PERIPHERAL VASCULAR DISEASE Restoring Vascular Nitric Oxide Formation by L-Arginine Improves the Symptoms of Intermittent Claudication in Patients With Peripheral Arterial Occlusive Disease

Background. Administration of L-arginine improves nitric oxide (NO) formation and endothelium-dependent vasodilation in atherosclerotic patients. Objectives. We investigated in this double-blind, controlled study whether prolonged intermittent infusion therapy with L-arginine improves the clinical symptoms of patients with intermittent claudication, as compared with the endotheliumindependent vasodilator prostaglandin E1, and control patients. Methods. Thirty-nine patients with intermittent claudication were randomly assigned to receive 2 3 8 g L-arginine/day, or 2 3 40 mg prostaglandin E1 (PGE1)/day or no hemodynamically active treatment, for 3 weeks. The pain-free and absolute walking distances were assessed on a walking treadmill at 3 km/h, 12% slope, and NO-mediated, flow-induced vasodilation of the femoral artery was assessed by ultrasonography at baseline, at 1, 2 and 3 weeks of therapy and 6 weeks after the end of treatment. Urinary nitrate and cyclic guanosine-3*, 5*-monophosphate (GMP) were assessed as indices of endogenous NO production. Results. L-Arginine improved the pain-free walking distance by 230 6 63% and the absolute walking distance by 155 6 48% (each p < 0.05). Prostaglandin E1 improved both parameters by 209 6 63% and 144 6 28%, respectively (each p < 0.05), whereas control patients experienced no significant change. L-Arginine therapy also improved endothelium-dependent vasodilation in the femoral artery, whereas PGE1 had no such effect. There was a significant linear correlation between the L-arginine/asymmetric dimethylarginine (ADMA) ratio and the pain-free walking distance at baseline (r 5 0.359, p < 0.03). L-Arginine treatment elevated the plasma L-arginine/ADMA ratio and increased urinary nitrate and cyclic GMP excretion rates, indicating normalized endogenous NO formation. Prostaglandin E1 therapy had no significant effect on any of these parameters. Symptom scores assessed on a visual analog scale increased from 3.51 6 0.18 to 8.3 6 0.4 (L-arginine) and 7.0 6 0.5 (PGE1; each p < 0.05), but did not significantly change in the control group (4.3 6 0.4). Conclusions. Restoring NO formation and endotheliumdependent vasodilation by L-arginine improves the clinical symptoms of intermittent claudication in patients with peripheral arterial occlusive disease. (J Am Coll Cardiol 1998;32:1336–44) ©1998 by the American College of Cardiology