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PubMed1982

Differential competition by L-alpha-methyldopa metabolites for adrenergic receptors in rat forebrain.

The capacity of a series of intraneuronal metabolites of L-alpha-methyldopa to compete for alpha-1 ([3H]prazosin, alpha-2([3H]clonidine and beta ([3H]dihydroalprenolol) receptor binding in rat forebrain was studied. Each metabolite studied had a unique order of activity at each receptor. These data show that (-)-erythro-alpha-methylnorepinephrine and (-)-erythro-alpha-methylepinephrine compete with high affinity for alpha-2 receptors, thereby supporting the suggestion that alpha-2 receptors mediate hypotensive effects of L-alpha-methyldopa . Furthermore, these metabolites of L-alpha-methyldopa competed with high potency for beta-1 receptors in forebrain and (-)-erythro-alpha-methylepinephrine was more potent than (-)-epinephrine, (-)-norepinephrine and (-)-erythro-alpha-methylnorepinephrine in competing for beta-2 receptors on human lymphocytes. These data suggest that beta receptor stimulation may be important in determining the net effects of L-alpha-methyldopa. L-alpha-Methyldopa metabolites were much less potent than (-)-epinephrine and (-)-norepinephrine in competition for alpha-1 receptors. (+/-)-alpha-Methyldopamine was less potent than other l-alpha-methyldopa metabolites at all three receptors, suggesting that it is unlikely to be an important hypotensive metabolite of L-alpha-methyldopa.

Animals↗
PubMed1991

Method for measuring endogenous 3-O-methyldopa in urine and plasma.

The present report describes a method using column liquid chromatography with electrochemical detection for assaying concentrations of 3-O-methyldopa in urine and plasma. The technique combines a one-step sample preparation scheme with post-column flow-through electrodes in series, allowing adequate chromatographic separation of 3-O-methyldopa from other endogenous substances in urine. The validity of the method was confirmed by markedly decreased urinary 3-O-methyldopa levels after administration of an inhibitor of catechol-O-methyltransferase to rats, radioactivity in chromatographic fractions corresponding to 3-O-methyldopa in urine of rats undergoing infusion of [3H]-L-DOPA, and correlations between excretion rates of 3-O-methyldopa and catechols in humans. In healthy humans, urinary excretion of 3-O-methyldopa averaged 974 +/- 707 (S.D.) nmol per day, and plasma levels of 3-O-methyldopa averaged 89 +/- 32 nmol/l. The method should be useful in studies about the metabolism of endogenous and exogenous DOPA.

Animals↗
PubMed1964

SOME OBSERVATIONS ON THE PHARMACOLOGY OF ALPHA-METHYLDOPA.

alpha-Methyldopa in high concentrations impaired the responses of rabbit isolated ileum and guinea-pig isolated vas deferens to stimulation of the sympathetic nerves and to noradrenaline, but these preparations taken from animals previously treated with alpha-methyldopa showed no sign of impairment. Contractions of the cat nictitating membrane were reduced but not abolished by alpha-methyldopa. In cats, dogs and rats, pressor responses to noradrenaline were usually slightly increased by alpha-methyldopa. Pressor responses to tyramine were not affected consistently. alpha-Methyldopa, alpha-methyldopamine and alpha-methylnoradrenaline behaved like dopa, dopamine and noradrenaline respectively in restoring the responses of tissues from reserpine-treated animals to stimulation of the sympathetic nerves to the rabbit ileum, the guinea-pig vas deferens and the cat nictitating membrane and in restoring responses to tyramine of the cat blood pressure and nictitating membrane, and the rat blood pressure. The potency of alpha-methylnoradrenaline relative to noradrenaline ranged from one-half to one-ninth on various preparations. The results are discussed in relation to the antihypertensive action of alpha-methyldopa.

Animals↗
PubMed1976

Antihypertensive efficacy of a single bedtime dose of methyldopa.

To compare the antihypertensive efficacy of methyldopa administered once at bedtime with the same total dose given three times daily, a double-blind crossover study was performed in 14 patients previously well controlled on methyldopa. Each patient received a total daily dose of 0.37 gm, 0.75 gm, or 1.5 gm of methyldopa, depending on the dose of drug that had previously been successful in that individual. The trial design included either 12 wk of methyldopa three times daily (TID) followed by 12 wk of single daily bedtime (HS) doses of methyldopa or administration of drug in the reverse order. Supine and erect blood pressures were recorded 4 times daily (8 a.m., 12 noon, 4 p.m., and 8 p.m.) every 4 wk throughout the study. Blood pressure control was excellent in all patients whether the drug was administered three times daily or at bedtime. Systolic pressures were slightly lower at 8 a.m., when methyldopa was given at bedtime than on doses three times daily, and systolic and diastolic pressures were slightly higher at 8 p.m. that at 8 a.m. on the bedtime regimen.

Aged↗
PubMedDate not supplied

Methyldopa does not alter the disposition of digoxin.

To investigate whether methyldopa alters digoxin disposition, eight healthy subjects received methyldopa titrated to 250 mg t.i.d. or placebo in a double-blind, cross-over manner for 16 consecutive days, with 0.25 mg intravenous digoxin coadministered on day 5 and 0.25 mg oral digoxin on days 9 to 16. Digoxin concentrations in plasma and urine were measured by RIA. Although assay sensitivity did not allow an adequate assessment of serum AUC(0-infinity) after intravenous administration, mean digoxin AUC(0-24) was 10.2 +/- 3.5 and 10.0 +/- 1.8 ng/ml X hr with placebo and methyldopa, respectively (P greater than 0.05). Mean urinary excretion after digoxin with or without methyldopa treatment was 0.204 +/- 0.34 and 0.197 +/- 0.38 mg, respectively. The mean steady-state serum concentrations of oral digoxin (AUC(0-24)/zeta) with and without methyldopa were 0.65 +/- 0.2 and 0.62 +/- 0.3 ng/ml, respectively. These data revealed no significant differences (P greater than 0.05) for various parameters with power of greater than 0.8 to detect meaningful differences of approximately 30 per cent. Thus, methyldopa did not alter digoxin disposition in healthy subjects, and a pharmacokinetic interaction in patients is unlikely.

Administration, Oral↗
PubMed2002

The effect of methyldopa treatment on uterine, umblical and fetal middle cerebral artery blood flows in preeclamptic patients.

The purpose of this study was to evaluate the efficacy of methyldopa in the treatment of preeclamptic patients. This study was performed on 24 preeclamptic women who were in between 25-36 weeks of gestational age. 24 healthy pregnant women were taken as control group. Before starting treatment, 24 preeclamptic patients were examined with Doppler ultrasound. Pulsatility index, resistance index, systolic/diastolic ratio of uterine, umblical and fetal middle cerebral arteries were measured. Preeclamptic patients were treated with totally 1 g methyldopa per day. After 7 d, patients were reexamined with Doppler ultrasound. The effect of methyldopa on uterine, umblical and fetal middle cerebral artery blood flows were detected. Only one control with Doppler ultrasound was done to the healthy pregnant women. Before methyldopa treatment to the preeclamptic women, pulsatility index (PI), resistance index (RI) and systolic/diastolic ratio (S/D) on uterine and umblical arteries were significantly higher than the control group. However, fetal middle cerebral artery (MCA) values were significantly lower than the control group. When Doppler results of preeclamptic patients before and after the methyldopa treatment were compared, no significant differences in terms of Pulsatility Index, Resistance IndexI and S/D ratio of umblical and fetal middle cerebral arteries were found. However, the results of uterine artery were significantly lower after the treatment in preeclamptic patients. Treatment with methyldopa lowered the uterine artery resistance in preeclamptic patients but did not effect the resistance of umblical and fetal middle cerebral artery.

Adult↗
PubMed1982

Effects of pindolol and methyldopa on blood pressure and plasma norepinephrine.

Thirty patients with essential hypertension (supine diastolic blood pressure 100 to 115 mm Hg) were treated in a randomized, double-blind study with either pindolol (mean dose 28 +/- 5 mg twice a day) or methyldopa (673 +/- 158 mg three times a day) for 12 weeks after a 3-week, single-blind placebo period. In 17 pindolol-treated patients mean supine blood pressure was 163 +/- 3/106 +/- 1 during the placebo period and 155 +/- 3/99 +/- 2 mm Hg (p less than 0.01) during the high-dose period. In 13 patients treated with methyldopa mean supine blood pressure fell from 160 +/- 4/104 +/- 1 to 156 +/- 5/97 +/- 2 mm Hg. Mean standing heart rate was reduced during pindolol therapy from 84 +/- 2 to 79 +/- 2 bpm (p less than 0.05) but was unchanged during methyldopa treatment. Mean supine pretreatment plasma norepinephrine fell from 379 +/- 40 to 337 +/- 33 pg/ml in patients on pindolol therapy and from 448 +/- 76 to 223 +/- 39 pg/ml (p less than 0.02) in the methyldopa-treated group. Although norepinephrine generally decreased in pindolol responders and not in nonresponders, changes in supine diastolic blood pressure and supine plasma norepinephrine did not correlate. In contrast, norepinephrine declined consistently in methyldopa-treated patients regardless of the blood pressure response; changes in diastolic blood pressure and norepinephrine correlated (r = 0.59; p less than 0.05). The results suggest that suppression of sympathetic nervous system activity may play a role in the hypotensive effect of both pindolol and methyldopa.

Blood Pressure↗
PubMed1983

A double-blind study of trimazosin and methyldopa in hypertensive patients receiving polythiazide.

Data are presented on 22 hypertensive patients in an 18-week, double-blind comparison of trimazosin and methyldopa during which treatment with polythiazide was continued. Maximum daily doses of trimazosin and methyldopa were 800 and 2000 mg, respectively. Eight of nine patients receiving trimazosin and 8 of 12 receiving methyldopa had excellent or good overall responses. (One trimazosin patient was not evaluated for overall response.) Quantitative criteria of blood pressure response indicated that trimazosin was as effective as methyldopa. There were no clinically significant changes in results of Holter monitor recordings, ECGs, chest x-ray films, cardiopulmonary tests, or ophthalmoscopy. There were no abnormalities in laboratory tests of trimazosin patients. One patient receiving methyldopa had a positive Coombs' test. Significant side effects developed in two methyldopa patients-syncope in one patient and postural hypotension in the other. No significant side effects occurred in the patients taking trimazosin.

Adult↗
PubMed1983

Treatment of severe hypertension with labetalol compared with methyldopa and furosemide. Results of a long-term, double-blind, multicenter trial.

Eighty-one severely hypertensive patients were enrolled in a multicenter, double-blind, parallel group study evaluating the efficacy and safety of labetalol alone or in combination with furosemide versus methyldopa in combination with furosemide. A one day to four week placebo lead-in phase was followed by a one- to six-week titration period and a one-year maintenance period. Treatment with labetalol alone or in combination with furosemide, as well as methyldopa plus furosemide, was associated with significant reductions in supine and standing blood pressure levels. Moreover, after six months and one year of treatment, respectively, labetalol caused a significantly (p less than 0.05) greater reduction in the systolic blood pressure than the methyldopa regimen. The antihypertensive effect of labetalol was associated with small, yet significant reductions in heart rate; in contrast, resting tachycardia was observed in methyldopa-treated patients. Side effect profiles of the two treatments were different, with nausea being the most commonly reported side effect during labetalol therapy, and asthenia, somnolence, and dry mouth during methyldopa therapy. Overall, 33 of 65 (53 percent) labetalol-treated and 28 of 60 (47 percent) methyldopa-treated patients had at least a good response (that is, standing diastolic blood pressure 90 to 94 mm Hg) to therapy, including 26 (40 percent) and 22 (37 percent) patients, respectively, who had standing diastolic blood pressure levels of less than 90 mm Hg. Thus, labetalol is a potentially safe and effective agent in the long-term management of the patient with severe hypertension.

Adult↗
PubMed1981

alpha-Methylepinephrine, a methyldopa metabolite that binds to alpha-receptors in rat brain.

The presence of phenylethanolamine-N-methyl transferase in those brain-stem nuclei where methyldopa is thought to act suggested to us that methylepinephrine could be an active metabolite of methyldopa. We assessed the potential of methylepinephrine to be an active metabolite by determining its capacity to compete for ligands which bind to alpha-receptors in rat brain. Thus, the abilities of epinephrine, norepinephrine, methyldopa, (+/-)-methylnorepinephrine and (+/-)-methylepinephrine to compete for alpha 1-([3H]WB-4101) and alpha 2-([3H]clonidine) binding sites in rat brain wee compared. Order of potency at each binding site was: [3H]WB-4101 -- (-)epinephrine = (-)-norepinephrine greater than (+/-)-methylnorepinephrine greater than (+/-)-methylepinephrine much greater than (-)-methyldopa; [3H]clonidine -- (-)-epinephrine greater than (+/-)-methylnorepinephrine greater than (-)-norepinephrine greater than (+/-)-methylepinephrine much greater than (-)-methyldopa. Since it can compete with a specific ligand for alpha 2-receptors, methylepinephrine could be a centrally active metabolite of methyldopa.

Animals↗
PubMed1989

alpha-Methyldopa metabolism in central serotonergic nerve terminals: effects on serotonin levels, synthesis and release.

The direct effects of in vivo methyldopa administration on serotonin (5-HT) neurochemistry was investigated. Specifically the ability of methyldopa to alter nerve terminal-associated 5-HT synthesis, storage and release and the possibility that 5-HT nerve terminals accumulate methyldopamine (the product of decarboxylation of methyldopa) was investigated. Synaptosomes isolated from rats given 200 mg/kg of methyldopa (calculated as the free amino acid) 2 h prior to killing exhibited a 25% reduction in intrasynaptosomal 5-HT and a 15% reduction in 5-HT synthesis when compared to synaptosomes from saline-treated animals. In addition a 15% reduction in synaptosomal tryptophan levels was observed. Despite these changes there was no apparent decrease in basal or depolarization-induced 5-HT release from synaptosomes of methyldopa-treated rats. The presence of methyldopamine within 5-HT-containing synaptosomes was confirmed by demonstrating that p-chloroamphetamine, a selective 5-HT releasing agent, could release both methyldopamine and 5-HT from synaptosomes and that this release could be selectively antagonised by fluoxetine, a selective 5-HT uptake inhibitor. The significance of these data with respect to the involvement of 5-HT neurons in the hypotensive action of methyldopa is discussed.

Animals↗
PubMed1984

Inhibition of brain acetylcholine biosynthesis by methyldopa in spontaneously hypertensive rats.

The formation of 3H-acetylcholine was measured in several brain regions of spontaneously hypertensive (SH) rats following intracerebroventricular injection of 3H-choline. Endogenous acetylcholine (ACh) also was measured and specific activity-time curves for brain ACh generated for control SH rats and for SH rats pretreated with methyldopa (100-200 mg/kg, IV). The relative turnover rates for ACh in several brain regions was estimated from the specific activity-time curves. The turnover rates of ACh in rostral hypothalamus, caudal hypothalamus, medulla oblongata and pons were reduced by 34-54%. Apparently synthesis was inhibited also since methyldopa produced relatively little effect on ACh levels. More rostral brain regions, thalamus-septum, midbrain and striatum, were not significantly affected by methyldopa. Methyldopa also reduced arterial pressure by 53/28 mmHg. The ability of methyldopa to inhibit the function of cholinergic neurons in selective brain regions may be responsible for its common "anticholinergic" side effects. Since centrally-acting anticholinergic drugs reduce arterial pressure in SH rats, it is possible that inhibition of brain ACh synthesis by methyldopa also may contribute to its antihypertensive action in experimental genetic hypertension.

Acetylcholine↗
PubMed1985

Methyldopa: effects on the murine immune system.

Mice were treated for 7 weeks with doses of methyldopa somewhat exceeding those given to man, and mixed immunotoxic effects were observed. Daily subcutaneous injections of 5 mg (in 0.1 ml) methyldopa or saline (0.1 ml) did not generally alter body weights, except on day 19, when the methyldopa-treated mice weighed significantly less. During treatment, all mice were immunized twice with sheep red blood cells (SRBC) and bled four times. Anti-SRBC titers were not affected by methyldopa treatment, but leukocyte counts were dramatically decreased, and hematocrits to a lesser degree. Although in methyldopa-treated mice spleen and kidneys were increased in size, liver, lung, heart, and thymus size was not affected. These results are discussed in the context of other studies on the mode of action of methyldopa in eliciting an autoimmune anemia in man treated therapeutically with this drug.

Animals↗
PubMed1980

Metabolic disposition of methyldopa in hypertensive and renal-insufficient children.

The serum levels of methyldopa and its principle metabolites were assessed in 22 hypertensive children, of whom 13 had impaired renal function. A significant correlation was found between the magnitude of the renal dysfunction and the serum levels of methyldopa, alpha-methyldopa-sulfate, alpha-methyldopamine, and alpha-methyldopamine-sulfate. The patients were divided into 2 groups: those with normal (serum creatinine less than or equal to 1.0 mg/100 ml) and those with abnormal (serum creatinine greater than 1.0 mg/100 ml) renal function. The serum level of alpha-methyldopa-sulfate and not of methyldopa was elevated in those with renal dysfunction. The serum levels of alpha-methyldopamine and, in particular, its 3-0 sulfate conjugate were markedly elevated in patients with renal disease. These data suggest that the enhanced sensitivity to methyldopa in patients with impaired renal function may be due in part to alpha-methyldopamine.

Adolescent↗
PubMed1972

The metabolism of 14 C-labelled -methyldopa in normal and hypertensive human subjects.

1. The fate of orally administered (14)C-labelled l-alpha-methyldopa has been examined in three normal men and in eight hypertensive patients who responded to the drug and three who did not. 2. The output of (14)C in the urine in 2 days and in the faeces in 4 days was not very different in any of the subjects. The normals excreted about 40% of the dose in the urine and 60% in the faeces, the responders 52% (range 35-60%) and 45% and the non-responders 42% and 41%. Most of the urinary (14)C radioactivity was eliminated in 24h after dosing. 3. The main metabolite in the urine was free and conjugated alpha-methyldopa (normal men, 23%; responders, 37%; non-responders, 25% of the dose). Free and conjugated 3-O-methyl-alpha-methyldopa was about 4% in all subjects, total amines (alpha-methyldopamine and 3-O-methyl-alpha-methyldopamine) about 6% and ketones (mainly 3,4-dihydroxyphenylacetone) about 3%. 4. The output of alpha-methyldopamine (2-4% of dose), 3-O-methyl-alpha-methyldopamine (0.3%) and 3,4-dihydroxyphenylacetone (3-5%) was similar in the one normal and two responders examined. 5. The faecal (14)C in all subjects was unchanged l-alpha-methyldopa. 6. In general, the amounts of the metabolites in the urine in normal men and in responding and non-responding patients were quantitatively similar, except in one non-responding patient who converted nearly two-thirds of the absorbed drug into amines and ketones. There appeared to be no correlation between metabolites in the urine and response or lack of response to the drug. 7. In two normal subjects 70-80% of d-alpha-methyldopa was excreted unchanged in the faeces. Of the absorbed compound most (9-14% of the dose) was excreted as the free and conjugated drug together with a small amount (1-2%) of 3-O-methyl-alpha-methyldopa. No amines and only traces of ketone were excreted.

Adult↗
PubMed1988

Alpha-methyldopa selectively reduces alae nasi activity.

1. Sedatives such as the benzodiazepines and alcohol reduce upper airway muscle activity. We hypothesized that a sedating antihypertensive, alpha-methyldopa, might have similar effects. To investigate this hypothesis we studied the effect of alpha-methyldopa on alae nasi electromyographic (EMG) activity during hypercapnia. 2. We studied ten healthy subjects and three subjects with obstructive sleep apnoea during CO2-stimulated breathing. In a preliminary study four subjects demonstrated a fall in alae nasi EMG activity 4 h after the ingestion of 500 mg of alpha-methyldopa during CO2 rebreathing. 3. In six additional normal subjects and three subjects with obstructive sleep apnoea, we studied the alae nasi EMG activity during steady-state hypercapnia with PCO2 held constant 5 torr (0.7 kPa) above baseline. On 2 separate days we studied subjects before and 2 h after they had ingested 750 mg of alpha-methyldopa or placebo. 4. In the normal subjects the mean alae nasi EMG activity fell by 34% 2 h after ingestion of alpha-methyldopa (P less than 0.05) without a change in other ventilatory parameters. 5. In the sleep apnoea group the individual mean alae nasi EMG activity fell 16-49%, with ventilation and tidal volume falling in one patient. 6. We conclude that alpha-methyldopa selectively reduces upper airway motor activity.

Adolescent↗
PubMed1980

Methyldopa inhibition of suppressor-lymphocyte function: a proposed cause of autoimmune hemolytic anemia.

To test the hypothesis that methyldopa induces red-cell autoantibodies by inhibiting the activity of suppressor lymphocytes, we studied its effect on several immune functions. Methyldopa inhibited T-lymphocyte suppression of IgG production by peripheral-blood mononuclear cells stimulated by poke-weed mitogens. This effect occurred in isolated T cells incubated with methyldopa and in T cells obtained from patients taking methyldopa. In addition, the drug caused a 30 to 80 per cent reduction in the proliferative response of peripheral-blood mononuclear cells to mitogens in vitro, and this reduction primarily involved the activation of T lymphocytes. Methyldopa also caused a persistent elevation of intracellular lymphocyte cyclic AMP in vitro and in vivo. We postulate that methyldopa alters the immune system by causing a persistent increase in lymphocyte cyclic AMP, which inhibits suppressor T-cell function. These effects may lead to unregulated autoantibody production by B cells in some patients.

Anemia, Hemolytic, Autoimmune↗
PubMed1990

Effect on atrial natriuretic peptides of chronic treatment with alpha-methyldopa and hydralazine in spontaneously hypertensive rats.

The present study was designed to examine the effect of antihypertensive therapy on plasma and atrial concentration of atrial natriuretic peptides (ANP) in spontaneously hypertensive rats (SHR) by using alpha-methyldopa and hydralazine. Methyldopa and hydralazine treatment reduced blood pressure (P less than .05, P less than .05, respectively); however, ventricular weight was reduced by methyldopa (P less than .05) but not by hydralazine. Plasma ANP concentration in untreated SHR was higher than that observed in Wistar-Kyoto rats (WKY). Methyldopa treatment decreased plasma ANP concentration, but hydralazine treatment did not. Moreover, plasma ANP concentration and ventricular weight were positively correlated in untreated and treated SHR. The left atrial ANP concentration in untreated SHR was lower than that observed in WKY. Methyldopa treatment increased left atrial ANP concentration, but hydralazine treatment did not. These results suggest that the ANP release from the left atrium is chronically stimulated in adult SHR, and that a decrease in plasma ANP concentration by methyldopa treatment is, in part, associated with the decline of ANP release from the heart due to the reductions of blood pressure and cardiac hypertrophy.

Animals↗