L-arginine improves vascular function by overcoming the deleterious effects of ADMA, a novel cardiovascular risk factor

Alternative Medicine Review, March, 2005 by Rainer H. Boger, Eyal S. Ron

In the first prospective clinical trial, ADMA was determined to be the strongest predictor of cardiovascular events and total mortality in 225 hemodialysis patients during three years of follow-up. Patients whose ADMA levels were within the highest quartile at the beginning of the study had a three-fold higher risk of death from any cause than patients with ADMA levels below the median. (25) Another study investigated factors related to outcome of patients undergoing intensive care unit treatment for multiple causes. Patients whose ADMA levels were in the highest quartile had a 17-fold increase in mortality compared to patients with ADMA levels in the lowest quartile. (32) In a third prospective study, the outcome of patients with stable angina pectoris after coronary balloon angioplasty was addressed, and patients with high ADMA levels were found to have an elevated risk of developing severe cardiovascular complications. (33) In each of these studies, other cardiovascular risk factors and confounding variables were included in the analyses, and ADMA was found to predict cardiovascular risk independent of other variables. Thus, it has recently been concluded that ADMA can be considered to be a novel cardiovascular risk factor. (34-36)

The Role of ADMA for Explaining the Beneficial

Effects of Nutritional L-Arginine Supplementation

Circulating L-arginine concentrations have been found to be within the normal range in most clinical conditions associated with endothelial dysfunction. Few patients experience pathologically low L-arginine concentrations. However, clinical and experimental evidence suggests elevation of ADMA can cause a relative L-arginine deficiency, even in the presence of "normal" L-arginine levels (which may, in fact, be too low in these conditions). As ADMA is a competitive inhibitor of eNOS, its inhibitory action can be overcome by increasing the concentration of the enzyme's substrate, L-arginine (Figure 2). The studies cited above indicate ADMA levels may be increased in conditions associated with cardiovascular diseases. Elevated ADMA concentration is one possible explanation for endothelial dysfunction and decreased NO production in these diseases. In this respect, the authors recently observed improved endothelium-dependent vasodilation after L-arginine administration in patients with congestive heart failure (who had elevated ADMA concentrations); whereas, L-arginine did not affect endothelium-dependent vasodilation in healthy human subjects (who had low ADMA concentrations). (37) Thus, nutritional supplementation with L-arginine may help to restore the physiological status by normalizing the L-arginine/ ADMA ratio; whereas, its effects are less pronounced in humans without a disturbed L-arginine/ADMA balance. Normally, L-arginine/ADMA ratio is in the range of 50:1 to 100:1, given a range of L-arginine levels between 50 and 100 umol/L, and ADMA concentrations between 0.3 and 0.7 [micro]mol/L.

A beneficial effect of L-arginine on vascular function has been found by several different groups of investigators in patients with impaired vascular function (see below); whereas, little or no effect is usually noted in healthy controls. (16) This makes sense, as the molecular function of L-arginine, as detailed above, is to restore endothelial NO production to normal, thereby normalizing vascular function. By replenishing eNOS with its natural substrate, no vasodilator effects beyond the physiological range can be expected. Thus, no exaggerated hypotensive action, orthostatic dysregulation, or adverse cardiac events related to reflex tachycardia need be considered. In contrast to L-arginine, exogenous NO donors such as the organic nitrates, which release NO after enzymatic conversion by the activity of enzymes different from eNOS, are associated with tolerance development and oxidative stress to the arterial wall. (38) In this respect, there is ample evidence to consider L-arginine a safe and beneficial dietary supplement.