TY - JOUR T1 - Ambrisentan attenuates lung and heart injury in a rat model of bronchopulmonary dysplasia JF - European Respiratory Journal JO - Eur Respir J VL - 38 IS - Suppl 55 SP - p780 AU - Gerry Wagenaar AU - Yvonne de Visser AU - El Houari Laghmani AU - Frans Walther Y1 - 2011/09/01 UR - http://erj.ersjournals.com/content/38/Suppl_55/p780.abstract N2 - The selective endothelin receptor type A antagonist ambrisentan may be a novel therapeutic agent in neonatal chronic lung disease by blocking the adverse effects of the potent vasoconstrictor endothelin-1, including pulmonary arterial hypertension (PAH)-induced right ventricular hypertrophy (RVH). The cardiopulmonary effects of ambrisentan were studied in neonatal rats with hyperoxia-induced lung injury. Ambrisentan treatment was investigated in 2 models of experimental BPD: a prophylactic model, in which pups were continuously exposed to hyperoxia and treated daily with either saline or ambrisentan (20 mg/kg body weight/day; injected subcutaneously), and an injury-recovery model, in which pups were exposed to hyperoxia for 9 days, followed by 9 days of recovery in room-air and treatment with ambrisentan was started on day 6 of oxygen exposure and continued during the recovery period. In the prophylactic model treatment with ambrisentan improved survival (p <0.01) by reducing lung fibrin deposition (3-fold, p <0.001), alveolar septum thickness (1.7-fold, p < 0.001) and medial wall thickness of small arterioles as a marker for PAH (1.7-fold, p <0.001), and preventing associated RVH (p <0.001). Treatment with ambrisentan did not have beneficial effects on alveolar enlargement, vascularization, the pulmonary influx of macrophages and neutrophils, and the mRNA expression of procoagulant and inflammatory markers. In the injury-recovery model treatment with ambrisentan attenuated PAH and RVH (p <0.001), demonstrating that established PAH-induced RVH is still reversible in the neonatal period. Beneficial effects on reduced pulmonary vascularization and alveolarization were absent. ER -