Involvement of intramural prostaglandin E2 in prenatal patency of the lamb ductus arteriosus

1986 ◽  
Vol 64 (6) ◽  
pp. 737-744 ◽  
Author(s):  
Flavio Coceani ◽  
Dayle Huhtanen ◽  
Nancy C. Hamilton ◽  
Isis Bishai ◽  
Peter M. Olley
Keyword(s):  
Release Rate ◽  
Enzyme System ◽  
Reduced Glutathione ◽  
Ductus Arteriosus ◽  
Prostaglandin E ◽  
Concomitant Treatment ◽  
Contractile State ◽  
Wet Weight ◽  
Near Term

Release of prostaglandin E2 (PGE2) was studied in isolated ductus arteriosus preparations from immature (103 or 104 days gestation; term, 147 days) and near-term fetal lambs. Mature preparations produced measurable amounts of the compound in most cases and the release rate was 19 ± 2 pg/(100 mg wet weight∙min) at a [Formula: see text] of 3–8 Torr (1 Torr = 133.3 Pa). PGE2 release increased with the [Formula: see text] of the medium, peak values (about 125 pg/(100 mg∙min)) being attained at 106–276 Torr when the oxygen-induced contraction was still submaximal. Experiments in which tissues were either contracted with excess potassium or relaxed with CO proved that PGE2 formation is independent from the contractile state. PGE2 was also released from ductus preparations lacking the adventitia, the intima, or both; however, release values were maximal when the adventitia was preserved. The magnitude of the intrinsic tone in these stripped preparations was inversely related to the rate of PGE2 formation. Reduced glutathione increased PGE2 release from the mature ductus, whole or stripped, and also relaxed hypoxic preparations; both effects were reversed by concomitant treatment with indomethacin. PGE2 synthesis tended to be greater in the immature than the mature ductus, maximal values (115 ± 27 pg/(100 mg∙min)) being observed at 6–8 Torr. We conclude that the ductus arteriosus is endowed with an enzyme system for the synthesis of PGE2 whose function accords with an effector role of the compound in the regulation of tone. These findings, together with the potent relaxation exerted by PGE2 at low [Formula: see text], indicate that the locally generated prostaglandin is well suited for keeping the ductus patent in the fetus.

Endothelin-1 release from lamb ductus arteriosus; relevance to postnatal closure of the vessel

1991 ◽  
Vol 69 (2) ◽  
pp. 218-221 ◽  
Author(s):  
Flavio Coceani ◽  
Lois Kelsey
Keyword(s):  
Key Words ◽  
Conformational Change ◽  
Contractile Response ◽  
Ductus Arteriosus ◽  
Endothelin 1 ◽  
Wet Weight ◽  
Presence And Absence ◽  
Near Term ◽  
Cytochrome P 450 ◽  
Postnatal Closure

Our previous investigations have shown that endothelin-1 (ET-1) is a singularly potent constrictor of the ductus arteriosus and that a cytochrome P-450 system located in the sarcolemma is crucial for the contractile response of the vessel to oxygen. We have now studied the release of ET-1 from isolated ductus arteriosus preparations of near-term fetal lambs. Preparations produced measurable amounts of ET-1 under basal conditions (about 0.04 pg/100 mg wet weight∙min) both in the presence and absence of the endothelium. Anisomycin (10−4 M) reduced this release by 50%, while thrombin (1 U/mL) doubled the release. Treatment with a CO mixture (CO/O2 ratio, 0.27) inhibited ET-1 release from intact and endothelium-denuded preparations. We propose that oxygen triggers closure of the ductus arteriosus at birth by causing a conformational change in a specific cytochrome P-450, which, in turn, provides the signal for the synthesis of the constrictor ET-1.Key words: ductus arteriosus closure, oxygen, cytochrome P-450, endothelin.

Release of prostaglandins from intact fetal lamb ductus arteriosus

1983 ◽  
Vol 61 (5) ◽  
pp. 240-247 ◽  
Author(s):  
C. R. Pace-Asciak ◽  
G. Rangaraj
Keyword(s):  
Gas Chromatography ◽  
Arachidonic Acid ◽  
Ductus Arteriosus ◽  
Significant Proportion ◽  
Calcium Ionophore ◽  
Major Product ◽  
Electron Capture Detection ◽  
Prostaglandin E ◽  
Physiological Importance ◽  
Near Term

Intact rings and slices of ductus arteriosus from fetal lambs near term (130–143 days gestation) were incubated with [14C]arachidonic acid and the fate of the label in the incubation fluid and tissue was followed by thin-layer radiochromatography (TLC). Prostaglandins formed from endogenous stores of arachidonic acid were assayed by capillary gas chromatography with electron-capture detection. In additional experiments, the prelabelled tissue was incubated with various drugs (e.g., angiotensin II, bradykinin, and calcium ionophore) to determine their effects on the release of 14C-labelled prostaglandins. Results indicate that the ductus arteriosus is oriented towards forming prostaglandin (PG) I2, with PGE2 being formed to a minor extent in all studies. While radiochromatographic studies (TLC) suggested a considerable complexity mostly because of overlapping products (PGs and metabolites), this was resolved using gas chromatography where a complete resolution of PGs from these metabolites was observed. In the tissue-labelling experiments most of the radioactivity remained in the incubation fluid and was recovered as unchanged arachidonic acid, although a small but significant proportion of label was observed in a mixture of prostaglandins (4.2 ± 0.6%, n = 16) with 6-keto PGF1α being the major product. The ductus tissue incorporated a small amount of label (3.4 ± 0.4%, n = 19) of which 49.7 ± 4.9% (n = 13) was found in the tissue phospholipids. Hydrolysis of tissue-bound [14C]arachidonic acid, which appeared in the perfusing medium together with 14C-labelled prostaglandins, was in the range of 28.0 ± 2.7% (n = 9) of total tissue radioactivity per experiment. Although 42.2 ± 2.5% (n = 18) of the radioactivity released by each of the drugs represented a mixture of prostaglandins and their metabolites (the rest recovered as arachidonic acid), no appreciable selectivity by any of the drugs was found for either the stimulation of phospholipase activity in this tissue or for the rerouting of the prostaglandin synthetic system to form prostaglandin E2 instead of I2. We conclude that prostaglandin I2 rather than E2 is probably of physiological importance in this unique fetal blood vessel.

Evidence for an effector role of endothelin in closure of the ductus arteriosus at birth

1992 ◽  
Vol 70 (7) ◽  
pp. 1061-1064 ◽  
Author(s):  
Flavio Coceani ◽  
Lois Kelsey ◽  
Eric Seidlitz
Keyword(s):  
Oxygen Concentration ◽  
Oxygen Tension ◽  
Ductus Arteriosus ◽  
Critical Role ◽  
Blood Oxygen ◽  
Endothelin 1 ◽  
A Value ◽  
Near Term ◽  
Oxygen Concentrations

The ductus arteriosus is a special muscular shunt that in the fetus allows blood to bypass the unexpanded lungs. It closes rapidly after birth and this event is initiated by the physiologic rise in blood oxygen tension. Endothelin-1 has been proposed by us as a local mediator for oxygen after demonstrating that it is formed within the ductus and is a potent ductus constrictor. To confirm this possibility, we have now measured the release of endothelin-1 from the isolated ductus of near-term fetal lambs at different oxygen concentrations of the medium. In addition, using the same preparation, we have examined the effect on contractile tone of compounds interfering with the synthesis (phosphoramidon, 50 μM) and action (BQ123, 1 μM) of endothelin-1. We report that release of endothelin-1 from the ductus tends to increase with the oxygen concentration up to a value mimicking the neonatal condition. Phosphoramidon and, to a greater degree, BQ123 inhibit the contraction of the vessel to oxygen. These results implicate endothelin-1 as the effector agent for oxygen in the ductus and, by extension, assign to this peptide a critical role in the closure of the vessel at birth.Key words: ductus arteriosus closure, oxygen, endothelin.

Prostanoid receptors: ontogeny and implications in vascular physiology

2001 ◽  
Vol 281 (5) ◽  
pp. R1343-R1360 ◽  
Author(s):  
D. Hamish Wright ◽  
Daniel Abran ◽  
Mousumi Bhattacharya ◽  
Xin Hou ◽  
Sylvie G. Bernier ◽  
...  
Keyword(s):  
Ductus Arteriosus ◽  
Carbon Dioxide Tension ◽  
Prostaglandin E ◽  
Prostanoid Receptors ◽  
Pharmacological Characterization ◽  
Vascular Physiology ◽  
G Protein Coupled ◽  
Made In

Prostanoids exert significant effects on circulatory beds. They play a role in the response of the vasculature to adjustments in perfusion pressure and oxygen and carbon dioxide tension, and they mediate the actions of numerous factors. The role of prostanoids in governing circulation of the perinate is suggested to surpass that in the adult. Prostanoids are abundantly generated in the perinate. They have been implicated in autoregulation of blood flow as studied in brain and eyes. Prostaglandins are also dominant regulators of ductus arteriosus tone. The effects of these autacoids are mediated through specific G protein-coupled receptors. In addition to the pharmacological characterization of the prostanoid receptors, important advances in understanding the biology of these receptors have been made in the last decade. Their cloning and the development of animals with disrupted genes of these receptors have been very informative. The involvement of prostanoid receptors in the developing subject, especially on brain and ocular vasculature and on ductus arteriosus, has also begun to be investigated; the expression of these receptors changes with development. Some but not all of the ontogenic changes in these receptors are attributed to homologous regulation. Interestingly, in the process of elucidating their effects, functional perinuclear prostaglandin E2receptors have been uncovered. This article reviews prostanoid receptors and addresses implications on the developing subject with attention to vascular physiology.

scholarly journals The Role of β-Adrenoreceptor Stimulation and Contractile State in the Preterm Lamb's Response to Altered Ductus Arteriosus Patency

1988 ◽  
Vol 23 (3) ◽  
pp. 316-322 ◽  
Author(s):  
Ronald I Clyman ◽  
David Teitel ◽  
James Padbury ◽  
Christine Roman ◽  
Francoise Mauray
Keyword(s):  
Ductus Arteriosus ◽  
Contractile State

scholarly journals Fibulin-1 Integrates Subendothelial Extracellular Matrices and Contributes to Anatomical Closure of the Ductus Arteriosus

2020 ◽  
Vol 40 (9) ◽  
pp. 2212-2226 ◽  
Author(s):  
Satoko Ito ◽  
Utako Yokoyama ◽  
Taichi Nakakoji ◽  
Marion A. Cooley ◽  
Takako Sasaki ◽  
...  
Keyword(s):  
Ductus Arteriosus ◽  
Pulmonary Arteries ◽  
Nuclear Factor Κb ◽  
Extracellular Matrices ◽  
Prostaglandin E ◽  
Matrix Remodeling ◽  
Binding Partner ◽  
Progressive Matrix ◽  
Hyaluronan Binding

Objective: The ductus arteriosus (DA) is a fetal artery connecting the aorta and pulmonary arteries. Progressive matrix remodeling, that is, intimal thickening (IT), occurs in the subendothelial region of DA to bring anatomic DA closure. IT is comprised of multiple ECMs (extracellular matrices) and migrated smooth muscle cells (SMCs). Because glycoprotein fibulin-1 binds to multiple ECMs and regulates morphogenesis during development, we investigated the role of fibulin-1 in DA closure. Approach and Results: Fibulin-1–deficient ( Fbln1 −/− ) mice exhibited patent DA with hypoplastic IT. An unbiased transcriptome analysis revealed that EP4 (prostaglandin E receptor 4) stimulation markedly increased fibulin-1 in DA-SMCs via phospholipase C-NFκB (nuclear factor κB) signaling pathways. Fluorescence-activated cell sorting (FACS) analysis demonstrated that fibulin-1 binding protein versican was derived from DA-endothelial cells (ECs). We examined the effect of fibulin-1 on directional migration toward ECs in association with versican by using cocultured DA-SMCs and ECs. EP4 stimulation promoted directional DA-SMC migration toward ECs, which was attenuated by either silencing fibulin-1 or versican. Immunofluorescence demonstrated that fibulin-1 and versican V0/V1 were coexpressed at the IT of wild-type DA, whereas 30% of versican-deleted mice lacking a hyaluronan binding site displayed patent DA. Fibulin-1 expression was attenuated in the EP4-deficient mouse ( Ptger4 −/− ) DA, which exhibits patent DA with hypoplastic IT, and fibulin-1 protein administration restored IT formation. In human DA, fibulin-1 and versican were abundantly expressed in SMCs and ECs, respectively. Conclusions: Fibulin-1 contributes to DA closure by forming an environment favoring directional SMC migration toward the subendothelial region, at least, in part, in combination with EC-derived versican and its binding partner hyaluronan.

THE ROLE OF PLANT PHENOLIC COMPOUNDS IN THE OXIDATION OF REDUCED DIPHOSPHOPYRIDINE NUCLEOTIDE BY PEROXIDASE

1961 ◽  
Vol 39 (7) ◽  
pp. 1113-1124 ◽  
Author(s):  
O. L. Gamborg ◽  
L. R. Wetter ◽  
A. C. Neish
Keyword(s):  
Hydrogen Peroxide ◽  
Ascorbic Acid ◽  
Indoleacetic Acid ◽  
Enzyme System ◽  
Reduced Glutathione ◽  
Maximum Activity ◽  
Coumaric Acid ◽  
Horse Radish Peroxidase ◽  
Competitive Inhibitors

Horse-radish peroxidase and dialyzed extracts from pea epicotyls and from spruce shoots oxidized reduced diphosphopyridine nucleotide in the presence of p-coumaric acid. Maximum activity was obtained when hydrogen peroxide, Mn+2, p-coumaric acid, and enzyme were present. p-Hydroxyphenylpropionic acid, p-hydroxyphenylpyruvic acid, tyrosol, or resorcinol could replace p-coumaric acid as the phenolic activator but they were less efficient. Ferulic and sinapic acids were competitive inhibitors while chlorogenic acid, caffeic acid, and hydroquinone were non-competitive inhibitors of the reaction. The oxidation of the reduced coenzyme was inhibited by citrate and pyrophosphate, enhanced by versene, and delayed by ascorbic acid, cysteine, and reduced glutathione. The results indicate that the peroxidase system may be identical with the enzyme system which oxidizes indoleacetic acid.

Ouabain binding to isolated frog gastric mucosa

1981 ◽  
Vol 241 (2) ◽  
pp. G104-G108
Author(s):  
V. M. France ◽  
R. P. Durbin
Keyword(s):  
Gastric Mucosa ◽  
Acid Secretion ◽  
Enzyme System ◽  
Specific Binding ◽  
Bathing Solution ◽  
Apical Surface ◽  
Ouabain Binding ◽  
High K ◽  
Wet Weight

Inhibition of gastric acid secretion by the cardiac glycoside, ouabain, is considerably reduced by elevating external K+ as first shown by Davenport (Proc. Soc. Exp. Biol. Med. 110: 613-615, 1962). To determine the possible role of K+ in this effect, we measured [3H]ouabain binding in isolated bullfrog gastric mucosa. Uptake of the labeled drug showed two components: one that saturated at 0.36 pmol ouabain per milligram wet weight and one that was linear with the external ouabain concentration. The former component is considered to represent specific binding to Na+-K+-ATPase; activity of this enzyme system in mucosal homogenates was 0.2 mumol per milligram protein per hour. Increase of K+ in the nutrient bathing solution from 3 to 30 mM, or replacement of Na+ by K+ in the secretory bathing solution, largely reversed inhibition of acid secretion by ouabain but did not affect maximum specific binding. The results fit a model in which Na+-K+-ATPase is normally required in oxyntic cells to maintain a high K+ level, which in turn supports exchange of K+ for H+ at the apical surface.

Occurrence of endothelium-derived relaxing factor – nitric oxide in the lamb ductus arteriosus

1994 ◽  
Vol 72 (1) ◽  
pp. 82-88 ◽  
Author(s):  
Flavio Coceani ◽  
Lois Kelsey ◽  
Eric Seidlitz
Keyword(s):  
Nitric Oxide ◽  
Methylene Blue ◽  
Ductus Arteriosus ◽  
Nonsteroidal Antiinflammatory Drugs ◽  
Prostaglandin E ◽  
Antiinflammatory Drugs ◽  
Relaxing Factor ◽  
Endothelium Derived Relaxing Factor ◽  
Near Term ◽  
Nitric Oxide Inhibitors

To determine whether the ductus arteriosus can form endothelium-derived relaxing factor – nitric oxide, we used isolated ductal strips from near-term fetal lamb and examined their response to bradykinin (a nitric oxide stimulator), L-arginine (a nitric oxide precursor), and agents interfering with the synthesis (Nω-nitro-L-arginine) and action (methylene blue) of nitric oxide. Bradykinin relaxed the indomethacin-contracted ductus dose dependently from a threshold of about 10−10 M, and peak relaxation was greater at high (176–210 mmHg; 1 mmHg = 133.3 Pa) than low (15–25 mmHg) [Formula: see text]. Bradykinin relaxation was nearly completely or completely abolished in endothelium-denuded preparations and, in its place, there was often a small contraction. Pretreatment with nitric oxide inhibitors also prevented, in part (methylene blue, 1 μM) or in full (Nω-nitro-L-arginine, 100 μM), the relaxant effect of bradykinin. Paradoxically, L-arginine (10 μM) had an inhibiting rather than an enhancing effect on the bradykinin relaxation. Nω-Nitro-L-arginine (100 μM) and methylene blue (1–100 μM) contracted by themselves the untreated ductus, and their action persisted after removal of the endothelium. These findings indicate the presence in the ductus arteriosus of a nitric oxide based relaxing mechanism, which may supplement prostaglandin E2 in keeping the vessel patent in the fetus. This mechanism may, on one hand, afford protection against nonsteroidal antiinflammatory drugs in utero and may, on the other hand, complicate the management of prematures with persistent ductus and account for failures of the indomethacin therapy.Key words: ductus arteriosus patency and closure, endothelium-derived relaxing factor – nitric oxide, prostaglandin.

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