Oral L-arginine Supplement and Nitric Oxide Generation:
Implication in Vascular Health (1/28/05)
L-arginine is an essential amino acid required by the constitutive enzyme, endothelial NO oxide synthase (eNOS), to produce NO. In healthy humans, L-arginine induces peripheral vasodilatation and inhibits platelet aggregation due to an increased NO production. Clinical trials to date support potential clinical applications of L-arginine in the treatment of coronary artery disease and peripheral arterial disease, as well as in the prevention of in-stent restenosis. We, the Cholesterol Center of the Jewish Hospital in Cincinnati, propose that L-arginine supplementation may be novel therapy for Buerger’s disease. A pilot study is underway to investigate the effectiveness of L-arginine in treating Buerger’s Disease.
L-arginine and Vascular Pathophysiology
L-arginine and NO release
Studies have shown that oral L-arginine supplements improve vascular health through NO generation. In healthy volunteers, systemic L-arginine administration (30 g/300 ml/30 min) significantly increased the release of nitrite/nitrate in urine. Plasma concentrations of c-GMP and L-citrulline, the by-product of NO from L-arginine, were also significantly increased [1]. One intravenous infusion of L-arginine (30 g, 60 minutes) in patients with critical limb ischemia (peripheral arterial occlusive disease stages Fontaine III or IV) showed significantly increased urinary NO3- and cGMP excretion, indicating an enhanced systemic NO production. Increased urinary NO3- excretion may be a sum effect of NO synthase substrate provision (L-arginine) [2]. A prospective, crossover clinical trial was performed in patients with type II diabetes and mild hypertension. After giving orally three grams of arginine per hour for 10 hours, the plasma citrulline level significantly increased, which may reflect an increased conversion of arginine into NO and citrulline [3]. In a prospective randomized, double-blind placebo-controlled study on men with organic erectile dysfunction, 6 weeks of orally administered L-arginine (5 g/day) significantly increased plasma and urine nitrite and nitrate, both of which are stable metabolites of NO [4]. However, conflicting reports regarding the effect of L-arginine supplements on NO release do exist. For example, oral L-arginine (9 g) daily for 1 month in a group of patients with coronary artery disease failed to show improvement of NO bioavailability [5]. Another study showed that L-arginine stimulates NO production and induces vasorelaxation in CAD patients, but not in patients with primary pulmonary hypertension [6]. We believe that the doses, routes (oral vs. intravenous), duration of treatment, and disease states in these studies may be contributing factors to this discrepancy.
L-arginine and Endothelial Function
The effect of L-arginine therapy on endothelial function has been studied in health and disease states. A study in healthy volunteers showed that postprandial endothelial impairment is partly abolished by L-arginine administration (6g/day, for 10days) [7]. Aging is associated with progressive endothelial dysfunction in normal humans. Endothelial cell function was improved by oral L-arginine supplementation (16g/day for 2 weeks) in a group of healthy elderly subjects [8]. L-arginine also improves endothelial function in hypercholesterolemic subjects [9]. In a prospective, double-blind, randomized crossover trial, oral L-arginine (7g/day for 3days) improve endothelium-dependent dilatation and reduce monocyte/endothelial cell adhesion in young men with coronary artery disease [10].
Improvement of endothelial function by L-arginine will lead to improved vasodilatation and therefore increased blood flow. For example, one single 6-g dose of L-arginine improved flow-mediated vasodilatation of the brachial artery in a small randomized double-blind trial of 35 patients with essential hypertension [11]. A single 30-g intravenous infusion of L-arginine improved basal femoral artery blood flow in patients with peripheral arterial disease and critical limb ischemia [2]. Twice daily administration of intravenous L-arginine (16 g total) for 3 wk improved flow-mediated vasodilatation of the superficial femoral artery in patients with intermittent claudication [12].
L-arginine and Platelet Aggregation
In healthy human subjects, L-arginine infusion (1 g/min for 30 min) significantly reduces platelet aggregation (20+/-4%), and blood viscosity [13]. In a prospective, double-blind, randomized crossover trial in young healthy subjects, oral L-arginine (21g/day for 3 days) 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 [14].
A double-blinded, placebo-controlled study demonstrated that dietary supplementation with L-arginine (8.4g/day for 2 weeks) can modestly attenuate the increased platelet reactivity seen in hypercholesterolemic patients. This effect persisted for 2 weeks after discontinuation of arginine [15].
L-arginine and homocysteine metabolism
Mild to moderate elevations of plasma homocysteine levels in healthy subjects activates coagulation, and modifies the adhesive properties of endothelium [16]. Mechanisms responsible for endothelial dysfunction in hyperhomocyst(e)inemia may involve impaired bioavailability of NO, possibly secondary to accumulation of the endogenous NO synthase inhibitor asymmetric dimethylarginine (ADMA) and increased oxidative stress [17-18]. In a randomized, placebo-controlled, crossover study, oral L-arginine (12 g/d for 3 wk) substantially reduced plasma levels of homocysteine. Relative to placebo, L-arginine changed plasma homocysteine (-2.0 umol/L) (P < 0.03). The change in plasma L-arginine was inversely correlated with the change in plasma homocysteine (r = -0.57, P = 0.03) [19]. In patients with peripheral arterial occlusive disease (PAOD) and hyperhomocyst(e)inemia, L-arginine (24 g/day for 8 wks) significantly improved endothelial function and flow-dependent vasodilation [17].
Pharmacokinetics of L-arginine
The vascular effects of L-arginine are closely correlated with its plasma concentrations [20]. Knowledge of the pharmacokinetics of L-arginine may be useful in the design of clinical trials involving this agent, as well as in the interpretation of the pharmacodynamics of this important precursor of nitric oxide. A study examined the disposition of L-arginine in hypercholesterolaemic subjects during long-term administration. Pharmacokinetic studies were performed at regular intervals (4 weeks) during a 12-week period of oral L-arginine administration (14-21 g/day). The average plasma L-arginine concentrations before (baseline) and during administration were 16.1+/-1.2 and 22.5+/-1.3 mcg/ml respectively (P<0.05). Plasma concentrations of L-arginine remained above baseline throughout weeks 2-12. The mean non-renal clearance of L-arginine during the four visits remained constant [21].
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