Lamb ductus arteriosus: Effect of prostaglandin synthesis inhibitors on the muscle tone and the response to prostaglandin E2

doi:10.1016/0090-6980(75)90034-9

Prostaglandins

Volume 9, Issue 2, February 1975, Pages 299-308

Prostaglandins

https://doi.org/10.1016/0090-6980(75)90034-9 Get rights and content

Abstract

The prostaglandin synthesis inhibitors, indomethacin and eicosa-5,8,11, 14-tetraynoic acid (ETA), have been tested on the isolated lamb ductus arteriosus at low and high PO₂ levels. Both compounds produced a gradual contraction of the hypoxic vessel, and at equal doses the effect of indomethacin was stronger. The maximal tension output of the hypoxic tissue under indomethacin was equal to that of the oxygen-contracted control. ETA- and indomethacin-treated preparations contracted further upon transfer from a low to a high oxygen environment, and the response under indomethacin exceeded significantly control values. Control preparations were relaxed markedly by PGE₂ in low oxygen but showed little or no response in high oxygen. In contrast, preparations pretreated with the inhibitors retained their sensitivity to PGE₂ during exposure to high oxygen. The data are consistent with the idea that E-type prostaglandins play a role in the regulation of the intrinsic tone of the ductus arteriosus during foetal life. It is also suggested that the sensitivity of ductal muscle to E-type prostaglandins is controlled by the rate of endogenous prostaglandin formation.

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The molecular mechanisms of oxygen-sensing in human ductus arteriosus smooth muscle cells: A comprehensive transcriptome profile reveals a central role for mitochondria
2021, Genomics
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Although prostaglandin E2 (PGE2) is primarily responsible for maintaining DA patency during fetal life [41–43], DA PGE2 sensitivity drops during gestation [44], in preparation for the impending closure of the DA. PGE2 is required for patency, and NSAIDs results in DA vessel contraction [45]. The loss of PGE2 vasodilation at birth is coupled with an active, oxygen-induced constriction of the DASMCs to achieve functional closure [46].
The ductus arteriosus (DA) connects the fetal pulmonary artery and aorta, diverting placentally oxygenated blood from the developing lungs to the systemic circulation. The DA constricts in response to increases in oxygen (O₂) with the first breaths, resulting in functional DA closure, with anatomic closure occurring within the first days of life. Failure of DA closure results in persistent patent ductus arteriosus (PDA), a common complication of extreme preterm birth. The DA's response to O₂, though modulated by the endothelium, is intrinsic to the DA smooth muscle cells (DASMC). DA constriction is mediated by mitochondrial-derived reactive oxygen species, which increase in proportion to arterial partial pressure of oxygen (PaO₂). The resulting redox changes inhibit voltage-gated potassium channels (Kv) leading to cell depolarization, calcium influx and DASMC constriction. To date, there has not been an unbiased assessment of the human DA O₂-sensors using transcriptomics, nor are there known molecular mechanisms which characterize DA closure. DASMCs were isolated from DAs obtained from 10 term infants at the time of congenital heart surgery. Cells were purified by flow cytometry, negatively sorting using CD90 and CD31 to eliminate fibroblasts or endothelial cells, respectively. The purity of the DASMC population was confirmed by positive staining for α-smooth muscle actin, smoothelin B and caldesmon. Cells were grown for 96 h in hypoxia (2.5% O₂) or normoxia (19% O₂) and confocal imaging with Cal-520 was used to determine oxygen responsiveness. An oxygen-induced increase in intracellular calcium of 18.1% ± 4.4% and SMC constriction (−27% ± 1.5% shortening) occurred in all cell lines within five minutes. RNA sequencing of the cells grown in hypoxia and normoxia revealed significant regulation of 1344 genes (corrected p < 0.05). We examined these genes using Gene Ontology (GO). This unbiased assessment of altered gene expression indicated significant enrichment of the following GOterms: mitochondria, cellular respiration and transcription. The top regulated biologic process was generation of precursor metabolites and energy. The top regulated cellular component was mitochondrial matrix. The top regulated molecular function was transcription coactivator activity. Multiple members of the NADH-ubiquinone oxidoreductase (NDUF) family are upregulated in human DASMC (hDASMC) following normoxia. Several of our differentially regulated transcripts are encoded by genes that have been associated with genetic syndromes that have an increased incidence of PDA (Crebb binding protein and Histone Acetyltransferase P300). This first examination of the effects of O₂ on human DA transcriptomics supports a putative role for mitochondria as oxygen sensors.
Genetics of the patent ductus arteriosus (PDA) and pharmacogenetics of PDA treatment
2018, Seminars in Fetal and Neonatal Medicine
Citation Excerpt :
Despite complex interactions between these contributors, developing a thorough understanding of the factors which affect the drug dose–exposure–response paradigm is an important first step in optimizing therapies. It has been known since 1975 that indomethacin and other non-steroidal anti-inflammatory drugs (NSAIDs) decrease systemic prostaglandins and promote PDA closure [31–33]. Soon thereafter, the treatment response to indomethacin in preterm infants was studied in multiple trials [34,35].
Patent ductus arteriosus (PDA) is a frequent, complex, and difficult to treat clinical syndrome among preterm infants in the neonatal intensive care unit. In addition to known clinical risk factors, there are emerging data about genetic predisposition to PDA in both animal and human models. Clinical response and toxicity from drugs used to treat PDA are highly variable. Developmental and genetic aspects of pharmacokinetics and pharmacodynamics influence exposure and response to pharmacologic therapies. Given the variable efficacy and toxicity of known drug therapies, novel therapeutic targets for PDA treatment offer the promise of precision medicine. This review addresses the known genetic contributions to prolonged ductal patency, variability in response to drug therapy for PDA, and potential novel drug targets for future PDA treatment discovery.
Changing patterns of patent ductus arteriosus surgical ligation in the United States
2018, Seminars in Perinatology
Citation Excerpt :
SL was the only curative treatment for PDA for nearly 40 years. In the 1970s, NSAIDs were reported to induce DA constriction43–46 and effectively close the PDA in preterm infants.13,14 Pharmacological therapy is now widely accepted as the first-line treatment for symptomatic PDA.
Optimal management of patent ductus arteriosus (PDA) is unclear. One treatment, surgical ligation, is associated with adverse outcomes. We reviewed data from the Kids’ Inpatient Database (2000–2012) to determine if PDA ligation rates: (1) changed over time, (2) varied geographically, or (3) influenced surgical complication rates. In 2012, 47,900 infants <1500 g birth weight were born in the United States, including 2,800 undergoing PDA ligation (5.9%). Ligation was more likely in infants <1000 g (85.9% vs. 46.2%), and associated with necrotizing enterocolitis (59.2% vs. 37.5%), BPD (54.6% vs. 15.2%), severe intraventricular hemorrhage (16.4% vs. 5.3%), and hospital transfer (37.6% vs. 16.4%). Ligation rates peaked in 2006 at 87.4 per 1000 hospital births, dropping to 58.8 in 2012, and were consistently higher in Western states. Infants undergoing ligation were more likely to experience comorbidities. Rates of ligation-associated vocal cord paralysis increased over time (1.2–3.9%); however, mortality decreased (12.4–6.5%). Thus, PDA ligation has become less frequent, although infants being ligated are smaller and more medically complex. Despite increase in some complications, mortality rates improved perhaps reflecting advances in care.
Novel drug targets for ductus arteriosus manipulation: Looking beyond prostaglandins
2018, Seminars in Perinatology
Citation Excerpt :
Along these lines, it is likely that future studies will identify small molecule antagonists/agonists that preferentially target the vascular channel isoform (Kir6.1/SUR2B), which will allow for a more specific way to modulate DA tone. In the 45 years since the first reports of indomethacin-induced DA closure,16–18,29,82,83 relatively little headway has been made in developing novel approaches for therapeutic modulation of DA tone. As a consequence, there has been little progress in establishing a standard of care over the subsequent decades, leading to significant variability in treatment strategies amongst neonatal care centers and even between providers in a single care center.84,85
Forty years ago, non-steroidal anti-inflammatory drugs were first reported to decrease systemic prostaglandin levels and promote ductus arteriosus (DA) closure. And yet, prolonged patency of the DA (PDA) remains a significant clinical problem, complicated by imperfect therapies and wide variations in treatment strategy. There are few pharmacology-based tools available for treating PDA (indomethacin, ibuprofen, and acetaminophen), or for maintaining DA patency (PGE₁) as is needed to facilitate corrective surgery for ductus-dependent congenital heart defects. Unfortunately, all of these treatments are inefficient and are associated with concerning adverse effects. This review highlights novel potential DA drug targets that may expand our therapeutic repertoire beyond the prostaglandin pathway.
Prophylactic Indomethacin Revisited
2017, Journal of Pediatrics
Managing the Patent Ductus Arteriosus in the Premature Neonate: A New Look at What We Thought We Knew
2012, Seminars in Perinatology
Over recent years, the clinical approach to patency of the ductus arteriosus in the premature neonate has been the subject of intensive reevaluation. What had once been considered inherently obvious is no longer to be taken for granted. In this review we will focus on some of the controversies surrounding various aspects of the pharmacologic treatment regimens for patent ductus arteriosus closure. The pros and cons of prophylactic vs therapeutic indomethacin, of early vs late therapy, of high- vs low-dose indomethacin, of single vs multiple courses of treatment, and of ibuprofen vs indomethacin will be considered. In addition, the possibility that patency of the ductus arteriosus is merely a physiological manifestation of extreme prematurity, and thus does not necessarily need to be therapeutically closed, has become a viable approach in some cases. As such, we will examine echocardiographic and biochemical criteria aimed at determining the clinical and hemodynamic significance of ductal shunting, and thereby of the need to treat. Finally, we speculate on potential therapeutic directions for the future, including individualized treatment regimens and multidrug treatment cocktails for those who fail initial monodrug therapy.

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Lamb ductus arteriosus: Effect of prostaglandin synthesis inhibitors on the muscle tone and the response to prostaglandin E2

Abstract

Biochem. Biophys. Res. Comm.

Biochim. Biophys. Acta

Biochem. Pharmacol.

The response of the ductus arteriosus to prostaglandins

Can. J. Physiol. Pharmacol.

On the action of prostaglandin E1 and prostaglandins from brain on the isolated rat stomach

Can. J. Physiol. Pharmacol.

On the contractile response of the isolated rat uterus to prostaglandin E1

Can. J. Physiol. Pharmacol.

Prostaglandins, oxygen tension and smooth muscle tone

Br. J. Pharmac.

Lamb ductus arteriosus: Effect of prostaglandin synthesis inhibitors on the muscle tone and the response to prostaglandin E₂

On the action of prostaglandin E₁ and prostaglandins from brain on the isolated rat stomach

On the contractile response of the isolated rat uterus to prostaglandin E₁