INHIBITION OF INDUCIBLE NITRIC-OXIDE SYNTHASE ATTENUATES ESTABLISHED ACUTE CARDIAC ALLOGRAFT-REJECTION

Background. We previously demonstrated that continuous treatment with aminoguanidine, a selective inhibitor of nitric oxide production by in ducible nitric oxide synthase, attenuated acute cardiac allograft reje ction. Methods. A rat transplant model was used to determine (1) when inducible nitric oxide synthase was expressed in the allograft heart d uring unmodified acute rejection and (2) whether pulse therapy with am inoguanidine attenuated the histologic changes of established acute re jection, in comparison with the effects of pulse therapy with corticos teroids. Results. Inducible nitric oxide synthase messenger RNA and pr otein were expressed during early and late acute rejection. Pulse ther apy with aminoguanidine inhibited nitric oxide production and attenuat ed the histologic changes of acute rejection, but not as effectively a s corticosteroid therapy (rejection scores of 4.1 +/- 0.4, 2.5 +/- 0.9 , and 1.4 +/- 0.6 on postoperative day 8, for untreated, aminoguanidin e-, and dexamethasone-treated allografts, respectively (scale, 0 to 5; p < 0.05). Conclusions. (1) Inducible nitric oxide synthase expressio n first occurs during early acute allograft rejection and persists thr oughout rejection and (2) nitric oxide is an important effector molecu le in acute rejection. Inducible nitric oxide synthase inhibition may offer a therapeutic adjunct in the management of acute rejection.