Document Detail

Effect of a novel inducible nitric oxide synthase inhibitor in prevention of rat chronic aortic rejections.
MedLine Citation:
PMID:  15912108     Owner:  NLM     Status:  MEDLINE    
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.
Jun Ouyang; Dasheng Xu; Xiaochun Zhang; Shijie Qi; Anlun Ma; Wenlei Jiang; Noboru Chida; Yuji Sudo; Kouichi Tamura; Pierre Daloze; Huifang Chen
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Transplantation     Volume:  79     ISSN:  0041-1337     ISO Abbreviation:  Transplantation     Publication Date:  2005 May 
Date Detail:
Created Date:  2005-05-24     Completed Date:  2005-06-27     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0132144     Medline TA:  Transplantation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1386-92     Citation Subset:  IM    
Laboratory of Experimental Surgery, Research Center of Centre Hospitalier de l'Université de Montréal, Notre-Dame Hospital, University of Montreal, Montreal, Quebec, Canada.
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MeSH Terms
Actins / metabolism
Aorta / pathology,  transplantation*
Body Weight / drug effects
Chronic Disease
Dose-Response Relationship, Drug
Drug Therapy, Combination
Enzyme Inhibitors / administration & dosage,  pharmacology*
Graft Rejection / prevention & control*
Graft Survival / drug effects
Immunosuppressive Agents / pharmacology
Muscle, Smooth, Vascular / cytology,  metabolism
Myocytes, Smooth Muscle / metabolism
Nitric Oxide Synthase / antagonists & inhibitors*
Nitric Oxide Synthase Type II
Piperidines / administration & dosage,  pharmacology*
Rats, Inbred ACI
Rats, Inbred Lew
Tacrolimus / pharmacology
Transplantation, Homologous
Tunica Intima / pathology*
Tunica Media / pathology
Reg. No./Substance:
0/Actins; 0/Enzyme Inhibitors; 0/FR260330; 0/Immunosuppressive Agents; 0/Piperidines; 109581-93-3/Tacrolimus; EC Oxide Synthase; EC Oxide Synthase Type II; EC protein, rat

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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