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) earl y after reperfusion remains a major issue in clinical lung transplanta tion. A potent vasoconstrictor peptide, endothelin-l plays an importan t role in various pulmonary pathophysiologic conditions and might indu ce increased PVR. We investigated the expression and influence of endo thelin-l, and the effects of an ETA and ETB nonselective endothelin re ceptor antagonist, TAK-044, at reperfusion after cold preservation in a canine lung transplantation model. Methods: Left single lung allotra nsplantation 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 wer e also preserved for 18 hours, and TAK-044 (5 mg/kg) was administered just before reperfusion. All donor lungs were flushed and preserved wi th low-potassium dextran glucose solution at 4 degrees C. Results: Six hours after reperfusion, arterial oxygen tension (mm Hg, inspired oxy gen fraction = 1.0) was 512.9 +/- 34.7 in group I, 152.4 +/- 46.7 in g roup 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 significan tly, and endothelin-1-like immunoreactivity was found in a variety of pulmonary vascular tissue and was seen less with immunohistochemical e valuation in group II in bronchial tissue. Conclusions: These results suggest that endothelin-l is expressed as a result of ischemia-reperfu sion injury and may worsen early graft function. TAK-044 is beneficial in protecting the graft from high pulmonary vascular resistance and p ulmonary edema during the early posttransplantation stage.