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Antenatal Sildenafil Treatment Attenuates Pulmonary Hypertension in Experimental Congenital Diaphragmatic Hernia.
MedLine Citation:
PMID:  21537000     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Background- Lung hypoplasia and persistent pulmonary hypertension of the newborn limit survival in congenital diaphragmatic hernia (CDH). Unlike other diseases resulting in persistent pulmonary hypertension of the newborn, infants with CDH are refractory to inhaled nitric oxide (NO). Nitric oxide mediates pulmonary vasodilatation at birth in part via cyclic GMP production. Phosphodiesterase type 5 (PDE5) limits the effects of NO by inactivation of cyclic GMP. Because of the limited success in postnatal management of CDH, we hypothesized that antenatal PDE5 inhibition would attenuate pulmonary artery remodeling in experimental nitrofen-induced CDH. Methods and Results- Nitrofen administered at embryonic day 9.5 to pregnant rats resulted in a 60% incidence of CDH in the offspring and recapitulated features seen in human CDH, including structural abnormalities (lung hypoplasia, decreased pulmonary vascular density, pulmonary artery remodeling, right ventricular hypertrophy), and functional abnormalities (decreased pulmonary artery relaxation in response to the NO donor 2-(N,N-diethylamino)-diazenolate-2-oxide). Antenatal sildenafil administered to the pregnant rat from embryonic day 11.5 to embryonic day 20.5 crossed the placenta, increased fetal lung cyclic GMP and decreased active PDE5 expression. Antenatal sildenafil improved lung structure, increased pulmonary vessel density, reduced right ventricular hypertrophy, and improved postnatal NO donor 2-(N,N-diethylamino)-diazenolate-2-oxide-induced pulmonary artery relaxation. This was associated with increased lung endothelial NO synthase and vascular endothelial growth factor protein expression. Antenatal sildenafil had no adverse effect on retinal structure/function and brain development. Conclusions- Antenatal sildenafil improves pathological features of persistent pulmonary hypertension of the newborn in experimental CDH and does not alter the development of other PDE5-expressing organs. Given the high mortality/morbidity of CDH, the potential benefit of prenatal PDE5 inhibition in improving the outcome for infants with CDH warrants further studies.
Authors:
Christina Luong; Juliana Rey-Perra; Arul Vadivel; Greg Gilmour; Yves Sauve; Debby Koonen; Don Walker; Kathryn G Todd; Pierre Gressens; Zamaneh Kassiri; Khurram Nadeem; Beverly Morgan; Farah Eaton; Jason R Dyck; Stephen L Archer; Bernard Thébaud
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-5-2
Journal Detail:
Title:  Circulation     Volume:  -     ISSN:  1524-4539     ISO Abbreviation:  -     Publication Date:  2011 May 
Date Detail:
Created Date:  2011-5-3     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Department of Pediatrics, Women and Children Health Research Institute, Cardiovascular Research Group.
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