Altered guanylyl-cyclase activity in vitro of pulmonary arteries from fetal lambs with congenital diaphragmatic hernia.
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.
Thébaud
Bernard
B
Service de Physiologie-Explorations Fonctionnelles, CHU Cochin, Assistance Publique-Hôpitaux de Paris, Université Paris V, France. bthebaud@ualberta.ca
Petit
Thierry
T
De Lagausie
Pascal
P
Dall'Ava-Santucci
Josette
J
Mercier
Jean-Christophe
JC
Dinh-Xuan
A Tuan
AT
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D000001:Calcimycin / Q000494:pharmacology; D006152:Cyclic GMP / Q000378:metabolism; D004195:Disease Models, Animal; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D005260:Female; D005333:Fetus / Q000201:enzymology / Q000601:surgery; D006162:Guanylate Cyclase; D006548:Hernia, Diaphragmatic / Q000201:enzymology*; D006976:Hypertension, Pulmonary / Q000201:enzymology; D007150:Immunohistochemistry; D007476:Ionophores / Q000494:pharmacology; D007537:Isometric Contraction / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000032:analysis / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III; D009599:Nitroprusside / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D012756:Sheep; D000071756:Soluble Guanylyl Cyclase; D014664:Vasodilation / Q000502:physiology
D007476:Ionophores; D018160:Receptors, Cytoplasmic and Nuclear; D009599:Nitroprusside; D009569:Nitric Oxide; D000001:Calcimycin; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP; D000109:Acetylcholine