Antenatal maternally-administered phosphodiesterase type 5 inhibitors normalize eNOS expression in the fetal lamb model of congenital diaphragmatic hernia

Abstract

Purpose Pulmonary hypertension (pHTN), a main determinant of survival in congenital diaphragmatic hernia (CDH), results from in utero vascular remodeling. Phosphodiesterase type 5 (PDE5) inhibitors have never been used antenatally to treat pHTN. The purpose of this study is to determine if antenatal PDE5 inhibitors can prevent pHTN in the fetal lamb model of CDH. Methods CDH were created in pregnant ewes. Postoperatively, pregnant ewes received oral placebo or tadalafil, a PDE5 inhibitor, until delivery. Near term gestation, lambs underwent resuscitations, and lung tissue was snap frozen for protein analysis. Results Mean cGMP levels were 0.53±0.11 in placebo-treated fetal lambs and 1.73±0.21 in tadalafil-treated fetal lambs (p=0.002). Normalized expression of eNOS was 82±12% in Normal-Placebo, 61±5% in CDH-Placebo, 116±6% in Normal-Tadalafil, and 86±8% in CDH-Tadalafil lambs. Normalized expression of β-sGC was 105±15% in Normal-Placebo, 82±3% in CDH-Placebo, 158±16% in Normal-Tadalafil, and 86±8% in CDH-Tadalafil lambs. Endothelial NOS and β-sGC were significantly decreased in CDH (p = 0.0007 and 0.01 for eNOS and β-sGC, respectively), and tadalafil significantly increased eNOS expression (p = 0.0002). Conclusions PDE5 inhibitors can cross the placental barrier. β-sGC and eNOS are downregulated in fetal lambs with CDH. Antenatal PDE5 inhibitors normalize eNOS and may prevent in utero vascular remodeling in CDH.

Transplacental sildenafil rescues lung abnormalities in the rabbit model of diaphragmatic hernia

“…This is not different from clinical reality, as in humans there is no robustly validated prenatal ultrasound predictor for PPHT. It would also be interesting to evaluate more selective PDE5 inhibitors, like tadalafil 40. However, use of tadalafil in the neonatal population is contraindicated due to lack of maturation of the glucuronidation pathway vital for drug metabolism 41.…”

Tadalafil Integrates Nitric Oxide-Hydrogen Sulfide Signaling to Inhibit High Glucose-induced Matrix Protein Synthesis in Podocytes

“…Recent reports suggest that PDE5 inhibitors act at other sites in the NO pathway. For instance, tadalafil augments the expression of eNOS in the lung (41). Sildenafil stimulates iNOS expression in cardiac myocytes and cytokine-primed vascular smooth muscle cells (44 -46).…”

“…Tadalafil has been reported to increase the expression of endothelial NOS (eNOS) in the lung (41). Preincubation with N -nitro-L-arginine methyl ester, a global NOS inhibitor, abrogated tadalafil stimulation of AMPK phosphorylation (Fig.…”

The Effect of Transplacental Administration of Glucagon-Like Peptide-1 on Fetal Lung Development in the Rabbit Model of Congenital Diaphragmatic Hernia

“…It adds to a small body of studies published in larger animal models (sheep or rabbit) in novel therapies for CDH. In sheep, only transplacental tadalafil has previously been investigated [17,45]. …”

“…Isolated studies on transplacental therapies in the nitrofen rat model have been published, including sildenafil (VEGF agonist), CGS-26303 (endothelin-converting enzyme-1 activator), PR-123319 (angiotensin 2 receptor antagonist), epidermal growth factor, ghrelin, estrogen, and tetrandrine (a Chinese herbal remedy) [10,11,12,13,14,15,16]. Only tadalafil has been used transplacentally in the sheep model [17]. Preclinical work has not translated into a clinical reality, with steroids not proving effective in a small clinical trial and prenatal vitamins not offered to patients due to concerns over teratogenesis [18,19].…”