title: Antenatal sildenafil treatment attenuates pulmonary hypertension in experimental congenital diaphragmatic hernia.
abstract: BACKGROUND
  Lung hypoplasia and persistent pulmonary hypertension of the newborn limit survival in congenital diaphragmatic hernia (CDH). Unlike other diseases resulting in persistent pulmonary hypertension of the newborn, infants with CDH are refractory to inhaled nitric oxide (NO). Nitric oxide mediates pulmonary vasodilatation at birth in part via cyclic GMP production. Phosphodiesterase type 5 (PDE5) limits the effects of NO by inactivation of cyclic GMP. Because of the limited success in postnatal management of CDH, we hypothesized that antenatal PDE5 inhibition would attenuate pulmonary artery remodeling in experimental nitrofen-induced CDH.
  
  
  RESULTS
  Nitrofen administered at embryonic day 9.5 to pregnant rats resulted in a 60% incidence of CDH in the offspring and recapitulated features seen in human CDH, including structural abnormalities (lung hypoplasia, decreased pulmonary vascular density, pulmonary artery remodeling, right ventricular hypertrophy), and functional abnormalities (decreased pulmonary artery relaxation in response to the NO donor 2-(N,N-diethylamino)-diazenolate-2-oxide). Antenatal sildenafil administered to the pregnant rat from embryonic day 11.5 to embryonic day 20.5 crossed the placenta, increased fetal lung cyclic GMP and decreased active PDE5 expression. Antenatal sildenafil improved lung structure, increased pulmonary vessel density, reduced right ventricular hypertrophy, and improved postnatal NO donor 2-(N,N-diethylamino)-diazenolate-2-oxide-induced pulmonary artery relaxation. This was associated with increased lung endothelial NO synthase and vascular endothelial growth factor protein expression. Antenatal sildenafil had no adverse effect on retinal structure/function and brain development.
  
  
  CONCLUSIONS
  Antenatal sildenafil improves pathological features of persistent pulmonary hypertension of the newborn in experimental CDH and does not alter the development of other PDE5-expressing organs. Given the high mortality/morbidity of CDH, the potential benefit of prenatal PDE5 inhibition in improving the outcome for infants with CDH warrants further studies.
authors.affiliation: Department of Pediatrics, Women and Children Health Research Institute, Cardiovascular Research Group, University of Alberta, Edmonton, Canada.
authors.forename: Christina
authors.initials: C
authors.lastname: Luong
authors.forename: Juliana
authors.initials: J
authors.lastname: Rey-Perra
authors.forename: Arul
authors.initials: A
authors.lastname: Vadivel
authors.forename: Greg
authors.initials: G
authors.lastname: Gilmour
authors.forename: Yves
authors.initials: Y
authors.lastname: Sauve
authors.forename: Debby
authors.initials: D
authors.lastname: Koonen
authors.forename: Don
authors.initials: D
authors.lastname: Walker
authors.forename: Kathryn G
authors.initials: KG
authors.lastname: Todd
authors.forename: Pierre
authors.initials: P
authors.lastname: Gressens
authors.forename: Zamaneh
authors.initials: Z
authors.lastname: Kassiri
authors.forename: Khurram
authors.initials: K
authors.lastname: Nadeem
authors.forename: Beverly
authors.initials: B
authors.lastname: Morgan
authors.forename: Farah
authors.initials: F
authors.lastname: Eaton
authors.forename: Jason R
authors.initials: JR
authors.lastname: Dyck
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Archer
authors.forename: Bernard
authors.initials: B
authors.lastname: Thébaud
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000196:embryology / Q000254:growth & development; D006152:Cyclic GMP / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006548:Hernia, Diaphragmatic / Q000139:chemically induced / Q000150:complications*; D065630:Hernias, Diaphragmatic, Congenital; D006976:Hypertension, Pulmonary / Q000209:etiology* / Q000503:physiopathology / Q000517:prevention & control*; D008168:Lung / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism; D010647:Phenyl Ethers / Q000009:adverse effects; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D011247:Pregnancy; D011651:Pulmonary Artery / Q000503:physiopathology; D011687:Purines / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D010647:Phenyl Ethers; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D009569:Nitric Oxide; D000068677:Sildenafil Citrate; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D006152:Cyclic GMP; C007350:nitrofen