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showed that when these two variables were controlled, the kidney was still able to increase sodium excretion in response to a salt load. Several lines of evidence argued for a small-molecule signal as a definitive modulator of sodium excretion by the kidney. However, the chemical nature of the suspected natriuretic agent remained unknown. Here we report the identification and natriuretic activity of two closely related small molecules isolated from human urine, xanthurenic acid 8-O-␤-D-glucoside and xanthurenic acid 8-O-sulfate. The two compounds were partially purified by activity-guided fractionation and subsequently identified by using NMR spectroscopic analyses of enriched active fractions. Both compounds caused substantial and sustained (1-to 2-h) natriuresis in rats and no or minimal concomitant potassium excretion. We believe these compounds constitute a class of kidney hormones that also could influence sodium transport in nonkidney tissues given that these tryptophan metabolites presumably represent evolutionarily old structures.diuresis ͉ kidney ͉ nonpeptidic ͉ sodium homeostasis ͉ NMR spectroscopy

Summary. Glucose titration studies were performed in rats with unilateral chronic pyelonephritis before and after removal of the contralateral control kidneys. Identical studies were performed in animals with unilateral partial renal infarction in which the experimental kidneys had a marked reduction in nephron population but no anatomic deformation in the surviving nephrons. In the initial studies, both groups of animals were free of clinical and chemical abnormalities of uremia. In the follow-up studies uremic abnormalities were present. Minimal splay was observed in the titration curves in the initial studies; marked splay was present in the group data from the same kidneys in the subsequent studies. Thus a marked reduction in the nephron population was associated with the evolution of splay in both groups of animals. In association with the increase in splay, the mean values for maximal glucose transport increased; thus a defect in glucose transport can be excluded as the basis of the splay. Glomerular filtration rate increased proportionately more than the maximal transport of glucose; hence the ratios of glomerular filtration rate to maximal glucose transport increased consistently. The possibility of asymmetric hypertrophy of glomerular and tubular functions among the nephron population imposed by scar tissue or other anatomic deformities was considered, but the results in the animals with partially infarcted kidneys militate against this explanation. The splay also could reflect an asymmetric alteration in the distribution of glomerulotubular balance among the residual units initiated by functional adaptations. Finally, the splay could relate to an alteration in the kinetics of glucose transport without any change in the level of functional homogeneity. The possible nature of these has been considered in the text.

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At least three independent groups of natriuretic hormones have been isolated over the past ten years. Two, atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP), are proteins and the third is made up of digitalis-like substances (DLS). The present report concerns the isolation, substantial purification and biologic actions of an entirely different natriuretic hormone (NH) which appears to be steroidal in nature and an isomer of cortisone. The source of NH was uremic urine. Purification involved successive chromatographic steps including gel filtration and multiple HPLC runs through C-18 resins. A translucent crystal ultimately was obtained. The product was examined using mass spectroscopy with trimethylsilyl derivatization. Only one compound was identifiable. The characteristics of the molecule include: a molecular weight, 360.4; a molecular formula, C21H28O5; a steroidal nucleus; UV absorption at 220 and 290 nm; and intrinsic fluorescence. The onset of action occurs within minutes both in the rat and, as previously shown, in several in vitro systems including the frog skin, toad bladder, fibroblasts and renal tubular epithelial cells grown in culture and isolated perfused cortical collecting tubules. In contrast to DLS, NH has been previously shown not to cross react with digoxin antibodies. Moreover, when given to intact rats, it produces a profound natriuresis but little or no kaliuresis. In contrast to ANF and BNP the compound is active orally as well as intravenously. It is clearly different from cortisone, based both on its biologic and mass spectroscopic characteristics.