262 ALPHA-METHYLDOPA METABOLISM IN HYPERTENSIVE AND RENAL INSUFFICIENT CHILDREN: IDENTIFICATION OF A NEW METABOLITE

Abstract

Despite extensive clinical use, the basis for the antihypertensive action of alpha-methyldopa (α-MD) has remained undefined. Alpha-methyldopamine (α-MDA), the decarboxylated product of α-MD, has been suggested as a possible mediator of these effects in the CNS. A sensitive and specific high-pressure liquid chromatographic system coupled to an electrochemical detector has been developed for the assay of α-MD, its metabolites and their sulfated conjugates in biological specimens. This technique has routinely detected 0.1 μg/ml of aromatic amine. In 7 hypertensive pediatric patients receiving α-MD therapy, the serum levels of α-MD and its 3-O-SO₄ conjugate were significantly elevated in subjects with impaired renal function (creatinine>2.0). The presence of α-MDA and its 3-O-SO₄ conjugate has also been demonstrated in serum. In renal dysfunction there is a 6-10 fold elevation of both α-MDA and its sulfated conjugate. The ratio α-MDA-3-O-SO₄:α-MDA (7-10) is significantly higher than the comparable α-MD-3-O-SO₄:α-MD ratio (2-4) in all patients. The accumulation of the presynaptically-active α-MDA and its sulfated conjugate in hypertensive patients with renal dysfunction may modify the response of these patients to α-MD. Studies in progress will attempt to define the mechanism of action of α-MD and relate its therapeutic effectiveness to metabolic products of this agent. (Supported by USPHS Grant #HD-08580).

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