Elevated ADMA - what are the therapeutic consequences?

According to our increasing understanding of the pathophysiological role of ADMA for the development of cardiovascular diseases during the last years, this molecule has become a novel goal for therapeutic intervention. This is all the more true, as ADMA has been shown to induce endothelial dysfunction not only in patients with cardiovascular or metabolic disesases, but in the elderly in general [76].

The most obvious option to antagonize the deleterious effects of ADMA on the endothelium is dietary supplementation with L-arginine. ADMA competes with L-arginine for binding at the NO synthase, and the inhibitory action of ADMA on this enzyme`s activity can be reversed by L-arginine [8, 22, 77]. Thus, the ratio of the concentrations of L-arginine versus ADMA determines NO synthase activity, as depicted in Figures 2a and 2b.
This means that elevated ADMA levels cause a relative, functional "L-arginine deficiency" even in the presence of L-arginine plasma levels within the normal range. Targeted dietary supplementation resulting in elevation of L-arginine`s plasma levels will normalize the L-arginine-to-ADMA ratio in the presence of high ADMA levels. Normally, sufficient provision of L-arginine cannot be maintained by modification of the usual Western diet alone in patients with "L-arginine deficiency diseases" (that are characterized by impaired NO-dependent vascular function). Regular intake of dietary L-arginine supplements is necessary in most patients to reach this therapeutic goal.

The ability of exogenous L-arginine to enhance vascular function, vascular structure, and clinical course of cardiovascular diseases has been proven in a multitude of experimental and clinical studies [49, 78-81]. These studies showed that L-arginine not only improves endothelial function in patient populations characterized by elevated ADMA levels, but also reduces clinical symptoms of overt cardiovascular disease [49, 78-81].
By using L-arginine, a specific preventive strategy is available for patients for whom an increased cardiovascular risk has been determined by measuring an elevated ADMA level. The clinical effectiveness of this preventive strategy is currently being investigated in ongoing clinical trials. However, this strategy is not based on pharmacotherapeutic intervention in the classical sense, but it is a nutritional strategy which aims at maintaining physiological functions of endogenous NO and which, therefore, has its place in very early stages (i.e., in primary prevention).
When elevated ADMA levels have been found in patients that already suffer from overt cardiovascular disease, dietary supplementation with L-arginine may also have a role in secondary prevention. There are a few early clinical studies that have now shown that statins, a drug class primarily used for lowering LDL cholesterol, exert many of their beneficial effects also by improving endothelial function. These effects have been shown to vary according to a patient`s ADMA concentration. Experimental data have proven that statins upregulate the gene expression of endothelial NO synthase. In patients with elevated ADMA levels, NO synthase will not exert its expected function because its activity is blocked [82, 83]. Indeed, a randomized clinical study has demonstrated for the first time that in patients with elevated ADMA concentration, statins only enhance endothelium-dependent vasodilation when they are administered concomitantly with dietary L-arginine [84].
Treatment with angiotensin converting enzyme inhibitors or angiotensin receptor blockers has been shown to lead to a small, but significant reduction of circulating ADMA levels. However, the clinical relevance of this finding for these drugs` therapeutic effects is still unclear [85, 86]. It can be speculated that combination with supplemental L-arginine might also increase the beneficial effects on the vascular endothelium for these classes of drugs. Other groups of drugs that have also been shown to reduce circulating ADMA levels are the drugs used for treating type II diabetic patients, metformin and rosiglitazone [87] and estrogens [88]. Substanes exerting their main action by interfering with ADMA metabolism have not yet been discovered.