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Reduced citrulline availability by OTC deficiency in mice is related to reduced nitric oxide production
Authors:Luiking Yvette C  Hallemeesch Marcella M  van de Poll Marcel C  Dejong Cornelis H C  de Jonge Wouter J  Lamers Wouter H  Deutz Nicolaas E P
Institution:Univ. of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Abstract: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 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-to-tracee ratios were measured by LC-MS. NO production was measured as the in vivo conversion of l-guanidino-(15)N(2)]arginine to l-guanidine-(15)N]citrulline; de novo arginine production was measured as conversion of l-ureido-(13)C-5,5-(2)H(2)]citrulline to l-guanidino-(13)C-5,5-(2)H(2)]arginine. Protein metabolism was measured using l-ring-(2)H(5)]phenylalanine and l-ring-(2)H(2)]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 of 2-4 (P < 0.001). NO production was twofold 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 ip), 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 cNOS-mediated NO production. When sufficient arginine is available after LPS stimulated net protein breakdown, NO production is unaffected by OTC deficiency.
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