Persistent pulmonary hypertension of the newborn is a life-threatening condition in which half of infants fail to respond to inhaled nitric oxide. Development of new therapeutic pathways is crucial. The adenosine triphosphate (ATP)-sensitive potassium channels (K(ATP)) may be important in this condition. Concentration-response curves to the K(ATP) channel opener (SR47063) were performed in isolated pulmonary arterial rings from normal newborn lambs (n = 8) and pulmonary hypertensive lambs (n = 7) induced by intrauterine ductus arteriosus ligation. The effect of endothelin (ET) receptor antagonists was analyzed. Expression in the lung of the subunit Kir 6.1 of the K(ATP) channel and of ET were analyzed using Western blot and immunohistochemistry. Relaxation to SR47063 was increased in ligated animals compared with the control group. Endothelium removal enhanced this response in ligated animals (p < 0.01). The inhibitory effect of the endothelium was reversed by the Endothelin-A receptor (ET-A) antagonist BQ 123 (p < 0.01). Kir 6.1 expression was not different between groups and that of endothelin-1 (ET-1) was increased threefold in ligated animals (p = 0.007). In pulmonary hypertensive lambs, vasodilation to K(ATP) channel openers was enhanced compared with controls and further potentiated by ET-A blockade. These data might lead to new therapeutic strategies in infants with pulmonary hypertension.