The nitric oxide/cyclic GMP pathway in organ transplantation: critical role in successful lung preservation.
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.
Pinsky
D J
DJ
Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032.
Naka
Y
Y
Chowdhury
N C
NC
Liao
H
H
Oz
M C
MC
Michler
R E
RE
Kubaszewski
E
E
Malinski
T
T
Stern
D M
DM
D000594:Amino Acid Oxidoreductases / Q000378:metabolism; D000818:Animals; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology / Q000502:physiology*; D007700:Kinetics; D008168:Lung / Q000502:physiology*; D016040:Lung Transplantation / Q000502:physiology*; D008297:Male; D008564:Membrane Potentials; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase; D009926:Organ Preservation; D009195:Peroxidase / Q000378:metabolism; D011652:Pulmonary Circulation / Q000187:drug effects*; D051381:Rats; D011917:Rats, Inbred Lew; D017382:Reactive Oxygen Species; D015424:Reperfusion; D013873:Thionucleotides / Q000494:pharmacology; D013997:Time Factors; D014655:Vascular Resistance / Q000187:drug effects
C090860:8-(4-chlorophenylthio)guanosine 3',5'-cyclic monophosphorothioate; D017382:Reactive Oxygen Species; D013873:Thionucleotides; C016276:8-bromocyclic GMP; D009569:Nitric Oxide; D009195:Peroxidase; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D006152:Cyclic GMP