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PubMed1996

Determination of alpha-methyldopa in human plasma by validated high-performance liquid chromatography with fluorescence detection.

A sensitive reversed-phase gradient elution high-performance liquid chromatographic method with fluorescence detection has been developed for the determination of alpha-methyldopa (AMD) in human plasma. Separation of the investigated compound and the 3,4-dihydroxyphenylalanine (DOPA) internal standard was achieved on a Nucleosil 7 C18 column with a 5 mM heptanesulphonic acid sodium salt containing 0.05 M potassium dihydrogenphosphate (pH 3.2)-acetonitrile mobile phase. The composition of the mobile phase was changed according to a linear gradient time program. Detection was performed at 270 nm fluorimetric excitation and 320 nm emission. The compounds were isolated from plasma by Bond-Elut C18 solid-phase extraction. The limit of quantitation was found to be 10 ng/ml plasma. The assay was validated with respect to accuracy, precision and system suitability. All validated parameters were found to be within the 20% required limits. On the basis of the sensitivity, linearity and validation parameters the developed analytical method was found to be suitable for application in a bioequivalency study.

Chromatography, High Pressure Liquid↗
PubMed1988

Depletion of brainstem epinephrine stores by alpha-methyldopa: possible relation to attenuated sympathetic outflow.

The antihypertensive effect of alpha-methyldopa (MD) is believed to be critically dependent on its ability to deplete endogenous catecholamines or cause the synthesis of false neurotransmitters. We used liquid chromatography with electrochemical detection (LCEC) and negative chemical ionization gas chromatography-mass spectrometry (GC-MS) for quantitation of catecholamines and MD metabolites in rat. MD intraperitoneally (100 mg/kg q12 hr X 12 days), significantly increased alpha-methylnorepinephrine (MNE) in brain (1.02 +/- 0.33 micrograms/g), heart (1.67 +/- 0.57 micrograms/g) and adrenal glands (114.93 +/- 50.47 micrograms/g) Endogenous norepinephrine (NE), epinephrine (E) and dopamine (DA) were reduced. ME levels were 2.19 +/- 0.44 micrograms/g (n = 6) in the adrenal gland but only 99 +/- 26 pg/g (n = 3) in the brainstem. MD-induced endogenous brainstem NE depletion was more than compensated by MNE production, but brainstem E depletion was not compensated for by a stoichiometric production of brainstem ME. We conclude (1) although ME is a metabolite of MD, it is present in extremely low concentrations in brainstem and (2) central epinephrine-containing neurons are depleted of neurotransmitter by MD therapy. If this selective epinephrine depletion occurs in the bulbospinal tract neurons responsible for maintaining sympathetic tone, then this effect could contribute to the antihypertensive effect of MD.

Adrenal Glands↗
PubMed1977

Methyldopa in treatment of neurogenic bladder disorders.

Fifty patients with neurogenic bladder dysfunction were treated with methyldopa (Aldomet). The preliminary results that are presented suggest a beneficial action in patients with upper neuron lesions. The probable mechanism of the drug's action is discussed.

Adrenergic Fibers↗
PubMed1991

Evaluation of mutagenic effect of the antihypertensive drug methyldopa (Aldomet) on mammalian systems in vivo and in vitro and on Allium cepa.

The antihypertensive drug methyldopa (Aldomet) was tested for possible clastogenic activity on normal and hypertensive rats and on human lymphocyte cultures and for its influence on the cell cycle of Allium cepa. The drug had no clastogenic effect on rat bone marrow cells but showed a toxic effect on A. cepa root tip cells and significantly increased the frequency of sister-chromatid exchanges in lymphocyte cultures, without any effect on the frequency of chromosome aberrations.

Allium↗
PubMed1994

Lack of involvement of the kallikrein-kinin system in the depressor effect of alpha-methyldopa in normotensive rats.

1. We evaluated the involvement of circulating kinins in the hypotensive effect of the antihypertensive drug alpha-methyldopa (alpha-MD) in normotensive rats. 2. The alpha-MD effects were more pronounced in urethane-anesthetized rats than in unanesthetized animals. 3. Treatment with alpha-MD did not affect the circulating levels of kininogen, the bradykinin precursor. 4. Pretreatment with captopril that potentiates the depressor effects of bradykinin did not potentiate the hypotension to alpha-MD. 5. The lack of changes in kininogen levels and the failure of captopril to potentiate the depressor effects of alpha-MD rules out an involvement of the circulating kallikrein-kinin system in the response to alpha-MD.

Animals↗
PubMed1975

Specific quantitative gas-liquid chromatographic analysis of methyldopa and some foreign related amino acids in raw material and commercial tablets.

A relatively simple gas-liquid chromatographic (GLC) procedure has been designed for the rapid detection and accurate quantitation of some theoretically possible foreign related amino acid contaminants in alpha-methyldopa raw material and commercial tablets. After trimethylsilylation of the drug or drug mixture with N,O-bis(trimethylsilyl)acetamide in acetonitrile at ambient temperature for 90 min, the derivatives are eluted from a methylsilicone column isothermally at 170 degrees. Quantitation of the components is effected by simple computation relative to dibenzyl succinate as the internal standard. The results obtained by applying the GLC procedure to the analysis of a number of multicomponent synthetic mixtures are in good agreement with the theoretical values. The percentage of label claim values obtained by the GLC method for commercial tablets are compared to those measured colorimetrically by the official U.S.P. procedure. No foreign related amino acid impurities were detected in any of the three commercial dosage forms examined.

Amino Acids↗
PubMed1983

Determination of the enantiomeric purity of levodopa, methyldopa, carbidopa and tryptophan by use of chiral mobile phase high-performance liquid chromatography.

Chiral mobile phase high-performance liquid chromatography was used successfully for the determination of the enantiomeric purity of levodopa, methyldopa, carbidopa and tryptophan. The method investigated uses phenylalanine and copper sulfate in the mobile phase and a C18 column. Linearity, precision, accuracy, detection limit and interference from expected impurities were assessed. The method is also applicable to the measurement of enantiomeric purity in levodopa tablets and capsules.

Capsules↗
PubMed1991

High-performance liquid chromatographic determination of L-3-(3,4-dihydroxyphenyl)-2-methylalanine (alpha-methyldopa) in human urine and plasma.

A procedure is described for the determination of alpha-methyldopa (MD) [L-3-(3,4-dihydroxyphenyl)-2-methylalanine], its metabolite and catecholamines in the urine and plasma of patients undergoing MD therapy, by high-performance liquid chromatography with dual working electrode coulometric detection. An efficient sample preparation procedure is presented for the isolation of endogenous MD, its metabolite and catecholamines from plasma or urine. After deproteinization of a plasma sample with methanol containing 2% of 0.5 M perchloric acid and dilution of a urine sample (1:200), MD, dihydroxyphenylacetic acid (DOPAC), 3-O-methylmethyldopa (3-OMMD) and homovanillic acid (HVA) were separated with a Supelcosil LC-18 column. Catecholamines were extracted from the supernatant of deproteinized plasma or from urine by ion exchange on a Sephadex CM-25 column and subsequent adsorption on alumina. The use of the same mobile phase for the concurrent assay of MD, its metabolite and catecholamines increased considerably the efficiency of sample separation. Recoveries were close to 100% for MD, DOPAC, 3-OMMD and HVA and 70% for catecholamines. The effects of various experimental parameters related to mobile phase composition on chromatographic performance are reported. The purity of the eluted compounds was tested by recording both the first detector response (oxidation current) and the second detector response (reduction current). The ratio of the detector responses yielded a chemical reversibility ratio for the detected compound. A number of applications such as monitoring data from patients under MD therapy are presented.

Chromatography, High Pressure Liquid↗
PubMed1986

Effect of alpha-methyldopa administration during pregnancy on the development of a child's sleep.

A male infant was born to a mother who had been suffering from primary hyperaldosteronism with the administration of alpha-methyldopa (MD) during pregnancy. His behavioral development, especially that of sleep, was studied by means of sleep-awake rhythm and polysomnography recordings (PSG) from 2 months to 2 years and 5 months of age. His daily sleep-awake rhythm showed some abnormal pattern. As to the PSG, the proportion of each sleep stage was normal and the two types of body movements (BM) showed various patterns. A paradoxical increase was seen in the twitch movement of some muscles. MD affects the catecholamine system in the CNS and human sleep. Since the sleep-awake rhythm and BM are thought to be related to the monoaminergic system in the CNS, we assume that his behavior and sleep disorders are the effects of the maternal MD administration during pregnancy.

Brain↗
PubMed1983

An intra-arterial profile of methyldopa.

The "Oxford" system for intra-arterial ambulatory blood pressure monitoring was used to monitor the blood pressure profile in 24 patients with essential hypertension who had received no therapy for 4 wk. The responses to tilt and isometric and dynamic bicycle exercise were recorded. Following the baseline study patients received methyldopa 125 mg t.i.d., which was titrated to a maximum of 500 mg t.i.d. according to blood pressure responses. The mean daily dosage was 1359 mg. Six weeks after the last dosage increment the experiment was repeated. Each patient was asked to take the total daily dosage once a day and the intra-arterial monitoring program was repeated after another 6 wk. Mean daytime intra-arterial blood pressure during three-times-daily dosing was reduced by 27/15 mm Hg; circadian curves were clearly separated during the day but not at night. Once-daily dosing did not control blood pressure as well. There was no evidence of postural hypotension and the absolute pressure response was lowered during both isometric and dynamic exercise. These results are comparable to those from similar studies with alpha- and beta-adrenoreceptor--blocking drugs.

Adult↗
PubMed1989

Utilization of hydralazine or alpha-methyldopa for the management of early puerperal hypertension.

Despite the importance of pregnancy-induced hypertension (PIH), there are few published investigations of therapeutic approaches for the postpartum management of such patients. Twenty-six gravida patients with PIH were prospectively studied during the first 24 hours after delivery while receiving intravenous magnesium sulfate. Each study subject was randomly assigned to a group also systemically administered either hydralazine or methyldopa. During the study interval, hourly measurements of blood pressure, pulse, fluid intake, and urine output were recorded. Hydralazine was found to be superior in its ability to effect more rapidly a lower mean arterial blood pressure. No significant differences in urine output or time until onset of diuresis were noted among treatment groups. No serious side effects were encountered with the use of either antihypertensive agent. Based on these preliminary findings, it appears that hydralazine is the less costly and more effective medication to lower mean arterial blood pressure in the immediate postpartum period.

Blood Pressure↗
PubMedDate not supplied

Precipitation by yohimbine of the withdrawal syndromes of clonidine, guanfacine, and methyldopa in the spontaneously hypertensive rat.

In conscious spontaneously hypertensive (SH) rats, continuously infused with clonidine (500 micrograms/kg/day s.c.) for 12 days, yohimbine (3 or 10 mg/kg i.p.) dose dependently precipitated an overshoot of heart rate and other withdrawal symptoms, such as blood pressure upswings, diarrhea, ptosis, body shivering, jumping, and wet-dog shakes. Naloxone (3 or 30 mg/kg i.p.) or prazosin (1 mg/kg i.p.) did not evoke withdrawal signs in clonidine-treated SH rats. In SH rats treated for 12 days with guanfacine (10 mg/kg/day s.c.), the administration of yohimbine elicited a withdrawal pattern similar in severity and appearance to that observed in clonidine-treated rats. In methyldopa-treated (200 mg/kg/day) SH rats, the yohimbine-precipitated withdrawal symptoms were much less pronounced than those observed in the clonidine- and guanfacine-treated animals, despite the equipotency of the infusions in reducing mean arterial pressure. These results indicate that the clonidine-withdrawal syndrome can be precipitated by acute alpha 2-adrenoceptor blockade. The previously observed minor severity of the guanfacine-discontinuation syndrome in the rat should be attributed to the longer half-life of this drug as compared to clonidine. On the other hand, alpha-methylnoradrenaline much less intensively triggers the mechanisms underlying withdrawal symptoms than clonidine or guanfacine.

Animals↗
PubMedDate not supplied

Effects of intracisternal and intravenous alpha-methyldopa and clonidine on haemodynamics and baroreceptor--heart rate reflex properties in conscious rabbits.

We determined the doses of intracisternal (i.c.) and intravenous (i.v.) clonidine and alpha-methyldopa (alpha-MD) that produced near-maximal falls in mean arterial pressure (MAP) in conscious rabbits. We then studied the haemodynamic mechanisms underlying the fall in MAP and changes in the properties of the baroreceptor-heart rate reflex. Intracisternal and intravenous administration of both drugs lowered MAP by approximately 25% of control, and the fall was about half due to the reduction in cardiac output and about half due to a fall in total peripheral resistance. Baroreceptor-heart rate reflex properties were studied by transiently inflating perivascular balloons to alter blood pressure and by deriving sigmoid curves relating MAP to heart period (HP, pulse interval). Both drugs produced very similar vagal facilitation during transient rises in MAP when given by the i.c. and i.v. routes; HP range (between upper and lower plateaus) increased to 145% of control, and gain rose to 190%. The effects of i.c. administration of both drugs on the cardiac sympathetic component of the baroreflex were studied in methscopolamine-treated rabbits. Clonidine produced more pronounced suppression of HP range and gain, while alpha-MD had little effect. These differences between drugs were still present with much larger i.c. doses. Our findings suggest that both drugs influence resting haemodynamics and the vagal component of the baroreflex through similar effects on the central autonomic pathways. But there are some differences in their central actions on cardiac sympathetic motoneurons.

Animals↗
PubMedDate not supplied

Contribution of noradrenergic and serotonergic neurons to the circulatory effects of centrally acting clonidine and alpha-methyldopa in rabbits.

The effects of intracisternal clonidine (0.04, 0.2, and 1.0 microgram/kg) and of alpha-methyldopa (alpha-MD; 400 micrograms/kg) on mean arterial pressure (MAP) and heart rate (HR) were studied in conscious rabbits before, and 7 and 14 days after, intracisternal injection of (a) vehicle, (b) 6-hydroxydopamine (6-OHDA; 600 micrograms/kg), or (c) 5,6-dihydroxytryptamine (5,6-DHT; 633 micrograms/kg) (n = 6 per group). In the initial control experiment clonidine and alpha-MD produced similar falls in MAP and HR in each group; there was also good reproducibility of responses in vehicle-treated rabbits on the 3 experimental days. But after 6-OHDA or 5,6-DHT administration the circulatory effects of clonidine and alpha-MD were markedly attenuated. On day 14 after injection of 6-OHDA, the clonidine-induced falls in MAP and HR averaged 38 and 18%, respectively, of the control responses (p less than 0.001). On day 14 after 5,6-DHT administration, the falls in MAP and HR after clonidine administration were reduced to 27 and 13% of control, respectively (p less than 0.01), while the corresponding responses after alpha-MD administration were 39 and 61% of control (p less than 0.05). Neurochemical findings suggest that 6-OHDA affected noradrenergic (NA), dopaminergic (DA), but not serotonergic (5HT) neurons, and that 5,6-DHT affected 5HT but not NA and DA neurons. We conclude that the circulatory effects of clonidine and alpha-MD are mediated through both central NA and 5HT neurons.

Animals↗
PubMedDate not supplied

Cardiovascular responses to central clonidine, alpha-methyldopa, and 6-hydroxydopamine in conscious normotensive and spontaneously hypertensive rats following naloxone.

The possible involvement of endogenous opioid peptides in the cardiovascular responses observed following central alpha-adrenoceptor stimulation with clonidine, alpha-methyldopa (alpha-MD), and 6-hydroxydopamine (6-OHDA) was examined in conscious normotensive Wistar and spontaneously hypertensive (SHR) rats. Clonidine [2.5 micrograms intracisternally (i.c.)] produced rapid hypotension (-36 +/- 2 mm Hg) and bradycardia (-53 +/- 5 beats/min) in SHR that were similar to observations in animals given either naloxone (50 micrograms i.c. or 10 mg/kg i.p.) or appropriate saline control injections. Peripheral doses of naloxone (1-2 mg/kg) or saline did not further change arterial pressure or heart rate in either Wistar rats or SHR given alpha-MD (1.0 mg i.c.) 3 h earlier. In addition, central doses of naloxone (3 X 50 micrograms i.c.) given at hourly intervals did not affect the responses to alpha-MD. Central administration of 6-OHDA acutely releases noradrenaline which produces an initial fall in arterial blood pressure and heart rate. Intracisternal 6-OHDA (400 micrograms) produced similar time course and maximum circulatory effects in rats given naloxone (50 micrograms i.c. before and at each subsequent hour) as in saline-treated animals. Naloxone (1 mg/kg s.c.) significantly attenuated morphine-induced analgesia. These findings do not support a critical role of endogenous opioids in mediating the acute antihypertensive actions of clonidine and alpha-MD or in the cardiovascular responses produced by noradrenaline release following central 6-OHDA.

Animals↗
PubMedDate not supplied

Mechanism of the tachycardia following systemic alpha-methyldopa administration in conscious rats.

The mechanism of the tachycardia observed in conscious rats following systemic administration of alpha-methyldopa (alpha-MD) was investigated. Heart rate and mean arterial pressure were monitored following peripheral (i.p. and i.v.) and central (lateral and fourth ventricle and cisterna magna) administration of alpha-MD. As little as 25 mg/kg i.p. produced the maximum tachycardia observed: 136 +/- 30 beats/min within 30 min. However, after central administration of alpha-MD--producing similar reductions in blood pressure--only a gradually developing bradycardia occurred (maximum at 3-4 h), suggesting that the tachycardia was peripheral in origin. Tachycardia following administration of 25 mg/kg alpha-MD i.p. was prevented by pretreatment with propranolol, desmethylimipramine, and the dopa-decarboxylase inhibitor R04-4602, but not by pretreatment with pentolinium, guanethidine, the dopamine-beta-hydroxylase inhibitor FLA-63, or by adrenalectomy or depletion of endogenous catecholamines. In isolated spontaneously beating atria, alpha-MD produced a maximum increase in rate similar to that of isoprenaline. This effect of alpha-MD was blocked by propranolol and R04-4602 but not by FLA-63. These results suggest that the tachycardia observed in conscious rats following alpha-MD administration is caused by stimulation of cardiac beta-adrenoceptors following its conversion to alpha-methyldopamine in cardiac sympathetic neurons.

Animals↗
PubMed1988

Relationships between the cardiovascular effects of alpha-methyldopa and its metabolism in pontomedullary noradrenergic neurons of the rabbit.

We compared the biotransformation of equipotent intracisternal (i.c., 600 micrograms/kg) and intravenous (i.v., 50 mg/kg) doses of alpha-methyldopa (alpha-MD) to alpha-methylnorepinephrine (alpha-MeNE) in the five major (A1, A2, A5, A6, and A7) noradrenergic nuclei of the rabbit brain, in relation to their cardiovascular effects. Peak effects on blood pressure and heart rate occurred 2-3 h after administration and persisted for 8 h. Three hours after i.v. alpha-MD, norepinephrine (NE) content throughout the five cell group regions was greatly reduced. However, total catecholamine (CA) content (NE plus alpha-MeNE) in the five cell groups increased by up to 300% due to accumulated alpha-MeNE. Eight hours after the i.v. dose, CA content throughout all five cell groups remained elevated. Following i.c. alpha-MD, a similar pattern of effect was observed in the A1, A2, and A5 regions. In the A6 and A7 regions, the effects were small and transient. Three hours after the i.c. dose, there was some biotransformation of alpha-MD but CA content was not affected. By 8 h, alpha-MeNE accounted for only a small fraction of the CA content. These results suggest that A1, A2, and A5 areas could be contributing to alpha-MD's cardiovascular effects. The elevation in CA content may be responsible for the activation of noradrenergic depressor pathways and blood pressure reduction.

Animals↗