ABSTRACT
Objective To evaluate the effects of a novel inducible nitric oxide synthase (iNOS) inhibitor (FR260330) in prevention of chronic rejection in a model of rat aortic allograft and to investigate the mechanism of the arterial wall lesion of chronically rejecting solid organ grafts. Methods Male Lewis (LEW, RT1~ l) rats received male ACI (RT1~ a) aorta allografts or LEW aorta isografts. Seven groups (n≥12) were involved in this study. FR260330 and/or tacrolimus were administered orally for 14 or 90 days according to protocol. The degree of intimal proliferation of graft aorta was determined by a computerized image system.Results Both low and high doses of FR260330 or tacrolimus treated grafts showed significantly decreased intima/(intima+media) ratios at day 90 compared with placebo controls. Combined therapy of low-dose of FR260330 with low-dose of tacrolimus produced a significant decrease of intima/(intima+media) ratios with intact endothelium as compared with placebo controls. Anti-?-actin immunohistochemical staining demonstrated that one of the mechanisms of intimal proliferation was related to migration of vascular smooth muscle cells. The intima in iNOS inhibition groups was more smooth than in placebo control group and low-dose FK506 treated groups.Conclusions A selective inhibitor of nitric oxide synthase, FR260330 plays a protective role in chronic aortic allograft rejection in the rat. Combined therapy of low-dose of FR260330 with tacrolimus produces significant protection of immune injury and may serve to improve long-term graft survival and function.