title: Plasma concentrations of arginine and asymmetric dimethylarginine do not reflect their intracellular concentrations in peripheral blood mononuclear cells.
abstract: OBJECTIVE
  Production of nitric oxide (NO) from arginine is inhibited by endogenously produced monomethylarginine (MMA) and asymmetric dimethylarginine (ADMA). Elevated levels of ADMA, by limiting NO production, may lead to endothelial dysfunction and cardiovascular disease. Symmetric dimethylarginine (SDMA) and the arginine homolog homoarginine have also been associated with cardiovascular disease. Although NO synthesis, as well as generation of MMA, ADMA, SDMA and homoarginine, occurs intracellularly, these biomarkers are usually measured in plasma. Despite extensive transmembrane transport, it is not clear whether plasma levels of these biomarkers are a valid proxy for their intracellular levels in the cardiovascular system. Since it is difficult to obtain vascular tissue from healthy humans, we explored the relations between concentrations of these biomarkers in plasma and intracellular concentrations in peripheral blood mononuclear cells (PBMC).
  
  
  METHODS
  In PBMC and plasma of 27 healthy subjects, concentrations of arginine, MMA, ADMA, SDMA, and homoarginine were determined using stable isotope dilution liquid chromatography tandem mass spectrometry.
  
  
  RESULTS
  In PBMC, significant positive correlations were observed among arginine and its methylated forms (ρ = 0.43 to 0.81) and these correlations were slightly less pronounced in plasma. Homoarginine was not significantly correlated with (methylated) arginine in either PBMC or plasma. Plasma concentrations of arginine and its methylated forms showed non-significant inverse associations with their respective intracellular concentrations in PBMC and only for homoarginine was a weak positive association observed (ρ = 0.37).
  
  
  CONCLUSIONS
  In healthy individuals, plasma levels of arginine, MMA, ADMA, and SDMA poorly reflect their intracellular levels in PBMC.
authors.affiliation: Metabolic Laboratory, Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands; Institute for Cardiovascular Research (ICaR-VU), VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Mariska
authors.initials: M
authors.lastname: Davids
authors.forename: Tom
authors.initials: T
authors.lastname: Teerlink
mesh_terms: D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood* / Q000378:metabolism; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D006709:Homoarginine / Q000097:blood / Q000378:metabolism; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism
chemical_list: D015415:Biomarkers; D006709:Homoarginine; D009569:Nitric Oxide; C024917:symmetric dimethylarginine; C018524:N,N-dimethylarginine; D001120:Arginine
keywords: ADMA; CAT; Cardiovascular disease; DDAH; Homoarginine; MMA; NO; NOS; Nitric oxide; PBMC; PRMT; SDMA; asymmetric dimethylarginine; cationic amino acid transporter; dimethylarginine dimethylaminohydrolase; monomethylarginine; nitric oxide; nitric oxide synthase; peripheral blood mononuclear cells; protein arginine methyltransferase; symmetric dimethylarginine