ASYMMETRIC DIMETHYLARGININE (ADMA) - A NOVEL RISK FACTOR FOR ENDOTHELIAL DYSFUNCTION - ITS ROLE IN HYPERCHOLESTEROLEMIA

Background-Asymmetric dimethylarginine (ADMA) is an endogenous competi tive inhibitor of nitric oxide (NO) synthase. Because endothelial NO e laboration is impaired in hypercholesterolemia, we investigated whethe r plasma concentrations of ADMA are elevated in young, clinically asym ptomatic hypercholesterolemic adults. We further studied whether such elevation of ADMA levels was correlated with impaired endothelium-depe ndent, NO-mediated vasodilation and urinary nitrate excretion. In a ra ndomized, double-blind, placebo-controlled study, we investigated whet her these changes could be reversed with exogenous L-arginine. Methods and Results-We measured plasma levels of L-arginine, ADMA, and symmet rical dimethylarginine (SDMA) by high-performance liquid chromatograph y in 49 hypercholesterolemic (HC) and 31 normocholesterolemic (NC) hum ans. In 8 HC subjects, endothelium-dependent forearm vasodilation was assessed before and after an intravenous infusion of L-arginine or pla cebo and compared with 8 NC control subjects. ADMA levels were signifi cantly elevated by >100% (2.17+/-0.15 versus 1.03+/-0.09 mu mol/L; P<0 .05) in HC subjects compared with NC adults. L-Arginine levels were si milar? resulting in a significantly decreased L-arginine/ADMA ratio in HC subjects (27.7+/-2.4 versus 55.7+/-5.4; P<0.05). In 8 HC subjects, intravenous infusion of L-arginine significantly increased the L-argi nine/ADMA ratio and normalized endothelium-dependent vasodilation and urinary nitrate excretion. ADMA levels were inversely correlated with endothelium-mediated vasodilation (R=0.762, P<0.01) and urinary nitrat e excretion rates (R=0.534, P<0.01). Conclusions-We find that ADMA is elevated in young HC individuals. Elevation of ADMA is associated with impaired endothelium-dependent vasodilation and reduced urinary nitra te excretion. This abnormality is reversed by administration of L-argi nine. ADMA may be a novel risk factor for endothelial dysfunction in h umans.