Antenatal maternally-administered phosphodiesterase type 5 inhibitors normalize eNOS expression in the fetal lamb model of congenital diaphragmatic hernia.
OBJECTIVE
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.
Department of Surgery, Division of Pediatric Surgery and Fetal Treatment Center, University of California, San Francisco, San Francisco, CA.
Eveline H
EH
Shue
Department of Surgery, Division of Pediatric Surgery and Fetal Treatment Center, University of California, San Francisco, San Francisco, CA.
Samuel C
SC
Schecter
Department of Pediatrics, University of California, San Francisco, San Francisco, CA.
Wenhui
W
Gong
Department of Surgery, Division of Pediatric Surgery and Fetal Treatment Center, University of California, San Francisco, San Francisco, CA.
Mozziyar
M
Etemadi
Department of Pediatrics, University of California, San Francisco, San Francisco, CA.
Michael
M
Johengen
Department of Surgery, Division of Pediatric Surgery and Fetal Treatment Center, University of California, San Francisco, San Francisco, CA.
Corey
C
Iqbal
Department of Surgery, Division of Pediatric Surgery and Fetal Treatment Center, University of California, San Francisco, San Francisco, CA.
S Christopher
SC
Derderian
Department of Pediatrics, University of California, San Francisco, San Francisco, CA.
Peter
P
Oishi
Department of Pediatrics, University of California, San Francisco, San Francisco, CA.
Jeffrey R
JR
Fineman
Department of Surgery, Division of Pediatric Surgery and Fetal Treatment Center, University of California, San Francisco, San Francisco, CA. Electronic address: doug.miniati@kp.org.
Doug
D
Miniati
D000818:Animals; D002243:Carbolines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D006152:Cyclic GMP / Q000032:analysis; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D005315:Fetal Diseases / Q000188:drug therapy*; D046128:Fetal Therapies; D006548:Hernia, Diaphragmatic / Q000150:complications / Q000196:embryology / Q000201:enzymology / Q000517:prevention & control; D065630:Hernias, Diaphragmatic, Congenital; D006976:Hypertension, Pulmonary / Q000196:embryology / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control; D017380:Hypertrophy, Right Ventricular / Q000196:embryology / Q000201:enzymology / Q000209:etiology; D008168:Lung / Q000737:chemistry / Q000187:drug effects / Q000196:embryology / Q000473:pathology; D008431:Maternal-Fetal Exchange; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis* / Q000235:genetics; D009929:Organ Size / Q000187:drug effects; D058986:Phosphodiesterase 5 Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011247:Pregnancy; D011897:Random Allocation; D015290:Second Messenger Systems / Q000187:drug effects; D012756:Sheep; D000068581:Tadalafil
D002243:Carbolines; D058986:Phosphodiesterase 5 Inhibitors; D000068581:Tadalafil; D052250:Nitric Oxide Synthase Type III; D006152:Cyclic GMP
Congenital diaphragmatic hernia; DH; PDE5 inhibitors; Phosphodiesterase type 5 inhibitors; Pulmonary hypertension