L-arginine polymer mediated inhibition of graft coronary artery disease after cardiac transplantation

Background. Nitric oxide (NO) limits the development of graft coronary arte ry disease (GCAD) in transplanted hearts. We hypothesized that L-arginine p olymers administered to cardiac allografts ex vivo would translocate across vascular cellular membranes, upregulate inducible nitric oxide synthase (i NOS) production of NO, and inhibit the development of GCAD, Methods, Three groups of PVG rat donor hearts were incubated with either 0. 8 mi phosphate-buffered saline, (PBS, n=12) or 50 muM L-arginine polymer so lutions of length five (R5, n=12) or nine (R9, n=12) prior to heterotopic t ransplantation into ACI recipients, Graft vessels were scored at POD 60 and 90 for percentage luminal narrowing (%LN), intima to media ratio (I/M), an d percentage affected vessels (%AV). Translocation efficiency was determine d by treatment with biotinylated polymers. NO production of treated aortic segments was determined in vitro by Griess reaction. Results. Translocation efficiencies were 89+/-19% (R9), 7+/-10% (R5), and 0 +/-0% PBS (ANOVA, P<0.001) which corresponded to NO production in treated a ortic segments of 0.175+/-0.17 (R9), 0.120+/-0.006 (R5), and 0.135+/-0.035 <mu>M/mg (PBS), (ANOVA, P=0.002), GCAD scores at POD 60 were: %LN: 3.2+/-3. 8% (R9), 12.6+/-6.7% (R5), 11.3+/-4.2% (PBS) (ANOVA, P=0.025); I/M: 0.03+/- 0.04 (R9), 0.13+/-0.07 (R5), 0.12+/-0.05 (PBS) (ANOVA, P=0.037); %AV: 7+/-7 % (R9), 19+/-7%(R5), 22+/-9%(PBS) (ANOVA, P=0.021). Reduction of GCAD param eters was maintained at POD 90, Conclusion. R9 efficiently translocated across cytoplasmic membranes, enhan ced vascular NO production, and decreased neointimal hyperplasia, This ex v ivo treatment may have a therapeutic role in preventing GCAD.