Sildenafil Stimulates and Dexamethasone Inhibits Pulmonary Vascular Development in Congenital Diaphragmatic Hernia Rat Lungs

Abstract

Background: A predictor of neonatal mortality in infants with congenital diaphragmatic hernia (CDH) is disrupted pulmonary vascular development, clinically expressed as pulmonary hypertension. Objective: To determine if prenatal corticosteroids and phosphodiesterase-5 (PDE-5) inhibitors have a beneficial effect on pulmonary vascular development in CDH lungs. Methods: We induced CDH in fetal rats by giving nitrofen. We then exposed them to dexamethasone or to sildenafil. We separated them into three groups: (1) DEX, 4 pregnant rats received dexamethasone at days E16, E18 and E20; (2) SILD, 4 pregnant rats received sildenafil and <smlcap>L</smlcap>-arginine between E14 and E22, and (3) placebo. We then analyzed the lung of each fetus with CDH at E22. We examined the number of arterioles and arteries, and their percent of medial wall thickness (%MWT). Results: We obtained 30 CDH-positive fetuses. We analyzed 3,560 arterioles and 211 arteries. SILD showed a significant increase in the number of arterioles, but no significant increase in the number of arteries. No change was noted in the arteriolar %MWT. In contrast, DEX showed significant decreases in the number of arterioles and arteries and a significant increase in %MWT. Conclusions: PDE-5 inhibitors may improve pulmonary arteriolar development in fetuses with CDH. In contrast, prenatal corticosteroids could have deleterious effects on arteriolar and arterial development in CDH lungs.

Antenatal sildenafil treatment improves neonatal pulmonary hemodynamics and gas exchange in lambs with diaphragmatic hernia

“…PVR was lower in DH-sildenafil, compared with DH-saline, lambs during the fetal instrumentation period immediately before birth. This finding is consistent with those of previous studies in DH rabbits receiving antenatal sildenafil treatment 33 , in which lower PVR was attributed to an improvement in fixed structural factors such as the density of distal pulmonary blood vessels 25,29,31,33 . However, the magnitude of the difference in PVR between DH-sildenafil and DH-saline lambs increased after birth, which may reflect a greater vasodilatory response to lung aeration and ongoing ventilation.…”

“…We focused primarily on the physiological effects of antenatal sildenafil treatment in DH lambs, so our study is limited by the absence of histological evidence to confirm the morphological and biochemical features underlying the observed physiology. However, the effects of sildenafil on pulmonary vascular development have been well described in other animal models of CDH and correlate well with our current findings. Interestingly, fetal plasma sildenafil concentrations in our lambs immediately prior to delivery (2–5 ng/mL) were similar to those obtained in rats by Mous et al ,.…”

“…Furthermore, antenatal treatment with the PDE‐5 inhibitor sildenafil has been shown to attenuate pulmonary vascular abnormalities in both a nitrofen‐induced CDH rodent model and a surgery‐induced CDH rabbit model, which is more clinically relevant in terms of lung development. In these animal studies, antenatal sildenafil treatment increased cGMP and vascular endothelial growth factor expression in lung tissue, increased distal pulmonary vessel density, decreased pulmonary vascular muscularization, reduced right ventricular wall thickness and increased distal airway complexity. However, it is unclear if these improvements in pulmonary vascular structure and biochemistry translate to improved pulmonary hemodynamics after birth.…”

“…This is supported by the finding that phosphodiesterase-5 (PDE-5) is upregulated in neonatal CDH lungs; PDE-5 suppresses NO-mediated vasodilatation by rapidly degrading cyclic guanosine monophosphate (cGMP) 24 . Furthermore, antenatal treatment with the PDE-5 inhibitor sildenafil has been shown to attenuate pulmonary vascular abnormalities in both a nitrofen-induced CDH rodent model and a surgery-induced CDH rabbit model, which is more clinically relevant in terms of lung development [25][26][27][28][29][30][31][32][33] . In these animal studies, antenatal sildenafil treatment increased cGMP and vascular endothelial growth factor expression in lung tissue, increased distal pulmonary vessel density, decreased pulmonary vascular muscularization, reduced right ventricular wall thickness and increased distal airway complexity [25][26][27][28][29][30][31][32][33] .…”

Effects of Simvastatin on Fetal Cardiac Impairment in the Diaphragmatic Experimental Hernia Model

“…Luong et al [16] demonstrated that prenatally administered sildenafil in the nitrofen CDH model increased lung capillary density. Kattan et al [40] reported that phosphodiesterase-5 inhibitors may improve angiogenesis during pulmonary vascular development in CDH fetuses. Mous et al [12] demonstrated that prenatal sildenafil started at a clinically relevant time point decreases lung hypoplasia and attenuates vascular remodeling in nitrofen-induced CDH in rats.…”