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(Circulation Research. 1996;79:773-783.)
© 1996 American Heart Association, Inc.

Articles

cAMP-Mediated Vascular Protection in an Orthotopic Rat Lung Transplant Model

Insights Into the Mechanism of Action of Prostaglandin E₁ to Improve Lung Preservation

Yoshifumi Naka, Dilip K. Roy, Hui Liao, Nepal C. Chowdhury, Robert E. Michler, Mehmet C. Oz, David J. Pinsky

the Departments of Physiology (Y.N., H.L.), Surgery (D.K.R., N.C.C., R.E.M., M.C.O.), and Medicine (D.J.P.), Columbia University College of Physicians and Surgeons, New York, NY.

Correspondence to David J. Pinsky, MD, Columbia University, College of Physicians and Surgeons, Department of Medicine, PH 10-Stem, 630 W 168th St, New York, NY 10032. E-mail djp5@columbia.edu.

Prostaglandin E₁ (PGE₁) is often added to the donor pulmonary flush solution to enhance clinical lung preservation for transplantation. Although PGE₁ is thought to act as a pulmonary vasodilator during the harvest period, the precise mechanism(s) of action whereby PGE₁ enhances lung preservation is unknown. Because cAMP levels decline in endothelial and vascular smooth muscle cells exposed to hypoxia, we hypothesized that a PGE₁-mediated increase in cAMP levels within the preserved lungs might improve pulmonary vascular homeostasis following lung transplantation. Rat lungs demonstrated a time-dependent decline in cAMP levels during hypothermic storage, with cAMP levels significantly increased by PGE₁ supplementation (2-fold by 6 hours, P<.0005). To test whether augmenting cAMP levels may enhance lung preservation, experiments were performed using an orthotopic rat left lung transplant model. Compared with controls, supplementing the preservation solution with the membrane-permeable cAMP analogue dibutyryl-cAMP resulted in dose-dependent preservation enhancement, marked by reduced pulmonary vascular resistance (6.0-fold, P<.01), improved arterial oxygenation (3.0-fold, P<.01), reduced graft neutrophil infiltration (1.5-fold, P<.05), and improved recipient survival (7.0-fold, P<.005). Similar preservation enhancement was observed with another cAMP analogue (8-bromo-cAMP) or the phosphodiesterase inhibitor indolidan. Stimulating the cAMP second messenger system by PGE₁ supplementation resulted in marked hemodynamic benefits and improved recipient survival, in parallel with reduced graft neutrophil infiltration, vascular permeability, and platelet deposition. These beneficial effects of PGE₁ were abrogated by simultaneous administration of the cAMP-dependent protein kinase antagonist Rp-cAMPS. Although an arterial vasodilator (minoxidil) resulted in significant pulmonary vasodilation during harvest, it lacked other nonvasodilating effects of PGE₁ and resulted in poor preservation. These data show that harvest vasodilation by itself is insufficient to enhance lung preservation and that PGE₁ enhances lung preservation by stimulating the cAMP-dependent protein kinase and promoting nonvasodilatory mechanisms of pulmonary protection.

Key Words: cAMP • prostaglandin E₁ • lung transplantation • protein kinase A • blood vessels

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