Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylcholine / pharmacology
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Animals
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Antihypertensive Agents / pharmacology
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Cyclic GMP / metabolism
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Dipyridamole / pharmacology
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Disease Models, Animal
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Endothelin Receptor Antagonists*
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Endothelin-1 / metabolism
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Endothelium, Vascular / chemistry
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Endothelium, Vascular / drug effects
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Endothelium, Vascular / metabolism
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Female
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Hernia, Diaphragmatic / metabolism*
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Hernia, Diaphragmatic / physiopathology
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Hernias, Diaphragmatic, Congenital*
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Hypertension, Pulmonary / congenital
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Hypertension, Pulmonary / metabolism
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Hypertension, Pulmonary / physiopathology
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Nitric Oxide / metabolism
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Nitroprusside / pharmacology
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Peptides, Cyclic / pharmacology
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Phosphodiesterase Inhibitors / pharmacology
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Pregnancy
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Pulmonary Circulation / drug effects
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Pulmonary Circulation / physiology
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Purinones / pharmacology
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Receptor, Endothelin A
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Receptor, Endothelin B
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Receptors, Endothelin / agonists*
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Receptors, Endothelin / metabolism*
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Sheep
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Vasoconstrictor Agents / pharmacology
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Vasodilator Agents / pharmacology
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Viper Venoms / pharmacology
Substances
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Antihypertensive Agents
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Endothelin Receptor Antagonists
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Endothelin-1
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Peptides, Cyclic
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Phosphodiesterase Inhibitors
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Purinones
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Receptor, Endothelin A
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Receptor, Endothelin B
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Receptors, Endothelin
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Vasoconstrictor Agents
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Vasodilator Agents
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Viper Venoms
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sarafotoxins s6
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Nitroprusside
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Nitric Oxide
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Dipyridamole
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zaprinast
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Cyclic GMP
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Acetylcholine
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cyclo(Trp-Asp-Pro-Val-Leu)