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

Abstract

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 μmol to 22.7 μmol (24.7 μmol excreted after placebo). Adding benserazide to the α -methyldopa-isoleucine dose regimen in an attempt to inhibit any residual, presumably peripheral, effects of α-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. © 1986 American Heart Association, Inc.