Asymmetric dimethylarginine, derangements of the endothelial nitric oxide synthase pathway, and cardiovascular diseases

Semin Thromb Hemost. 2000;26(5):539-45. doi: 10.1055/s-2000-13210.


Analogues of L-arginine that are chemically modified at the terminal guanidino nitrogen group, such as Nomega-monomethy-L-arginine (L-NMMA), have been used for nitric oxide synthase inhibition. However, L-NMMA and other methylated L-arginine analogues are also endogenously formed. Among these, asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) have been shown to be the most abundant. Like L-NMMA, ADMA is an inhibitor of NO synthase, whereas SDMA is inactive. ADMA is synthesized by N-methyltransferases, a family of enzymes that methylate L-arginine residues within specific proteins. Free ADMA is released during proteolytic cleavage of methylated proteins; it can be detected in plasma and urine, but its intracellular concentrations appear to be much higher. ADMA is metabolized by the enzyme dimethylarginine dimethylaminohydrolase (DDAH), and inhibition of DDAH activity has been shown to lead to increased ADMA levels and endothelial dysfunction. Plasma levels of ADMA are elevated in endstage renal failure, in atherosclerosis and hypercholesterolemia, in hypertension, and in heart failure. Although the molecular cause for elevation of ADMA concentration in these diseases has not been fully elucidated, evidence is accumulating that ADMA is one cause of endothelial dysfunction in these diseases. Moreover, it may be a marker or even a risk factor for cardiovascular disease. Therefore, pharmacological modulation of ADMA concentration may be a novel therapeutic target in cardiovascular diseases.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Arginine / adverse effects
  • Arginine / analogs & derivatives*
  • Arginine / blood*
  • Arteriosclerosis / blood
  • Arteriosclerosis / etiology
  • Cardiovascular Diseases / blood*
  • Cardiovascular Diseases / etiology
  • Endothelium, Vascular / pathology*
  • Humans
  • Nitric Oxide Synthase / antagonists & inhibitors*


  • symmetric dimethylarginine
  • Arginine
  • Nitric Oxide Synthase