Tetrahydrobiopterin compounds prolong allograft survival independently of their effect on nitric oxide synthase activity.

Background: In previous work, the four-amino analogue of tetrahydrobiopterin, a novel, selective inhibitor of inducible nitric oxide synthase, has been shown to prolong survival of murine cardiac allografts.

Methods: To further elucidate the underlying molecular immunosuppressive mechanism, we compared the effect of four-amino tetrahydrobiopterin with that of the unsubstituted parent compound tetrahydrobiopterin and of N-(iminoethyl)-L-lysine (L-NIL), a nonpterin inhibitor of inducible nitric oxide synthase using a murine cardiac transplant model. We analyzed allograft survival, intragraft gene expression in grafts by microarray and real-time polymerase chain reaction, graft nitrotyrosine staining by immunohistochemistry and plasma nitrite plus nitrate levels by high-performance liquid chromatography.

Tetrahydro-4-aminobiopterin attenuates dendritic cell-induced T cell priming independently from inducible nitric oxide synthase.

Formation of NO by NO synthases (NOSs) strictly depends on tetrahydrobiopterin. Its structural analog, tetrahydro-4-aminobiopterin, is an inhibitor of all NOS isoenzymes, which prolongs allograft survival in acute murine cardiac rejection and prevents septic shock in the rat. In this study, we show that murine bone marrow-derived dendritic cells treated with tetrahydro-4-aminobiopterin had a reduced capacity to prime alloreactive murine T cells in oxidative mitogenesis.

Tetrahydropteridines suppress gene expression and induce apoptosis of activated RAW264.7 cells via formation of hydrogen peroxide.

Tetrahydrobiopterin, a redox-active cofactor, is essential for nitric oxide (NO) biosynthesis. Previous work showed that intracellular tetrahydrobiopterin levels modulate activity of nitric oxide synthases (NOSs). The 4-amino analog of tetrahydrobiopterin is an effective inhibitor of all three purified NOS isoforms that, in intact cells, preferentially targets the inducible isoenzyme.