Endothelin receptor blockade reduces ventricular dysfunction and injury after reoxygenation

Background. Reoxygenation of hypoxic myocardium during repair of congenital heart defects results in poor ventricular function and cellular injury. En dothelin-1 (ET-1), a potent vasoconstrictor that increases during hypoxia, may suppress myocardial function and activate leukocytes. The objective was to determine whether administration of an endothelin receptor antagonist c ould improve ventricular function and decrease cardiac injury after hypoxia and reoxygenation. Methods. Fourteen piglets underwent 90 minutes of ventilator hypoxia, 1 hou r of reoxygenation on cardiopulmonary bypass, and 2 hours of recovery (cont rols). Nine additional animals received an infusion of Bosentan, an ET(A/B) receptor antagonist, (5 mg/kg per hour) during hypoxia and reoxygenation. Results. Right and left ventricular dP/dt in controls decreased to 78% and 52% of baseline, respectively, after recovery (p < 0.05). In contrast, Bose ntan-treated animals had complete preservation of RV dP/dt and less depress ion of LV dP/dt. Bosentan reduced the hypoxia and reoxygenation-induced ele vation of ET-1 and iNOS mRNA at the end of recovery (p < 0.05). Bosentan-tr eated animals had diminished myocardial myeloperoxidase activity and lipid peroxidation compared with controls (p < 0.05). Myocardial apoptotic index, elevated by hypoxia and reoxygenation, was lower in the Bosentan-treated a nimals (p < 0.05). Conclusions. Endothelin-1 receptor antagonism improved functional recovery and decreased leukocyte-mediated injury after reoxygenation. The reduction in cardiac cell death might also improve long-term outcome after reoxygenat ion injury. (C) 2001 by The Society of Thoracic Surgeons.