HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 295/6/E1315    most recent 00055.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Luiking, Y. C. Articles by Deutz, N. E. P. Search for Related Content PubMed PubMed Citation Articles by Luiking, Y. C. Articles by Deutz, N. E. P.

Reduced citrulline availability by OTC deficiency in mice is related to reduced nitric oxide production

¹Center for Translational Research in Aging and Longevity, Donald W. Reynolds Institute on Aging, University of Arkansas for Medical Sciences, Little Rock, Arkansas; ²Maastricht University, Departments of Surgery and ³Anatomy and Embryology, Nutrition and Toxicology Research Institute Maastricht, Maastricht; and ⁴AMC Liver Centre, Academic Medical Centre, Amsterdam, The Netherlands

Submitted 26 January 2008 ; accepted in final form 8 August 2008

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-¹⁵N₂]arginine to L-[guanidine-¹⁵N]citrulline; de novo arginine production was measured as conversion of L-[ureido-¹³C-5,5-²H₂]citrulline to L-[guanidino-¹³C-5,5-²H₂]arginine. Protein metabolism was measured using L-[ring-²H₅]phenylalanine and L-[ring-²H₂]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.

ornithine transcarbamoylase; sepsis; metabolism; protein breakdown