Expression of endothelin-1 and effects of an endothelin receptor antagonist, TAK-044, at reperfusion after cold preservation in a canine lung transplantation model

Background: Rapid increase of pulmonary vascular resistance (PVR) early after reperfusion remains a major issue in clinical lung transplantation. A potent vasoconstrictor peptide, endothelin-l plays an important role in various pulmonary pathophysiologic conditions and might induce increased PVR. We investigated the expression and influence of endothelin-l, and the effects of an ETA and ETB nonselective endothelin receptor antagonist, TAK-044, at reperfusion after cold preservation in a canine lung transplantation model. Methods: Left single lung allotransplantation procedures were performed in three groups of animals. In group I (n = 5) lungs were preserved for 12 hours; in group II (n = 5) lungs were preserved for 18 hours; and in group III (n = 6) lungs were also preserved for 18 hours, and TAK-044 (5 mg/kg) was administered just before reperfusion. All donor lungs were flushed and preserved with low-potassium dextran glucose solution at 4 degrees C. Results: Six hours after reperfusion, arterial oxygen tension (mm Hg, inspired oxygen fraction = 1.0) was 512.9 +/- 34.7 in group I, 152.4 +/- 46.7 in group II, and 509.6 +/- 29.0 in group III; PVR index (dyne sec cm(-5) m(2)) was 1130 +/- 142 in group I, 1820 +/- 142 in group II, and 1287 +/- 191 in group III. Plasma endothelin-l level was elevated significantly, and endothelin-1-like immunoreactivity was found in a variety of pulmonary vascular tissue and was seen less with immunohistochemical evaluation in group II in bronchial tissue. Conclusions: These results suggest that endothelin-l is expressed as a result of ischemia-reperfusion injury and may worsen early graft function. TAK-044 is beneficial in protecting the graft from high pulmonary vascular resistance and pulmonary edema during the early posttransplantation stage.