Response to Letter Regarding Article, “L-Arginine Supplementation in Peripheral Arterial Disease: No Benefit and Possible Harm”
We thank Dr Teerlink for his comments regarding the unexpected results of our study.1 Pre-clinical studies and short-term trials in patients with coronary or peripheral arterial disease showed that supplemental L-arginine improved endothelium-dependent vasodilation and increased nitric oxide (NO) production. Accordingly, we hypothesized that long-term administration of L-arginine would improve vascular function and enhance collateral blood flow, thereby increasing walking distance in patients with peripheral arterial disease. To our surprise, long-term L-arginine supplementation tended to impair vascular function and to limit the improvement in walking distance over time in patients with peripheral arterial disease.
As Dr Teerlink commented, the metabolic fate of L-arginine is highly complex and tightly regulated.2 However, plasma L-arginine levels rose in the supplemented group, so it is unlikely that induction of intestinal arginase activity fully explains our findings. Despite the increased plasma L-arginine levels, citrulline did not rise in the L-arginine–treated group. Furthermore, as compared with the placebo group, there was a significant decrement in endothelium-dependent vasodilation and nitric oxide production. These observations indicate the presence of a countervailing mechanism that opposed an arginine-induced increase in NO production. The apparent reversal of arginine-induced NO production could be due to an opposing increase in asymmetric dimethylarginine (the endogenous NOS inhibitor).3 Although plasma asymmetric dimethylarginine levels were elevated at baseline in both peripheral arterial disease groups, there were no group differences after treatment. Another possible explanation may be that vascular arginase expression and/or activity was increased, as Dr Teerlink suggested. Increased endothelial arginase II expression has been shown to downregulate endothelial NO synthase activity.4 It is also possible that an increase in arginine metabolites such as ornithine may have led to adverse vascular effects as Dr Teerlink suggests. However, this would not explain the failure of citrulline and NO to rise in the L-arginine–treated group, unless the elevated ornithine levels somehow led to NO synthase inhibition.
Whatever mechanisms are invoked to explain the surprising findings in this double-blind, randomized clinical trial, the results are clinically relevant, as L-arginine supplements are available over the counter and are currently being taken by a range of subject groups. We agree with Dr Teerlink that alternate explanations for lack of benefit or even potential adverse effects should be sought.
Dr Cooke is the inventor of patents owned by Stanford University for diagnostic and therapeutic applications of the NO synthase pathway from which he receives royalties. Dr Cooke is a consultant to Ajinomoto and United Therapeutics. The other authors report no conflicts.
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.
Morris SM Jr. Arginine metabolism: boundaries of our knowledge. J Nutr. 2007; 137 (Suppl 2): 1602S–1609S.
Cooke JP. Asymmetrical dimethylarginine: the uber marker? Circulation. 2004; 109: 1813–1818.
Lim HK, Lim HK, Ryoo S, Benjo A, Schuleri K, Miriel VA, Baraban E, Camara A, Soucy KG, Nyhan D, Shoukas A, Berkowitz D. Mitochondrial arginase II constrains endothelial NOS-3 activity. Am J Physiol Heart Circ Physiol. 2007; 293: H3317–H3324.