The 4-amino analogue of tetrahydrobiopterin efficiently prolongs murine cardiac-allograft survival

We tested the 4-amino analogue of tetrahydrobiopterin (H₄aminobiopterin), a novel pterin-based inhibitor of nitric oxide synthases, for its efficacy in a murine cardiac-transplant model employing an improved cuff technique. We treated groups of 5 animals each for the first 7 post-operative days with various doses of H₄aminobiopterin, with Cyclosporin A (15 mg/kg/day), or no treatment. H₄aminobiopterin (3 times 50 mg/kg/day) proved to be as efficient as high-dose Cyclosporin A (15 mg/kg/day) in prolonging allograft survival and in suppressing histologic changes caused by the immunoreaction. Surprisingly, the doses of H₄aminobiopterin effective in prolonging allograft survival did not change the plasma nitrite plus nitrate, or the expression of inducible nitric oxide synthase, interferon-γ, tumor necrosis factor-α, and B7-1 (CD80), indicating that H₄aminobiopterin may act through a novel, yet undiscovered mechanism.