The nitric oxide/cyclic GMP pathway in organ transplantation: Critical role in successful lung preservation

David J. Pinsky, Yoshifumi Naka, Nepal C. Chowdhury, Hui Liao, Mehmet C. Oz, Robert E. Michler, Eugeniusz Kubaszewski, Tadeusz Malinski, David M. Stern

Research output: Contribution to journalArticle

171 Scopus citations

Abstract

Reestablishment of vascular homeostasis following ex vivo preservation is a critical determinant of successful organ transplantation. Because the nitric oxide (NO) pathway modulates pulmonary vascular tone and leukocyte/endothelial interactions, we hypothesized that reactive oxygen intermediates would lead to decreased NO (and hence cGMP) levels following pulmonary reperfusion, leading to increased pulmonary vascular resistance and leukostasis. Using an orthotopic rat model of lung transplantation, a porphyrinic microsensor was used to make direct in vivo measurements of pulmonary NO. NO levels measured at the surface of the transplanted lung plummeted immediately upon reperfusion, with levels moderately increased by topical application of superoxide dismutase. Because cGMP levels declined in preserved lungs after reperfusion, this led us to buttress the NO pathway by adding a membrane-permeant cGMP analog to the preservation solution. Compared with grafts stored in its absence, grafts stored with supplemental 8-Br-cGMP and evaluated 30 min after reperfusion demonstrated lower pulmonary vascular resistances with increased graft blood flow, improved arterial oxygenation, decreased neutrophil infiltration, and improved recipient survival. These beneficial effects were dose dependent, mimicked by the type V phosphodiesterase inhibitor 2-o-propoxyphenyl-8-azapurin-6-one, and inhibited by a cGMP-dependent protein kinase antagonist, the R isomer of 8-(4- chlorophenylthio)guanosine 3',5'-cyclic monophosphorothioate. Augmenting the NO pathway at the level of cGMP improves graft function and recipient survival following lung transplantation.

Original languageEnglish (US)
Pages (from-to)12086-12090
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume91
Issue number25
DOIs
StatePublished - Dec 6 1994
Externally publishedYes

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Keywords

  • endothelium
  • leukocyte

ASJC Scopus subject areas

  • General

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