title: FK409, a spontaneous nitric oxide releaser, attenuates allograft vasculopathy in a rat aortic transplant model.
abstract: Although systemic administration of NO donors has been shown to attenuate the 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 the development of allograft vasculopathy, using a rat aortic transplant model. Thoracic aortas from ACI rats were transplanted heterotopically into the abdominal aorta of Wistar-Furth rats. Postoperatively, recipients received FK409 orally every 8 hours from the day of transplantation to the time of euthanization. Morphometric and immunohistochemical analyses were performed on the aortic grafts 8 weeks after transplantation. Control allografts showed severe neointimal hyperplasia, which consists mainly of alpha-actin-containing vascular smooth muscle cells. The FK409-treated allografts showed a dose-dependent reduction (statistically significant compared with the control) in the neointimal thickness as the dose increased from 1 to 10 mg/kg (thrice per day). However, there was no significant difference in the neointimal thickness between groups treated with 10 and with 20 mg/kg. FK409 treatment (10 mg/kg) caused a significant decrease in DNA synthesis (5-bromo-2-deoxyuridine [BrdU] uptake), an increase in DNA fragmentation (terminal deoxynucleotidyltransferase-mediated uridine nick-end labeling [TUNEL]), and upregulation 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.
authors.affiliation: Departments of Surgery, University of Miami School of Medicine, Miami, Florida, USA.
authors.forename: J
authors.initials: J
authors.lastname: Fukada
authors.forename: S
authors.initials: S
authors.lastname: Schena
authors.forename: I
authors.initials: I
authors.lastname: Tack
authors.forename: P
authors.initials: P
authors.lastname: Ruiz
authors.forename: Y
authors.initials: Y
authors.lastname: Kurimoto
authors.forename: M
authors.initials: M
authors.lastname: Pang
authors.forename: A
authors.initials: A
authors.lastname: Aitouche
authors.forename: T
authors.initials: T
authors.lastname: Abe
authors.forename: L J
authors.initials: LJ
authors.lastname: Striker
authors.forename: S M
authors.initials: SM
authors.lastname: Pham
mesh_terms: D000818:Animals; D001011:Aorta / Q000473:pathology / Q000637:transplantation*; D017209:Apoptosis / Q000187:drug effects; D001973:Bromodeoxyuridine / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology; D007150:Immunohistochemistry; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D009574:Nitro Compounds / Q000494:pharmacology*; D051381:Rats; D011912:Rats, Inbred ACI; D011920:Rats, Inbred WF; D014184:Transplantation, Homologous
chemical_list: D020030:Nitric Oxide Donors; D009574:Nitro Compounds; D016572:Cyclosporine; C061872:FK 409; D001973:Bromodeoxyuridine