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

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.