(Circulation. 1997;95:1863-1869.)
© 1997 American Heart Association, Inc.
Articles |
Local Intramural Delivery of L-Arginine Enhances Nitric Oxide Generation and Inhibits Lesion Formation After Balloon Angioplasty
From the Division of Cardiovascular Medicine, Stanford (Calif) University School of Medicine.
Correspondence to Alan C. Yeung, MD, Stanford University School of Medicine, Division of Cardiovascular Medicine, 300 Pasteur Dr, Stanford, CA 94305.
Background Long-term oral administration of L-arginine has been shown to enhance production of nitric oxide (NO) and to reduce lesion formation. The goal of this study was to determine whether local intramural administration of L-arginine could enhance NO generation and reduce intimal thickening.
Methods and Results New Zealand White rabbits (n=27) received a 1% cholesterol diet. For the short-term study, after 1 week of diet, both iliac arteries were balloon injured. Four weeks later, vasoreactivity was assessed angiographically during infusion of acetylcholine (Ach) before and after delivery of L-arginine or saline into the right or left iliac artery (800 mg/5 mL; 0.2 mL/min, 15 minutes) by use of a local drug-delivery balloon. Vessels were then harvested for measurements of NO. For the long-term study, after balloon injury, drugs were delivered as above into the iliac arteries. Two and 4 weeks after L-arginine delivery, vasoreactivity was determined. Subsequently, the iliac arteries were harvested for histomorphometric analysis and measurements of NO. In the short-term study, local delivery of L-arginine restored endothelium-dependent vasodilatation (Ach 10-5 mol/L; L-arginine +35±10%; saline -14±5%; P<.001) and enhanced local production of nitrogen oxides (L-arginine 152±28; saline 78±12 nmol/L per milligram of tissue per hour; P<.04). In the long-term study, local administration of L-arginine enhanced vascular NO production as long as 1 week after the injury (L-arginine 394.4±141.6; saline 86.3±34.3 nmol/L per milligram of tissue per hour; P<.01) and reduced intimal thickening 4 weeks later (intima/media ratio: L-arginine 0.56±0.1; saline 1.40±0.2; P<.001), largely due to suppression of macrophage accumulation.
Conclusions A single intramural administration of L-arginine enhances vascular NO generation and inhibits lesion formation. Local augmentation of NO production at the site of balloon angioplasty may be a novel strategy to prevent restenosis.
Key Words: endothelium-derived factors • l-arginine • restenosis • macrophages
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