CORTICOSTEROIDS INHIBIT EXPRESSION OF INDUCIBLE NITRIC OXIDE SYNTHASE DURING ACUTE CARDIAC ALLOGRAFT REJECTION1,2

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Abstract
We have recently demonstrated that (1) nitric oxide (NO) is produced during experimental cardiac allograft rejection by the expression of inducible nitric oxide synthase (iNOS) in the rejecting organ and that (2) inhibition of NO production by iNOS attenuated acute rejection. The present study examined the interaction of corticosteroids, iNOS gene expression, and iNOS enzyme activity in a rat cardiac transplant model. Increased NO production in rejecting allografts was demonstrated by elevated serum nitrite/nitrate levels (67 +/- 5 versus 18 +/- 2 microM for isografts; P < 0.001) that were significantly reduced by pulse therapy with dexamethasone for 2 days prior to animal sacrifice or continuous dexamethasone treatment (34 +/- 2 and 19 +/- 4 microM, respectively; P < 0.001 versus untreated allografts). Increased iNOS enzyme activity was demonstrated in the allograft heart (5.11 +/- 1.00 versus 0.3 +/- 0.05 pmol L-citrulline.mg protein-1.min-1 for isografts) and was significantly reduced with dexamethasone treatment (1.13 +/- 0.47 for 2-day pulse-treated allografts and 0.02 +/- 0.01 for continuously treated allografts). Increased allograft iNOS enzyme activity resulted from induction of iNOS mRNA expression, which was more than 99% inhibited by dexamethasone treatment. Dexamethasone pulse therapy reduced but did not eliminate the histological changes of acute rejection. Thus corticosteroid treatment results in inhibition of iNOS expression during allograft rejection. These results further demonstrate that iNOS expression during acute rejection is immune-mediated and suggest that the immunosuppressive actions of corticosteroids in the treatment of acute rejection may include inhibition of iNOS expression.