Pharmacodynamic effects of alpha-methyl dopa in hypertensive subjects

Onesti, Gaddo; Brest, Albert N.; Novack, Paul; Kasparian, Hratch; Moyer, John H.

doi:10.1016/0002-8703(64)90395-3

Cited by 81 publications

(21 citation statements)

References 6 publications

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“…Indeed, several groups have reported either an increased GFR even in patients with chronic renal insufficiency,46 or at least no impairment in renal excretory function during treatment. 40 Similar responses have been observed in studies of other organ circulations in patients with hypertension. Thus, one report demonstrated increased central blood flow and decreased cerebral vascular resistance after two weeks' therapy with methyldopa.47 Myocardial blood flow has also been reported to be increased following IV methyldopa therapy in hypertensive patients.4' These findings are consistent with studies performed in experimental normotensive and hypertensive animals.…”

Section: Regional Blood Flowssupporting

confidence: 74%

Methyldopa. Mechanisms and treatment 25 years later

Ed¹

1980

Archives of Internal Medicine

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Methyldopa, an adrenergic-inhibiting compound, has been used for over 25 years as a safe and effective antihypertensive agent. The postulated mechanisms for the antihypertensive action of this compound have been varied and parallel our broadening knowledge of the role of the adrenergic nervous system in controlling arterial pressure. This review outlines the mechanisms of adrenergic control of the circulation and how the proposed mechanisms of action of methyldopa (ie, dopa decarboxylation, false neurotransmission, inhibition of renin release, and stimulation of alpha receptor sites in the brain) seem to account for the depressor action of the drug. Physiologic effects as well as immunologic and other clinical effects are also discussed.

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Section: Regional Blood Flowssupporting

confidence: 74%

Methyldopa. Mechanisms and treatment 25 years later

Ed¹

1980

Archives of Internal Medicine

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“…However, the somewhat greater hypotensive effect of methyldopa on the hyperaemic calf blood flow might have slightly biased the results. The potential positive effect of methyldopa on vascular resistance (Morin et al, 1964;Onesti et al, 1964) was masked during reactive hyperaemia. Contrary to metoprolol (Eliasson et al, 1982), methyldopa has been observed to elicit an inhibitory effect on peripheral vasospasm (Varadi & Lawrence, 1969).…”

Section: Discussionmentioning

confidence: 99%

Chronic effects of metoprolol and methyldopa on calf blood flow in intermittent claudication.

Lepäntalo¹

1984

Brit J Clinical Pharma

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In a placebo-controlled double-blind study 14 hypertensive patients with intermittent claudication were treated with metoprolol (100-200 mg daily) and methyldopa (500-1000 mg daily) for 3 weeks and their effects on heart rate, blood pressure as well as on resting and hyperaemic calf blood flow and vascular resistance were compared.In their antihypertensive effect metoprolol and methyldopa did not differ significantly. In 23 diseased limbs the calf blood flow and vascular resistance remained unchanged at rest during the trial. The active drugs reduced hyperaemic flow (P < 0.05). The peak flow was reduced by 20% (P > 0.01) with metoprolol and by 15% with methyldopa below the initial level and by 17% and by 12% below the level recorded on placebo, respectively. Neither of the drugs influenced vascular resistance during reactive hyperaemia.Thus, in patients with intermittent claudication antihypertensives should be used with care.

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“…Clonidine tends to lower blood pressure by reducing cardiac output and has little or no effect on TPR. 26 '" In contrast, acute therapeutic doses of a-methyldopa that are administered orally, as in the present study, or intravenously, 28 and chronic, oral doses 29 lower blood pressure by reducing peripheral resistance. We did not investigate whether higher oral doses also reduced cardiac output.…”

Section: Discussionmentioning

confidence: 56%

Evidence for a predominantly central hypotensive effect of alpha-methyldopa in humans.

Bobik

Jennings²,

Jackman³

et al. 1986

Hypertension

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SUMMARY We examined the time course and extent to which central and peripheral mechanisms contribute to the short-term effects of a 500-mg oral dose of a-methyldopa on supine mean arterial pressure, cardiac output, and total peripheral resistance, as well as its effects on total urinary excretion of norepinephrine and its metabolites, in five subjects with essential hypertension. Total peripheral resistance was reduced significantly 1 hour after a-methyldopa administration and remained so for the ensuing 7 hours of the study (p < 0.05). A small but significant reduction in mean arterial pressure occurred 7 hours after the dose (p < 0.05), while cardiac output did not change significantly. Total 24-hour urinary norepinephrine and metabolite excretion was reduced by 8.1 fimol (35% compared with placebo). The relative distribution of urinary norepinephrine metabolites was unaffected by a-methyldopa, and the catecholamine metabolites of a-methyldopa, a-methy lnorepinephrine and a-methylnormetanephrine did not account for this reduction. Competitive inhibition of methyldopa transport across the blood-brain barrier and into the central nervous system by large oral doses of isoleucine antagonized most of the effect of a-methyldopa. The effects on total peripheral resistance were completely abolished, and small, insignificant changes during the 7-hour study were similar to those observed after placebo. Changes in mean arterial pressure were not significant; however, 24-hour total urinary norepinephrine and metabolite excretion increased by 6.1 //.mol to 22.7 fimol (24.7 fimol excreted after placebo). Adding benserazide to the a-methyldopa-isoleucine dose regimen in an attempt to inhibit any residual, presumably peripheral, effects of a-methyldopa caused little, if any, further antagonism. Our results suggest that short-term oral administration of amethyldopa inhibits norepinephrine release from sympathetic nerves by central mechanisms, and the responses in mean arterial pressure, although small, are consistent with this hypothesis. The reductions in total peripheral resistance also appear to be centrally mediated. pa's action in humans. 6 ' 7 Since a-methyldopa must be metabolized to active metabolites within the central nervous system to exert centrally mediated hypotensive effects, 4 these studies have concentrated on comparing the hypotensive effects of a-methyldopa before and after inhibition of central or peripheral dopa decarboxylase, or both. In general, these methods have not been able to attenuate the cardiovascular effects. Thus, the question of whether the central or the peripheral action of a-methyldopa is the more important in humans is still unanswered.Recently, Zavisca and Wurtman 8 reported that a cocktail of large, neutral amino acids administered intraperitoneally to spontaneously hypertensive rats could partially attenuate the fall in blood pressure produced by a-methyldopa. This effect appeared to be due to a reduction in the amount of a-methyldopa entering the brain.

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Pharmacodynamic effects of alpha-methyl dopa in hypertensive subjects

Cited by 81 publications

References 6 publications

Methyldopa. Mechanisms and treatment 25 years later

Methyldopa. Mechanisms and treatment 25 years later

Chronic effects of metoprolol and methyldopa on calf blood flow in intermittent claudication.

Evidence for a predominantly central hypotensive effect of alpha-methyldopa in humans.

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