L-arginine polymers inhibit the development of vein graft neointimal hyperplasia

Objective: We sought to determine whether L-arginine polymer treatment of vein grafts enhances vascular production of nitric oxide and inhibits the development of neointimal hyperplasia. Methods: External jugular veins of New Zealand White rabbits (n = 42) were harvested; treated intraluminally for 15 minutes with phosphate-buffered saline solution or L-arginine polymer 5, 7, or 9 at either 10 or 100 μmol/L; and then grafted into the contralateral carotid artery. Rabbits were killed after 28 days, and 5-μm sections of vessels were stained with hematoxylin and scored for intima/media ratio by using computerized morphometric analysis. Separate veins were treated in a similar fashion with biotinylated polymers and phosphate-buffered saline solution to assess for translocation efficiencies. Finally, vein segments pretreated with either phosphate-buffered saline solution or L-arginine polymers were cultured in Dulbecco's modified Eagle's medium containing lipopolysaccharide (100 μg/mL) and interferon μ (200 U/mL) for 48 hours before measuring nitric oxide levels by means of the Griess reaction. Results: Biotinylated L-arginine polymers demonstrated a dose- and length-dependent uptake into intimal and medial cells of treated vessels. Nitric oxide levels were significantly higher in vein segments treated with 100 μmol/L of L-arginine polymer 9 compared with control segments. Finally, the intima/media ratio also reflected both length- and concentration-dependent inhibition of neointimal hyperplasia. Intima/media ratio PBS R5 R7 R9 10 μmol/L 0.909±0.072 0.920±0.073 0.861±0.138 0.710±0.122 100 μmol/L 0.924±0.061 0.581±0.089* 0.529±0.093* PBS, Phosphate-buffered saline solution; R, L-arginine polymer. *P < .001 versus phosphate-buffered saline solution and L-arginine polymer 5 controls (Bonferroni-corrected value). Conclusions: Arginine polymers of sufficient length and concentration were effective in increasing nitric oxide levels and reducing neointimal hyperplasia in this vein graft model.