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PubMed2000

Study of the evolution of blood and striatal levels of methyldopa: a microdialysis study in sinaortic denervated rats.

Pharmacokinetic of methyldopa (50 mg kg(-1)i.p.) was studied in anesthetized sham operated and sinoaortic denervated (SAD) rats by using the microdialysis technique. Vascular shunt probe was inserted into the carotid artery and concentric probe was placed in the striatum. Levels of methyldopa were measured by HPLC-EC. The number of animals in each group was six and normal distribution of the variables of the study was assumed. Peak concentrations in arterial blood of methyldopa were similar in both groups of rats but the elimination rate constant was 0.31+/-0.09 h(-1)for sham rats (n =6) and 1.28+/-0.31 h(-1)for SAD rats (n =6, P<0.05). Low levels of methyldopa and a more pronounced decrease were seen in striatum of sinoaortic denervated rats. In conclusion, by using a microdialysis technique, different kinetic profiles of methyldopa were observed in sham operated and sinoaortic denervated rats.

Adrenergic alpha-Agonists↗
PubMed1982

The influence of SK & F 64139, a phenylethanolamine-N-methyltransferase inhibitor, on centrally mediated cardiovascular effects of alpha-methyldopa and clonidine.

The inhibitor of phenylethanolamine-N-methyl transferase (PNMT), SK&F 64139 (7, 8-dichloro-1, 2, 3, 4-tetrahydroisoquinoline), when given i.v. (5 mg/kg), did not prevent the decrease of blood pressure induced in conscious spontaneously hypertensive rats (SHR) by alpha-methyldopa (50 mg/kg i.v.). However, i.c.v. administration of SK&F 64139 (5 mg/kg) to conscious SHR reduced both the alpha-methyldopa- and the clonidine-induced hypotension. Bradycardia in response to clonidine was also prevented by i.c.v. SK & F 64139. When the antihypertensive effect of alpha-methyldopa or clonidine was fully established, i.c.v. administration of SK & F 64139 returned blood pressure within a few minutes to the initial value. Similarly, the bradycardia after clonidine was promptly reversed by i.c.v. SK & F 64139. In pithed rats the pressor responses to both methoxamine and clonidine were antagonized by SK & F 64139 suggesting blockade of vascular alpha 1-and alpha 2-adrenoceptors by the PNMT inhibitor. Blockade of central alpha-adrenoceptors by SK & F 64139 appears to adequately explain the inhibition of the antihypertensive effects of alpha-methyldopa and clonidine. The present results do not support the claim (Gerkens et al. 1980) that inhibition of the central formation of alpha-methyladrenaline is the mechanism underlying the antagonism of alpha-methyldopa-induced hypotension by SK & F 64139.

Adrenergic alpha-Antagonists↗
PubMed1979

Selective stimulation of central alpha-autoreceptors following treatment with alpha-methyldopa and FLA 136.

1. The accumulation of normetanephrine in the rat brain induced by the monoamine oxidase inhibitor nialamide was inhibited following alpha-methyldopa and 4-amino-3-(2,6-dichlorobenzylidenehydrazino)-1,2,4-triazole (FLA 136). It was not changed following alpha-methylmetatyrosine despite a greater disappearance of noradrenaline than after alpha-methyldopa. The alpha-adrenoreceptor blocking agent yohimbine increased the nialamide-induced accumulation of normetanephrine and completely antagonized the actions of alpha-methyldopa and FLA 136, indicating that the effects of the two drugs are due to stimulation of alpha-adrenoreceptors. 2. The flexor reflex activity of spinalized rats was not influenced by alpha-methyldopa and alpha-methylmetatyrosine at the doses used in the biochemical experiments, as previously found for FLA 136, indicating no stimulation of classical, postsynaptic, central alpha-adrenoreceptors. 3. The biochemical effects of alpha-methyldopa and FLA 136 might be caused by stimulation of alpha-autoreceptors on the cell bodies and the nerve terminals of noradrenaline neurons. A similar mechanism might be involved in the hypotension reported by other investigators following these drugs.

Adrenergic alpha-Agonists↗
PubMed1984

Reduced peripheral vascular symptoms in elderly patients treated with alpha-methyldopa--a comparison with propranolol.

A multicentre study of 6-10 weeks duration was performed in 60 ambulant hypertensive patients aged over 60 years to compare the efficacy of methyldopa and propranolol with particular reference to the occurrence of cold extremities and sleep disturbances. Blood pressure was effectively controlled by both drugs being reduced from a mean of 180/108 mmHg to 161/93 with methyldopa and 180/108 to 162/94 with propranolol. More patients treated with methyldopa (74%) achieved the target diastolic blood pressure of 95 mmHg or below compared with those treated with propranolol (58%). Side effects were more frequent in the propranolol group necessitating the withdrawal of four patients from the study. Only one patient on methyldopa was withdrawn. The incidence of cold extremities was significantly greater with propranolol. The occurrence of sleep disturbances was similar in both groups. In this group of elderly patients methyldopa was better tolerated than propranolol.

Aged↗
PubMed1976

Comparative study of metoprolol and alpha-methyldopa in untreated essential hypertension.

The hypotensive actions of metoprolol and alpha-methyldopa have been compared in 37 men with previously untreated essential hypertension; 36 belonged to stage 1 and 1 to stage 2 of the WHO classification. After four weeks of placebo treatment the patients were randomly allocated to treatment with either of the two drugs. Treatment was started with metoprolol 75 mg daily or alpha-methyldopa 375 mg and was doubled after eight weeks. Satisfactory blood pressure control was defined as systolic blood pressure below 160 mm Hg and diastolic below 95 mm Hg. The patients were examined every four weeks and in those with unsatisfactory control the dose was gradually increased up to a maximum daily dose of metoprolol 450 mg or alpha-methyldopa 2250 mg. The trial lasted for 24 weeks after randomization. Five patients dropped out of the study. After six months, satisfactory blood pressure control was recorded in 16 out of 17 patients and 14 out of 15 patients treated with metoprolol and alpha-methyldopa, respectively. The average reduction in blood pressure produced by the two drugs was comparable. One patient in the alpha-methyldopa group developed drug exanthema and two patients a positive Coombs' test. Other side effects were few and did not differ between the two compounds.

Blood Pressure↗
PubMed1979

The effects of desmethylimipramine on the pharmacological actions of alpha methyldopa in man.

The effect of pretreatment with the tricyclic antidepressant desmethylimipramine (DMI) 75 mg daily for 3 days on the action of oral methyldopa 750 mg was investigated in a double blind crossover design in volunteers. DMI pretreatment caused a small but not significant increase in supine systolic and diastolic blood pressure and heart rate. However, the effects of methyldopa on lying and standing blood pressure and heart rate were not markedly altered by pretreatment. In particular, the fall in standing blood pressure after methyldopa was present with and without DMI and the sedative action of methyldopa was similar. DMI alone reduced saliva production. No evidence was found that tricyclic antidepressant drugs significantly modify the hypotensive effect of methyldopa in man.

Adult↗
PubMed1978

Methyldopa-induced pancreatitis.

An acute febrile illness associated with gastrointestinal upset developed in a patient within one week after starting treatment with methyldopa. The illness was characterized by prompt subsidence of symptoms when the patient withdrew therapy secondary to gastrointestinal upset, and recrudescence of symptoms when methyldopa therapy was reinitiated. This was associated with hyperamylasemia, hyperlipasemia, hyperpyrexia, and epigastric pain, both on admission to the hospital and upon rechallenge with methyldopa. Although gastrointestinal upset has been reported as an untoward side effect of methyldopa, this is the first report to our knowledge of documented methyldopa-induced hyperamylasemia and hyperlipasemia secondary to pancreatitis.

Amylases↗
PubMed1978

Adverse reactions to methyldopa with particular reference to hypotension.

Of 26,294 consecutive patients monitored in a comprehensive drug surveillance program, 1067 (4 per cent) received methyldopa for treatment of hypertension. Adverse reactions attributed to methyldopa were reported in 149 patients (14 per cent), the most frequent being hypotension. Life-threatening adverse effects were reported in nine patients (6 per cent of reactors)--the major problems being hypotension associated in several patients with signs of cardiac or cerebral ischemia. Hypotension attributed to methyldopa was more frequent in younger patients, in those with uremia, in lighter subjects, and in those receiving a high daily dose. Marked interaction between these factors was demonstrated and eightfold differences in the frequency of hypotension were observed in different sub-groups of methyldopa recipients. Adverse effects other than hypotension were reported infrequently and did not correlate well with the previously mentioned factors. The findings suggest that methyldopa therapy should be commenced cautiously in younger patients, in the non-obese, and in those with impairment of renal function as manifest by elevated blood urea nitrogen levels.

Adult↗
PubMed1976

Methyldopa Hepatitis. A report of six cases and review of the literature.

Six cases of methyldopa hepatitis, including two in which the patients died are reported; and 77 cases from the literature are reviewed. Patients in whom severe hepatotoxic reactions to methyldopa develop usually complain of prodromal symptoms typical of hepatitis, often with fever, one to four weeks after therapy is initiated. Jaundice, when it occurs, is usually manifest within three months. Asymptomatic, transient elevations of serum transaminase levels may occur in patients receiving methyldopa. However, since the clinical and histologic features of hepatic injury from methyldopa are indistinguishable from viral hepatitis, it is suggested that the incidence of this iatrogenic disease is higher than generally appreciated. Serum transaminase levels should be determined at the initiation of therapy with methyldopa and four weeks later. Moreover, any patient who has unexplained fever or the prodromal symptoms of hepatitis should undergo liver chemistry studies immediately.

Adrenal Cortex Hormones↗
PubMed1994

Inhibition of human glutathione S-transferases by dopamine, alpha-methyldopa and their 5-S-glutathionyl conjugates.

The reversible and irreversible inhibition of human glutathione S-transferases (GST) by dopamine, alpha-methyldopa and their 5-S-glutathionyl conjugates (termed 5-GSDA and 5-GSMDOPA, respectively) was studied using purified isoenzymes. The reversible inhibition, using CDNB as substrate and expressed as I50, ranged from 0.18-0.24 (GST M1a-1a), 0.19-0.24 (GST M1b-1b) to 0.5-0.54 mM (GST A1-1) for 5-GSDA and 5-GSMDOPA, respectively. About 20% inhibition was observed for GST A2-2 and P1-1, using 0.5 mM of both 5-GSDA and 5-GSMDOPA. No significant reversible inhibition was observed with dopamine and alpha-methyldopa. Tyrosinase was used to generate ortho-quinones from dopamine and alpha-methyldopa which may bind covalently to GST and thereupon irreversibly inhibit GST. In this respect, GST P1-1 was by far the most sensitive enzyme. The inhibition (expressed as a % of control) after incubating 0.5 microM GST in the presence of 100 units/ml tyrosinase with 5 microM of the catecholamines for 10 min at 25 degrees, was 99% and 67% for dopamine and alpha-methyldopa, respectively. Moderate irreversible inhibition of GST A1-1 by both dopamine and alpha-methyldopa (33% and 25%, respectively), and of GST M1b-1b by dopamine (45%) was also observed. GST P1-1 is also the only isoenzyme susceptible to irreversible inhibition by 5-GSDA (33% inhibition), while no significant inhibition was observed with 5-GSMDOPA. A minor part of the inhibition by dopamine (23%), and the complete inhibition by 5-GSDA was restored by reduction with dithiotreitol. This suggests that GST P1-1 is inhibited by disulfide formation in the case of 5-GSDA, while this oxidative pathway also substantially contributes to the inactivation by dopamine. This was supported by the HPLC-profile of the GST P1-1 subunit which was strongly affected by dopamine, while for 5-GSDA after reduction with dithiotreitol the original elution profile of the subunit returned.

Cysteinyldopa↗
PubMed1976

Studies on the mechanism of the cardiovascualr effects of methyldopa.

Oral administration of methyldopa (100 mg/kg, twice daily for 3 days) to mongrel dogs produced a significant decrease in blood pressure and heart rate. The drug treatment affected neither the resting venous tone nor the cardiac output. Thus, the hypotensive effect of the drug was predominantly due to a reduction in total peripheral resistance. Vasoconstrictor responses of the renal vasculature to sympathetic nerve stimulation were significantly impaired after methyldopa at all the frequencies, while mesenteric vasoconstrictor responses to sympathetic nerve stimulation were impaired only at the lower stimulation frequencies. In addition, methylnorepinephrine was a significantly less potent vasoconstrictor than norepinephrine in the renal vasculature, but was equipotent to norepinephrine in the mesentery. The finding of a reduction in the renal vascular resistance of methyldopa-treated dogs, with no such alteration in the mesenteric vascular resistance, is consistent with the nerve stimulation studies. Therefore, the results of the present investigation indicate that in addition to the existing evidence favoring a central site of action for methyldopa, the impairment of peripheral sympathetic neuronal function is also of importance in accounting for the hemodynamic alterations observed following treatment with methyldopa.

Animals↗
PubMed1986

Study of alpha-methyldopa oxidation by tyrosinase.

The pathway for alpha-methyldopa oxidation to alpha-methyldopachrome, by mushroom tyrosinase, is proposed. Characterization of intermediates in this oxidative reaction and stoichiometry determination have both been undertaken. The steps for alpha-methyldopa transformation into its aminochrome would be: alpha-methyldopa----o-alpha-methyldopaquinone-H+----o-alpha- methyldopaquinone----leuko-alpha-methyldopachrome----alpha- methyldopachrome. The stoichiometry for this conversion corresponded to the equation: 2 o-alpha-methyldopaquinone-H+----alpha-methyldopa + alpha-methyldopachrome. At very acid pH values, another route implying the addition of water to the quinonic ring, competes with the first one. Two chemical pathways can be proposed from alpha-methyldopaquinone-H+, the relative importance of which is determined by the pH. A theoretical and experimental kinetic approach was applied to this oxidative reaction. Rate constants and thermodynamic activation parameters of the chemical steps, have been evaluated. The results obtained confirmed that alpha-methyldopa oxidation by tyrosinase followed a scheme similar to that established for L-dopa and alpha-methylnoradrenaline.

Catechol Oxidase↗
PubMed1984

Further studies on the effect of chronic alpha-methyldopa administration upon the central nervous system and sexual function in male rats.

Previous studies in our laboratory have demonstrated that alpha-methyldopa, a potent inhibitor of catecholamine synthesis, reduced both libido and erectile function in sexually mature male rats as it does in humans. In this report, those studies were extended to identify the drug's effect upon catecholamine content in the brain, spinal cord and penile erectile tissue in mature male rats. Because many men report that the adverse effects of alpha-methyldopa upon their sexual performance continue after withdrawal from the drug, a 2nd group of animals was retested after the drug was stopped. Results of the group I study showed diminished copulatory and erectile activity as well as penile and brain norepinephrine content. In the group II rats there was a continued significant reduction in erectile and copulatory activity. At the same time, brain, spinal cord and penile tissue content of norepinephrine returned to normal levels. In another experiment an alpha 2-receptor antagonist was administered with alpha-methyldopa and no inhibition of the effects of alpha-methyldopa was observed. These findings imply that the effect of alpha-methyldopa on sexual function is mediated in the central nervous system as an abnormality of receptor function.

Animals↗
PubMed1982

Biochemical and dynamic responses to single and repeated doses of methyldopa and propranolol during dynamic physical activity.

Our purpose was to describe changes in potassium disposition with antirenin antihypertensives during dynamic physical activity in normal subjects receiving methyldopa and propranolol. Before the study, 2 hr after dosing and coincident with immediate preexercise on treadmill (at graded increases of exercise), and 2 hr after exercise, blood was sampled for determination of potassium, renin, aldosterone, and catecholamine levels. Blood pressure and heart rate were measured. The results demonstrate no greater increase in potassium after single or multiple doses of methyldopa than after placebo. After the first dose of propranolol there was a greater rise in potassium over that with placebo, but it was not observed after multiple doses, which may be related to the low doses. There were minor, but significant, changes in norepinephrine, renin, and systolic pressure with multiple-dose methyldopa and in renin, heart rate, and systolic and diastolic pressure with propranolol. Overall, the adrenergic responses to exercise win methyldopa and propranolol were biochemically altered rather than functionally impaired. The latter is related to dose and the underlying age and state of health of our subjects. Methyldopa (or clonidine) may be useful in patients with hypertension who exercise and are predisposed to pertubations in potassium disposition.

Adult↗
PubMed1982

Effect of methyldopa, clonidine, and hydralazine on cardiac mass and haemodynamics in Wistar Kyoto and spontaneously hypertensive rats.

Prolonged treatment of spontaneously hypertensive (SHR) rats with either methyldopa or clonidine significantly and similarly reduced mean arterial pressure. Heart rate increased with methyldopa but decreased with clonidine; other haemodynamic effects were similar. SHR treated methyldopa, but not clonidine, had significantly reduced cardiac masses and heart weight to body weight ratios than did rats receiving the vehicle. Normotensive Wistar Kyoto (WKY) rats treated with methyldopa also had lower cardiac masses than their controls, but exhibited no significant changes in systemic haemodynamics. Treatment with the vasodilator hydralazine increased cardiac output and decreased total peripheral resistance in both SHR and WKY, but the decrease in mean arterial pressure was significant only in SHR. Heart rate was decreased and heart weight to body weight in WKY was elevated. Cardiac mass did not change. Minimal changes in regional haemodynamics were noted, with hydralazine eliciting a decrease in most organ vascular resistances. The data indicate that regression of hypertrophy following antihypertensive therapy was not solely dependent upon haemodynamic factors; nor was it necessarily the effect of suppression of the adrenergic system, since the results obtained with methyldopa and clonidine was similar.

Animals↗
PubMed1985

No evidence of association between methyldopa and biliary carcinoma.

Cancer of the bile ducts is rare and little is known about its risk factors. Recently, an association between methyldopa therapy and biliary carcinoma was reported in a retrospective case-control study. If this association were real, it would represent a significant health hazard, because methyldopa is widely prescribed. Using analysis of covariance to study the relationship between biliary tract cancer rates (obtained from 11 cancer registries in the US, Canada, Europe, and Asia) and per capita methyldopa sales (obtained from its manufacturer), this possible association was re-examined. For the rates of all biliary tract cancers combined, using both three- and ten-year lag periods between drug sales and disease, there were no associations between methyldopa and biliary carcinoma. When the rates for the biliary tract cancer sites were examined separately, one small positive regression coefficient was observed with extrahepatic biliary tract cancer, using the ten-year lag period only (p = 0.03). Since the majority of biliary tract cancers are extrahepatic in origin, it is likely that most of the cancers coded as 'biliary tract cancer, part unspecified' are actually extrahepatic. Also, the magnitude of the slope is very small, contrary to what one would expect with a common drug exposure and an uncommon disease. For these reasons, we believe that the negative results obtained with the combined rates for biliary tract cancer are more meaningful than the results obtained for each cancer site separately. In conclusion, our data do not support the presence of an association between methyldopa and biliary tract cancer.

Biliary Tract Neoplasms↗
PubMedDate not supplied

Midline B3 serotonin nerves in rat medulla are involved in hypotensive effect of methyldopa.

Previous experiments in this laboratory have shown that microinjection of methyldopa onto the ventrolateral cells of the B3 serotonin neurons in the medulla elicits a hypotensive response mediated by a projection descending into the spinal cord. The present experiments were designed to investigate the role of the midline cells of the B3 serotonin neurons in the medulla, coinciding with the raphe magnus. In spontaneously hypertensive, stroke-prone rats, microinjection of methyldopa into the area of the midline B3 serotonin cell group in the ventral medulla caused a potent hypotension of 30-40 mm Hg, which was maximal 2-3 h after administration and was abolished by the serotonin neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) injected intracerebroventricularly. However, intraspinal injection of 5,7-DHT to produce a more selective lesion of only descending serotonin projections in the spinal cord did not affect this hypotension. Further, 5,7-DHT lesion of serotonin nerves travelling in the median forebrain bundle, one of the main ascending pathways from the B3 serotonin cells, did not affect the fall in blood pressure associated with a midline B3 serotonin methyldopa injection. It is concluded therefore that, unlike the ventrolateral B3 cells which mediate a methyldopa-induced hypotension via descending projections, the midline serotonin B3 cells in the medulla contribute to the hypotensive action of methyldopa, either by way of an ascending projection which does not pass through the median forebrain bundle, or through a projection restricted to the caudal brainstem.

5,7-Dihydroxytryptamine↗
PubMedDate not supplied

Sympathetic inhibition with methyldopa in heart failure.

The hypothesis that withdrawal of increased sympathetic activity may be beneficial in heart failure was tested by administration of the centrally acting adrenergic inhibitor methyldopa. Fourteen subjects with chronic, stable New York Heart Association Functional Class 2 or 3 heart failure receiving digitalis and diuretics were randomized to methyldopa (n = 8) 500-1000 mg daily or placebo (n = 6). Clinical, hemodynamic, neurohumoral, and platelet alpha 2-receptor effects were studied after chronic (3 weeks) administration. Sympathetic inhibition did not alter symptom status or exercise duration but reduced plasma norepinephrine concentration during exercise and permitted the same level of exercise to be attained at a lower pressure-rate product, indicating reduced myocardial oxygen consumption. Left ventricular ejection fraction and stroke volume tended to increase, and systemic vascular resistance tended to decrease during exercise after methyldopa administration, suggesting enhanced vasodilation. Upright plasma renin activity increased from 8.2 +/- 2.2 to 13.3 +/- 3.0 ng/nl/h (p = 0.03) after methyldopa, but plasma antidiuretic hormone concentration changed insignificantly. In a subset of patients, platelet alpha 2-receptor density and affinity were unaltered. Renal function was also unchanged. Thus, sympathetic inhibition induced by methyldopa in selected patients with chronic, stable heart failure does not worsen symptom status or exercise performance, and may produce a beneficial effect by withdrawal of excess sympathetic activity with reduction of plasma norepinephrine levels.

Adult↗