Abstract
Xanthurenic acid 8-o-β-d-glucoside is an endogenous derivative of tryptophan metabolism, isolated from urine of patients with chronic renal disease. This compound was suggested previously to act as a natriuretic hormone based on its ability to block short circuit currents in a frog skin assay and to induce a sustained natriuresis when injected into rats (C. D. Cain et al., Proc. Natl. Acad. Sci. USA 2007: 17873–17878). The present communication describes the effects of the compound on renal clearance and hemodynamic parameters in male Sprague–Dawley rats maintained on a normal salt (0.4–0.5%) diet. Intravenous administration of synthetic xanthurenic acid 8-o-β-d-glucoside in two consecutive incremental doses (6.3 and 31.5 nmol) resulted in a significant increase (P < 0.05), in urine flow (43.91 ± 6.31 μL/min vs. 10.54 ± 2.21 μL/min), absolute rate of sodium excretion (3.99 ± 0.95 μEq/min vs. 1.15 ± μEq/min), and percentage sodium excretion (1.63 ± 0.46% vs. 0.37 ± 0.12%, peak response vs. baseline, respectively). The natriuretic/diuretic effect was associated also with a significant increase in potassium excretion. These effects were not related to changes in renal hemodynamics or in arterial blood pressure. Pretreatment with the sodium channel blocker, amiloride, completely abolished the natriuretic and kaluretic actions of the compound. Administration of the xanthurenic acid derivative caused a dose-related increase in urinary nitrite/nitrate excretion. Moreover, under chronic nitric oxide blockade by l-NG-Nitro-Arginine-Methyl-Esther (l-NAME) sodium excretion was similar in rats treated or untreated with the compound. Our data demonstrate that xanthurenic acid 8-o-β-d-glucoside has significant diuretic/natriuretic and kaluretic properties. An intact amiloride-sensitive sodium channel is required for the renal effects of the compound. The data further suggest that the natriuretic effect is mediated in part by a nitric oxide-dependent mechanism.
Highlights
IntroductionThe notion that endogenous agents acting to promote sodium excretion by the kidney is released in response to salt loading and extracellular fluid volume expansion, was originally proposed in the early 1960s by De Wardener et al (1961).Since numerous in vivo and in vitro studies provided additional evidence to the existence of such “natriuretic hormones” (for reviews see Bricker et al 1975; de Wardener and Clarkson 1985; Buckalew and Paschal-McCormick 1989)
The notion that endogenous agents acting to promote sodium excretion by the kidney is released in response to salt loading and extracellular fluid volume expansion, was originally proposed in the early 1960s by De Wardener et al (1961).Since numerous in vivo and in vitro studies provided additional evidence to the existence of such “natriuretic hormones”
Xanthurenic acid is a metabolic product of the essential amino acid tryptophan, via the kynurenine pathway (Schwarcz and Pellicciari 2002; Stone and Darlington 2002)
Summary
The notion that endogenous agents acting to promote sodium excretion by the kidney is released in response to salt loading and extracellular fluid volume expansion, was originally proposed in the early 1960s by De Wardener et al (1961).Since numerous in vivo and in vitro studies provided additional evidence to the existence of such “natriuretic hormones” (for reviews see Bricker et al 1975; de Wardener and Clarkson 1985; Buckalew and Paschal-McCormick 1989). Several studies reported the natriuretic activity of low-molecular-weight (
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