Prevention of lethal murine pancreas ischemia reperfusion injury is specific for tetrahydrobiopterin.

Abstract

Tetrahydrobiopterin has been shown to efficiently abrogate ischemia reperfusion injury (IRI). However, it is unclear, whether its beneficial action relies on cofactor activity of one of the five known tetrahydrobiopterin-dependent reactions or on its antioxidative capacity. We therefore compared tetrahydrobiopterin with the pterin derivate tetrahydroneopterin (similar biochemical properties, but no nitric oxide synthase cofactor activity) and the antioxidants vitamin C and 5-methyltetrahydrofolate. Donor mice were pretreated with tetrahydrobiopterin, tetrahydroneopterin, vitamin C, or 5-methyltetrahydrofolate. Pancreatic grafts were subjected to 16-h cold ischemia time and implanted in syngeneic recipients. Untreated and nontransplanted animals served as controls. Following 2-h reperfusion, microcirculation was analyzed by intravital fluorescence microscopy. Graft damage was assessed by histology and nitrotyrosine immunostaining, and tetrahydrobiopterin levels were determined by HPLC. Recipient survival served as ultimate readout. Prolonged cold ischemia time resulted in microcirculatory breakdown. Only tetrahydrobiopterin pretreatment succeeded to preserve the capillary net, whereas all other compounds showed no beneficial effects. Along with increased intragraft tetrahydrobiopterin levels during recovery and implantation, only tetrahydrobiopterin pretreatment led to significant reduction of IRI-related parenchymal damage enabling recipient survival. These results show a striking superiority of tetrahydrobiopterin in preventing lethal IRI compared with related compounds and suggest nitric oxide synthases as treatment target.

• Authors: Manuel Maglione, Benno Cardini, Rupert Oberhuber, Katrin Watschinger, Marcel Jenny, Johanna Gostner, Martin Hermann, Peter Obrist, Raimund Margreiter, Johann Pratschke, Gerald Brandacher, Ernst R Werner
• Journal: Transplant international : official journal of the European Society for Organ Transplantation (Transpl Int) Vol. 25 Issue 10 Pg. 1084-95 (Oct 2012) ISSN: 1432-2277 [Electronic] Switzerland
• PMID: 22805419 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2012 The Authors. Transplant International © 2012 European Society for Organ Transplantation.

Chemical References

• Antioxidants
• Tetrahydrofolates
• Biopterin
• tetrahydroneopterin
• Nitric Oxide
• sapropterin
• Ascorbic Acid
• 5-methyltetrahydrofolate

Topics

• Animals
• Antioxidants (metabolism)
• Ascorbic Acid (metabolism)
• Biopterin (analogs & derivatives, chemistry, pharmacology)
• Cold Ischemia
• Immunohistochemistry (methods)
• Ischemia
• Liver (pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Microcirculation
• Microscopy, Confocal (methods)
• Nitric Oxide (chemistry)
• Organ Preservation
• Pancreas (pathology)
• Pancreas Transplantation (methods)
• Reperfusion Injury (prevention & control)
• Tetrahydrofolates (chemistry)
• Time Factors