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Circulation. 2007 Jul 10;116(2):188-95. Epub 2007 Jun 25.

L-arginine supplementation in peripheral arterial disease: no benefit and possible harm.

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Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, Calif 94305, USA.



L-arginine is the precursor of endothelium-derived nitric oxide, an endogenous vasodilator. L-arginine supplementation improves vascular reactivity and functional capacity in peripheral arterial disease (PAD) in small, short-term studies. We aimed to determine the effects of long-term administration of L-arginine on vascular reactivity and functional capacity in patients with PAD.


The Nitric Oxide in Peripheral Arterial Insufficiency (NO-PAIN) study was a randomized clinical trial of oral L-arginine (3 g/d) versus placebo for 6 months in 133 subjects with intermittent claudication due to PAD in a single-center setting. The primary end point was the change at 6 months in the absolute claudication distance as assessed by the Skinner-Gardner treadmill protocol. L-arginine supplementation significantly increased plasma L-arginine levels. However, measures of nitric oxide availability (including flow-mediated vasodilation, vascular compliance, plasma and urinary nitrogen oxides, and plasma citrulline formation) were reduced or not improved compared with placebo. Although absolute claudication distance improved in both L-arginine- and placebo-treated patients, the improvement in the L-arginine-treated group was significantly less than that in the placebo group (28.3% versus 11.5%; P=0.024).


In patients with PAD, long-term administration of L-arginine does not increase nitric oxide synthesis or improve vascular reactivity. Furthermore, the expected placebo effect observed in studies of functional capacity was attenuated in the L-arginine-treated group. As opposed to its short-term administration, long-term administration of L-arginine is not useful in patients with intermittent claudication and PAD.

[Indexed for MEDLINE]

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