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.


OBJECTIVE
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 microg 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 83+/-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.
Böger
R H
RH
Institute of Clinical Pharmacology, Hannover Medical School, Germany. boeger.rainer@mh-hannover.de
Bode-Böger
S M
SM
Thiele
W
W
Creutzig
A
A
Alexander
K
K
Frölich
J C
JC
D000368:Aged; D000369:Aged, 80 and over; D000527:Alprostadil / Q000008:administration & dosage / Q000627:therapeutic use; D001120:Arginine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000627:therapeutic use*; D001157:Arterial Occlusive Diseases / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism; D001783:Blood Flow Velocity; D002908:Chronic Disease; D006152:Cyclic GMP / Q000652:urine; D004311:Double-Blind Method; D005080:Exercise Test; D005260:Female; D005263:Femoral Artery / Q000000981:diagnostic imaging / Q000503:physiopathology; D005500:Follow-Up Studies; D006801:Humans; D007262:Infusions, Intravenous; D007383:Intermittent Claudication / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D007866:Leg / Q000098:blood supply; D008297:Male; D008875:Middle Aged; D009566:Nitrates / Q000652:urine; D009569:Nitric Oxide / Q000096:biosynthesis*; D016491:Peripheral Vascular Diseases / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism; D016896:Treatment Outcome; D018616:Ultrasonography, Doppler, Duplex; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000627:therapeutic use
D009566:Nitrates; D014665:Vasodilator Agents; D009569:Nitric Oxide; C018524:N,N-dimethylarginine; D001120:Arginine; D000527:Alprostadil; D006152:Cyclic GMP