title: L-arginine supplementation in peripheral arterial disease: no benefit and possible harm.
abstract: 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.
  
  
  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.
authors.affiliation: Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, Calif 94305, USA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Wilson
authors.forename: Randall
authors.initials: R
authors.lastname: Harada
authors.forename: Nandini
authors.initials: N
authors.lastname: Nair
authors.forename: Naras
authors.initials: N
authors.lastname: Balasubramanian
authors.forename: John P
authors.initials: JP
authors.lastname: Cooke
mesh_terms: D000368:Aged; D001120:Arginine / Q000009:adverse effects* / Q000627:therapeutic use*; D001916:Brachial Artery / Q000502:physiology / Q000503:physiopathology; D019587:Dietary Supplements; D005260:Female; D006801:Humans; D007383:Intermittent Claudication / Q000453:epidemiology / Q000517:prevention & control; D008297:Male; D008875:Middle Aged; D019001:Nitric Oxide Synthase / Q000378:metabolism; D018579:Patient Selection; D016491:Peripheral Vascular Diseases / Q000188:drug therapy*; D010919:Placebos; D011446:Prospective Studies; D044469:Racial Groups
chemical_list: D010919:Placebos; D001120:Arginine; D019001:Nitric Oxide Synthase