Antenatal BAY 41-2272 reduces pulmonary hypertension in the rabbit model of congenital diaphragmatic hernia

Abstract

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.