Oral l-arginine inhibits platelet aggregation but does not enhance endothelium-dependent dilation in healthy young men

Objectives.Our aim was to assess the effect of oral l-arginine on endothelial or platelet physiology in humans.Background.l-Arginine is the substrate for nitric oxide synthesis, and in cholesterol-fed rabbits, oral l-arginine improves endothelium-dependent dilation, inhibits platelet aggregation and reduces atheroma. In hypercholesterolemic humans, intravenous l-arginine immediately improves endothelium-dependent dilation; however, the vascular effects of oral l-arginine in healthy humans have not previously been investigated.Methods.In a prospective, double-blind, randomized crossover trial, 12 healthy young men 27 to 37 years old took l-arginine (7 g three times daily) or placebo for 3 days each, separated by a washout period of 7 to 14 days.Results.After l-arginine, plasma levels of arginine (mean ± SEM 303 ± 36 vs. 128 ± 12μmol/liter, p = 0.01) and urea (6.7 ± 0.5 vs. 5.2 ± 0.2 mmol/liter, p < 0.01) were higher than levels measured after placebo, and platelet aggregation in response to adenosine diphosphate was markedly impaired (37 ± 12% vs. 81 ± 3%, p = 0.02). The inhibition of platelet aggregation correlated with the plasma level of l-arginine (r = 0.74, p = 0.01), and it could be completely or partially reversed by ex vivo incubation with N-monomethyl-l-arginine, a specific nitric oxide synthase inhibitor. Platelet cyclic guanosine monophosphate levels were higher after oral l-arginine than at baseline (1.91 ± 0.46 vs. 1.38 ± 0.40 pmol/109platelets, p = 0.04). No changes were seen in fasting lipid levels, heart rate, blood pressure, endotheliumdependent dilation of the brachial artery (measured in response to reactive hyperemia, using external vascular ultrasound) (6.1 ± 0.7% vs. 6.5 ± 0.7%, p = NS) or in plasma levels of nitrosylated proteins (a marker of in vivo nitric oxide production) (3.5 ± 0.5 vs. 3.3 ± 0.4 μmol/liter, p = NS) 1 to 1.5 h after the last dose of l-arginine.Conclusions.In these healthy young adult men, oral l-arginine inhibited platelet aggregation by way of the nitric oxide pathway. However, it had no effect on systemic hemodynamic variables, plasma nitrosylated protein levels or endothelium-dependent dilation. Therefore, at certain doses, oral l-arginine may result in a relatively platelet-specific increase in nitric oxide production