SELECTIVE-INHIBITION OF NITRIC-OXIDE PRODUCTION DURING CARDIAC ALLOGRAFT-REJECTION CAUSES A SMALL INCREASE IN GRAFT-SURVIVAL

Nitric oxide production is increased in allograft rejection and may ha ve both beneficial and deleterious effects on graft function and survi val. In animal models, conventional immunosuppressive agents have been shown to decrease nitric oxide production. The aim of our study was t o determine what effect augmentation and selective inhibition of nitri c oxide production may have on graft survival by using the model of he terotopic cardiac transplantation in the rat, L-Arginine, the naturall y occurring substrate for nitric oxide production, was administered su bcutaneously at 200 mg/kg/day. L-NG-monomethyl-L-arginine (L-NMMA) is a selective inhibitor of nitric oxide synthase and was administered at 500 mg/kg/day to allograft recipients from the day of operation, Endo genous nitric oxide production was quantified by analysis of urinary n itrate excretion, and time to rejection was determined by graft palpat ion, L-Arginine did not significantly alter urinary nitrate excretion by iso- or allografts, suggesting that nitric oxide production is not a substrate-limited process in this model, Graft survival in this grou p was unchanged. L-NMMA produced a small increase in graft survival fr om 5.1+/-0.1 to 6.3+/-0.3 days compared with control allografts (P=0.0 01) and abolished the rise in urinary nitrate excretion seen with cont rol allografts. Lower doses of L-NMMA produced dose-related decrements in urinary nitrate excretion, but did not alter graft survival. We fo und that allograft rejection can proceed to graft loss despite complet e inhibition of the increase in nitric oxide production that occurs du ring untreated rejection, The small increase in graft survival suggest s that nitric oxide plays a minor role as a cytotoxic effector molecul e in this model of acute rejection.