ADMA

ADMA, or asymmetric dimethylarginine, is an endogenous derivative of the amino acid arginine. It is formed when arginine residues within proteins are methylated by protein arginine N-methyltransferases and are released during proteolysis. ADMA is a primary endogenous inhibitor of nitric oxide synthase (NOS), the enzyme responsible for producing nitric oxide (NO).

Biochemical fate and related molecules: ADMA is predominantly metabolized by dimethylarginine dimethylaminohydrolase (DDAH) to citrulline and dimethylamine; a portion is excreted by the kidneys. Symmetric dimethylarginine (SDMA) is a related methylarginine but does not directly inhibit NOS, though it may affect arginine transport. Plasma levels of ADMA and SDMA reflect both production and clearance and are influenced by renal function and oxidative stress.

Mechanism of action: ADMA competes with L-arginine at the NOS active site, reducing NO synthesis. NO is a key mediator of vasodilation and vascular homeostasis; thus elevated ADMA can contribute to endothelial dysfunction, altered vascular tone, platelet aggregation, and inflammatory processes. The effect of ADMA can be modulated by cellular L-arginine availability and redox state.

Clinical significance: Higher plasma ADMA levels are associated with endothelial dysfunction and increased cardiovascular risk. Elevated ADMA is observed in chronic kidney disease, diabetes, hypertension, and atherosclerosis, and has been linked to adverse outcomes in several studies. As a biomarker, ADMA can aid risk assessment, though its utility is context-dependent and influenced by renal function and other factors.

Measurement: ADMA is measured in plasma or serum, typically by liquid chromatography–tandem mass spectrometry or high-performance liquid chromatography. Reference ranges vary by assay and population. Therapeutic strategies to lower ADMA focus on enhancing DDAH activity or optimizing arginine availability, but clinical benefits remain under investigation.