Suppression of intimal hyperplasia in experimental vein grafts by oral L-arginine supplementation and single ex vivo immersion in deferoxamine manganese

Purpose: Vein grafts undergo morphologic and functional changes after insertion into the arterial circulation with the development of intimal hyperplasia, as well as significant alterations in endothelial and smooth muscle cell physiologic responses. Methods: Forty New Zealand white rabbits underwent jugular vein interposition grafting of the common carotid artery. Ten animals were controls, 10 animals received 2.25% L-arginine supplementation in their drinking water (200 ml/day; 2 gm/kg) 7 days before surgery and continued thereafter until harvest, in 10 animals the veins were immersed in deferoxamine manganese (DFMn; 10(-3) mol/L in heparinized Ringer's lactate for 15 minutes) before implantation, and 10 received both L-arginine supplementation and DFMn therapy. Twenty-eight days after the operation, the vein grafts were harvested for either histologic (n = 6) or isometric tension studies (n = 4). The function of vein grafts was compared with that of jugular veins. Results: Treatment with DFMn, L-arginine, and DFMn/L-arginine produced decreases in mean intimal thickness of 39% (51 +/- 7 mu m; p < 0.05), 51% (41 +/- 7 mu m; p < 0.05), and 65% (29 +/- 6 mu m; P < 0.01), respectively, compared with control vein grafts (83 +/- 12 mu m). Compared with the control group, the intimal ratio ([intima]/[intima + media]) decreased by 16% (difference not significant), 8% (difference not significant), and 47% (p < 0.01) in the DFMn-, L-arginine- and DFMn/L-arginine-treated vein grafts, respectively. Jugular veins relaxed to acetylcholine (53% +/- 12% maximal relaxation), whereas control vein grafts did not relax. In contrast, vein grafts from each of the experimental groups relaxed to acetylcholine with maximal relaxations of 26% +/- 7% (p < 0.05 compared with the jugular vein), 22% +/- 8% (P < 0.05), and 44% +/- 14% (difference not significant) in the DFMn, L-arginine, and DFMn/L-arginine groups, respectively. Neither DFMn nor L-arginine had a significant effect on the alterations in smooth muscle cell contractility that occur in control vein grafts. Conclusion: This study demonstrates that an agent that modulates free radical production combined with a precursor of nitric oxide formation will lead to a significant decrease in the formation of intimal hyperplasia in arterial vein grafts with the preservation of endothelial-derived relaxation.