l -Arginine Supplementation in Peripheral Arterial Disease

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. 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%; Pϭ0.024). 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.

Tetrahydrobiopterin, L-Arginine and Vitamin C Act Synergistically to Decrease Oxidative Stress, Increase Nitric Oxide and Improve Blood Flow after Induction of Hindlimb Ischemia in the Rat

“…Dietary supplementation with L-arginine alone has a beneficial effect when given acutely (that is, via intravenous infusion [14] or for short duration [2 months] [15]), and these clinical results are consistent with the positive effects observed in rats provided with dietary L-arginine. However, long-term administration of L-arginine (6 months) not only failed to demonstrate a beneficial effect, but resulted in a degree of eNOS-dependent vascular reactivity significantly less than that of the placebo group (16). The present findings demonstrated increased iNOS activity after induction of ischemia.…”

“…Although it is well established that endothelial dysfunction related to vascular oxidative stress is a critical factor in PAD pathogenesis, dietary supplementation with L-arginine or antioxidants, such as vitamin C, have had equivocal effects on long-term outcome (12,13,16). Dietary supplementation with L-arginine alone has a beneficial effect when given acutely (that is, via intravenous infusion [14] or for short duration [2 months] [15]), and these clinical results are consistent with the positive effects observed in rats provided with dietary L-arginine.…”

“…Vitamin C levels are low in PAD patients (9), and acute (10) or short-term (11) vitamin C supplementation reduces PAD symptoms; however, cross-sectional epidemiological surveys have failed to find a clear link between long-term vitamin C intake and PAD symptoms or disease progression (12,13). L-arginine supplementation showed exciting promise in short-term studies of PAD (14,15), but this effect was not observed in a subsequent long-term study by the same group (16). BH4 improves eNOS-dependent vasodilation in long-term smokers and patients with type 2 diabetes, conditions associated with increased oxidative stress (17,18).…”

Critical Role of the Nitric Oxide/Reactive Oxygen Species Balance in Endothelial Progenitor Dysfunction

“…However, in patients with peripheral arterial disease, long-term L-arginine supplementation did not increase nitric oxide synthesis or improved vascular reactivity (127). Thus, a contribution of L-arginine supplementation for vascular protection needs further investigations.…”

An increased need for dietary cysteine in support of glutathione synthesis may underlie the increased risk for mortality associated with low protein intake in the elderly

“…Studies of arginine supplementation which have demonstrated physiological effects have typically employed 6 g daily or more (Boger 2008)-a higher amount than that provided by average diets. A 6-month study evaluating 3 g of supplemental arginine daily-an amount comparable to the differential arginine content between high protein and low protein diets-in patients with peripheral artery disease, failed to observe any favorable clinical impact on symptoms or markers of NO activity (Wilson et al 2007).…”