How is the concentration of ADMA in human blood regulated?

The biosynthesis of ADMA occurs during methylation of protein residues, which release unbound ADMA upon their proteolytic degradation during physiological protein turnover. Thus, ADMA is formed in the cytoplasm of cells; it can then be released into the extracellular space and into blood plasma.
Human endothelial cells are capable of synthesizing ADMA. Accordingly, there is evidence to assume that ADMA acts as an autocrine regulator of endothelial NO synthase activity (i.e., within the same cell in which it is formed - by contrast to hormones, which act upon cells different from those in which they are formed). In the presence of native or oxidized LDL cholesterol ADMA release is significantly increased [11]. Elevated ADMA levels may thus be responsible for part of the detrimental action of LDL cholesterol on endothelial cell function (Figure 9).

Figure 9. Formation of ADMA and SDMA by human endothelial cells in culture. The release of ADMA, but not that of SDMA, is significantly increased in the presence of LDL cholesterol (Data from[11]).

Both isomers, ADMA and SDMA, are being excreted via the urine. In their first report on ADMA as an endogenous inhibitor of NO synthesis [2], Vallance and co-workers already showed that ADMA levels are significantly elevated in patients with end-stage renal disease. In subsequent studies several groups of researchers independently of each other confirmed the observation that the levels of ADMA and SDMA are elevated in chronic renal failure. In most of the studies, SDMA levels showed a stronger tendency to increase than ADMA levels [23], suggesting that ADMA may be excreted by different, metabolic pathways, whereas renal excretion is the only way of elimination for SDMA (Figure 10).

Figure 10. Biosynthesis and metabolism of ADMA in the human body. For details see text (from [20] with kind permission of the publishers).

Indeed, ADMA, but not SDMA, is metabolized by an enzyme named dimethylarginine dimethylaminohydrolase (DDAH) to yield L-citrulline and dimethylamine [24]. Pharmacological inhibition of DDAH causes a concentration-dependent constriction of isolated arterial segments in vitro which can be restored by excess L-arginine [25]. This latter finding most specifically that the regulation of intracellular ADMA levels achieved by changes in DDAH activity can lead to changes in NO production.
DDAH activity, which mediates the metabolic degradation of ADMA, appears to underlie complex regulatory mechanisms which have not yet been fully elucidated. Oxidative stress leads to a reduced DDAH activity. This was shown not only in cultured endothelial cells, but also in tissue homogenates from aorta, kidneys and liver of hypercholesterolemic rabbits [26]. Homocysteine, a known cardiovascular risk factor, increases ADMA concentration, which was put down to a redox-induced downregulation of DDAH activity by homcoysteine [27] or, alternatively, .by increased methylation of L-arginine residues and subsequently increased release of ADMA [11]. Taken together, these data allow to conclude that ADMA is formed during protein methylation and is continuously released into the extracellular space after its release from proteins during physiological protein turnover. Its accumulation in the body is prevented in healthy humans by renal excretion on the one hand, and by metabolic degradation by DDAH on the other hand. Changes in renal excretory function or changes in DDAH activity, like they can be induced by cardiovascular risk factors, lead to elevated ADMA levels in various cardiovascular and metabolic diseases.