrasonographic blood flow data before and after 1 week of methyldopa treatment was conducted at the Department of Obstetrics and Gynecology, National University Hospital, Singapore, in 20 women (mean 35 weeks' gestation) with pregnancy-induced hypertension. The main outcome measures were maternal blood pressure, maternal and fetal heart rate, and blood velocity waveforms characterized by the pulsatility index in the fetal ascending aorta, middle cerebral artery, umbilical artery, and maternal uterine and arcuate arteries. Statistical evaluation was performed with t tests for paired observations. RESULTS: Maternal mean arterial blood pressure was reduced 9.7 mm Hg (95% confidence interval -13.8 to -5.6), and mean heart rate decreased 6.3 beats/min (95% confidence interval -11.1 to -1.4). Mean pulsatility index in the uterine (0.93 to 0.92) and arcuate arteries (0.61 to 0.73) were unchanged after treatment. Fetal hemodynamic changes before and after treatment were not significant. Fetal and neonatal outcome was uneventful. CONCLUSION: Short-term treatment with methyldopa in the last trimester in women with pregnancy-induced hypertension reduced maternal blood pressure and heart rate but had no adverse effects on uteroplacental and fetal hemodynamics.

Adult↗
PubMed1976

Comparison of oxprenolol and methyldopa in hypertension. A within-patient double-blind trial.

Oxprenolol or methyldopa were administered in double-blind fashion to 29 patients shown to be persistently hypertensive. After a dose-finding, assessment, and washout period, the second drug was given. 24 patients completed a period of treatment with each drug. Blood-pressure falls were similar with each drug in the supine, standing, and post-exercise state. Half the patients responded will to low dosage (oxprenolol less than or equal to 320 mg, methyldopa less than or equal to 1 g, a day) and 9 of 11 such patients responded satisfactorily to each drug. In those whose response was inadequate, oxprenolol was increased to 960 mg or methyldopa to 3 g a day. Increasing dosage had no consistent pressure-lowering effect. Side-effects were assessed by questionnaire and no clear preference emerged. It is recommended that an inadequate response to modest dosage of either drug should lead to the use of an additional agent rather than heavier dosage.

Adult↗
PubMed2001

The use of a response surface methodology on HPLC analysis of methyldopa, amiloride and hydrochlorothiazide in tablets.

A multifactor optimisation technique is successfully applied to develop a new HPLC method in which methyldopa, hydrochlorothiazide and amiloride were analysed and determined on a C18 column with detection at 286 nm. The optimal conditions of HPLC separation were determined with the aid of the response surface diagram -- 'window diagram'. The effect of simultaneously varying the pH, proportion aqueous acetic acidum and methanol in the mobile phase were studied to optimise the separation. The mobile phase composition that provides an acceptable resolution methyldopa, hydrochlorothiazide and amiloride in a short elution time is water--methanol (75:25) and pH 3.60. The k' values for methyldopa, hydrochlorothiazide and amiloride after optimisation were 1.40, 2.50 and 5.33, respectively. Relative retention (alpha) for ratio hydrochlorothiazide/methyldopa and amiloride/hydrochlorothiazide were 1.767 and 2.159, respectively. Correlation coefficients of the calibration curves for all analytes were greater than 0.995 and the R.S.D. values for the slope and the intercept with respect to the linearity were less than 2%. A method is applied for the quantitative analysis of Alatan tablets (Lek-Ljubljana). The powdered tablets are extracted with methanol, containing caffeine as the internal standard and assayed by comparison of peak areas after liquid chromatography. The high recovery (for all analytes about 100%) and the low R.S.D. (<2%) confirm good precision and reproducibility of the chromatographic method.

Amiloride↗
PubMed1999

Direct high-performance liquid chromatographic determination of the enantiomeric purity of levodopa and methyldopa: comparison with pharmacopoeial polarimetric methods.

Chiral high-performance liquid chromatography was employed for determination of the enantiomeric purity of levodopa and methyldopa. The determination of D-DOPA in levodopa was accomplished using a chiral ligand-exchange chromatograpy with an ordinary C18 column and a chiral mobile phase containing N,N-dimethyl-L-phenylalanine and Cu(II) acetate or by means of LC on a teicoplanin column in conjunction with ethanol-water (65:35, v/v). Both methods gave good performance, however, the latter was faster and more convenient and suitable for routine analyses. For the determination of D-methyldopa a LC method based on the use of a teicoplanin column in polar organic mode with methanol-acetic acid-triethylamine (1,000:0.05:0.05, v/v/v) mobile phase was developed. The precision, accuracy, linearity and selectivity were satisfactory. In comparison with pharmacopoeial polarimetric methods (according to the European Pharmacopoeia and the Pharmacopoea Bohemoslovaca), the LC methods proved to be much more sensitive giving detection limits 0.04% of D-DOPA and 0.3% of D-methyldopa.

Chromatography, High Pressure Liquid↗
PubMed1998

Reaction of dopa decarboxylase with alpha-methyldopa leads to an oxidative deamination producing 3,4-dihydroxyphenylacetone, an active site directed affinity label.

Dopa decarboxylase (DDC) catalyzes the cleavage of alpha-methylDopa into 3,4-dihydroxyphenylacetone and ammonia, via the intermediate alpha-methyldopamine, which does not accumulate during catalysis. The ketone has been identified by high-performance liquid chromatography and mass spectroscopic analysis, and ammonia by means of glutamate dehydrogenase. Molecular oxygen is consumed during the reaction in a 1:2 molar ratio with respect to the products. The kcat and Km of this reaction were determined to be 5.68 min-1 and 45 microM, respectively. When the reaction is carried out under anaerobic conditions, alpha-methyldopamine is formed in a time-dependent manner and neither ammonia nor ketone is produced to a significant extent. The reaction is accompanied by a time- and concentration-dependent inactivation of the enzyme with kinact of 0. 012 min-1 and Ki of 39.3 microM. Free 3,4-dihydroxyphenylacetone binds to the active site of DDC and inactivates the enzyme in a time- and concentration-dependent manner with a kinact/Ki value similar to that of alpha-methylDopa. d-Dopa, a competitive inhibitor of DDC, protects the enzyme against inactivation. Taken together, these findings indicate the active site directed nature of the interaction of DDC with 3,4-dihydroxyphenylacetone and provide evidence that the ketone generated by the reaction of DDC with alpha-methylDopa dissociates from the active site before it inactivates the enzyme. Inactivation of the enzyme by ketone followed by NaB3H4 reduction and chymotryptic digestion revealed that the lysine residue which binds pyridoxal 5'-phosphate (PLP) in the native enzyme is the site of covalent modification. Together with the characterization of the adduct released from the inactivated DDC, these data suggest that the enzyme is inactivated by trapping the coenzyme in a ternary adduct with ketone and the active site lysine. As recently reported for serotonin (5-HT) [Bertoldi, M., Moore, P. S., Maras, B., Dominici, P., and Borri Voltattorni, C. (1996) J. Biol. Chem. 271, 23954-23959], the conversion of dopamine (DA) into 3,4-dihydroxyphenylacetaldehyde and ammonia catalyzed by DDC is accompanied by irreversible loss of decarboxylase activity. However, the comparison between the absorbance, fluorescence, and CD features of DDC after 5-HT- or 3, 4-dihydroxyphenylacetone-induced inactivation shows that a different covalent adduct is formed between either of these two molecules and DDC-bound PLP.

Acetone↗
PubMed1980

Effects of methyldopa on renal hemodynamics and tubular function.

To determine the effects of methyldopa on renal function, clearance studies were performed on hypertensive subjects during sustained steady-state water diuresis. The data reveal an acute fall in glomerular filtration rate and sodium clearance, whereas renal blood flow was unchanged. The antinatriuresis was the result of decreased filtration of sodium and possibly enhanced proximal tubular sodium reabsorption. These changes occurred before any demonstrable fall in systemic blood pressure; thus a direct effect of the drug on arteriolar resistance within the renal circulation is suggested. Chronic administration of methyldopa for 1 wk induced sustained reduction in blood pressure and resulted in the same changes in renal hemodynamics and sodium excretion noted after acute administration. These data suggest that methyldopa, like other antihypertensives, reduces glomerular filtration rate and increases sodium retention.

Adult↗
PubMed1980

Disparate effects of methyldopa and clonidine on cardiac mass and haemodynamics in rats.

1. Wistar-Kyoto and spontaneously hypertensive rats were given either methyldopa (400 mg day-1 kg-1) or clonidine (0.1 or 0.3 mg day-1 kg-1) for 3 weeks commencing at 20 weeks of age. 2. Both drugs significantly decreased mean arterial pressure in spontaneously hypertensive but not Wistar-Kyoto rats. Heart rate was significantly increased in spontaneously hypertensive rats by methyldopa, whereas clonidine significantly decreased heart rate. The higher dose of clonidine also decreased heart rate in Wistar-Kyoto rats. Both cardiac output and total peripheral resistance decreased slightly, but not significantly, with both agents. 3. Methyldopa, but not the lower equipotent depressor dose of clonidine, reduced left ventricular hypertrophy in spontaneously hypertensive rats. However, the higher dose of clonidine also significantly decreased the heart to body weight ratio despite an increased total peripheral resistance presumably due to the alpha-adrenergic agonist effect. 4. Minimal changes in organ blood flows were noted with both drugs. 5. These results suggest that neither systemic haemodynamics nor central inhibition of adrenergic drive are primary factors responsible for the regression of hypertrophy.

Animals↗
PubMed1985

Impaired reticuloendothelial function in patients treated with methyldopa.

In about 20 per cent of patients taking the antihypertensive agent methyldopa, IgG autoantibodies form against red cells, but most such patients do not have hemolysis. The reason for this is uncertain; it does not appear to be explained by known characteristics of the autoantibody. Since antibody-dependent reticuloendothelial function is an important determinant of cell clearance, we measured reticuloendothelial function in nine patients taking methyldopa. We did this by measuring the rate of clearance of radiolabeled autologous red cells sensitized with anti-D alloantibody. Five patients had a positive direct antiglobulin test, and four did not. Only one patient had laboratory evidence of hemolysis. The patients without hemolysis had significantly impaired reticuloendothelial clearance. In contrast, the patient with hemolysis did not have impaired reticuloendothelial function. This study suggests that in patients taking methyldopa who have a positive direct antiglobulin test the absence of hemolysis may be caused by an impairment in reticuloendothelial function. That the drug itself may be responsible for the impairment is suggested by the occurrence of abnormal reticuloendothelial function in patients taking the drug who have a negative direct antiglobulin test.

Anemia, Hemolytic, Autoimmune↗
PubMed1986

Evidence for regulatory variants of the dopa decarboxylase and alpha-methyldopa hypersensitive loci in Drosophila.

We have analyzed two variants of Drosophila melanogaster (RS and RE) which lead to the dual phenotype of elevated DDC activity and increased resistance to dietary alpha-methyldopa relative to Oregon-R controls. Both phenotypes show tight genetic linkage to the dopa decarboxylase, Ddc, and l(2)amd genes (i.e., less than 0.05 cM distant). We find that low (Oregon-R), medium (RS) and high (RE and Canton-S) levels of DDC activity seen at both pupariation and eclosion in these strains are completely accounted for by differences in accumulation of DDC protein as measured by immunoprecipitation. Genetic reconstruction experiments in which Ddc+ and amd+ gene doses are varied show that increasing DDC activity does not lead to a measurable increase in resistance to dietary alpha-methyldopa. This suggests that the increased resistance to dietary alpha-methyldopa is not the result of increased DDC activity but, rather, results from increased l(2)amd+ activity. Both cytogenetic and molecular analyses indicate that these overproduction variants are not the result of small duplications of the Ddc and amd genes, nor are they associated with small (greater than or equal to 100 bp) insertions or deletions. Measurements of DDC activity in wild-type strains of Drosophila reveal a unimodal distribution of activity levels with the Canton-S and RE strains at the high end of the scale, the Oregon-R control at the low end and RS near the modal value. We conclude that accumulated changes in a genetic element (or elements) in close proximity to the Ddc+ and amd+ genes lead to the coordinated changes in the expression of the Ddc and amd genes in these strains.

Animals↗
PubMedDate not supplied

Case report. Immunological studies in a case of hepatitis following methyldopa administration.

Jaundice with evidence of hepatocellular damage of moderate severity was observed in a patient who received methyldopa. The diffuse mononuclear infiltration of the liver tissue was found to consist of 90% E-rosette-forming cells. Peripheral lymphocytes gave a markedly positive macrophage migration inhibition (MIF) test against methyldopa. The number of T lymphocytes in the peripheral blood was at the lower limit of normal but they proved to be functionally inactive, as demonstrated by the results of a local xenogeneic graft-vs-host reaction test. The liver disease was associated with hyperglobulinemia, a decrease of the third and fourth components of complement and the presence of incomplete erythrocytic antibodies, leukoagglutinins, antinuclear factor, and smooth muscle antibody. Follow-up after discontinuation of the drug revealed a gradual return to normal of liver function and MIF tests, normalization of cellular immunity, and disappearance of the humoral antibodies. It is assumed that sensitization by methyldopa triggered the autoaggressive phenomena and their ultimate manifestation in the liver.

Biopsy, Needle↗
PubMed1975

The effects of atenolol (tenormin) and methyldopa on simple tests of central nervous function.

Two identical studies, one comparing the effect of single doses of a new beta-adrenoceptor blocker, atenolol (Tenormin) (50 mg and 100 mg) and placebo, and the other comparing the effect of single doses of methyldopa (250 mg and 500 mg) and placebo, in healthy volunteers, were carried out. 2 In both studies the effect of the drugs upon reaction time, critical flicker frequency, subjective drowsiness, pulse rate and blood pressure was measured. 3 Atenolol produced no effect upon reaction time, critical flicker frequency or subjective feelings, while methyldopa produced a statistically significant prolongation of reaction time and a statistically significant increase in the subjective sensation of drowsiness. 4 Atenolol produced statistically significant reductions in systolic and diastolic blood pressure and in pulse rate while methyldopa was without effect. 5 It is concluded that atenolol is unlikely to produce the side effects of sedation or drowsiness.

Adrenergic beta-Antagonists↗
PubMed1978

Standardized stress and hypertension: comparison of effect of propranolol and methyldopa.

1 Using a standardized form of mental stress, 21 patients with idiopathic hypertension were investigated before and after treatment with placebo (n=8), propranolol (n=7) or methyldopa (n=6). 2 Blood pressure was satisfactorily controlled in the propranolol and methyldopa groups but only the propranolol group showed modification of the pressor response to stress testing. 3 These results suggest that propranolol may provide more uniform control of blood pressure than methyldopa in patients with essential hypertension.

Adult↗