ABSTRACT
Analogues of L-arginine that are chemically modified at the terminal guanidino nitrogen
group, such as Nω-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 end-stage 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.
KEYWORD
Asymmetric dimethylarginine - atherosclerosis - nitric oxide synthase - cardiovascular
risk factors - end-stage renal disease
