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: Anthony de Buys Roessingh, Virginie Fouquet, Yves Aigrain, Jean-Christophe Mercier, Pascal de Lagausie, Anh Tuan Dinh-Xuan
• Journal: Journal of pediatric surgery (J Pediatr Surg) Vol. 46 Issue 8 Pg. 1516-22 (Aug 2011) ISSN: 1531-5037 [Electronic] United States
• PMID: 21843717 (Publication Type: Journal Article)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• Phosphodiesterase 5 Inhibitors
• Nitroprusside
• Nitric Oxide
• Cyclic Nucleotide Phosphodiesterases, Type 5
• Guanylate Cyclase

Topics

• Animals
• Cyclic Nucleotide Phosphodiesterases, Type 5 (metabolism)
• Fetus (abnormalities, enzymology)
• Guanylate Cyclase (metabolism)
• Hernia, Diaphragmatic (complications, embryology, enzymology)
• Hernias, Diaphragmatic, Congenital
• Hypertension, Pulmonary (embryology, enzymology, etiology)
• Nitric Oxide (metabolism)
• Nitroprusside (metabolism)
• Phosphodiesterase 5 Inhibitors (metabolism)
• Pulmonary Artery (metabolism)
• Sheep
• Signal Transduction
• Vascular Resistance (drug effects)