Ductus arteriosus: Developmental response to oxygen and indomethacin

doi:10.1016/0090-6980(78)90041-2

Prostaglandins

Volume 15, Issue 6, June 1978, Pages 993-998

Prostaglandins

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Abstract

It has been suggested that ineffective constriction in response to an increase in PO₂ is the primary cause for delayed closure of the ductus arteriosus in preterm infants. We studied the isometric contractile effects of increased PO₂ and indomethacin on isolated rings of lamb ductus arteriosus from animals of different gestational ages (87 to 147 days, term is 150 days). Rings from animals less than 110 days have a significantly smaller oxygen-induced contraction (2.53 ± .30 g/mm², n = 16) when compared with rings from animals near term (4.59 ± .69 g/mm², n = 9). Oxygen contracted rings from all gestational ages contract further upon addition of 1 μg/ml indomethacin. Rings from animals less than 110 days have a significantly larger indomethacin induced contraction (1.10 ± .17 g/mm², n = 16) than vessels near term (0.52 ± .12 g/mm², n = 9). Inhibition of prostaglandin production in rings less than 110 days results in a total combined oxygen and indomethacin induced tension that is not significantly different from the oxygen or oxygen and indomethacin induced tension developed in rings from animals near term. This is consistent with the hypothesis that, early during gestation, endogenous prostaglandins inhibit the vessel's ability to contract in response to oxygen. These observations are also consistent with the ability of indomethacin to constrict the patient ductus arteriosus in pre-term infants.

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Concentration-activity profile of the modulation of cyclooxygenase product formation by reduced glutathione in microsomal fractions from the goat lung
1990, Biochimica et Biophysica Acta (BBA)/Lipids and Lipid Metabolism
Age-related changes in pulmonary formation of arachidonic acid (AA) metabolites are thought to play an important role in regulating cardiopulmonary function. This study addresses the potential role of reduced glutathione (GSH) in modulating cyclooxygenase product formation in the developing lung. Prostaglandin H₂ (PGII₂) metabolism was studied in microsomal fractions isolated from the lungs of unventilated fetal, neonatal and adult goats. GSH-dependent PGH₂ to PGE₂ isomerase activity in microsomal fractions from the perinatal (fetal and neonatal) goat lung was not saturable with respect to GSH and can respond to changes in GSH concentration over the range of 0.01 to 30 mM, which encompasses the full range the intracellular GSH levels reported in the literature. However, in fractions from the adult, a lower rate of PGE₂ formation is observed at higher GSH concentrations. In addition, the tissue levels of GSH exhibited developmental stage-related differences with fetal being higher than neonatal or adult. The present observations may have physiologic relevance, in that decreases in pulmonary GSH levels after birth may contribute to decreases in plasma PGE₂ levels by decreasing pulmonary PGE₂ synthesis, thereby contributing to closure of the ductus arteriosus; conversely, increased GSH levels associated with hyperoxia may contribute to persistence of ductal patency. Formation of 6-keto-PGF_1α and of TXB₂ (the stable metabolites of prostacyclin and TXA₂) was decreased when PGE₂ formation was increased by GSH activation of PGE₂ isomerase in fractions isolated from all three developmental stages. A similar pattern of product formation was observed when AA was employed as substrate. These data suggest the possibility that changes in GSH concentration may modulate eicosanoid formation in cells that contain GSH-dependent PGE₂ isomerase, as well as either or both prostacyclin or thromboxane synthase(s).
Inhibition of the oxygen-induced contraction of the isolated human umbilical artery by indomethacin, flurbiprofen, aspirin and drugs modifying Ca<sup>2+</sup> disposition
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In this study we have quantified the potency of three cyclo-oxygenase inhibitors, indomethacin, flurbiprofen and aspirin to reduce the vasoconstriction of isolated strips of human umbilical artery (HUA) to changing the oxygen-tension (PO₂) of the bathing medium. The inhibitory potencies (IC₅₀) of indomethacin and flurbiprofen were similar (IC₅₀ = 2.1 × 10⁻⁹M and 7.6 × 10⁻⁹M respectively) while aspirin (IC₅₀ = 2.5 × 10⁻⁵M) was approximately 12, 000 fold less potent than indomethacin. At the physiological PO₂ of 15mmHg the isolated HUA was found to have an inherent cyclo-oxygenase induced tone since either reducing the PO₂ from 15 to OmmHg or adding cyclo-oxygenase inhibitors caused vasorelaxation. O₂-induced contractions were partly dependent on extracellular Ca²⁺: nifedine and Bay K 8644 inhibited and enhanced oxygen-induced contractions, respectively, but did not have a significant effect on calcium-dependent 5-hydroxy-tyrptamine-induced (5-HT) contractions. Therefore cyclo-oxygenase products and 5-hydroxytryptamine-induced contractions of the HUA may both utilise extracellular calcium but through different processes.
Work in progress. Ductus arteriosus closure may result from suppression of prostacyclin synthetase by an intrinsic hydroperoxy fatty acid
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Fetal sheep ductus arteriosus readily synthesized prostacyclin from exogenous prostaglandin endoperoxides, and in the presence of the high oxygen tension, this synthesis is markedly suppressed. Fetal aorta and pulmonary artery also synthesize prostacyclin; however, this synthesis is much less suppressed by high oxygen tension. We propose that ductal closure may be regulated by the oxygen dependent synthesis of hydroperoxy fatty acid which would block the production of the vasodilatory prostacyclin and expose the direct contractile properties of the intrinsic prostaglandin endoperoxide. This mechanism would result in ductal closure at birth.

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Ductus arteriosus: Developmental response to oxygen and indomethacin

Abstract

Prostaglandins

Prostaglandins

Eur. J. Pharmacol.

Prostaglandins

Prostaglandins

Prostaglandins