Letter by Teerlink Regarding Article, “L-Arginine Supplementation in Peripheral Arterial Disease: No Benefit and Possible Harm”
To the Editor:
I read with interest the article by Wilson et al1 on the Nitric Oxide in Peripheral Arterial Insufficiency (NO-PAIN) study, which showed that long-term supplementation of L-arginine was less effective than placebo in improving absolute claudication distance in patients with peripheral arterial disease. Most surprising was the finding that flow-mediated vasodilation of the brachial artery decreased after 6 months of L-arginine supplementation, whereas flow-mediated vasodilation in the placebo group increased. The results of this long-term study are discordant with results of previous studies of shorter duration that showed an improvement in vascular reactivity of coronary and peripheral arteries in patients with cardiovascular disease, presumably due to increased NO production. The authors1 speculate that counterregulatory mechanisms induced by prolonged administration of the NO precursor L-arginine may lead to L-arginine tolerance, that is, a paradoxical reduction in NO production.
I would like to point out that L-arginine is involved in a plethora of biochemical pathways,2,3 and possibly an alternative explanation should be sought in a metabolic route other than the arginine–NO pathway. Specifically, arginase, the enzyme that splits L-arginine into L-ornithine and urea, may be relevant in this context. Arginase has a very high Michaelis-Menten constant (Km) with respect to arginine, which implies that under physiological conditions, the enzyme is not fully saturated. Accordingly, in the NO-PAIN study, L-arginine supplementation resulted in increased ornithine levels. Most important, ornithine is a precursor of polyamines and proline. Polyamines are required for cell proliferation and proline is an essential component of collagen, a major constituent of extracellular matrix.2,3 Hence, sustained stimulation of ornithine production by induction of cell proliferation and extracellular matrix deposition may induce or accelerate vascular remodeling. The resulting alterations in elastic properties of the vessel wall, that is, increased stiffness and reduced compliance, limit the ability of the vessel to react to any vasodilatory stimulus.4,5 This mechanism offers an explanation for the reduced flow-mediated vasodilation after prolonged L-arginine administration, even if NO production is unaltered or increased.
Overall, the beneficial short-term effects and harmful long-term effects of L-arginine supplementation may reflect stimulation of different metabolic pathways in which L-arginine is rate limiting. Stimulation of NO synthesis has an acute beneficial effect on vascular function, whereas in the long run, vascular function may be adversely affected by ornithine-induced stimulation of cell proliferation and matrix formation.