Sildenafil extends survival and graft function in a large animal lung transplantation model

Objective: Restoring intracellular cGMP and inducing NO-synthesis attenuates ischemia-associated early pulmonary allograft dysfunction. Phosphodiesterase-5 (PDE), predominantly expressed in lung tissue, plays a pivotal role in modulating the cGMP/NO-synthase pathway in endothelial and epithelial cells. In this study, we evaluate the effect of employing sildenafil (Viagra (R)), a specific inhibitor of PDE-5, to counteract ischemia/reperfusion (I/R) injury in a single lung transplantation model of extended ischemia. Methods: Donor animals (weight matched outbred pigs, 28-35 kg) in the treatment group (1) (n = 5) were injected with 0.7 mg sildenafil/kg into the pulmonary artery (PA) prior to inflow occlusion. For perfusion, Perfadex (R)), containing 0.7 mg sildenafil/l was used, and the graft stored at 1 degrees C in the per-fusion solution. After 24 h ischemia, unilateral left lung transplantation was performed. Starting at reperfusion, group I received continuous sildenafil (0.7 mg sildenafil/kg), over 6 h. Except for the sildenafil application, the control group (11) (n = 4) was treated identically (PGE1 was injected into the PA). One hour after reperfusion, the right main bronchus (MB) and right PA were occluded. Over the next 5 h, cardiopulmonary parameters (systemic aterial, PA, central venous, left atrial. pressure, pCO(2), pO(2)) were measured, including extravascular lung water (EVLW). Thiobarbituric acid-reactive substance assay (TBARS) and myeloperoxidase (MPO) analysis from lung tissue were run. Results: All recipients of group I survived the 6-h reperfusion period; in contrast, all control animals died within 1-2 h after occlusion of the right side. In comparison to a marked rise in pulmonary vascular resistance (PVR) in group 11 (> 1000 dyne s cm(-5)), PVR in group I remained stable, moderately elevated from baseline (baseline: 150180 dyne S cm(-5) vs endpoint: 1000 dyne S cm(-5)). EVI2W in group I did not increase during reperfusion (baseline: 6.75 +/- 1.4 mg/kg vs endpoint: 6.7 +/- 1.0 mg/kg), in contrast to group 11, where pulmonary edema at 2-h reperfusion preceded terminal graft failure (group 1: 9.7 +/- 0.1 mg/kg vs group 11: 6.48 +/- 1.8 mg/kg). Tissue reactive free radicals at endpoint measurement in group I did not differ significantly from native tissue. Yet, when compared to specimen taken from group 11 at time of terminal graft failure, a significant increase in free radicals was noted (group 1: 13.8 +/- 1.6 pmol/g vs group It: 18.5 +/- 3.0 pmol/g, p < 0.05). Conclusion: Sildenafil treatment prevents terminal early graft failure, allowing lung transplantation after 24-h ischemia time. Reperfusion edema was strikingly diminished, preserving pulmonary structural and functional integrity while prolonging graft ischemia time. Employing the established PDE-5 inhibitor sildenafil during lung perfusion, storage, and implantation, ischemic tolerance may be extended and early graft function improved. (c) 2005 Elsevier B.V. All rights reserved.