NOX 100, a nitric oxide scavenger, enhances cardiac allograft survival andpromotes long-term graft acceptance

Citation
Am. Roza et al., NOX 100, a nitric oxide scavenger, enhances cardiac allograft survival andpromotes long-term graft acceptance, TRANSPLANT, 69(2), 2000, pp. 227-231
Citations number
25
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Medical Research Diagnosis & Treatment
Journal title
TRANSPLANTATION
ISSN journal
0041-1337 → ACNP
Volume
69
Issue
2
Year of publication
2000
Pages
227 - 231
Database
ISI
SICI code
0041-1337(20000127)69:2<227:N1ANOS>2.0.ZU;2-A
Abstract
Background, We examined the role of nitrosative stress in allograft destruc tion. Methods. Rats undergoing cardiac transplants received NOX-100, a water-solu ble nitric oxide (NO) scavenger with antioxidant properties, with or withou t low-dose cyclosporine (CsA), Graft survival, NO production, and nuclear f actor kappa B (NF-kappa B) activity were studied. Results. Using NOX-100 daily until rejection prolonged graft survival (11.6 +/-0.6 vs. 7.4+/-0.2 days; P<0.05). Daily low-dose CsA (2.5 mg/kg im) for 7 days or until rejection also prolonged survival (12.6+/-0.5 and 21.6+/-1.6 days, respectively; P<0.01 vs, Controls). Low-dose CsA for 7 days and NOX- 100 for 30 days prolonged graft survival (45.0+/-4.7days; P<0.01 vs. all gr oups.). NOX-100 had no effect on whole blood CsA levels. Combination therap y until Day 100 resulted in 1 graft loss at Day 116 and indefinite survival in 3 animals (>300 days), which accepted a second WF strain heart without further immunosuppressive therapy but promptly rejected a third party (ACI) cardiac allograft. NOX-100 and CsA reduced nitrate and nitrite, and combin ation therapy completely normalized NO through to Day 30, Electron paramagn etic resonance spectroscopic analysis demonstrated reduction of signals for nitrosylmyoglobin and nitrosylheme with NOX-100 and elimination of signals with CsA alone or combination therapy. Activity of myocardial NF-kappa B d ecreased with monotherapy vs. untreated allografts. Combination therapy res ulted in further inhibition of NF-kappa B up to Day 30, The extent of graft survival correlated with the extent of NO scavenging and NF-kappa B inhibi tion. Short-term combination therapy had no effect on graft lymphocytic inf iltrate on Days 15, 20, and 30. Conclusion. These data support a role for both oxidative and nitrosative st ress in rejection and the immunoregulatory potential of antioxidant therapy after transplantation.