The therapeutic potential of targeting endogenous inhibitors of nitric oxide synthesis

Asymmetric dimethylarginine (ADMA) — a naturally occurring amino acid that is a product of protein breakdown — is released into the cytoplasm following the post-translational methylation of arginine residues within proteins and the subsequent proteolysis of these arginine-methylated proteins. ADMA inhibits all three isoforms of nitric oxide synthase and therefore has the potential to produce diverse biological effects, particularly in the cardiovascular system. In addition to its renal clearance, endogenously produced ADMA is metabolized to L-citrulline and dimethylamine by the dimethylarginine dimethylaminohydrolase (DDAH) enzymes. Pharmacological modification of DDAH has therefore been proposed as a mechanism for manipulating endogenous ADMA concentrations and regulating the production of nitric oxide in situations where alterations in nitric oxide signalling have been shown to contribute to pathophysiology. This Review describes the biology of ADMA and the potential therapeutic utility of manipulating DDAH activity