Faculty Collaboration Database

Variable efficacy of N6-(1-iminoethyl)-L-lysine in acute cardiac transplant rejection. Am J Physiol Heart Circ Physiol 2004 Feb;286(2):H525-34

Date

01/13/2004

Pubmed ID

14715498

DOI

10.1152/ajpheart.00356.2003

Scopus ID

2-s2.0-19244374793 (requires institutional sign-in at Scopus site)   8 Citations

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.

Author List

Pieper GM, Nilakantan V, Hilton G, Zhou X, Khanna AK, Halligan NL, Felix CC, Kampalath B, Griffith OW, Hayward MA, Roza AM, Adams MB

Authors

Owen Griffith PhD Emeritus Professor in the Biochemistry department at Medical College of Wisconsin
Allan Roza MD Emeritus Professor in the Surgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Disease Models, Animal
Electron Spin Resonance Spectroscopy
Enzyme Inhibitors
Graft Rejection
Heart Transplantation
Hemeproteins
Lysine
Nitric Oxide Synthase
Nitric Oxide Synthase Type II
Rats
Rats, Sprague-Dawley
Time Factors
Transplantation, Homologous