A Comparison of the Renal and Neuroendocrine Effects of Two 5-Hydroxytryptamine Renal Prodrugs in Normal Man

Abstract

1. The effects of 1 h intravenous infusions of equimolar amounts (45 nmol min−1 kg−1) of two putative 5-hydroxytryptamine renal prodrugs, 5-hydroxy-L-tryptophan and γ-L-glutamyl-5-hydroxy-L-tryptophan, were investigated in a randomized, placebo-controlled, cross-over study in nine healthy male subjects. 2. Cumulative urinary 5-hydroxytryptamine excretion over the 3 h observation period rose by about 370-fold after 5-hydroxy-L-tryptophan and 390-fold after γ-L-glutamyl-5-hydroxy-L-tryptophan when compared with placebo infusion. Urinary 5-hydroxy-L-tryptophan excretion was three times higher after administration of γ-L-glutamyl-5-hydroxy-L-tryptophan than after 5-hydroxy-L-tryptophan infusion. Urinary 5-hydroxyindole-3-acetic acid excretion after 5-hydroxy-L-tryptophan infusion was significantly greater than that after γ-L-glutamyl-5-hydroxy-L-tryptophan administration. Urinary dopamine excretion was not affected by either compound when compared with placebo. 3. 5-Hydroxy-L-tryptophan significantly reduced urine flow rate and urinary sodium excretion. γ-L-Glutamyl-5-hydroxy-L-tryptophan was antinatriuretic but did not affect urine output. These changes occurred without significant alterations in effective renal plasma flow and glomerular filtration rate. 4. Both 5-hydroxy-L-tryptophan and γ-L-glutamyl-5-hydroxy-L-tryptophan significantly increased plasma aldosterone concentration without a concomitant rise in plasma renin activity. The increase after γ-L-glutamyl-5-hydroxy-L-tryptophan was smaller and delayed. 5-Hydroxy-L-tryptophan, but not γ-glutamyl-5-hydroxy-L-tryptophan, increased serum growth hormone concentration. 5. There was a significant increase in diastolic blood pressure after 5-hydroxy-L-tryptophan administration, but not after γ-L-glutamyl-5-hydroxy-L-rryptophan. 6. These results show that both prodrugs generate 5-hydroxytryptamine. The antinatriuresis after both compounds is presumably mediated by intrarenally generated 5-hydroxytryptamine and this appears to be predominantly a tubular effect. The urinary metabolite data and greater extrarenal effects produced by 5-hydroxy-L-tryptophan indicate that the glutamyl derivative is relatively more selective for the kidney than 5-hydroxy-L-tryptophan.