Regulation of urea synthesis by agmatine in the perfused liver: studies

Nissim, Itzhak, Oksana Horyn, Yevgeny Daikhin, Ilana Nissim, Adam Lazarow, and Marc Yudkoff. Regulation of urea synthesis by agmatine in the perfused liver: studies with 15N. Am J Physiol Endocrinol Metab 283: E1123–E1134, 2002. First published August 13, 2002; 10.1152/ajpendo.00246.2002.—Administration of arginine or a high-protein diet increases the hepatic content of N-acetylglutamate (NAG) and the synthesis of urea. However, the underlying mechanism is unknown. We have explored the hypothesis that agmatine, a metabolite of arginine, may stimulate NAG synthesis and, thereby, urea synthesis. We tested this hypothesis in a liver perfusion system to determine 1) the metabolism of L-[guanidino-N2]arginine to either agmatine, nitric oxide (NO), and/or urea; 2) hepatic uptake of perfusate agmatine and its action on hepatic N metabolism; and 3) the role of arginine, agmatine, or NO in regulating NAG synthesis and ureagenesis in livers perfused with 15N-labeled glutamine and unlabeled ammonia or NH4Cl and unlabeled glutamine. Our principal findings are 1) [guanidino-N2]agmatine is formed in the liver from perfusate L-[guanidino-N2]arginine ( 90% of hepatic agmatine is derived from perfusate arginine); 2) perfusions with agmatine significantly stimulated the synthesis of 15N-labeled NAG and [15N]urea from 15N-labeled ammonia or glutamine; and 3) the increased levels of hepatic agmatine are strongly correlated with increased levels and synthesis of 15N-labeled NAG and [15N]urea. These data suggest a possible therapeutic strategy encompassing the use of agmatine for the treatment of disturbed ureagenesis, whether secondary to inborn errors of metabolism or to liver disease.