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(Circulation. 2008;117:e157.)
© 2008 American Heart Association, Inc.

Correspondence

Letter by Teerlink Regarding Article, "L-Arginine Supplementation in Peripheral Arterial Disease: No Benefit and Possible Harm"

Tom Teerlink, PhD

Department of Clinical Chemistry, VU University Medical Center, Amsterdam, the Netherlands

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 (K_m) 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.

	Acknowledgments

 
Disclosures

None.

	References

Top References

 
1. Wilson AM, Harada R, Nair N, Balasubramanian N, Cooke JP. L-arginine supplementation in peripheral arterial disease: no benefit and possible harm. Circulation. 2007; 116: 188–195.[Abstract/Free Full Text]

2. Wu G, Morris SM Jr. Arginine metabolism: nitric oxide and beyond. Biochem J. 1998; 336: 1–17.[Medline] [Order article via Infotrieve]

3. Huynh NN, Chin-Dusting J. Amino acids, arginase and nitric oxide in vascular health. Clin Exp Pharmacol Physiol. 2006; 33: 1–8.[CrossRef][Medline] [Order article via Infotrieve]

4. Witte DR, van der Graaf Y, Grobbee DE, Bots ML. Measurement of flow-mediated dilatation of the brachial artery is affected by local elastic vessel wall properties in high-risk patients. Atherosclerosis. 2005; 182: 323–330.[CrossRef][Medline] [Order article via Infotrieve]

5. Lind L. Arterial compliance influences the measurement of flow-mediated vasodilation, but not acetylcholine-mediated forearm blood flow: the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. Atherosclerosis. 2007; 190: 212–215.[CrossRef][Medline] [Order article via Infotrieve]

This Article Extract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Teerlink, T. Search for Related Content PubMed Articles by Teerlink, T. Related Collections Smooth muscle proliferation and differentiation Peripheral vascular disease Other Treatment Endothelium/vascular type/nitric oxide