Variable efficacy of N6-(1-iminoethyl)-L-lysine in acute cardiac transplant rejection.

Abstract

We examined the efficacy and mechanism of action of N(6)-(1-iminoethyl)-L-lysine (L-NIL), a highly selective inhibitor of inducible nitric oxide (NO) synthase (iNOS), on acute cardiac transplant rejection. L-NIL produced a concentration-dependent attenuation of plasma NO by-products and a decrease in nitrosylation of heme protein without altering protein levels of iNOS. At postoperative day 4, L-NIL did not alter the increased binding activities for transcription factors nuclear factor-kappaB and activator protein-1. Whereas L-NIL decreased inflammatory cell infiltration, graft survival was only prolonged at the dose of 1.0 microg/ml that incompletely blocked NO production. Higher L-NIL concentrations (30 and 60 microg/ml) ablated the increased NO production but failed to improve graft survival and even potentiated NF-kappaB binding activity examined at day 6. Alloimmune activation indicated by increased cytokine gene expression for interferon-gamma, interleukin-6, and interleukin-10 was inhibited in grafts only by treatment with 1.0 microg/ml L-NIL. These findings suggest a complex role of NO in acute cardiac allograft rejection. Partial inhibition of iNOS is beneficial to graft survival, whereas total ablation may oppose any benefits to graft survival. These studies have important implications in understanding the dual role of NO in acute rejection and help to reconcile discrepancies in the literature.