A comparison of the effects of two putative 5‐hydroxytryptamine renal prodrugs in normal man.

Abstract

1. The effects of 1 h intravenous infusions of equimolar amounts of two putative 5‐hydroxytryptamine (5‐HT) renal prodrugs, 5‐hydroxy‐L‐ tryptophan (5‐HTP, 10 micrograms kg‐1 min‐1) and gamma‐L‐glutamyl‐5‐ hydroxy‐L‐tryptophan (glu‐5‐HTP, 16.6 micrograms kg‐1 min‐1) were examined in five healthy male volunteers in a randomised, placebo‐ controlled, cross‐over study. 2. Both compounds increased urinary excretion of 5‐HT and there was greater extra‐renal formation of 5‐HT following 5‐HTP administration than after glu‐5‐HTP. 3. Glu‐5‐HTP was significantly antinatriuretic. 5‐HTP reduced mean urinary sodium excretion but this effect was not statistically significant. 4. 5‐HTP, but not glu‐5‐HTP, significantly increased plasma aldosterone. There was no increase in plasma renin activity with either compound. 5. There were no significant changes in pulse rate or blood pressure. Two subjects complained of nausea at the end of 5‐HTP infusion but none had any adverse reactions with glu‐5‐HTP. 6. The results of this study suggest that both prodrugs generate 5‐HT in man and that glu‐5‐HTP is antinatriuretic. The glutamyl derivative may have greater renal specificity than 5‐HTP and, as a result, causes less systemic side effects.

The antinatriuretic action of gamma‐L‐glutamyl‐5‐hydroxy‐L‐tryptophan is dependent on its decarboxylation to 5‐hydroxytryptamine in normal man.

“…4 Pretreatment with carbidopa substantially attenuated the increase in 5-HT excretion after glu-5-HTP and abolished its antinatriuretic effect. 5 These results are in keeping with the proposition that the antinatriuretic action of glu-5-HTP is dependent on its decarboxylation to 5-HT.…”

“…TrD A xmal man [5,6]. The prodrug also increases aldosterone production as previously reported but the time course of the changes in sodium excretion and the lack of effect on urinary potassium excretion suggest that the antinatriuresis occurs independently of the known actions of aldosterone [6,9].…”

“…PAH, 5-HTP, 5-HT and dopamine were measured by h.p.l.c. and polyfructosan and 5-HIAA by spectrophotometry as described previously [5,6]. The values of the lower limit of detection of the assays for 5-HTP, 5-HT, 5-HIAA and dopamine were 45 nmol 1-1, 45 nmol 1-l, 5.2 ,umol 1-l, and 26 nmol l-l respectively.…”

“…5-HTP is decarboxylated by aromatic L-amino acid decarboxylase (LAAD) to 5-HT. The latter is degraded primarily by monoamine oxidase to produce 5-hydroxyindoleacetic acid (5-HIAA) which is the major catabolic and excretory product of 5-HT metabolism.…”

“…The enzyme y-glutamyl transferase (yGT) is also present in high concentrations and the kidney is highly active in the uptake and metabolism of y-glutamyl derivatives of amino acids [3,4]. We previously demonstrated marked increases in urinary 5-HT excretion after infusion of the 5-HT prodrug, y-L-glutamyl-5-hydroxy-L-tryptophan (glu-5-HTP), in keeping with intrarenal synthesis of 5-HT following the conversion of glu-5-HTP to 5-HTP by yGT and its subsequent decarboxylation by renal LAAD to 5-HT [5,6]. Glu-5-HTP was relatively more selective for the kidney than 5-HTP.…”