The 4-amino analogue of tetrahydrobiopterin efficiently prolongs murine cardiac-allograft survival.
We tested the 4-amino analogue of tetrahydrobiopterin (H(4)aminobiopterin), 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 H(4)aminobiopterin, with Cyclosporin A (15 mg/kg/day), or no treatment. H(4)aminobiopterin (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 H(4)aminobiopterin effective in prolonging allograft survival did not change the plasma nitrite plus nitrate, or the expression of inducible nitric oxide synthase, interferon-gamma, tumor necrosis factor-alpha, and B7-1 (CD80), indicating that H(4)aminobiopterin may act through a novel, yet undiscovered mechanism.
Brandacher
G
G
Department of Transplant Surgery, University Hospital Innsbruck, Innsbruck, Austria.
Zou
Y
Y
Obrist
P
P
Steurer
W
W
Werner-Felmayer
G
G
Margreiter
R
R
Werner
E R
ER
D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology*; D016572:Cyclosporine / Q000008:administration & dosage / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D006085:Graft Survival / Q000187:drug effects*; D006207:Half-Life; D016027:Heart Transplantation; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D007371:Interferon-gamma / Q000032:analysis / Q000187:drug effects; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009204:Myocardial Revascularization / Q000379:methods; D009206:Myocardium / Q000473:pathology; D009336:Necrosis; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D023001:Transplantation Tolerance / Q000187:drug effects
D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; C106930:4-amino-tetrahydrobiopterin; D001708:Biopterins; D007371:Interferon-gamma; D016572:Cyclosporine; D019001:Nitric Oxide Synthase