NOX 100, a nitric oxide scavenger, enhances cardiac allograft survival and promotes long-term graft acceptance.
BACKGROUND
We examined the role of nitrosative stress in allograft destruction.


METHODS
Rats undergoing cardiac transplants received NOX-100, a water-soluble nitric oxide (NO) scavenger with antioxidant properties, with or without low-dose cyclosporine (CsA). Graft survival, NO production, and nuclear factor kappa B (NF-kappaB) 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+/-4.7 days; P<0.01 vs. all groups.). NOX-100 had no effect on whole blood CsA levels. Combination therapy 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 combination therapy completely normalized NO through to Day 30. Electron paramagnetic resonance spectroscopic analysis demonstrated reduction of signals for nitrosylmyoglobin and nitrosyl-heme with NOX-100 and elimination of signals with CsA alone or combination therapy. Activity of myocardial NF-kappaB decreased with monotherapy vs. untreated allografts. Combination therapy resulted in further inhibition of NF-kappaB up to Day 30. The extent of graft survival correlated with the extent of NO scavenging and NF-kappaB inhibition. Short-term combination therapy had no effect on graft lymphocytic infiltrate on Days 15, 20, and 30.


CONCLUSIONS
These data support a role for both oxidative and nitrosative stress in rejection and the immunoregulatory potential of antioxidant therapy after transplantation.
Roza
A M
AM
Department of Pathology, and The Biophysics Research Institute, Medical College of Wisconsin, Milwaukee 53226, USA.
Cooper
M
M
Pieper
G
G
Hilton
G
G
Dembny
K
K
Lai
C S
CS
Lindholm
P
P
Komorowski
R
R
Felix
C
C
Johnson
C
C
Adams
M
M
D000818:Animals; D001706:Biopsy; D016572:Cyclosporine / Q000493:pharmacokinetics; D016166:Free Radical Scavengers / Q000494:pharmacology*; D006085:Graft Survival / Q000187:drug effects; D016027:Heart Transplantation / Q000276:immunology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D011920:Rats, Inbred WF; D013012:Sorbitol / Q000031:analogs & derivatives
D016166:Free Radical Scavengers; D016328:NF-kappa B; C404528:nitric oxide scavenger 100; D009569:Nitric Oxide; D013012:Sorbitol; D016572:Cyclosporine