CORTICOSTEROIDS INHIBIT EXPRESSION OF INDUCIBLE NITRIC-OXIDE SYNTHASEDURING ACUTE CARDIAC ALLOGRAFT-REJECTION

We have recently demonstrated that (1) nitric oxide (NO) is produced d uring experimental cardiac allograft rejection by the expression of in ducible 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 mu M for isografts; P<0.001) that were significantly reduced by pulse therapy w ith dexamethasone for 2 days prior to animal sacrifice or continuous d examethasone treatment (34+/-2 and 19+/-4 mu M, respectively; P<0.001 versus untreated allografts). Increased iNOS enzyme activity was demon strated in the allograft heart (5.11+/-1.00 versus 0.3+/-0.05 pmol L-c itrulline mg protein(-1). min(-1) for isografts) and was significantly reduced with dexamethasone treatment (1.13+/-0.47 for 2-day pulse-tre ated allografts and 0.02+/-0.01 for continuously treated allografts). Increased allograft iNOS enzyme activity resulted from induction of iN OS 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 treat ment results in inhibition of iNOS expression during allograft rejecti on. These results further demonstrate that iNOS expression during acut e rejection is immune-mediated and suggest that the immunosuppressive actions of corticosteroids in the treatment of acute rejection may inc lude inhibition of iNOS expression.