Nitroglycerin maintains graft vascular homeostasis and enhances preservation in an orthotopic rat lung transplant model

Abstract

Transplanted lungs often fail during the peritransplantation period for poorly understood reasons. Because the nitric oxide pathway regulates pulmonary vascular tone, helps to maintain the integrity of the endothelial barrier, and modulates neutrophil adhesivity and activation, we hypothesized that perturbation of this pathway during the preservation and reperfusion of transplanted lungs might play a critical role in mediating early graft failure. To evaluate whether supplementing the preservation solution with the nitric oxide donor nitroglycerin enhances lung preservation for transplantation, we obtained hemodynamic measurements in a model of orthotopic left lung transplantation in the rat after ligation of the native right pulmonary artery. In these experiments, recipient survival and hemodynamics depended solely on the transplanted lung. The left lung was harvested from 22 rats, flushed with either lactated Ringer's solution alone (control, n = 11) or Ringer's solution supplemented with nitroglycerin (0.1 mg/ml, n = 11), preserved for 4 hours at 4 degrees C, and then transplanted using a rapid cuff technique for bronchial and vascular anastomoses. Nitroglycerin significantly improved arterial blood oxygenation (339 +/- 66 versus 130 +/- 12 mm Hg, p < 0.05), increased pulmonary arterial flow (7.6 +/- 1.9 versus 0.9 +/- 0.2 ml/min, p < 0.005), decreased pulmonary vascular resistance (1.7 +/- 0.4 versus 6.6 +/- 1.9 x 10(3) Wood units, p < 0.05), and enhanced recipient survival (64% versus 0%, p < 0.05). Control grafts had significantly greater neutrophil accumulation (50% greater as quantified by myeloperoxidase activity, p < 0.05) than grafts preserved in the presence of nitroglycerin. These studies show that supplementation of the preservation solution with the nitric oxide donor nitroglycerin maintains graft vascular homeostasis and significantly improves pulmonary function and recipient survival after transplantation.

Extinguishing Egr‐1‐dependent inflammatory and thrombotic cascades following lung transplantation

“…The left lung was then excised, and the pulmonary arterial and pulmonary venous stumps were cross-clamped to prevent seepage of preservation solution. Orthotopic left lung transplantation into gender/strain/size matched recipients was performed as described (10,25). Depending on the particular experiment, preservation duration was 4 h or 6 h, and reperfusion duration ranged from 30 min to 4 h (indicated in the figure legends).…”

Mitochondrial Injuries in Rat Lungs Preserved for 17 h: An Ultrastructural Study

“…In groups B-E (n = 5 in each group), the [15,16], nitroglycerin [17,18] and N-acetylcystein [19][20][21], three compounds that are expected to protect vascular endothelium.…”

Nebulized nitrite protects rat lung grafts from ischemia reperfusion injury

“…In addition to evidence of cytoprotection by inhaled NO in rat lungs, 23 much evidence suggests that several NO donors can inhibit lung IRI, including nitroglycerin and nitroprusside. 24,25 As opposed to inhaled NO, a benefit of nitrite is that NO generation from nitrite would occur in tissue beds undergoing oxidative stress and at physiologic concentrations, thus minimizing the possibility of deleterious effects. Second, nitrite does not produce a tolerance phenomenon, which limits the therapeutic efficiency of nitroglycerin.…”