Pharmacologic Contributors to Patent Ductus Arteriosus

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Project Summary Vascular adaptation after birth is dependent on closure of the ductus arteriosus (DA), a fetal vascular shunt connecting the pulmonary artery and aorta. Failure of DA closure results in persistent patency of the DA (PDA), a common disorder associated with increased morbidity and mortality in the most vulnerable infants. Current pharmacological treatments for PDA are limited and only focus on a single therapeutic pathway – cyclooxygenase-mediated prostaglandin (PG) synthesis. However, recent data reveal complex networks of genes and druggable pathways involved in the vasodilatory-to-vasoconstrictive shift that drives postnatal DA closure. Efforts to identify new DA-selective vasoconstrictors overlook the possibility that ongoing vasodilatory stimuli perpetuate DA relaxation and inhibit its closure. Because critically ill preterm newborns are exposed to multiple medications during the time that DA closure takes place, we postulate that pharmacologic agents used in the neonatal ICU prevent DA closure and contribute to PDA. The DA of prematurely-born infants is developmentally primed to respond to vasodilatory signals. Our prior studies using mouse models and human data show that drugs frequently used in preterm infants have unexpected vasodilatory effects on the DA, including specific antibiotics, antacids, and diuretics. These data suggest that drug-induced DA relaxation is a modifiable contributor to PDA, but this has not been systematically evaluated. We therefore hypothesize that drugs commonly used in the NICU have an adverse effect on closure of the premature DA and that specific drug combinations act synergistically to impair postnatal DA closure. Mouse and human tissues will be used to test this hypothesis in three Aims: 1) Determine whether drugs in the neonatal pharmacopeia prevent the initial phase of DA closure - smooth muscle constriction - that leads to physiologic closure of the DA lumen; 2) Determine whether drugs in the neonatal pharmacopeia impair the second phase of DA closure - fibromuscular remodeling - that leads to permanent sealing of the constricted DA; 3) Identify drug combinations that interact to adversely affect either phase of DA closure. Drug effects will be examined using primary (in vitro) high throughput screening (HTS) of preterm mouse DA smooth muscle cells. A series of secondary screening assays will prioritize single- and synergistic combinations of hits based on potency/efficacy, DA-selectivity, and toxicity for further study of their ex vivo and in vivo vasoactive effects on the DA. A novel ex vivo mouse DA-reopening assay will be used to screen for drugs of interest. The effect of hit DA-vasodilatory compounds will be examined on ex vivo human neonatal DA segments and in a large national database of preterm infants. These studies have high translational potential and will definitively identify which drugs or drug combinations pose increased risks for PDA in preterm infants, providing an innovative approach to enhance conservative PDA management efforts in the NICU.