ADMA - what is it?

ADMA is the abbreviation for asymmetric dimethylarginine.
This is an endogenous molecule which can be detected in human blood and urine. It shows structural homology to the amino acid L-arginine, and it acts as an inhibitor of nitric oxide (NO) synthesis.
NO is synthesized from the amino acid precursor L-arginine. This reaction is made possible by an enzyme named nitric oxide synthase (NO synthase). NO is one of the most prominent small molecule mediators in the human body, and it plays an important role in many physiological functions as described further below. In 1992, Patrick Vallance and co-workers from London were the first to describe substances that show structural homology to L-arginine, but differ from it in that they contain one or two methyl groups, act as inhibitors of NO synthesis [1]. These substances which have accordingly been named mono- (containing one methyl group) or di-methylarginines (containing two methyl groups) are present endogenously in human plasma and urine. Vallance and colleagues reported that asymmetric dimethylarginine was the one member of this group of substances that is present in sufficiently high concentrations to inhibit NO synthesis. Indeed, they showed that after its isolation from human urine, ADMA induced a significant and concentration-dependent inhibition of NO production by isolated human cells in vitro [2]. By contrast to ADMA, its structural isomer symmetric dimethylarginine (SDMA) had no effect on NO production (Figure 1).

Figure 1. Schematic representation of the structural formula of the amino acid L-arginine, the physiological substrate of the enzyme NO synthase, as well as of L-NMMA and ADMA, its endogenous competitive inhibitors, and the biologically inactive regioisomer, SDMA

Experimental studies in various laboratories around the globe have since shown that ADMA inhibits NO production in vitro within a concentration range that can be measured in plasma of patients with cardiovascular or metabolic diseases [3-5]. In cultured human macrophages (which express the inducible isoform of NO synthase) ADMA inhibits NO production in a concentration-dependent manner [2]. Moreover, experiments with isolated, purified, cloned isoforms of NO synthase in vitro [6] as well as clinical studies in patients with varying plasma concentrations of this substance also demonstrated that ADMA concentration-dependently inhibits NO production (Figure 2) [7-9].

Figure 2. The ratio of the concentrations of L-arginine and ADMA determines the activity of NO synthase in vivo and thereby influences vascular function.
a. In healthy individuals, L-arginine by far outweighs ADMA,resulting in an active NO-modulated vascular tone and structure.
b. In patients with elevated ADMA levels, NO synthase is blocked by ADMA, and No-dependent vasodilation and the manifold inhibitory effects of NO on cell-cell interactions, cell proliferation, and on free radical reactions in the blood vessel are impaired. This is called endothelial dysfúnction.