Enhanced Preservation of Orthotopically Transplanted Rat Lungs by Nitroglycerin but Not Hydralazine

Abstract

Abstract Nitric oxide (NO) produced within the lungs maintains pulmonary vascular homeostatic properties, modulating leukocyte traffic, platelet aggregation, and vasomotor tone. Because reactive oxygen intermediates generated during reperfusion react rapidly with available NO, we hypothesized that the NO donor nitroglycerin (NTG) would enhance lung preservation for transplantation by improving graft blood flow and reducing graft neutrophil and platelet sequestration. By use of an orthotopic rat left lung transplant model, with ligation of the native right pulmonary artery to ensure that recipient survival and physiological measurements depend entirely on the transplanted lung, transplants were performed in 70 male Lewis rats after 6-hour 4°C preservation in Euro-Collins solution (EC) alone or EC with supplemental NTG. Compared with EC alone, supplemental NTG significantly increased pulmonary arterial flow (2.2±1.4 to 21.4±2.9 mL/min, P <.01), decreased pulmonary vascular resistance (7.4±2.0 to 1.4±0.1×10 3 Woods units, P <.05), improved arterial oxygenation (163±57 to 501±31 mm Hg, P <.01), and enhanced recipient survival (17% to 100%, P <.001). These beneficial effects of NTG were dose dependent over a range of 0.001 to 0.1 mg/mL. Although NTG caused significant pulmonary vasodilation during the harvest/flushing period, the direct-acting vasodilator hydralazine caused greater vasodilation than did NTG but was associated with poor graft function, elevated pulmonary vascular resistance, and poor recipient survival. To explore nonvasodilator protective mechanisms of NTG, graft neutrophil and platelet sequestration were studied; supplemental NTG significantly reduced both neutrophil and platelet accumulation compared with either hydralazine or EC alone. These findings suggest that vasodilation alone at the time of harvest is insufficient to protect the lungs. NTG, which produces antineutrophil and antiplatelet effects as well as harvest vasodilation, appears to be a simple and effective additive that will improve lung preservation for transplantation.