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 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-15N2]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 15NH4Cl and unlabeled glutamine. Our principal findings are 1) [guanidino-15N2]agmatine is formed in the liver from perfusate l-[guanidino-15N2]arginine ( approximately 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.
Nissim
Itzhak
I
Children's Hospital of Philadelphia and Division of Child Development and Rehabilitation, Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Horyn
Oksana
O
Daikhin
Yevgeny
Y
Nissim
Ilana
I
Lazarow
Adam
A
Yudkoff
Marc
M
D000376:Agmatine / Q000378:metabolism* / Q000493:pharmacokinetics; D000643:Ammonium Chloride / Q000378:metabolism; D000818:Animals; D001120:Arginine / Q000378:metabolism* / Q000494:pharmacology; D003600:Cytosol / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005971:Glutamates / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism; D066298:In Vitro Techniques; D008099:Liver / Q000737:chemistry / Q000378:metabolism*; D008297:Male; D008930:Mitochondria, Liver / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009587:Nitrogen Isotopes / Q000378:metabolism; D010101:Oxygen Consumption; D010477:Perfusion / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D014508:Urea / Q000378:metabolism*
D005971:Glutamates; D020030:Nitric Oxide Donors; D009587:Nitrogen Isotopes; D000643:Ammonium Chloride; D005973:Glutamine; D009569:Nitric Oxide; D000376:Agmatine; D014508:Urea; D001120:Arginine; C016195:N-acetylglutamic acid