Renal Metabolism and Effects of the Glutamyl Derivatives of l-Dopa and 5-Hydroxytryptophan in Man

Abstract

1. Equimolar amounts of y-l-glutamyl-l-3,4-dihydroxyphenylalanine (gludopa) and γ-l-glutamyl-5-hydroxy-l-tryptophan were infused separately and together in eight healthy, salt-replete male subjects in a placebo-controlled, cross-over study to investigate whether the administration of one amine precursor affects the renal metabolism of the other and to determine whether dopamine or 5-hydroxytryptamine would be generated preferentially. The overall effect on sodium excretion was also measured when both precursors were administered simultaneously. 2. Administration of gludopa was associated with marked increases in the urinary excretion of l-dopa, dopamine and 3,4-dihydroxyphenylacetic acid, together with a rise in the urinary excretion of sodium. γ-l-Glutamyl-5-hydroxy-l-tryptophan, on the other hand, produced marked increases in the urinary excretion of 5-hydroxy-l-tryptophan, 5-hydroxytryptamine and 5-hydroxyindoleacetic acid, and this was accompanied by a slight, but non-significant, reduction in sodium excretion. About 27% of the infused dose of gludopa (on a molar basis) was recovered in the urine as dopamine whereas 15% of the given dose of γ-l-glutamyl-5-hydroxy-l-tryptophan was excreted as 5-hydroxytryptamine. 3. The urinary excretion values of l-dopa, dopamine and 3,4-dihydroxyphenylacetic acid after the simultaneous infusion of gludopa and γ-l-glutamyl-5-hydroxy-l-tryptophan were not significantly different from those observed after infusion of gludopa only. Similarly, the urinary excretion values of 5-hydroxy-l-tryptophan, 5-hydroxytryptamine and 5-hydroxyindoleacetic acid during the co-infusion were similar to those measured after administration of γ-l-glutamyl-5-hydroxy-l-tryptophan only. The net effect of the concomitant infusion of both glutamyl derivatives was an increase in urinary sodium excretion. 4. Our study in salt-replete individuals suggests that dopamine rather than 5-hydroxytryptamine was preferentially produced when equimolar amounts of their precursors were provided and that the natriuretic effect of dopamine, generated intrarenally from gludopa, was greater than the sodium retaining action of 5-hydroxytryptamine derived from γ-l-glutamyl-5-hydroxy-l-tryptophan. Comparison of the urinary metabolite data after the separate and concomitant infusion of the two glutamyl compounds provided no evidence of competitive inhibition of synthesis of either amine.