Inhibition of Toad Bladder Sodium Transport and Na++K+Stimulated Adenosinetriphosphatase by Extracts of Human Urine: Studies of Patients with Virilizing Adrenal Hyperplasia1

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Abstract
In order to detect the presence of a possible sodium transport inhibitor, urine extracts were tested directly in 2 in vitro systems: (A) sodium transport across the urinary bladder of the toad and (B) Na++K+ stimulated adenosine triphosphatase (Na-K-ATPase). The sodium transport across the toad bladder, which remained 60 min after urine extract was added, was compared to the sodium transport before the addition and expressed as a ratio, R60. The R60 in children with virilizing adrenal hyperplasia (VAH) (R60=.33±.05) and in normal adults (R60=.39±.08) was significantly lower than normal prepubertal children (R60=.79±.03), indicating more inhibitory activity in the former 2 groups. The effect of urine extracts on Na-K-ATPase was similar to the effect on the bladder (children with VAH-46.9±7.0% of control ethanol additions, normal adults 46.8±7.7% of control, and normal children 75.6±2.6% of control). Among the children with VAH, there was no difference in the inhibitory activity of urine extracts for either test system when patients losing sodium were compared with those not losing sodium. Nor was there a difference when those receiving suppressive therapy were compared with the patients without treatment. Paper chromatography showed the inhibitory material from children with VAH to be less polar than cortisone and that from normal adults to be less polar than 11-dehydrocorticosterone. There was no inhibitory activity in any fraction of the urine extracts from normal children. Controls were used to exclude the possibility that the effect observed was an artifact of the extraction procedures. Many C19 and C21 steroids (3×10−5 to 3×1O−4m) failed to inhibit Na-K-ATPase or sodium transport across the toad bladder under the condition of the experiments. Oxygen consumption by the toad bladder was inhibited as rapidly and to the same degree as was sodium transport across this membrane. This suggested a nonspecific toxic effect. The inhibitory material was quite labile after extraction and concentration. It is not known whether the sodium transport inhibitor, yet unidentified, contributes etiologically to excessive sodium loss in patients with VAH or to other disturbances in this condition. The effects of the inhibitory material on sodium transport across the toad bladder and on Na-K-ATPase did not resemble effects of known adrenal steroid competitors of aldosterone. Because of the apparent toxic effect of the urine extracts on both assay systems, the doubtful application of findings in the toad bladder to the mammalian kidney, and the lack of correlation between the sodium losing state and the presence of inhibitory material in urine, the inhibitor cannot be assigned any specific role in human physiology or in the pathophysiology of VAH at this time.

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