Arginine disposal in health and endotoxemia

Abstract

Previous research in Arginase II ko (ArgII) mice have shown that these animals have higher arginine (Arg) fluxes than their WT control littermates. This led us to hypothesize that a substantial catabolism of arginine occurs before the arginine released during protein turnover enters the general circulation. To test this hypothesis, the fluxes of arginine (after correcting for the contribution of ‘de novo' arginine synthesis) and phenylalanine were determined in ArgII and WT mice after saline (control) or i.v. LPS challenge utilizing stable isotopes. Arginine flux was greater in ArgII mice (P < 0.01) than in WT animals and LPS reduced (P < 0.01) the flux of Arg and Phe in both genotypes. The Arg/Phe flux ratio was greater (P 0.001) in ArgII (1.16±0.15) than in WT mice (0.93±0.07), demonstrating that ~20% of the Arg released during protein turnover disappeared under basal (saline) conditions due to hydrolysis by arginase II. After LPS challenge, these ratios decreased to 0.96±0.06 (ArgII) and 0.74±0.06 (WT), indicating that during endotoxemia there is an additional ~20% increase in the catabolism of Arg before it enters the circulating pool. Although the precise mechanism still remains to be elucidated, arginase I is likely responsible for these observations during LPS challenge due to the magnitude of arginine disappearance. These novel observations explain the arginine depletion that occurs during sepsis and offer new targets to increase arginine availability.