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.

Pulmonary hypertension secondary to congenital diaphragmatic hernia: factors and pathways involved in pulmonary vascular remodeling

“…In fact, in the rabbit model, only two studies have been published and have reported a decrease in eNOS in CDH lungs compared with controls, but no disruption in VEGF or ET pathways. 139,140 In the sheep model of CDH, there are a few more studies, indicating similar findings to those observed in the nitrofen model: an altered interaction between dysfunctional EC and PASMCs via increased expression of ET-1 and decreased eNOS. [141][142][143] However, contrarily to what has been reported in the nitrofen model, ECs of CDH lamb lungs had a higher expression of VEGF and its receptors compared with those of controls.…”

Emerging antenatal therapies for congenital diaphragmatic hernia-induced pulmonary hypertension in preclinical models

“…Rabbits with surgical diaphragmatic hernias received a single dose of BAY 41–2272 via tracheal instillation on E28 ( 58 ), and were retrieved at term. Results showed reduced right ventricular pressure and ameliorated vascular remodeling with decreased medial thickening in small arteries and increased capillary formation.…”

Congenital Diaphragmatic Hernia: State of the Art in Translating Experimental Research to the Bedside

“…Rojas-Moscoso et al and Vuckovic et al reported that different soluble guanylyl cyclase activators (BAY 60-2770 and BAY 41-2272) induced relaxant responses of the pulmonary artery in vitro, as well as in vivo when administered intratracheally. 146,147 Russo et al performed an antenatal maternal treatment with sildenafil during the last 6 days of rabbit pregnancy (from 24 to 30 days of gestation) and demonstrated rescue of vascular branching and architecture, decreased pulmonary vascular resistances, and improved airway morphometry and respiratory mechanics. 148…”