Am. J. Respir. Cell Mol. Biol.,
Volume 27, Number 1, July, 2002 42-47
Altered Guanylyl-Cyclase Activity In Vitro of Pulmonary Arteries from
Fetal Lambs with Congenital Diaphragmatic Hernia
Bernard
Thébaud,
Thierry
Petit,
Pascal
de Lagausie,
Josette
Dall'Ava-Santucci,
Jean-Christophe
Mercier,
and
A. Tuan
Dinh-Xuan
Service de Physiologie-Explorations Fonctionnelles, CHU Cochin, Assistance Publique-Hôpitaux de Paris, Université Paris V,
Paris; Service de Réanimation Néonatale, Hôpital Antoine Béclère, Assistance Publique-Hôpitaux de Paris, Université Paris-Sud,
Clamart; Service de Chirurgie Viscérale Infantile, CHRU Caen, Caen; Service de Chirurgie Viscérale Pédiatrique, Hôpital Robert Debré,
Université Paris VII, Paris; Ecole de Chirurgie, Assistance Publique-Hôpitaux de Paris, Paris; and Service de Réanimation Pédiatrique,
Hôpital Robert Debré, Assistance Publique-Hôpitaux de Paris, Université Paris VII, Paris, France
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.
Abbreviations: acetylcholine, ACh; congenital diaphragmatic hernia, CDH;
cyclic guanosine 3',5' monophosphate, cGMP; endothelium-derived hyperpolarizing factor, EDHF; N
-nitro-L-arginine, L-NA; nitric oxide, NO;
phosphate-buffered saline, PBS; phosphodiesterase, PDE; persistent pulmonary hypertension of the newborn, PPHN; soluble guanylyl cyclase, sGC; sodium nitroprusside, SNP.
