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Biomedical subjects

M H Sullivan

Publications and source records attributed to M H Sullivan.

At least 55 records · Page 3Linked to original sources
PubMed1994

Angiotensin II (AT1) vascular binding sites in human placentae from normal-term, preeclamptic and growth retarded pregnancies.

Angiotensin II (ANG II) is a potent vasoconstrictor in isolated human placental cotyledons and may contribute to the regulation of fetoplacental perfusion. We have used quantitative in vitro receptor autoradiography to examine antagonist ((Sar1,Ile8)-[125I]ANG II) and agonist ligand ([125I]ANG II) binding sites in normal-term, preeclamptic and fetal (intrauterine) growth retarded pregnancies. A similar distribution of binding sites was demonstrated using both ligands, localized to blood vessels in placental villi. Binding density was inversely related to vessel size, being significantly greater on microvessels in distal regions of the villous tree than on proximal vessels in main stem villi. Binding sites exhibited the characteristics of the AT1 class of ANG II receptor, ligand binding being sensitive to dithiothreitol, completely inhibited by nonpeptide AT1 antagonists (Losartan, EXP3174 and SKF108566) and not inhibited by the AT2 antagonist (PD123319). Guanine nucleotides also inhibited [125I]ANG II binding and abolished the high affinity component of agonist inhibition of (Ser1,Ile8)-[125I]ANG II binding, indicating G protein coupling. The capacity and affinity of the binding sites were significantly lower in placentae from pregnancies complicated by preeclampsia and intrauterine growth retardation compared to that in normal-term controls. These differences were apparently not due to prior receptor occupancy by endogenous ligand, but may reflect activation of the placental renin-angiotensin system and receptor down-regulation. Locally generated ANG II, acting via AT1 receptors, may contribute to the regulation of fetoplacental blood flow and influence placental perfusion in preeclamptic and growth retarded pregnancies.

Angiotensin II↗
PubMed1994

Increased platelet volume and aggregation precede the onset of preeclampsia.

OBJECTIVE: To determine whether changes in platelet aggregation, numbers, or mean volume precede the onset of preeclampsia in patients given anti-platelet therapy. METHODS: Changes in platelet aggregation, numbers, and volumes were followed longitudinally in 17 women who had previously lost 44 of 56 pregnancies and were thus considered to be at risk of preeclampsia. The subjects were treated with low-dose aspirin. Mean platelet volume, platelet numbers, and platelet aggregation were monitored every 2-4 weeks during pregnancy. RESULTS: All eight subjects who developed preeclampsia delivered growth-retarded infants before term. All showed increased platelet aggregation in vitro, accompanied by increased platelet volumes (by at least 0.8 fL) and decreased platelet numbers (by at least 60 x 10(9)/L) in five subjects, increased volumes alone in one, and decreased numbers alone in one. The increases in platelet aggregation and volumes predated the development of preeclampsia by 2-5 weeks. Nine subjects had pregnancies that progressed normally to term (beyond 37 weeks), with the delivery of eight normal and one growth-retarded infant; platelet aggregation, numbers, and volumes did not change to the same extent as in the subjects who developed preeclampsia. CONCLUSION: Increased mean platelet volume and increased platelet aggregation compared to the individual patient's first-trimester data were detected 2-5 weeks before the development of all cases of preeclampsia. In contrast, normal pregnancies did not show significant changes in mean platelet volume or platelet aggregation.

Adult↗
PubMed1993

Expression of the human neuropeptide tyrosine Y1 receptor.

Neuropeptide tyrosine (NPY) is the predominant peptide in the innervation of many human tissues and is considered to play a role in the regulation of blood flow, gastrointestinal secretion and motility, and renal function. Three NPY receptors have been identified (Y1, Y2, and Y3) and the cDNAs encoding the human Y1 and bovine Y3 receptors have recently been cloned. We have demonstrated the expression of the Y1 receptor subtype in several fetal and adult human tissues, including the colon, kidney, adrenal gland, heart, and placenta. A single transcript was identified (approximately 2.2 kb) and localized in tissue sections by in situ hybridization. In the colon the receptor is expressed in the mucosa and basal glands, as well as the myenteric and submucous plexuses. Y1 receptor mRNA was detected in renal collecting ducts, loop of Henle, and juxtaglomerular apparatus and in the syncytiotrophoblast layer of placental villi. Fetal aorta and adult intramyocardial, colonic, and renal blood vessels also exhibited receptor expression, localized to the intima as well as the media. The distribution of Y1 receptor expression correlates with that of NPY-immunoreactive nerves and the apparent actions of NPY in the intestine, kidney, and heart. Although the placenta is devoid of nerves, an NPY-like transcript was detected in the villous trophoblast layer. The results indicate a tissue-specific regulation of NPY Y1 receptor expression.

Adult↗
PubMed1993

Effects of a thromboxane synthetase inhibitor on platelet function; possible risks of use in pregnancy.

It has been proposed that thromboxane synthetase inhibitors may be of use in the treatment of hypertensive disorders of pregnancy. A patient in whom aspirin did not prevent the development of pre-eclampsia in a previous pregnancy was treated with a thromboxane synthetase inhibitor (dazmegrel, Pfizer) in addition to low-dose aspirin. Increased urinary levels of 6-keto-prostaglandin F1 alpha were found throughout pregnancy, which is consistent with the mode of action. At 17-18 weeks of gestation urinary prostaglandin E2 and F2 alpha levels were increased compared with control pregnancies. These increases in PGE2 and PGF2 alpha production were associated with mid-trimester abortion. In vitro studies were carried out to determine the effects of dazmegrel on platelet eicosanoid production. In whole blood from non-pregnant female volunteers this compound inhibited thromboxane B2 production and significantly enhanced prostaglandin E2 production and slightly increased prostacyclin production, demonstrating a redirection of prostaglandin endoperoxides. This suggested that similar changes in arachidonic acid metabolite production may occur in vivo and in vitro, and that thromboxane synthetase inhibitors should not be used during early pregnancy, since increased production of prostaglandins E2 and F2 alpha may result in preterm labour or abortion.

6-Ketoprostaglandin F1 alpha↗
PubMed1993

The effects of interleukins 1 alpha and 1 beta on prostaglandin production by cultured human fetal membranes.

The effects of IL-1 alpha and IL-1 beta on cultured human fetal membranes were studied. These cytokines are known to regulate prostaglandin synthesis by the separated components of the fetal membranes (amnion, chorion and decidua), but their effects on intact tissue are unknown. IL-1 alpha increased PGE2 levels on the fetal side of the membrane, indicating increased production of prostaglandin from the amnion, but had little effect on levels of PGE2 on the maternal side of the membrane. Low levels of IL-1 beta (0.1-1.0 ng/ml) increased PGE2 levels on the fetal side of the membrane, and also increased the production of PGE2 metabolites and PGF2 alpha, suggesting that this cytokine stimulated the decidua as well as the amnion. High concentrations of both cytokines appeared able to stimulate prostaglandin production by the side of the membrane opposing that to which they were added, but it is not clear whether this was mediated by factors released by the stimulated membrane, or by direct transfer of small quantities of cytokines through the membrane. Taken together, these results indicate that IL-1 beta was a potent stimulator of the synthesis of prostaglandins by decidua and by amnion, whereas IL-1 alpha only stimulated the amnion.

Culture Techniques↗
PubMed1993

The "interleukin 1 receptor antagonist" is a partial agonist of prostaglandin synthesis by human decidual cells.

In many systems the interleukin-1 receptor antagonist opposes the effects of interleukin-1 beta. We considered that it might block interleukin-1 beta-stimulated prostaglandin production from human decidual cells. Very high levels of interleukin-1 receptor antagonist (> 1000 pg/ml) had limited inhibitory effects on IL-1 beta-stimulated PGE2 synthesis, and lower levels of antagonist (< 1000 pg/ml) increased the effects of IL-1 beta. Low concentrations of the antagonist alone (1-100 pg/ml) increased basal PGE2 production, whereas higher levels (10-100 ng/ml) had less effect. It seems, therefore, that in human decidua the "antagonist" is more accurately described as a partial agonist. It has been suggested that the IL-1 receptor antagonist could be used to inhibit decidual prostaglandin synthesis and thereby prevent preterm labor, but this report shows that caution should be exercised before using the receptor antagonist.

Cycloheximide↗
PubMed1993

Effects of interleukin-6 and tumor necrosis factor-alpha on prostaglandin production by cultured human fetal membranes.

In this study we investigated the effects of the cytokines interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) on prostaglandin production by cultured human fetal membranes. These cytokines stimulate prostaglandin synthesis by isolated components of human fetal membranes, but their effects on the intact tissue comprising amnion, chorion and decidua were not known. TNF-alpha added to the maternal side of the membrane activated decidual production of PGF2 alpha but had no effects on synthesis of PGE2 or PGE2 metabolites. Addition of TNF-alpha to the fetal side of the membrane increased production of PGE2 by amnion and PGE2 metabolites from chorion. The addition of IL-6 to the fetal or the maternal side of the membrane increased production of PGE2 from amnion and PGE2m from chorion, suggesting that IL-6 might pass through the fetal membrane. IL-6 had no effect on decidual PGF2 alpha production. These results suggest that TNF-alpha may be involved in labor by increasing decidual prostaglandin synthesis, whereas IL-6 is less likely to have a role.

Amnion↗
PubMed1993

Evidence for decidua-trophoblast interactions in early human pregnancy.

Medium conditioned by decidual cells decreased the growth of cultured BeWo choriocarcinoma cells. The degree of inhibition was dependent on the concentration of the conditioned medium used, and suggested that maternal decidua might regulate the growth of the fetal placenta. Medium from BeWo cells and primary trophoblast had the opposing effect and increased the growth of cultured decidual cells for up to 120 h of culture. These results suggest that a regulatory loop to control placental and decidual growth exists at the materno-fetal interface, and this may be an important factor in the development of adequate placentation and the subsequent growth of the placenta during pregnancy.

Cell Communication↗
PubMed1993

Changes in platelet reactivity following aspirin treatment for pre-eclampsia.

OBJECTIVE: To determine whether aspirin therapy in women at risk of pre-eclampsia alters in vitro platelet aggregation. DESIGN: Longitudinal observational study. SETTING: RPMS Institute of Obstetrics and Gynaecology, Hammersmith Hospital, London. SUBJECTS: Six pregnant women at-risk or with pre-eclampsia. METHODS: Women considered to be at risk of pre-eclampsia or with the disorder were treated with aspirin. In vitro platelet aggregation in response to platelet-activating factor (PAF) and adenosine diphosphate (ADP) before and after aspirin therapy were analysed. RESULTS: Prior to aspirin therapy platelet aggregation was decreased compared with normal pregnant women. After aspirin therapy platelet aggregation in response to PAF and ADP was greater, but did not return to levels associated with normal pregnancy. CONCLUSIONS: In women with pre-existing decreased platelet aggregation suggestive of platelet exhaustion, aspirin increased aggregation. This suggests that aspirin decreases in vivo platelet activation and thereby decreases the platelet exhaustion revealed by the in vitro studies.

Aspirin↗
PubMed1993

Differential localization of endothelin ETA and ETB binding sites in human placenta.

1. The localization and differential distribution of endothelin (ET) receptor subtypes (ETA and ETB) was investigated in sections of human placenta by use of quantitative in vitro autoradiography and receptor selective ligands. 2. Specific, high density [125I]-ET-1 binding sites were localized to the decidua and foetal membranes as well as to arteries and veins in the chorionic plate and throughout the villous tree. Moderate to low density binding was found in the extravillous and villous trophoblast respectively. 3. [125I]-ET-1 binding sites exhibited a rank order of inhibition by unlabelled peptide sequences (ET-1 > ET-3 > [Ala3,11,18Nle7]-ET-1 > BQ123 > or = sarafotoxin 6c). However, in contrast to the monophasic inhibition curve of ET-1, the other sequences produced a significantly better fit to a two component inhibition curve suggesting the presence of a heterogeneous population of ET binding sites. 4. ETA and ETB receptors were distinguished by competitive inhibition of [125]-ET-1 binding with increasing concentrations of unlabelled ET-3, [Ala3,11,18Nle7]-ET-1, sarafotoxin 6c and BQ123 and by incubating sections with the ETB agonist, [125I]-BQ3020. ET receptor subtypes exhibited a differential distribution in the placenta. ETA type binding sites predominated (approximately 80% of the total) on veins and arteries in the chorionic plate. Veins in stem villi, blood vessels in distal regions of the villous tree and decidual cells displayed a high density (approximately 60-70% of the total) of the ETB receptor subtype. 5. No difference was detected in either the relative density of [125I]-ET-1 binding sites or the proportion of ETA to ETB sites in placentae from pregnancies complicated by pre-eclampsia compared with normal term controls.6. ET may have a local autocrine or paracrine role in the placenta, acting via specific receptors to influence foetoplacental blood flow and other aspects of placental function.

Adult↗
PubMed1993

The amnion produces little of the prostaglandin E2 detected on the decidual side of human fetal membranes.

Cultured intact fetal membrane disks initially produced high levels of prostaglandin E2 (PGE2) on the fetal and maternal sides which declined during four days of culture. The transfer of a bolus of PGE2 from the fetal side to the maternal side of the membrane ranged from 1% to 3% after 24 hours of culture, and was a minimum over the period of 48-72 hours from the start of the incubation. To assess the handling of PGE2 synthesized by the amnion, 3H-arachidonic acid was incorporated into cultured amnion and into the amnion side of cultured intact fetal membrane disks. Labelled amnion released 3H-PGE2 on both sides of the tissue, whereas similarly labelled cultured intact fetal membrane only had detectable levels of 3H-PGE2 on the fetal side. It was calculated that no more than 9.7 +/- 1.4% of the PGE2 synthesised by the amnion crossed to the maternal side of the membrane without being metabolised during the transfer through the membrane. These results are consistent with similar indirect methods which suggested that PGE2 from the amnion may have only a limited role in human labor, and indicates the importance of using appropriate culture systems to investigate intra-uterine prostaglandin production.

Amnion↗
PubMed1992

Metabolism of prostaglandins E2 and F2 alpha by human fetal membranes.

Prostaglandin E2 (PGE2) is important in the early stages of human labour, leading particularly to cervical ripening and dilatation. The source of PGE2 is thought to be either the amnion or the decidua, but the chorion interposes between the amnion and the target tissues, namely the myometrium and cervix. In order to investigate the role of the chorion in modulating prostanoid production, [3H]PGE2 was added to the amnion side of fetal membranes, and the production of metabolites on both sides of the fetal membrane followed by HPLC. The major metabolite was 13,14-dihydro-15-oxo-PGE2 with smaller amounts of 13,14-dihydro-15-oxo-PGA2 and PGB2. The production of all metabolites of PGE2 was time dependent. [3H]PGF2 alpha, which is normally produced by the decidua, was also added to fetal membranes and found to be metabolised to 13,14-dihydro-15-oxo-PGF2 alpha and PGE2. These results suggest that the metabolic enzymes in the chorion may determine intra-uterine levels of prostaglandins, and may also determine the identity of the eicosanoids released by intact fetal membranes.

Amnion↗
PubMed1992

Interleukin-1 beta stimulates decidual stromal cell cyclo-oxygenase enzyme and prostaglandin production.

The cytokine interleukin-1 (IL-1 beta) increased prostaglandin production by decidual stromal cells in culture in a time and dose dependent manner. Optimum conditions for stimulation were found to be for 24 hours at a concentration of 100 pg IL-1 beta/ml. An apparent increase in cyclo-oxygenase enzyme synthesis accompanied the increase in prostaglandin production, and both changes were inhibited by the protein synthesis inhibitor cycloheximide. This implicates protein synthesis in the stimulatory effects of IL-1 beta, which may be mediated through the increase in cyclo-oxygenase enzyme. A pre-incubation period of 72 hours was found to be necessary to observe the stimulatory effect of IL-1 beta on prostaglandin production, but this did not seem to be due to any change in the sensitivity of the cells to IL-1 beta; the increase in the number of cyclo-oxygenase positive cells was the same if IL-1 beta was added on day 1, day 2 or day 3 of culture, even though prostaglandin production was not stimulated on day 1 or day 2. Cycloheximide increased prostaglandin production on the first two days of culture and had no effect on the third day of culture. This was interpreted as indicating that a factor inhibiting cyclo-oxygenase activity was synthesised during the initial period of culture, which prevented any increase in prostaglandin production following the increase in enzyme synthesis.

Cycloheximide↗
PubMed1992

Effects of platelet-activating factor on prostaglandin E2 production by intact fetal membranes.

OBJECTIVE: The hypothesis tested in this study is that platelet-activating factor increases prostaglandin E2 synthesis from fetal membranes. STUDY DESIGN: Fetal membrane disks obtained before or after labor were incubated with or without platelet-activating factor for time periods of up to 24 hours. The production of prostaglandin E2 and its inactive metabolites was determined by specific radioimmunoassays. RESULTS: Platelet-activating factor (1 to 10 mumol/L) stimulated the production of prostaglandin E2 and its metabolites by intact fetal membranes and chorion-decidua threefold to fourfold after 24 hours of incubation. Platelet-activating factor had far greater effects on the production of prostaglandin E2 by intact fetal membranes obtained after the onset of labor, such that prostaglandin E2 production was increased by tenfold to 100-fold. CONCLUSION: These results suggest that platelet-activating factor mainly stimulates prostaglandin E2 production by the chorion-decidua before labor and that it may act in synergism with other stimulatory factors present in the fetal membranes during labor.

Amnion↗
PubMed1992

Changes in decidual stromal cell function associated with labour.

OBJECTIVE: To determine whether decidual cells produce altered levels of prostaglandins after labour. DESIGN: Decidual stromal cells and macrophages were isolated before and after labour, and the production of prostaglandins E2 and F2 alpha measured. Changes in the numbers of cyclooxygenase enzyme positive cells were assessed by immunocytochemistry. RESULTS: Decidual stromal cells obtained after labour produced 30 times more prostaglandins E2 and F2 alpha in culture than cells obtained before labour. The increased production persisted for up to 72 h of culture, and was associated with an increase in the numbers of cyclooxygenase-positive cells from less than 5% to greater than 95%. No changes in macrophage function were observed. CONCLUSION: Increased levels of prostaglandins E2 and F2 alpha were released from decidual stromal cells after labour, suggesting that these cells may be an important source of prostaglandins in labour.

Decidua↗
PubMed1992

Transfer and metabolism of platelet-activating factor by fetal membranes, amnion and chorio-decidua.

OBJECTIVE: To determine the metabolism of 3H-Platelet-activating factor (3H-PAF) during transfer through human fetal membranes. DESIGN: 3H-PAF was added to the fetal side of cultured intact fetal membranes, amnion and chorio-decidua obtained from three pregnancies ending in elective caesarean section. MAIN OUTCOME MEASURES: Radioactivity was measured on both sides of the tissue, and in the tissue itself. In some experiments, the metabolism of 3H-PAF was assessed by thin-layer chromatography. RESULTS: Very little 3H-PAF crossed the intact fetal membrane (< 2%) during 24 h of culture. Most of the 3H-PAF which accumulated in the membrane was converted to a range of metabolites in the chorio-decidua. CONCLUSIONS: These results suggest that PAF in amniotic fluid may not reach the decidua, and therefore is unlikely to be involved in the control of prostaglandin production from this tissue.

Amniotic Fluid↗