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

Abstract

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.

Reproductive Endocrinology and Pregnancy in Women on Hemodialysis

“…. consistent with pituitary hyperplasia" in three women and one man with elevated prolactins (6 1-434 ng/ml) on amethyl dopa, which decreases hypothalamic dopa-mine content, causing prolactin secretion (28). These patients also were the only ones in the study to evidence galactorrhea (10).…”

Central Sympatholytic Drugs

“…Half‐life on average is between 1 and 2 hours in healthy patients and hypertensive patients 23,24 but is increased to 4 to 6 hours in patients with renal failure, resulting in a prolonged hypotensive action in these patients 25 . Following oral administration, an effect of α‐methyldopa on BP is detectable within 1 hour, reaching a peak effect within 6 to 8 hours 23 . Plasma renin activity is also reduced during α‐methyldopa treatment 26 .…”

“…The usual daily dosage of α‐methyldopa is 500 mg to 2 g, divided into 2 to 4 doses. In hypertensive patients, methyldopa reduces BP mainly by reducing TPR with minimal effects on heart rate or cardiac output 23 . Although once a mainstay of antihypertensive therapy, α‐methyldopa is currently used mainly in pregnant women with hypertension because of lack of teratogenicity or fetal side effects.…”

Molecular Dynamics Simulation of the Permeation of Methyldopa through POPC Phospholipid Bilayer Membrane

“…5,15 甲基多巴(图 1)是具有旋光性的多巴类物质, 通 过阻断中枢神经系统的肾上腺素能神经, 作为降血 压药物, 应用于临床已经多年. 17,18 甲基多巴(左旋体) 的药理机制是通过血脑屏障, [19][20][21] 在中枢神经细胞系 统中脱羧和β-羟化转变为α-甲基去甲肾上腺素, 22,23…”