title: Nitric oxide activity through guanylate cyclase and phosphodiesterase modulation is impaired in fetal lambs with congenital diaphragmatic hernia.
abstract: BACKGROUND
  Congenital diaphragmatic hernia (CDH) is associated with pulmonary hypertension and death. Administration of nitric oxide (NO) alone remains ineffective in CDH cases. We investigated in near full-term lambs with and without CDH the role of guanylate cyclase (GC), the enzyme activated by NO in increasing cyclic 3'-5'-guanylosine monophosphate, and the role of phosphodiesterase (PDE) 5, the enzyme-degrading cyclic 3'-5'-guanylosine monophosphate.
  
  
  METHODS
  Congenital diaphragmatic hernia was surgically created in fetal lambs at 85 days of gestation. Pulmonary hemodynamics were assessed by means of pressure and blood flow catheters (135 days). In vitro, we tested drugs on rings of isolated pulmonary vessels.
  
  
  RESULTS
  In vivo, sodium nitroprusside, a direct NO donor, and methyl-2(4-aminophenyl)-1,2-dihydro-1-oxo-7-(2-pyridinylmethoxy)-4-(3,4,5 trimethoxyphenyl)-3-isoquinoline carboxylate sulfate (T-1032) and Zaprinast, both PDE 5 blockers, reduced pulmonary vascular resistance in CDH and non-CDH animals. The activation of GC by sodium nitroprusside and the inhibition of PDE 5 by T-1032 were less effective in CDH animals. In vitro, the stimulation of GC by 3(5'hydroxymethyl-2'furyl)-1-benzyl indazole (YC-1) (a benzyl indazole derivative) and the inhibition of PDE 5 by T-1032 were less effective in pulmonary vascular rings from CDH animals. The YC-1-induced vasodilation in rings from CDH animals was higher when associated with the PDE 5 inhibitor T-1032.
  
  
  CONCLUSIONS
  Guanylate cyclase and PDE 5 play a role in controlling pulmonary vascular tone in fetal lambs with or without CDH. Both enzymes seem to be impaired in fetal lambs with CDH.
authors.affiliation: Department of Pediatric Surgery, Robert Debré Hospital, Assistance Publique-Hôpitaux de Paris, Sérurier, 75019 Paris, France. anthony.debuys-roessingh@chuv.ch
authors.forename: Anthony
authors.initials: A
authors.lastname: de Buys Roessingh
authors.forename: Virginie
authors.initials: V
authors.lastname: Fouquet
authors.forename: Yves
authors.initials: Y
authors.lastname: Aigrain
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Mercier
authors.forename: Pascal
authors.initials: P
authors.lastname: de Lagausie
authors.forename: Anh Tuan
authors.initials: AT
authors.lastname: Dinh-Xuan
mesh_terms: D000818:Animals; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism*; D005333:Fetus / Q000002:abnormalities / Q000201:enzymology; D006162:Guanylate Cyclase / Q000378:metabolism*; D006548:Hernia, Diaphragmatic / Q000150:complications / Q000196:embryology / Q000201:enzymology; D065630:Hernias, Diaphragmatic, Congenital; D006976:Hypertension, Pulmonary / Q000196:embryology / Q000201:enzymology* / Q000209:etiology; D009569:Nitric Oxide / Q000378:metabolism*; D009599:Nitroprusside / Q000378:metabolism; D058986:Phosphodiesterase 5 Inhibitors / Q000378:metabolism; D011651:Pulmonary Artery / Q000378:metabolism; D012756:Sheep; D015398:Signal Transduction; D014655:Vascular Resistance / Q000187:drug effects
chemical_list: D058986:Phosphodiesterase 5 Inhibitors; D009599:Nitroprusside; D009569:Nitric Oxide; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D006162:Guanylate Cyclase