Treatment of rat congenital diaphragmatic hernia with sildenafil and NS-304, selexipag's active compound, at the pseudoglandular stage improves lung vasculature.

Treatment of rat congenital diaphragmatic hernia with sildenafil and NS-304, selexipag's active compound, at the pseudoglandular stage improves lung vasculature.

Am J Physiol Lung Cell Mol Physiol. 2018 May 10;:

Authors: Mous DS, Kool HM, Burgisser PE, Buscop-van Kempen MJ, Nagata K, Boerema-de Munck A, van Rosmalen J, Dzyubachyk O, Wijnen RM, Tibboel D, Rottier RJ

Abstract
Patients with congenital diaphragmatic hernia (CDH) often suffer from severe pulmonary hypertension and the choice of current vasodilator therapy is mostly based on trial and error. Since pulmonary vascular abnormalities are already present early during development, we performed a study to modulate these pulmonary vascular changes at an early stage during gestation. Pregnant Sprague-Dawley rats were treated with nitrofen at day 9.5 of gestation (E9.5) to induce CDH in the offspring and subsequently the phosphodiesterase-5 inhibitor sildenafil and/or the novel prostaglandin-I receptor agonist selexipag (NS-304) were administered from E17.5 until E20.5. The clinical relevant start of the treatment corresponds to week 20 of gestation in human, when CDH is usually detected by ultrasound. CDH pups showed increased density of air saccules which was reverted after the use of only sildenafil. The pulmonary vascular wall was thickened and right ventricular hypertrophy was present in the CDH group and improved both after single treatment with sildenafil or selexipag, whereas the combination therapy with both compounds did not have additive value. In conclusion, antenatal treatment with sildenafil improved airway morphogenesis and pulmonary vascular development, while selexipag only acted positively on pulmonary vascular development. The combination of both compounds did not act synergistically, probably because of a decreased efficiency of both compounds caused by CYP interaction and induction. These new insights create important possibilities for future treatment of pulmonary vascular abnormalities in CDH patients already in the antenatal period of life.

PMID: 29745254 [PubMed - as supplied by publisher]

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