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

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.