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CLINICAL STUDIES

Restoring vascular nitric oxide formation by L-arginine improves the symptoms of intermittent claudication in patients with peripheral arterial occlusive disease

Rainer H. Böger, MD^*, Stefanie M. Bode-Böger, MD^*, Wolfgang Thiele^*, Andreas Creutzig, MD, Klaus Alexander, MD and J.ürgen C. Frölich, MD^*

^* Institute of Clinical Pharmacology, Hannover Medical School, Hannover, Germany
Department of Angiology, Hannover Medical School, Hannover, Germany

Manuscript received February 12, 1998; revised manuscript received June 17, 1998, accepted July 6, 1998.

Address for correspondence: Dr. Rainer H. Böger, Institute of Clinical Pharmacology, Hannover Medical School, 30623 Hannover, Germany
boeger.rainer{at}mh-hannover.de

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 endothelium-independent vasodilator prostaglandin E₁, and control patients.

Methods. Thirty-nine patients with intermittent claudication were randomly assigned to receive 2 x 8 g L-arginine/day, or 2 x 40 µg 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 ± 63% and the absolute walking distance by 155 ± 48% (each p < 0.05). Prostaglandin E₁ improved both parameters by 209 ± 63% and 144 ± 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 = 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 ± 0.18 to 8.3 ± 0.4 (L-arginine) and 7.0 ± 0.5 (PGE₁; each p < 0.05), but did not significantly change in the control group (4.3 ± 0.4).

Conclusions. Restoring NO formation and endothelium-dependent vasodilation by L-arginine improves the clinical symptoms of intermittent claudication in patients with peripheral arterial occlusive disease.

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