Reduction of myocardial nitrosyl complex formation by a nitric oxide scavenger prolongs cardiac allograft survival

Nitric oxide synthase (NOS) inhibitors have been shown to reduce NO but yie ld conflicting results on cardiac allograft survival. In this study, we pro vide an alternative approach specifically to examine the efficacy of a NO s cavenger on nitrosyl complex formation and graft survival in a model of het erotopic cardiac transplantation. Efficacy was examined under both acute an d chronic conditions (i.e., without or with immunosuppression, respectively ). Electron paramagnetic resonance (EPR) spectroscopy of frozen myocardial tissue from untreated allografts showed progressive increases in nitrosylhe me and nitrosomyoglobin before graft failure. These signals were not seen i n either isografts or native hearts of allograft recipients. Both plasma ni trate plus nitrite and myocardial nitrosyl complex formation in cardiac all ografts were significantly decreased in recipient animals treated with the NO scavenger, NOX-100, or by low-dose cyclosporine (CsA). Both intervention s were nearly equivalent in significantly prolonging graft survival. The sh ort-term combination treatment of both NOX-100 plus CsA completely eliminat ed myocardial nitrosyl complex formation and synergistically prolonged graf t survival. Long-term combination drug treatment (days 0-100) followed by c essation of therapy resulted in permanent graft acceptance with no evidence for nitrosyl complex formation. These studies support a role of NO in card iac allograft rejection. Furthermore, these studies indicate a potential th erapeutic value of NO scavengers in preventing organ rejection.