title: Circulating levels of advanced glycation end products (AGE) and interleukin-6 (IL-6) are independent determinants of serum asymmetric dimethylarginine (ADMA) levels in patients with septic shock.
abstract: There is a growing body of evidence that nitric oxide (NO) excess plays a central role in the pathogenesis of hypotension and organ failure in patients with septic shock. In addition, recently, asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase, has been shown to contribute to the regulation of vascular tone via modulation of NO generation in vivo. However, the kinetics and regulation of serum levels of ADMA in patients with septic shock are largely unknown. Since high mobility group box 1 (HMGB1)-receptor for advanced end products (RAGE) axis is supposed to be involved in the lethality in septic shock, we examined the correlations among serum levels of ADMA, endotoxin, interleukin-6 (IL-6), soluble form of RAGE (sRAGE) and RAGE ligands such as HMGB1 and advanced glycation end products (AGE) in septic shock patients. Fifteen septic shock patients (10 males and 15 females, mean age: 70.1+/-8.5 years) and fifteen age- and sex-matched healthy volunteers were included in this study. The criteria of the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference were used for diagnosis of septic shock. All the subjects underwent a complete history and physical examination, determination of blood chemistries, including serum levels of ADMA, endotoxin, IL-6, HMGB1, AGE and sRAGE. Linear and multiple stepwise regression analysis were performed for the determinants of serum levels of ADMA. Serum levels of ADMA were significantly higher than those in healthy volunteers (0.98+/-0.21nmol/mL vs. 0.30+/-0.05nmol/mL, p<0.0001). In univariate analysis, creatinine (p<0.005), endotoxin (p<0.001), IL-6 (p<0.001), HMGB1 (p<0.001), AGE (p<0.001) and sRAGE (p<0.001) were significantly associated with serum ADMA levels. After performing multivariate stepwise regression analyses, IL-6 (p=0.001), AGE (p=0.002) and creatinine (p=0.013) still remained significant independently. The present study is the first demonstration that ADMA levels were significantly elevated in patients with septic shock and that serum IL-6, AGE and creatinine levels were independent determinants of ADMA in these patients. Given the harmful effects of NO excess in septic shock, ADMA levels may be increased as a counter-system against inflammation and oxidative stress in this life-threatening disorder.
authors.affiliation: Department of Internal Medicine, Shinmatsudo Central General Hospital, Chiba, Japan.
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Nakamura
authors.forename: Eiichi
authors.initials: E
authors.lastname: Sato
authors.forename: Nobuharu
authors.initials: N
authors.lastname: Fujiwara
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kawagoe
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Suzuki
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Ueda
authors.forename: Shingo
authors.initials: S
authors.lastname: Yamada
authors.forename: Hisataka
authors.initials: H
authors.lastname: Shoji
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Takeuchi
authors.forename: Seiji
authors.initials: S
authors.lastname: Ueda
authors.forename: Takanori
authors.initials: T
authors.lastname: Matsui
authors.forename: Hisashi
authors.initials: H
authors.lastname: Adachi
authors.forename: Seiya
authors.initials: S
authors.lastname: Okuda
authors.forename: Sho-ichi
authors.initials: S
authors.lastname: Yamagishi
mesh_terms: D000368:Aged; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood; D015415:Biomarkers / Q000097:blood; D005260:Female; D017127:Glycation End Products, Advanced / Q000097:blood*; D006801:Humans; D015850:Interleukin-6 / Q000097:blood*; D008297:Male; D008875:Middle Aged; D012772:Shock, Septic / Q000097:blood* / Q000175:diagnosis
chemical_list: D015415:Biomarkers; D017127:Glycation End Products, Advanced; D015850:Interleukin-6; C018524:N,N-dimethylarginine; D001120:Arginine