Gut and liver handling of asymmetric and symmetric dimethylarginine in the rat under basal conditions and during endotoxemia.
OBJECTIVE
Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide (NO) synthase enzymes, whereas symmetric dimethylarginine (SDMA) competes with arginine transport. Although both dimethylarginines may be important regulators of the arginine-NO pathway, their metabolism is largely unknown. In previous studies, evidence was found for the liver in the metabolism of dimethylarginines. We aimed to investigate dimethylarginine handling of the gut and the liver in detail under basal conditions and during endotoxemia.


METHODS
Twenty-one male Wistar rats were used for this study. Endotoxemia was induced by lipopolysaccharide (LPS) infusion (8 mg/kg). Blood flow was measured using radiolabeled microspheres according to the reference sample method. Concentration of dimethylarginines were measured by high-performance liquid chromatography. The combination of arteriovenous concentration difference and organ blood flow allowed calculation of net organ fluxes and fractional extraction (FE) rates.


RESULTS
Arterial plasma concentration of ADMA was lower in LPS rats, in contrast to a higher SDMA concentration. For the gut, net release of ADMA was found, which was higher in LPS rats. In contrast, for the gut, net uptake of SDMA was found, which was lower in LPS rats. For the liver, a high net uptake of ADMA was found in both groups, while FE was significantly increased in LPS rats. Hepatic handling of SDMA was negligible.


CONCLUSIONS
The liver plays an important role in eliminating ADMA from the circulation and endotoxemia stimulates this capacity. In contrast to the liver, the gut releases ADMA. Endotoxemia results in a reduced systemic ADMA concentration.
Department of Surgery, VU University Medical Center, 1007 MB Amsterdam, the Netherlands.
Robert J
RJ
Nijveldt
Michiel P C
MP
Siroen
Tom
T
Teerlink
Antonie A
AA
van Lambalgen
Jan A
JA
Rauwerda
Paul A M
PA
van Leeuwen
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood*; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000097:blood* / Q000139:chemically induced; D041981:Gastrointestinal Tract / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012039:Regional Blood Flow; D013152:Splanchnic Circulation; D014781:Viscera / Q000187:drug effects / Q000378:metabolism*
D008070:Lipopolysaccharides; C487735:dimethylarginine; D001120:Arginine