The nitric oxide synthase cofactor tetrahydrobiopterin reduces allograft ischemia-reperfusion injury after lung transplantation

Objective: Exogenous nitric oxide reduces ischemia-reperfusion injury after solid organ transplantation. Tetrahydrobiopterin, an essential cofactor fo r nitric oxide synthases, may restore impaired endothelium-dependent nitric oxide synthesis. We evaluated whether tetrahydrobiopterin administration t o the recipient attenuates lung reperfusion injury after transplantation in swine. Methods: Unilateral left lung transplantation was performed in 15 w eight-matched pigs (24-31 kg), Donor lungs were flushed with 1.5 L cold (1 degrees C) low-potassium-dextran solution and preserved for 20 hours, Group I animals served as controls. Group TT and III animals were treated with a bolus of tetrahydrobiopterin (20 mg/kg). In addition, in group III a conti nuous infusion of tetrahydrobiopterin (10 mg/kg per hour over 5 hours) was given. One hour after reperfusion, the recipient right lung was occluded. C yclic guanosine monophosphate levels were measured in the pulmonary venous and central venous blood. Extravascular lung water index, hemodynamic varia bles, lipid peroxidation, and neutrophil migration to the allograft were as sessed. Results: In group III a significant reduction of extravascular lung water was noted in comparison with the controls (P = .0047). Lipid peroxid ation in lung allograft tissue was significantly reduced in group II (P = . 0021) and group III (P = .0077) in comparison,vith group I. Pulmonary venou s levels of cyclic guanosine monophosphate increased up to 23 +/- 1 pmol/mL at 5 hours in group II and up to 40 +/- 1 pmol/mL in group III (group I, 4 .1 +/- 0.5 pmol/mL [I vs III]; P < .001), whereas central venous levels of cyclic guanosine monophosphate were unchanged in all groups. Conclusion: Te trahydrobiopterin administration during lung allograft reperfusion may redu ce posttransplantation lung edema and oxygen-derived free radical injury in the graft. This effect is mediated by local enhancement of the nitric oxid e/cyclic guanosine monophosphate pathway.