Local Intramural Delivery of l -Arginine Enhances Nitric Oxide Generation and Inhibits Lesion Formation After Balloon Angioplasty

Abstract

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.