Background-Asymmetric dimethylarginine (ADMA) is an endogenous competitive inhibitor of nitric oxide (NO) synthase. Because endothelial NO elaboration is impaired in hypercholesterolemia, we investigated whether plasma concentrations of ADMA are elevated in young, clinically asymptomatic hypercholesterolemic adults. We further studied whether such elevation of ADMA levels was correlated with impaired endothelium-dependent, NO-mediated vasodilation and urinary nitrate excretion. In a randomized, double-blind, placebo-controlled study, we investigated whether these changes could be reversed with exogenous L-arginine. Methods and Results-We measured plasma levels of L-arginine, ADMA, and symmetrical dimethylarginine (SDMA) by high-performance liquid chromatography in 49 hypercholesterolemic (HC) and 31 normocholesterolemic (NC) humans. In 8 HC subjects, endothelium-dependent forearm vasodilation was assessed before and after an intravenous infusion of L-arginine or placebo and compared with 8 NC control subjects. ADMA levels were significantly elevated by Ͼ100%

Aims Recent studies in patients with cardiovascular diseases suggest potential for the use of orally administered l‐arginine, the precursor of nitric oxide, as a therapeutic agent. This crossover study was designed to examine the pharmacokinetics of single i.v. and oral doses of l‐arginine in healthy volunteers (n=10). Methods A preliminary control study (n=12) was performed to assess the variation in plasma l‐arginine concentrations when ingesting a normal diet. The observed variation was taken into account when interpreting the pharmacokinetic data obtained after exogenous administration. Results The mean baseline plasma concentration of l‐arginine in the control study was 15.1±2.6 μg ml−1. After intravenous administration (30 g over 30 min), the plasma concentration reached 1390±596 μg ml−1. The disappearance of l‐arginine appeared biphasic, with an initial rapid disappearance due to concentration‐dependent renal clearance followed by a slower fall in plasma concentrations due to nonrenal elimination. The peak concentration after oral administration (10 g) was 50.0±13.4 μg ml−1, occurring 1 h after administration. Renal elimination was not observed after oral administration of this dose. The absolute bioavailability of a single oral 10 g dose of l‐arginine is ≈20%. Conclusions This study provides basic knowledge of l‐arginine pharmacokinetics in healthy humans. Intravenous and oral administrations show at minimum a biphasic pattern. Further studies will assess whether a similar profile is observed when the drug is administered to patients.

Abstract-Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, is elevated in hypercholesterolemia. This study was designed to determine the role of ADMA in the increased mononuclear cell adhesiveness observed in human hypercholesterolemia. In patient studies, plasma ADMA levels were determined by high-performance liquid chromatography. Functional mononuclear leukocyte adhesion assays were performed in parallel, and flow cytometry was used to characterize bound monocytes and T lymphocytes. Hypercholesterolemic patients were then placed on an oral L-arginine regimen of 14 or 21 g/d and studied over 12 weeks. In cell culture studies, bovine aortic endothelial cells were incubated with varied concentrations of ADMA. Monocytoid cells were cocultured with these bovine aortic endothelial cells, and their adhesiveness was assessed by use of a binding assay. Flow cytometry was used to quantify adhesion molecule expression. Plasma ADMA levels and adhesiveness of mononuclear cells (specifically, monocytes and T lymphocytes) were elevated in hypercholesterolemic patients. Adhesiveness was inversely correlated with the plasma L-arginine/ADMA ratio. Oral administration of L-arginine normalized plasma L-arginine/ADMA ratios and attenuated monocyte and T-lymphocyte adhesiveness. ADMA had no direct effect on the adhesiveness of mononuclear cells. However, monocytes became hyperadhesive when cocultured with ADMA-exposed endothelial cells. In human hypercholesterolemia, the plasma L-arginine/ADMA ratio is inversely correlated with mononuclear cell adhesiveness. Restoration of the L-arginine/ADMA ratio to control levels normalizes mononuclear cell adhesiveness. Our studies suggest that the elaboration of endothelium-derived nitric oxide affects the behavior of circulating T lymphocytes and monocytes. Key Words: L-arginine Ⅲ atherosclerosis Ⅲ monocytes Ⅲ endothelium Ⅲ T lymphocytes M onocytes and T lymphocytes are the predominant inflammatory cells found in atherosclerotic plaques. Indeed, the adhesion of mononuclear cells to the endothelium is a key initial event in atherogenesis that precedes the formation of fatty streaks. [1][2][3] In hypercholesterolemic (HC) humans, peripheral blood mononuclear cells exhibit increased adhesiveness for endothelial cells in ex vivo adhesion assays. 4,5 Differences in monocyte surface markers have been detected by flow cytometry between HC and normocholesterolemic (NC) humans, although the functional significance is unclear. 6 Molecular signaling mechanisms for the altered behavior of mononuclear cells are likely multifactorial and may involve inflammatory cytokines, 7 LDL, 8,9 platelet-activating factor, 10 circulating soluble adhesion molecules, 11 and reduced bioactivity of endotheliumderived nitric oxide (NO).NO has been shown to modulate the behavior of circulating blood elements. In vivo, NO inhibits leukocyte adherence in the early stages of hypercholesterolemia in the rat. 12 Furthermore, endothelium-derived NO is able to increase cGMP and reduce the abili...