title: Blood content of asymmetric dimethylarginine: new insights into its dysregulation in renal disease.
abstract: BACKGROUND
  Plasma asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, is significantly elevated in patients with kidney disease and is a potential risk factor for cardiovascular disease. Here, we tested whether human whole blood (WB), as in rodent blood, can accumulate free ADMA and whether this accumulation is a function of disease burden.
  
  
  METHODS
  In 16 healthy control subjects (CO), 18 patients with ESRD and 18 matched hypertensive patients with normal renal function (HTN), we compared using high-pressure liquid chromatography baseline plasma and WB supernatant (WBSUP) ADMA and symmetrical dimethylarginine (SDMA) concentrations and accumulation during a 5-h incubation. We measured protein turnover in incubated WBSUP to determine if proteolytic processes drive ADMA accumulation.
  
  
  RESULTS
  Elevated plasma ADMA was confirmed in ESRD and HTN populations while basal WBSUP ADMA was significantly higher in ESRD subjects than controls (P = 0.05 versus CO; P = 0.02 versus HTN). Plasma SDMA followed a similar pattern. Incubation of WBSUP resulted in ADMA release from protein-incorporated stores while SDMA was unaffected. ADMA accumulation in ESRD samples was significantly greater than that in HTN (P = 0.03). CO and HTN men showed significantly greater ADMA accumulation than women (P = 0.01 and P = 0.003, respectively) but no gender difference was observed in the ESRD group (P = 0.26). ADMA accumulation correlated with ex vivo protein turnover (R = 0.76, P < 0.0001).
  
  
  CONCLUSIONS
  Human blood is capable of releasing physiologically significant quantities of ADMA via proteolytic pathways. Dysregulated ADMA release from WB reservoirs may contribute to the distinctly high plasma ADMA levels in ESRD populations.
authors.affiliation: University of Michigan Medical School, Simpson Memorial Institute, Rm 310, 102 Observatory Road, Ann Arbor, MI 48109-5725, USA.
authors.forename: Scott S
authors.initials: SS
authors.lastname: Billecke
authors.forename: Louis G
authors.initials: LG
authors.lastname: D'Alecy
authors.forename: Raylene
authors.initials: R
authors.lastname: Platel
authors.forename: Steven E
authors.initials: SE
authors.lastname: Whitesall
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jamerson
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Perlman
authors.forename: Crystal A
authors.initials: CA
authors.lastname: Gadegbeku
mesh_terms: D000328:Adult; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D004912:Erythrocytes / Q000378:metabolism; D005260:Female; D006801:Humans; D006973:Hypertension / Q000097:blood; D007676:Kidney Failure, Chronic / Q000097:blood*; D008297:Male; D008875:Middle Aged; D010447:Peptide Hydrolases / Q000097:blood; D010949:Plasma / Q000378:metabolism
chemical_list: D015415:Biomarkers; C024917:symmetric dimethylarginine; C018524:N,N-dimethylarginine; D001120:Arginine; D010447:Peptide Hydrolases
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