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(Circulation. 2007;116:188-195.)
© 2007 American Heart Association, Inc.

Vascular Medicine

L-Arginine Supplementation in Peripheral Arterial Disease

No Benefit and Possible Harm

Andrew M. Wilson, MBBS, PhD; Randall Harada, MD; Nandini Nair, MD, PhD; Naras Balasubramanian, PhD; John P. Cooke, MD, PhD

From the Division of Cardiovascular Medicine (A.M.W., R.H., N.N., J.P.C.) and Department of Biostatistics (N.B.), Stanford University School of Medicine, Stanford, Calif.

Correspondence to John P. Cooke, MD, PhD, Division of Cardiovascular Medicine, Stanford University Medical Center, Falk Cardiovascular Research Institute, 300 Pasteur Dr, Stanford, CA 94305. E-mail john.cooke{at}stanford.edu

Received December 20, 2006; accepted May 3, 2007.

Background— 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.

Methods and Results— 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).

Conclusions— 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.

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