ISOTOPIC STUDIES OF UREA METABOLISM IN RABBITS.

1. The half-life of [(15)N]urea was found to be significantly longer than that of [(14)C]urea injected at the same time, the differences being due to endogenous catabolism of urea, which is accompanied by little or no reutilization of (14)C but is approx. 20% for (15)N. [(15)N]Urea therefore appears to be valueless as an indicator of nitrogen metabolism unless the extents of endogenous catabolism of urea and of fractional reutilization of (15)N can be separately estimated. 2. Though measurements of the radioactivity of expired (14)CO(2) confirmed the existence of considerable urea catabolism these could not be used for quantitative assessments. 3. Alternative graphical methods based on [(14)C]urea specific activities in plasma and urine samples were used to calculate the fraction of urea production that is excreted. Values by the two methods were in good agreement and showed that some animals excrete less than half the urea that they produce. 4. Specific activity differences between simultaneous samples of urinary and plasma urea reflect the presence of a pool of urea in the kidney that is not in equilibrium with the body urea pool. Calculations indicate the presence of urea in the kidney that in some cases may represent as much as 15% of the body pool, and in two animals in which post-mortem renal analyses were performed the masses of urea found agreed closely with the calculated values. 5. A model for urea metabolism is proposed that includes this pool in the excretory pathway. The related theory is shown to be adequate to explain the shape of the specific activity curves of urinary urea from the time of injection and the constant delay of the specific activity of urinary urea, relative to that of plasma urea, that is observed after a short preliminary equilibration period. 6. The body urea pool was calculated from the activity retained at 1.5hr. by excluding renal activity and the corrected specific activity of plasma urea at the same time. The urea pool was calculated to be distributed at the plasma concentration in a substantially smaller water volume than that found by injecting tritiated water in five animals. Reasons for this are discussed. 7. Urea synthesis rates calculated from the pool values are in close agreement with rates calculated from the mass of urea recovered in the urine and the fraction of newly synthesized urea that is excreted.