Antenatal Sildenafil Treatment Attenuates Pulmonary Hypertension in Experimental Congenital Diaphragmatic Hernia

Abstract

Background-Lung hypoplasia and persistent pulmonary hypertension of the newborn limit survival in congenital diaphragmatic hernia (CDH). Unlike other diseases resulting in persistent pulmonary hypertension of the newborn, infants with CDH are refractory to inhaled nitric oxide (NO). Nitric oxide mediates pulmonary vasodilatation at birth in part via cyclic GMP production. Phosphodiesterase type 5 (PDE5) limits the effects of NO by inactivation of cyclic GMP. Because of the limited success in postnatal management of CDH, we hypothesized that antenatal PDE5 inhibition would attenuate pulmonary artery remodeling in experimental nitrofen-induced CDH. Methods and Results-Nitrofen administered at embryonic day 9.5 to pregnant rats resulted in a 60% incidence of CDH in the offspring and recapitulated features seen in human CDH, including structural abnormalities (lung hypoplasia, decreased pulmonary vascular density, pulmonary artery remodeling, right ventricular hypertrophy), and functional abnormalities (decreased pulmonary artery relaxation in response to the NO donor 2-(N,N-diethylamino)-diazenolate-2-oxide). Antenatal sildenafil administered to the pregnant rat from embryonic day 11.5 to embryonic day 20.5 crossed the placenta, increased fetal lung cyclic GMP and decreased active PDE5 expression. Antenatal sildenafil improved lung structure, increased pulmonary vessel density, reduced right ventricular hypertrophy, and improved postnatal NO donor 2-(N,N-diethylamino)-diazenolate-2-oxide-induced pulmonary artery relaxation. This was associated with increased lung endothelial NO synthase and vascular endothelial growth factor protein expression. Antenatal sildenafil had no adverse effect on retinal structure/function and brain development. Conclusions-Antenatal sildenafil improves pathological features of persistent pulmonary hypertension of the newborn in experimental CDH and does not alter the development of other PDE5-expressing organs. Given the high mortality/ morbidity of CDH, the potential benefit of prenatal PDE5 inhibition in improving the outcome for infants with CDH warrants further studies. (Circulation. 2011;123:2120-2131.)

Local Fetal Lung Renin-Angiotensin System as a Target to Treat Congenital Diaphragmatic Hernia

“…Therefore, PD-123319 maternal administration partially reversed pulmonary arterial structural abnormality that characterizes CDH and decreased molecular markers of PH, which suggest that PD-123319 might reduce pulmonary vascular reactivity, and the risk of postnatal persistent PH observed in CDH neonates. Regarding other antenatal pharmacological strategies to decrease PH in CDH, Luong et al demonstrated recently that antenatal sildenafil treatment (from 11.5 to 20.5 dpc, daily subcutaneous injection) attenuates PH in experimental CDH (3). In fact, that study demonstrated that antenatal sildenafil treatment improved lung structure, increased pulmonary vessel density and reduced right ventricular hypertrophy in CDH (3).…”

“…For many years, this malformation was thought to be a surgical emergence, solely related to a diaphragmatic defect, and potentially curable by surgical closure of this defect after birth, which allowed lung expansion. However, during 90 years, CDH pathophysiology progressed for a physiological emergence (3,4). It is now clear that lung hypoplasia and consecutive persistent pulmonary hypertension (PH) associated with this disorder are the key determinants of mortality (1)(2)(3)(4).…”

“…It is now clear that lung hypoplasia and consecutive persistent pulmonary hypertension (PH) associated with this disorder are the key determinants of mortality (1)(2)(3)(4). Despite the improvements in understanding CDH pathophysiology and advances in neonatal care, such as the use of extra corporeal membrane oxygenation and inhaled nitric oxide, the mortality (50%) and morbidity rate in CDH newborns remains exceedingly high (1)(2)(3)(4). In humans, CDH can be accurately diagnosed at second trimester during routine ultrasound examination.…”

“…However, fetal surgical interventions, such as fetal tracheal occlusion, are invasive, technically demanding, limited by the maternal and fetal risks, and their efficacy is still not determined, with controversial results in survival and morbidity rates (5,6). Therefore, less invasive approaches such as antenatal pharmacological treatment to stimulate lung growth before birth and to treat PH are also under investigation (3,(7)(8)(9)(10).…”

Pulmonary vascular development in congenital diaphragmatic hernia

“…We and others have performed some studies on the antenatal use of the phosphodiesterase-5 inhibitor sildenafil in different animal models of CDH, showing improvement in alveolarisation and pulmonary vascular development [57][58][59][60][61]. However, the pulmonary pathology in these treated animals did not show complete reversal to the normal lung histology.…”