N-OMEGA-MONOMETHYL-L-ARGININE INHIBITS NITRIC-OXIDE PRODUCTION IN MURINE CARDIAC ALLOGRAFTS BUT DOES NOT AFFECT GRAFT-REJECTION

Endogenous nitric oxide biosynthesis in mice receiving allogeneic hete rotopic heart transplants was monitored as a function of time post-tra nsplant. Nitric oxide production was measured by daily urine nitrate l evels and by formation of paramagnetic heme-nitrosyl complexes in the cardiac tissue. Exogenous sources of urine nitrate and EPR signal were minimized by maintaining the animals on a low nitrite/nitrate diet. U rine nitrate peaked on postoperative day 7. A heme-nitrosyl EPR signal also appeared in the cardiac tissue on postoperative day 7 and remain ed unchanged in size until rejection on postoperative day 9 at which t ime the peak height of the signal nearly tripled. Some of the animals in the study were treated with the nitric oxide synthase inhibitor, N- omega-monomethyl-L-arginine which caused marked inhibition of urinary nitrate excretion and prevented heme-nitrosyl complex formation in bea ting hearts. However, administration of the inhibitor did not increase graft survival time. Low intensity heme-nitrosyl signals were identif ied in inhibitor-treated allogeneic hearts after rejection. Syngeneic heart transplants did not induce urinary nitrate excretion nor EPR sig nal formation. These results show that cytokine induced high output ni tric oxide synthesis from L-arginine is a prominent biochemical compon ent of the cell-mediated immune response to cardiac allografts in mice . However, nitric oxide production was not essential for rejection of cardiac allografts mismatched at the major histocompatibility locus.