Effect of a novel inducible nitric oxide synthase inhibitor in prevention of rat chronic aortic rejections.
BACKGROUND
Cytotoxic nitric oxide (NO) is produced during ischemia-reperfusion injury and acute and chronic rejection in allografts by expression of inducible (i) NO synthase (NOS). Therefore, continuous inhibition of iNOS may prevent early graft dysfunction and immune injury (rejection) and consequently improve graft survival. FR260330 is a potent and selective inhibitor of iNOS activity that works by preventing iNOS monomers from dimerization. In this study, the authors evaluated the effect of FR260330 in prevention of chronic rejection in a model of rat aortic allografts.


METHODS
Male Lewis (LEW, RT1l) rats received male ACI (RT1a) aorta allografts or LEW aorta isografts. Fourteen groups (n > or = 6) were involved in this study. FR260330, tacrolimus, or both 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. Combination therapy of low-dose FR260330 with low-dose tacrolimus produced a significant decrease of intima/(intima+media) ratios with intact endothelium compared with placebo controls. Anti-alpha-actin immunohistochemical staining demonstrated that one of the mechanisms of intimal proliferation is related to migration of vascular smooth muscle cells.


CONCLUSIONS
A selective inhibitor of NOS, FR260330 plays a protective role in chronic aortic allograft rejection in the rat. Combination therapy of low-dose FR260330 with tacrolimus produces significant protection of immune injury and may serve to improve long-term graft survival and function.
Ouyang
Jun
J
Laboratory of Experimental Surgery, Research Center of Centre Hospitalier de l'Université de Montréal, Notre-Dame Hospital, University of Montreal, Montreal, Quebec, Canada.
Xu
Dasheng
D
Zhang
Xiaochun
X
Qi
Shijie
S
Ma
Anlun
A
Jiang
Wenlei
W
Chida
Noboru
N
Sudo
Yuji
Y
Tamura
Kouichi
K
Daloze
Pierre
P
Chen
Huifang
H
D000199:Actins / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000473:pathology / Q000637:transplantation*; D001835:Body Weight / Q000187:drug effects; D002908:Chronic Disease; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D006084:Graft Rejection / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects; D006965:Hyperplasia; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D011912:Rats, Inbred ACI; D011917:Rats, Inbred Lew; D016559:Tacrolimus / Q000494:pharmacology; D014184:Transplantation, Homologous; D017539:Tunica Intima / Q000473:pathology*; D017540:Tunica Media / Q000473:pathology
D000199:Actins; D004791:Enzyme Inhibitors; C501443:FR260330; D007166:Immunosuppressive Agents; D010880:Piperidines; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D016559:Tacrolimus