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(Circulation Research. 2000;87:66.)
© 2000 American Heart Association, Inc.

Integrative Physiology

FK409, a Spontaneous Nitric Oxide Releaser, Attenuates Allograft Vasculopathy in a Rat Aortic Transplant Model

Johji Fukada, Stefano Schena, Ivan Tack, Phillip Ruiz, Yoshihiko Kurimoto, Manhui Pang, Abdelouahab Aitouche, Tomio Abe, Liliane J. Striker, Si M. Pham

From the Departments of Surgery (J.F., S.S., M.P., A.A., S.M.P.), Medicine (I.T., L.J.S.), and Pathology (P.R.), University of Miami School of Medicine, Miami, Fla, and the Department of Thoracic and Cardiovascular Surgery (Y.K., T.A.), Sapporo Medical University, Sapporo, Japan.

Correspondence to Si M. Pham, MD, Division of Cardiothoracic Surgery, University of Miami School of Medicine, Highland Professional Building, 5th Floor, 1801 NW 9th Ave, Miami, FL 33136. E-mail spham{at}med.miami.edu

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 -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. (Circ Res. 2000;87:66-72.)

Key Words: FK409 • allograft • apoptosis • in situ nick-end labeling • Fas