L-ARGININE PREVENTS HEART-TRANSPLANT ARTERIOSCLEROSIS BY MODULATING THE VASCULAR CELL PROLIFERATIVE RESPONSE TO INSULIN-LIKE GROWTH-FACTOR-I AND INTERLEUKIN-6

Background: L-arginine, a nitric oxide precursor, inhibits myointimal hyperplasia induced by balloon injury in native vessels. No studies ar e published on L-arginine effects on transplant arteriosclerosis. Insu lin-like growth factor-I and interleukin-6 are mitogenic for smooth mu scle cells and are involved in the cell-mediated and humoral immune re sponse. Methods: New Zealand White rabbits received cardiac allografts from Dutch Belted rabbits. All animals were fed a 0.5% cholesterol di et and received drinking water with (eight pairs) or without (eight pa irs) L-arginine (2.5%) from day 7 to until they were killed al day 42. The recipients received cyclosporine A 10 mg/kg/day from transplantat ion until the time they were killed. Results: Dietary L-arginine reduc es myointimal hyperplasia in allograft coronary arteries from 44% +/- 4% in the non-L-arginine group to 16% +/- 2% (p < 0.002). The L-argini ne significantly inhibits graft vascular cell proliferation induced by (1) insulin-like growth factor-I, from 328% +/- 66% to 154% +/- 28% ( p < 0.05), (2) interleukin-6, from 376% +/- 97% to 138% +/- 30% (p < 0 .05) and (3) the combination of insulin-like growth factor-I and inter leukin-6 from 710% +/- 201% to 226% +/- 72% (p < 0.05). In recipient n ative aorta explants L-arginine also abolishes vascular cell prolifera tion stimulated by insulin-like growth factor-I and interleukin-6. The rejection grading is similar in the L-arginine (2.9 +/- 0.1) and cont rol groups (2.7 +/- 0.1), Class II major histocompatibility antigen ex pression, T-lymphocyte, and macrophage infiltration in the cardiac all ograft are unaffected by L-arginine. However, the diet significantly i ncreased plasma nitric oxide from 15.4 +/- 2.3 to 45.1 +/- 11 mu mol ( p < 0.05). Conclusions: Dietary L-arginine attenuates transplant arter iosclerosis in vivo without affecting rejection. The protective effect seen in these experiments may relate to the generation of sufficient nitric oxide to prevent smooth muscle cell response to mitogens like i nsulin-like growth factor-I and interleukin-6.