title: Antenatal use of bosentan and/or sildenafil attenuates pulmonary features in rats with congenital diaphragmatic hernia.
abstract: BACKGROUND
  Lung hypoplasia, pulmonary persistent hypertension of the newborn and its morphological changes are the main features in congenital diaphragmatic hernia (CDH). This study was undertaken to investigate if antenatal use of sildenafil and/or bosentan attenuates vascular remodeling, promotes branching, and improves alveolarization in experimental nitrofeninduced CDH.
  
  
  METHODS
  Nitrofen (100 mg) was gavage-fed to pregnant rats at post conception day (PCD) 9 to induce CDH. The rats were randomized to 5 groups: 1) control; 2) nitrofen; 3) nitrofen+sildenafil 100 mg/kg per day at PCD 16-20; 4) nitrofen+bosentan 30 mg/kg per day, at PCD 16-20, and 5) nitrofen+bosentan+sildenafil, same doses and administration days. After cesarean delivery, the offsprings were sacrificed. The diaphragmatic defect and pulmonary hypoplasia were identified, and the lungs were dissected. Arterial wall thickness, bronchiolar density and alveolarization were assessed.
  
  
  RESULTS
  The offsprings with CDH were characterized by severe pulmonary hypoplasia (lung weight-to-body weight ratio: 0.0263 [95% confidence interval (CI) 0.0242-0.0278)] in the nitrofen group versus 0.0385 (95% CI 0.0355-0.0424) in the control group (P=0.0001). Pulmonary arterial wall thickness was decreased to 3.0 (95% CI 2.8-3.7) μm in the nitrofen+sildenafil group versus 5.0 (95% CI 4.1-4.9) μm in the nitrofen group (P=0.02). Terminal bronchioles increased to 13.7 (95% CI 10.7-15.2) μm in the nitrofen+bosentan group in contrast to 8.7 (95% CI 7.2-9.4) μm in the nitrofen group (P=0.002). More significant differences (P=0.0001) were seen in terminal bronchioles in the nitrofen+sildenafil+bosentan group than in the nitrofen group [14.0 (95% CI 12.5-15.4) μm versus 8.5 (95% CI 7.1-9.3) μm]. Pulmonary arterial wall thickness was also decreased in the former group.
  
  
  CONCLUSIONS
  In this rat model, antenatal treatment with sildenafil attenuates vascular remodeling. Bosentan promotes the development of terminal bronchioles in nitrofen-induced CDH.
authors.affiliation: Division of Neonatology, High Specialty Medical Unit, Pediatric Hospital, Western National Medical Center, Mexican Social Security Institute, Guadalajara, Jalisco, México.
authors.forename: María de Lourdes
authors.initials: Mde L
authors.lastname: Lemus-Varela
authors.forename: Amed
authors.initials: A
authors.lastname: Soliz
authors.forename: Belinda Claudia
authors.initials: BC
authors.lastname: Gómez-Meda
authors.forename: Ana Lourdes
authors.initials: AL
authors.lastname: Zamora-Perez
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Ornelas-Aguirre
authors.forename: Valery
authors.initials: V
authors.lastname: Melnikov
authors.forename: Blanca Miriam
authors.initials: BM
authors.lastname: Torres-Mendoza
authors.forename: Guillermo Moisés
authors.initials: GM
authors.lastname: Zúñiga-González
mesh_terms: D000818:Animals; D000077300:Bosentan; D004195:Disease Models, Animal; D005260:Female; D065630:Hernias, Diaphragmatic, Congenital / Q000150:complications* / Q000188:drug therapy*; D008168:Lung / Q000002:abnormalities* / Q000098:blood supply; D008171:Lung Diseases / Q000209:etiology* / Q000517:prevention & control*; D010647:Phenyl Ethers; D010879:Piperazines / Q000494:pharmacology*; D011247:Pregnancy; D011687:Purines / Q000494:pharmacology; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D000068677:Sildenafil Citrate; D013449:Sulfonamides / Q000494:pharmacology*; D066253:Vascular Remodeling / Q000187:drug effects
chemical_list: D010647:Phenyl Ethers; D010879:Piperazines; D011687:Purines; D013449:Sulfonamides; D000068677:Sildenafil Citrate; C007350:nitrofen; D000077300:Bosentan