TY - JOUR
T1 - Reduced citrulline availability by OTC deficiency in mice is related to reduced nitric oxide production.
AU - Luiking, Y.C.
AU - Hallemeesch, M.M.
AU - van de Poll, M.C.
AU - Dejong, C.H.
AU - de Jonge, W.J.
AU - Lamers, W.H.
AU - Deutz, N.E.
PY - 2008/1/1
Y1 - 2008/1/1
N2 - The amino acid arginine is the sole precursor for nitric oxide (NO) synthesis. We recently demonstrated that an acute reduction of circulating arginine does not compromise basal or lipopolysaccharide (LPS)-inducible NO production in mice. In the present study, we investigated the importance of citrulline availability in ornithine transcarbamoylase-deficient spf(ash) (OTCD) mice on NO production, using stable isotope techniques and C57BL6/J (wild-type) mice controls. Plasma amino acids and tracer-tracee ratios were measured by LC-MS. NO production was measured as the in vivo conversion of L-[guanidino -(15)N2]arginine to L-[guanidine-(15)N]citrulline; de novo arginine production as conversion of L-[ureido-(13)C-5,5-(2)H2]citrulline to L-[guanidino -(13)C-5,5-(2)H2]arginine. Protein metabolism was measured using L-[ring-(2)H5]phenylalanine and L-[ring-(2)H2]tyrosine. OTC deficiency caused a reduction of systemic citrulline concentration and production to 30-50% (P<0.001), reduced de novo arginine production (P<0.05), reduced whole-body NO production to 50% (P<0.005) and increased net protein breakdown by a factor 2-4 (P<0.001). NO production was 2-fold higher in female than in male OTCD mice, in agreement with the X-linked location of the OTC gene. In response to LPS treatment (10 mg/kg i.p.), circulating arginine increased in all groups (P<0.001), and NO production was no longer affected by the OTC deficiency due to increased net protein breakdown as a source for arginine. Our study shows that reduced citrulline availability is related to reduced basal NO production via reduced de novo arginine production. Under basal conditions this is probably c-NOS mediated NO production. When sufficient arginine is available after LPS stimulated net protein breakdown, NO production is unaffected by OTC deficiency. Key words: arginine, OTC, sepsis. LA - ENG PT - JOURNAL ARTICLE DEP - 20080812 TA - Am J Physiol Endocrinol Metab JT - American journal of physiology. Endocrinology and metabolism JID - 100901226
AB - The amino acid arginine is the sole precursor for nitric oxide (NO) synthesis. We recently demonstrated that an acute reduction of circulating arginine does not compromise basal or lipopolysaccharide (LPS)-inducible NO production in mice. In the present study, we investigated the importance of citrulline availability in ornithine transcarbamoylase-deficient spf(ash) (OTCD) mice on NO production, using stable isotope techniques and C57BL6/J (wild-type) mice controls. Plasma amino acids and tracer-tracee ratios were measured by LC-MS. NO production was measured as the in vivo conversion of L-[guanidino -(15)N2]arginine to L-[guanidine-(15)N]citrulline; de novo arginine production as conversion of L-[ureido-(13)C-5,5-(2)H2]citrulline to L-[guanidino -(13)C-5,5-(2)H2]arginine. Protein metabolism was measured using L-[ring-(2)H5]phenylalanine and L-[ring-(2)H2]tyrosine. OTC deficiency caused a reduction of systemic citrulline concentration and production to 30-50% (P<0.001), reduced de novo arginine production (P<0.05), reduced whole-body NO production to 50% (P<0.005) and increased net protein breakdown by a factor 2-4 (P<0.001). NO production was 2-fold higher in female than in male OTCD mice, in agreement with the X-linked location of the OTC gene. In response to LPS treatment (10 mg/kg i.p.), circulating arginine increased in all groups (P<0.001), and NO production was no longer affected by the OTC deficiency due to increased net protein breakdown as a source for arginine. Our study shows that reduced citrulline availability is related to reduced basal NO production via reduced de novo arginine production. Under basal conditions this is probably c-NOS mediated NO production. When sufficient arginine is available after LPS stimulated net protein breakdown, NO production is unaffected by OTC deficiency. Key words: arginine, OTC, sepsis. LA - ENG PT - JOURNAL ARTICLE DEP - 20080812 TA - Am J Physiol Endocrinol Metab JT - American journal of physiology. Endocrinology and metabolism JID - 100901226
U2 - 10.1152/ajpendo.00055.2008
DO - 10.1152/ajpendo.00055.2008
M3 - Article
C2 - 18697914
SN - 0193-1849
VL - 295
SP - E1315-1322
JO - American Journal of Physiology : Endocrinology and Metabolism
JF - American Journal of Physiology : Endocrinology and Metabolism
IS - 6
ER -