Document Detail

Altered guanylyl-cyclase activity in vitro of pulmonary arteries from fetal lambs with congenital diaphragmatic hernia.
MedLine Citation:
PMID:  12091244     Owner:  NLM     Status:  MEDLINE    
Nitric oxide (NO) plays a major role in the modulation of perinatal pulmonary vascular tone. Congenital diaphragmatic hernia (CDH), a major cause of severe persistent pulmonary hypertension of the newborn (PPHN), is often refractory to inhaled NO. Alterations in NO/cyclic guanosine 3',5' monophosphate (cGMP)-mediated pulmonary vasodilatation may contribute to PPHN in CDH. We assessed NO/cGMP-mediated pulmonary vasorelaxation in vitro in 140-d gestational lamb fetuses with surgically created left CDH (term = 147 d) to age-matched controls. Relaxation of fourth generation intralobar pulmonary artery rings in response to the endothelium-dependent vasodilator, acetylcholine (ACh), and to the specific inhibitor of cGMP-phosphodiesterase (PDE), zaprinast, did not differ between the two groups. By contrast, relaxation in response to the calcium ionophore A23187 was impaired in CDH as compared with control animals. Relaxation in response to the NO donor sodium nitroprusside (SNP) (a direct activator of soluble guanylyl cyclase [sGC]) was also impaired in CDH animals as compared with controls. Repeating the challenge increased vasorelaxation in response to SNP in CDH as compared with control animals. Immunohistochemistry revealed the presence of endothelial NO-synthase in the endothelium of pulmonary arteries from both control and CDH animals. We conclude that endothelium-dependent vasodilatation in response to ACh and A23187 was differently affected in the fetal surgical CDH-lamb model. Furthermore, activity of sGC but not that of PDE was impaired in CDH animals. PPHN and decreased inhaled NO responsiveness in CDH may involve decreased sGC activity.
Bernard Thébaud; Thierry Petit; Pascal De Lagausie; Josette Dall'Ava-Santucci; Jean-Christophe Mercier; A Tuan Dinh-Xuan
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  American journal of respiratory cell and molecular biology     Volume:  27     ISSN:  1044-1549     ISO Abbreviation:  Am. J. Respir. Cell Mol. Biol.     Publication Date:  2002 Jul 
Date Detail:
Created Date:  2002-07-01     Completed Date:  2002-09-11     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  8917225     Medline TA:  Am J Respir Cell Mol Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  42-7     Citation Subset:  IM    
Service de Physiologie-Explorations Fonctionnelles, CHU Cochin, Assistance Publique-Hôpitaux de Paris, Université Paris V, France.
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MeSH Terms
Acetylcholine / pharmacology
Animals, Newborn
Calcimycin / pharmacology
Cyclic GMP / metabolism
Disease Models, Animal
Epithelium / drug effects,  metabolism,  physiology
Fetus / enzymology,  surgery
Guanylate Cyclase
Hernia, Diaphragmatic / enzymology*
Hypertension, Pulmonary / enzymology
Ionophores / pharmacology
Isometric Contraction / physiology
Nitric Oxide / metabolism
Nitric Oxide Synthase / analysis,  metabolism*
Nitric Oxide Synthase Type III
Nitroprusside / pharmacology
Pulmonary Artery / drug effects,  enzymology*,  metabolism
Receptors, Cytoplasmic and Nuclear / metabolism*
Vasodilation / physiology
Reg. No./Substance:
0/Ionophores; 0/Receptors, Cytoplasmic and Nuclear; 10102-43-9/Nitric Oxide; 15078-28-1/Nitroprusside; 51-84-3/Acetylcholine; 52665-69-7/Calcimycin; 7665-99-8/Cyclic GMP; EC Oxide Synthase; EC Oxide Synthase Type III; EC Cyclase; EC guanylyl cyclase

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