FK409, a spontaneous nitric oxide releaser, attenuates allograft vasculopathy in a rat aortic transplant model

Although systemic administration of NO donors has been shown to attenuate t he development of neointimal hyperplasia in the balloon injury model, this strategy has not been tested in a model of allograft vasculopathy. In this study, we investigated the effect of FK409, a spontaneous NO releaser, on t he development of allograft vasculopathy, using a rat aortic transplant mod el. Thoracic aortas from ACI rats were transplanted heterotopically into th e abdominal aorta of Wistar-Furth rats. Postoperatively, recipients receive d FK409 orally every 8 hours from the day of transplantation to the time of euthanization. Morphometric and immunohistochemical analyses were performe d on the aortic grafts 8 weeks after transplantation. Control allografts sh owed severe neointimal hyperplasia, which consists mainly of cr-actin-conta ining vascular smooth muscle cells. The FK409-treated allografts showed a d ose-dependent reduction (statistically significant compared with the contro l) in the neointimal thickness as the dose increased from 1 to 10 mg/kg (th rice per day). However, there was no significant difference in the neointim al thickness between groups treated with 10 and with 20 mg/kg. FK409 treatm ent (10 mg/kg) caused a significant decrease in DNA synthesis (5-bromo-2-de oxyuridine [BrdU] uptake), an increase in DNA fragmentation (terminal deoxy nucleotidyltransferase-mediated uridine nick-end labeling [TUNEL]), and upr egulation of Fas expression, in the neointimal vascular smooth muscle cells . These data suggest that FK409 attenuates the allograft vasculopathy in a rat aortic transplant model.