title: Evaluation of endogenous nitric oxide synthesis in congenital urea cycle enzyme defects.
abstract: Nitric oxide (NO) is synthesized from arginine and O(2) by nitric oxide synthase (NOS). Citrulline, which is formed as a by-product of the NOS reaction, can be recycled to arginine by the 2 enzymes acting in the urea cycle: argininosuccinate synthetase (ASS) and argininosuccinate lyase (ASL). Although the complete urea cycle is expressed only in the liver, ASS and ASL are expressed in other organs including the kidney and vascular endothelium. To examine possible alterations of the NO pathway in urea cycle defects, we measured plasma concentrations of arginine and citrulline and serum concentrations of nitrite/nitrate (NOx(-), stable NO metabolites) and asymmetric dimethylarginine (ADMA, an endogenous NOS inhibitor) in patients with congenital urea cycle disorders of 3 types: ornithine transcarbamylase (OTC) deficiency, ASS deficiency, and ASL deficiency. All were receiving oral arginine replacement at the time of this study. The same parameters were also measured in healthy subjects, who participated as controls. The OTC-deficient patients had significantly high NOx(-) and nonsignificantly high ADMA concentrations. Their NOx(-) was significantly positively correlated with arginine. The ASS-deficient patients had significantly low NOx(-) and significantly high ADMA concentrations. The ASL-deficient patients had normal NOx(-) and nonsignificantly high ADMA concentrations. In ASS-deficient and ASL-deficient patients, the NOx(-) was significantly inversely correlated with citrulline. These results suggest that NO synthesis is enhanced in OTC-deficient patients while receiving arginine but that NO synthesis remains low in ASS-deficient patients despite receiving arginine. They also suggest that endogenous NO synthesis is negatively affected by citrulline and ADMA in ASS-deficient and ASL-deficient patients. Although the molecular mechanisms remain poorly understood, we infer that the NO pathway might play a role in the pathophysiology related to congenital urea cycle disorders.
authors.affiliation: Division of Metabolism, Chiba Children's Hospital, Chiba 266-0007, Japan. nagasa-hirono@k2.dion.ne.jp
authors.forename: Hironori
authors.initials: H
authors.lastname: Nagasaka
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Tsukahara
authors.forename: Tohru
authors.initials: T
authors.lastname: Yorifuji
authors.forename: Takashi
authors.initials: T
authors.lastname: Miida
authors.forename: Kei
authors.initials: K
authors.lastname: Murayama
authors.forename: Tomoko
authors.initials: T
authors.lastname: Tsuruoka
authors.forename: Tomozumi
authors.initials: T
authors.lastname: Takatani
authors.forename: Masaki
authors.initials: M
authors.lastname: Kanazawa
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Okano
authors.forename: Masaki
authors.initials: M
authors.lastname: Takayanagi
mesh_terms: D001120:Arginine / Q000097:blood; D001123:Argininosuccinate Lyase / Q000378:metabolism*; D001124:Argininosuccinate Synthase / Q000378:metabolism*; D002675:Child, Preschool; D002956:Citrulline / Q000097:blood; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D009954:Ornithine Carbamoyltransferase / Q000378:metabolism; D020163:Ornithine Carbamoyltransferase Deficiency Disease / Q000097:blood*; D014508:Urea / Q000378:metabolism*
chemical_list: D002956:Citrulline; D009569:Nitric Oxide; D014508:Urea; D001120:Arginine; D019001:Nitric Oxide Synthase; D009954:Ornithine Carbamoyltransferase; D001123:Argininosuccinate Lyase; D001124:Argininosuccinate Synthase