Antenatal maternally-administered phosphodiesterase type 5 inhibitors normalize eNOS expression in the fetal lamb model of congenital diaphragmatic hernia

Eveline H. Shue, Samuel C. Schecter, Wenhui Gong, Mozziyar Etemadi, Michael Johengen, Corey Iqbal, S. Christopher Derderian, Peter Oishi, Jeffrey R. Fineman, Doug Miniati*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

Purpose Pulmonary hypertension (pHTN), a main determinant of survival in congenital diaphragmatic hernia (CDH), results from in utero vascular remodeling. Phosphodiesterase type 5 (PDE5) inhibitors have never been used antenatally to treat pHTN. The purpose of this study is to determine if antenatal PDE5 inhibitors can prevent pHTN in the fetal lamb model of CDH. Methods CDH was created in pregnant ewes. Postoperatively, pregnant ewes received oral placebo or tadalafil, a PDE5 inhibitor, until delivery. Near term gestation, lambs underwent resuscitations, and lung tissue was snap frozen for protein analysis. Results Mean cGMP levels were 0.53 ± 0.11 in placebo-treated fetal lambs and 1.73 ± 0.21 in tadalafil-treated fetal lambs (p = 0.002). Normalized expression of eNOS was 82% ± 12% in Normal-Placebo, 61% ± 5% in CDH-Placebo, 116% ± 6% in Normal-Tadalafil, and 86% ± 8% in CDH-Tadalafil lambs. Normalized expression of β-sGC was 105% ± 15% in Normal-Placebo, 82% ± 3% in CDH-Placebo, 158% ± 16% in Normal-Tadalafil, and 86% ± 8% in CDH-Tadalafil lambs. Endothelial NOS and β-sGC were significantly decreased in CDH (p = 0.0007 and 0.01 for eNOS and β-sGC, respectively), and tadalafil significantly increased eNOS expression (p = 0.0002). Conclusions PDE5 inhibitors can cross the placental barrier. β-sGC and eNOS are downregulated in fetal lambs with CDH. Antenatal PDE5 inhibitors normalize eNOS and may prevent in utero vascular remodeling in CDH.

Original languageEnglish (US)
Pages (from-to)39-45
Number of pages7
JournalJournal of pediatric surgery
Volume49
Issue number1
DOIs
StatePublished - Jan 2014

Keywords

  • Congenital diaphragmatic hernia
  • DH
  • PDE5 inhibitors
  • Phosphodiesterase type 5 inhibitors
  • Pulmonary hypertension

ASJC Scopus subject areas

  • Surgery
  • Pediatrics, Perinatology, and Child Health

Fingerprint Dive into the research topics of 'Antenatal maternally-administered phosphodiesterase type 5 inhibitors normalize eNOS expression in the fetal lamb model of congenital diaphragmatic hernia'. Together they form a unique fingerprint.

Cite this