Regulation of urea synthesis by agmatine in the perfused liver: studies with 15N

Administration of arginine or a high-protein diet increases the hepatic content ofN-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 ofl-[guanidino-15N2]arginine to either agmatine, nitric oxide (NO), and/or urea; 2) hepatic uptake of perfusate agmatine and its action on hepatic N metabolism; and3) the role of arginine, agmatine, or NO in regulating NAG synthesis and ureagenesis in livers perfused with15N-labeled glutamine and unlabeled ammonia or15NH4Cl and unlabeled glutamine. Our principal findings are 1) [guanidino-15N2]agmatine is formed in the liver from perfusatel-[guanidino-15N2]arginine (∼90% of hepatic agmatine is derived from perfusate arginine);2) perfusions with agmatine significantly stimulated the synthesis of 15N-labeled NAG and [15...