HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Stephan Korom André Dutly Walter Weder Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Korom, S. Articles by Weder, W. Search for Related Content PubMed PubMed Citation Articles by Korom, S. Articles by Weder, W. Related Collections Lung - transplantation

Eur J Cardiothorac Surg 2006;29:288-293
© 2006 Elsevier Science NL

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

Department of Thoracic Surgery, University Hospital Zurich, Raemistrasse 100, CH-8091 Zurich, Switzerland

Received 1 October 2005; received in revised form 24 November 2005; accepted 2 December 2005.

^_* Corresponding author. Tel.: +41 1 255 88 02; fax: +41 1 255 88 05. (Email: walter.weder{at}usz.ch).

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^®), 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 (I) (n = 5) were injected with 0.7 mg sildenafil/kg into the pulmonary artery (PA) prior to inflow occlusion. For perfusion, Perfadex^®, containing 0.7 mg sildenafil/l was used, and the graft stored at 1 °C in the perfusion 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 (II) (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, pCO₂, pO₂) 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 II (>1000 dyne s cm^–5), PVR in group I remained stable, moderately elevated from baseline (baseline: 150–180 dyne s cm^–5 vs endpoint: 1000 dyne s cm^–5). EVLW 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 II, where pulmonary edema at 2-h reperfusion preceded terminal graft failure (group I: 9.7 ± 0.1 mg/kg vs group II: 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 II at time of terminal graft failure, a significant increase in free radicals was noted (group I: 13.8 ± 1.6 pmol/g vs group II: 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.

Key Words: Lung transplantation • I/R injury • Sildenafil

This article has been cited by other articles:

				N. Pizanis, V. Milekhin, K. Tsagakis, I. Aleksic, M. Kamler, and H. Jakob PDE-5 inhibitor donor intravenous preconditioning is superior to supplementation in standard preservation solution in experimental lung transplantation Eur. J. Cardiothorac. Surg., July 1, 2007; 32(1): 42 - 47. [Abstract] [Full Text] [PDF]

				M. Hanif and S. F. Hashmi Better lung preservation with sildenafil? Eur. J. Cardiothorac. Surg., August 1, 2006; 30(2): 415 - 415. [Full Text] [PDF]