ET(A)-receptor blockade and ET(B)-receptor stimulation in experimental congenital diaphragmatic hernia.
The aim of this study was to assess the role of nitric oxide (NO) and endothelin (ET)-1 in the pathophysiology of persistent pulmonary hypertension of the newborn in fetal lambs with a surgically created congenital diaphragmatic hernia (CDH). The pulmonary vascular response to various agonists and antagonists was assessed in vivo between 128 and 132 days gestation. Age-matched fetal lambs served as control animals. Control and CDH lambs had similar pulmonary vasodilator responses to acetylcholine, sodium nitroprusside, zaprinast, and dipyridamole. The ET(A)-receptor antagonist BQ-123 caused a significantly greater pulmonary vasodilatation in CDH than in control animals. The ET(B)-receptor agonist sarafotoxin 6c induced a biphasic response, with a sustained pulmonary vasoconstriction after a transient pulmonary vasodilatation that was not seen in CDH animals. We conclude that the NO signaling pathway in vivo is intact in experimental CDH. In contrast, ET(A)-receptor blockade and ET(B)-receptor stimulation significantly differed in CDH animals compared with control animals. Imbalance of ET-1-receptor activation favoring pulmonary vasoconstriction rather than altered NO-mediated pulmonary vasodilatation is likely to account for persistent pulmonary hypertension of the newborn in fetal lambs with a surgically created CDH.
Thébaud
B
B
Service de Physiologie-Explorations Fonctionnelles, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris-Université Paris V, 75014 Paris, France.
de Lagausie
P
P
Forgues
D
D
Aigrain
Y
Y
Mercier
J C
JC
Dinh-Xuan
A T
AT
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D006152:Cyclic GMP / Q000378:metabolism; D004176:Dipyridamole / Q000494:pharmacology; D004195:Disease Models, Animal; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism; D004730:Endothelium, Vascular / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006548:Hernia, Diaphragmatic / Q000378:metabolism* / Q000503:physiopathology; D065630:Hernias, Diaphragmatic, Congenital; D006976:Hypertension, Pulmonary / Q000151:congenital / Q000378:metabolism / Q000503:physiopathology; D009569:Nitric Oxide / Q000378:metabolism; D009599:Nitroprusside / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011247:Pregnancy; D011652:Pulmonary Circulation / Q000187:drug effects / Q000502:physiology; D011688:Purinones / Q000494:pharmacology; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000819:agonists* / Q000378:metabolism*; D012756:Sheep; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology; D014757:Viper Venoms / Q000494:pharmacology
D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D010456:Peptides, Cyclic; D010726:Phosphodiesterase Inhibitors; D011688:Purinones; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D014757:Viper Venoms; C057354:sarafotoxins s6; D009599:Nitroprusside; D009569:Nitric Oxide; D004176:Dipyridamole; C011145:zaprinast; D006152:Cyclic GMP; D000109:Acetylcholine; C072247:cyclo(Trp-Asp-Pro-Val-Leu)