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Antenatal BAY 41-2272 reduces pulmonary hypertension in the rabbit model of
congenital diaphragmatic hernia
#MMPMID26873974
Vuckovic A
; Herber-Jonat S
; Flemmer AW
; Strizek B
; Engels AC
; Jani JC
Am J Physiol Lung Cell Mol Physiol
2016[Apr]; 310
(7
): L658-69
PMID26873974
show ga
Infants with congenital diaphragmatic hernia (CDH) fail to adapt at birth because
of persistent pulmonary hypertension (PH), a condition characterized by excessive
muscularization and abnormal vasoreactivity of pulmonary vessels. Activation of
soluble guanylate cyclase by BAY 41-2272 prevents pulmonary vascular remodeling
in neonatal rats with hypoxia-induced PH. By analogy, we hypothesized that
prenatal administration of BAY 41-2272 would improve features of PH in the rabbit
CDH model. Rabbit fetuses with surgically induced CDH at day 23 of gestation were
randomized at day 28 for an intratracheal injection of BAY 41-2272 or vehicle.
After term delivery (day 31), lung mechanics, right ventricular pressure, and
serum NH2-terminal-pro-brain natriuretic peptide (NT-proBNP) levels were
measured. After euthanasia, lungs were processed for biological or histological
analyses. Compared with untouched fetuses, the surgical creation of CDH reduced
the lung-to-body weight ratio, increased mean terminal bronchial density, and
impaired lung mechanics. Typical characteristics of PH were found in the
hypoplastic lungs, including increased right ventricular pressure, higher serum
NT-proBNP levels, thickened adventitial and medial layers of pulmonary arteries,
reduced capillary density, and lower levels of endothelial nitric oxide synthase.
A single antenatal instillation of BAY 41-2272 reduced mean right ventricular
pressure and medial thickness of small resistive arteries in CDH fetuses.
Capillary density, endothelial cell proliferation, and transcripts of endothelial
nitric oxide synthase increased, whereas airway morphometry, lung growth, and
mechanics remained unchanged. These results suggest that pharmacological
activation of soluble guanylate cyclase may provide a new approach to the
prenatal treatment of PH associated with CDH.
|Abnormalities, Multiple/drug therapy
[MESH]
|Animals
[MESH]
|Drug Evaluation, Preclinical
[MESH]
|Enzyme Activators/*pharmacology/therapeutic use
[MESH]
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