scholarly journals Regulation of the Endothelin/Endothelin Receptor System by Interleukin-1β in Human Myometrial Cells

Endocrinology ◽  
2005 ◽  
Vol 146 (11) ◽  
pp. 4878-4886 ◽  
Author(s):  
Michelle Breuiller-Fouché ◽  
Catherine Morinière ◽  
Emmanuelle Dallot ◽  
Stéphanie Oger ◽  
Régis Rebourcet ◽  
...  
Keyword(s):  
Prolonged Exposure ◽  
Receptor Expression ◽  
Receptor Subtype ◽  
Mrna Levels ◽  
Receptor System ◽  
Myometrial Cell ◽  
Myometrial Cells ◽  
Uterine Contractions ◽  
Eta Receptor ◽  
Etb Receptor

Proinflammatory cytokines produced at the fetomaternal interface, such as IL-1β, have been implicated in preterm and term labor. The present study was performed to evaluate the influence of IL-1β on the endothelin (ET)/ET receptor system in human myometrial cells. We report that myometrial cells under basal conditions not only respond to but also secrete ET-1, one of the main regulators of uterine contractions. Prolonged exposure of the cells to IL-1β led to a decrease in prepro-ET-1 and ET-3 mRNA correlated with a decrease in immunoreactive ET-1 and ET-3 levels in the culture medium. Whereas ETA receptor expression at both protein and mRNA levels was not affected by IL-1β treatment, we demonstrated an unexpected predominance of the ETB receptor subtype under this inflammatory condition. Whereas the physiological function of ETB remains unclear, we confirmed that only ETA receptors mediate ET-1-induced myometrial cell contractions under basal conditions. By contrast, prolonged exposure of the cells to IL-1β abolished the contractile effect induced by ET-1. Such a regulation of IL-1β on the ET release and the balance of ETA to ETB receptors leading to a loss of ET-1-induced myometrial cell contractions suggest that complex regulatory mechanisms take place to constraint the onset of infection-induced premature contractions.

Characterization of type A endothelin receptors in cultured human myometrial cells

1995 ◽  
Vol 268 (5) ◽  
pp. E825-E831 ◽  
Author(s):  
V. Heluy ◽  
M. Breuiller-Fouche ◽  
F. Cavaille ◽  
T. Fournier ◽  
F. Ferre
Keyword(s):  
Inositol Phosphate ◽  
Receptor Subtype ◽  
Receptor Subtypes ◽  
Binding Studies ◽  
Myometrial Cells ◽  
Cells In Culture ◽  
Competition Binding ◽  
Half Maximal Effective Concentration ◽  
Eta Receptor ◽  
Etb Receptor

The aim of the present study was to characterize endothelin (ET)-receptors in human myometrial cells in culture. 125I-labeled ET-1 binding to myometrial cells was specific and saturable, with a dissociation constant of 64.2 +/- 12.8 pM. Competition binding studies showed the following order of potency: ET-1 > ET-3, which is consistent with the presence of the ETA receptor subtype. FR-139317 and BQ-123, two ETA antagonists, both inhibited 125I-ET-1 binding. BQ-123 only elicited a partial inhibition. The fraction resistant to BQ-123 did not represent the ETB receptor subtype, since no specific 125I-ET-3 binding could be detected. ET-1 and ET-3 were found to stimulate [3H]inositol phosphate (IP) accumulation in cultured myometrial cells, with corresponding half-maximal effective concentration values of 0.26 +/- 0.04 and 87 +/- 17 nM, respectively. Both ETA antagonists inhibited ET-1-induced accumulation of [3H]IP. BQ-123 was only a partial inhibitor, whereas FR-139317 totally suppressed ET-1-stimulated production of [3H]IP. We conclude that human myometrial cells in culture exclusively possess ETA receptor subtypes coupled to phospholipase C.

Functional expression of purinergic P2X7 receptors in pregnant rat myometrium

2010 ◽  
Vol 298 (4) ◽  
pp. R1117-R1124 ◽  
Author(s):  
Hiroshi Miyoshi ◽  
Kaoru Yamaoka ◽  
Satoshi Urabe ◽  
Miho Kodama ◽  
Yoshiki Kudo
Keyword(s):  
P2x7 Receptor ◽  
Uterine Contraction ◽  
Extracellular Atp ◽  
Receptor Expression ◽  
P2x Receptor ◽  
Receptor Subtype ◽  
P2x7 Receptors ◽  
Pregnant Rat ◽  
Myometrial Cells ◽  
Induced Currents

ATP has been reported to enhance the membrane conductance of myometrial cells and uterine contractility. Purinergic P2 receptor expression has been reported in the myometrium, using molecular biology, but the functional identity of the receptor subtype has not been determined. In this study, ATP-induced currents were recorded and characterized in single myometrial cells from pregnant rats using whole cell patch clamping. Extracellular ATP was applied in the range of 10 μM-1 mM and induced currents with an EC50 of 74 μM, with no desensitization, time dependency, or voltage dependency. The currents induced carried multiple monovalent cations, with conductances ranked as K+ > Cs+ > Li+ > Na+. They were activated by P2X receptor agonists, with their effectiveness ranked as 2′,3′- O-(4-benzoylbenzoyl)-ATP >> ATP > αβ-methylene-ATP > 2-methylthio ATP ≥ UTP ≥ GTP > ADP. These currents were blocked by the selective P2X7 receptor antagonist 3-[5-(2,3-dichlorophenyl)-1 H-tetrazol-1-yl]methyl pyridine (A-438079). We therefore concluded that ATP-induced currents in rat myometrial cells crossed cell membranes via P2X7 receptors. We further showed that the ATP-induced currents were blocked by extracellular Mg2+ (IC50 = 0.26 mM). Clinically, administering extracellular Mg2+ is known to inhibit uterine contraction. It therefore seems likely that uterine contraction may be induced by raised extracellular ATP and suppressed via Mg2+ inhibiting P2X7 receptors. Further research is needed into the P2X7 receptor as a therapeutic target in abnormal uterine contraction, as a possible treatment for premature labor.

Endothelin-1 and -3 cause endothelium-dependent hyperpolarization in the rat mesenteric artery

1993 ◽  
Vol 265 (6) ◽  
pp. H2137-H2141 ◽  
Author(s):  
M. Nakashima ◽  
P. M. Vanhoutte
Keyword(s):  
Mesenteric Artery ◽  
Mesenteric Arteries ◽  
Receptor Subtype ◽  
Spontaneously Hypertensive ◽  
Rat Mesenteric Artery ◽  
Significant Difference ◽  
Eta Receptor ◽  
Etb Receptor ◽  
Wistar Kyoto ◽  
Eta Receptor Antagonist

The present study was designed to determine whether endothelin (ET) induces endothelium-dependent hyperpolarization in the isolated rat mesenteric artery and, if so, to identify the receptor subtype involved. Main superior mesenteric arteries of Wistar-Kyoto and spontaneously hypertensive rats were used for the measurement of electrical responses of smooth muscle cells, using glass microelectrode. In tissues with endothelium of both strains, ET-1 (10(-8) M) caused an initial transient hyperpolarization followed by a sustained depolarization. In tissues without endothelium, only depolarization was observed. ET-3 (10(-8) M) produced transient hyperpolarizations only in preparations with endothelium. There was no significant difference in maximal amplitude of hyperpolarization between the two strains. BQ-123 (selective ETA-receptor antagonist) blocked the depolarization to ET-1 but did not inhibit hyperpolarizing responses to either isopeptide. IRL-1620 (specific ETB-receptor agonist) produced transient membrane hyperpolarizations in tissues with endothelium. The hyperpolarizations induced by ET were not affected by NG-nitro-L-arginine. These data suggest that both ET-1 and ET-3 can cause endothelium-dependent hyperpolarization in the rat mesenteric artery and that the endothelial receptor involved may belong to ETB subtype.

scholarly journals Modulation of glomerular endothelin and endothelin receptor gene expression in aminonucleoside-induced nephrosis.

1995 ◽  
Vol 5 (8) ◽  
pp. 1585-1590
Author(s):  
T Nakamura ◽  
I Ebihara ◽  
M Fukui ◽  
S Osada ◽  
Y Tomino ◽  
...  
Keyword(s):  
Gene Expression ◽  
Receptor Gene ◽  
Mrna Level ◽  
Experimental Period ◽  
Receptor Expression ◽  
Mrna Levels ◽  
Puromycin Aminonucleoside ◽  
Receptor Mrna ◽  
Etb Receptor ◽  
Receptor Gene Expression

This study assessed glomerular endothelin (ET)-1, ET-3, and ET-receptor A and B mRNA levels in puromycin aminonucleoside (PAN)-induced nephrosis. During the nephrotic stage, 8 days after PAN injection, ET-1 and ETB receptor mRNA were elevated by 2.8 +/- 0.8-fold (P < 0.01) and 2.4 +/- 0.9-fold (P < 0.01), respectively, as compared with controls. These mRNA levels decreased to control levels by Day 20, when the nephrosis was in remission. In contrast, glomerular ETA receptor mRNA levels did not change in PAN nephrosis or control rats during the experimental period. ET-3 mRNA was not detected in the glomeruli of PAN nephrosis or control rats. Additionally, plasma ET concentration and glomerular ET production were measured in PAN nephrosis and control rats by radio-immunoassay. Eight days after PAN injection, ET-1 levels in plasma and glomeruli were not significantly altered in rats with PAN-induced nephrosis (glomeruli, 104.68 +/- 16.46 pg/mg of protein versus 98.24 +/- 13.68 pg/mg of protein; plasma, 2.68 +/- 1.10 versus 2.52 +/- 0.98 pg/mL). The administration of methylprednisolone to PAN rats resulted in the rapid disappearance of proteinuria and partially attenuated the increased ET-1 and ETB receptor gene expression in the glomeruli. These data indicate that glomerular ET-1 and ETB receptor expression in PAN nephrosis in increased at the mRNA level and that methylprednisolone treatment results in an attenuated increase.

scholarly journals Autocrine effects of endothelin-1 on leukocyte-endothelial interaction: stimulation of endothelin B receptor subtype reduces endothelial adhesiveness via a nitric oxide-dependent mechanism

Blood ◽  
1996 ◽  
Vol 88 (10) ◽  
pp. 3894-3900 ◽  
Author(s):  
T Murohara ◽  
AM Lefer
Keyword(s):  
Nitric Oxide ◽  
Receptor Antagonist ◽  
Receptor Subtype ◽  
Endothelin 1 ◽  
Eta Receptor ◽  
Etb Receptor ◽  
Endothelin B ◽  
Eta Receptor Antagonist ◽  
Inhibition Of Thrombin

The effects of endothelin-1 (ET-1) on P-selectin-mediated leukocyte endothelial interaction were examined in vitro. Adherence of autologous polymorphonuclear leukocytes (PMNs) to the endothelium was markedly enhanced by endothelial stimulation with either (2 U/mL) thrombin, (1 mumol/L) histamine, or (100 nmol/L) phorbol myristate acetate (PMA). In contrast, ET-1 alone (10 and 100 nmol/L) only slightly increased the number of adhering PMNs. The increased PMN adherence to thrombin- or histamine-stimulated endothelium, which was blocked by an anti-P-selectin monoclonal antibody, was also significantly attenuated by preincubation of coronary segments with (100 nmol/L) ET-1. We further investigated the mechanism of this anti-adherence action of ET-1 on thrombin-stimulated endothelial adhesiveness. Preincubation of coronary segments with a selective ETA receptor antagonist, BQ485 (1 mumol/L), had no effect on ET-1 inhibition of thrombin-induced PMN adherence. In contrast, preincubation with a selective ETB receptor antagonist, BQ788 (1 mumol/L) significantly reversed ET-1 inhibition of thrombin-induced PMN adherence, whereas the selective ETB receptor agonist BQ-3020 mimicked the inhibitory action of ET-1 on thrombin-induced PMN adherence. Furthermore, (100 mumol/L) N omega-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase (NOS) inhibitor, significantly attenuated ET-1 inhibition of thrombin-stimulated PMN adherence. These results suggest that ET-1 may inhibit P-selectin-mediated leukocyte-endothelial interaction via ETB receptor stimulation and subsequent endothelial NO formation. This autocrine effect of ET-1 may be involved in pathophysiologic states such as early atherogenesis by preventing leukocyte-endothelial interaction in constricted blood vessels.

Perichondrial localization of ETA receptor in rat tracheal and xiphoid cartilage and in fetal rat epiphysis

1995 ◽  
Vol 268 (2) ◽  
pp. C496-C502 ◽  
Author(s):  
K. M. Lodhi ◽  
H. Sakaguchi ◽  
S. Hirose ◽  
S. Shibabe ◽  
H. Hagiwara
Keyword(s):  
Endochondral Bone Formation ◽  
Receptor Subtype ◽  
Endothelin Receptor ◽  
Connective Tissues ◽  
Receptor System ◽  
Endochondral Bone ◽  
Fetal Rat ◽  
Eta Receptor ◽  
Subtype A

Autoradiographic studies using 125I-labeled endothelin-1 (ET-1) on sections of rat cartilage tissues, including the trachea, xiphisternum, and fetal rat epiphysis, revealed dense localization of endothelin receptors in the perichondrium. In contrast, the binding of ET-1 was not detected in the chondrocytes, cartilage matrix, and other connective tissues of the cartilage tissues tested. The perichondrial binding of 125I-ET-1 was completely abolished with BQ-123 [an endothelin receptor subtype A (ETA) antagonist] but not with BQ-3020 (an ETB agonist), and we demonstrated the perichondrial localization of ETA receptors. [3H]thymidine incorporation in vitro was significantly increased in rat xiphoid cartilage tissues exposed to ET-1. These findings suggest that the ET-1/ETA receptor system plays an important role in regulating cartilage metabolism and endochondral bone formation.

Abstract P016: Sex Differential Effects Of Hyperoxia And Thioredoxin Reductase-1 Inhibition On The Kidney Endothelin-1 System

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Carmen De Miguel ◽  
Aleena George ◽  
Sara N Biswal ◽  
Abigayle Kraus ◽  
Katelyn Dunigan ◽  
...  
Keyword(s):  
Thioredoxin Reductase ◽  
Kidney Injury ◽  
Fold Increase ◽  
Receptor Expression ◽  
Diabetes Research ◽  
Endothelin 1 ◽  
Thioredoxin Reductase 1 ◽  
Eta Receptor ◽  
Etb Receptor ◽  
Glomerular Morphology

The vasoactive peptide endothelin-1 (ET-1) is critical in lung and kidney injury. Notably, renal damageand hyperoxia-induced lung disease are more prevalent in males than females. Aurothioglucose (ATG),an inhibitor of thioredoxin reductase-1, attenuates hyperoxia-induced lung injury in mice; however, theeffects of hyperoxia and/or ATG treatment on the kidney ET-1 system remain unknown. Wehypothesized that hyperoxia would activate the renal ET-1 system and that ATG treatment wouldattenuate this activation. Male and female adult C57Bl/6 mice received a single injection of saline orATG (25mg/Kg, i.p.) and were exposed to room air (RA) or >90% O2 for 72 hours. Kidney and spleen werecollected for assessment of the ET-1 system by RT-PCR and glomerular morphology and immune cellinfiltration were evaluated by histology and immunohistochemistry, respectively. In male mice,hyperoxia reduced the cortical expression of ET-1 (RA vs. hyperoxia: 1 ± 0.05 vs. 0.34 ± 0.04, p<0.05;n=3-4/group) and ameliorated the expression of ETA receptor. In RA males, treatment with ATGsignificantly halved the expression of ET-1 and ETB receptor (saline vs. ATG, ET-1: 1 ± 0.05 vs. 0.45 ± 0.07,p<0.05; n=3-4/group; ETB receptor: 1 ± 0.09 vs. 0.37 ± 0.10, p<0.05; n=3-4/group), but had no effect inhyperoxic males. Contrarily, hyperoxic females demonstrated a 3-fold upregulation of corticalETB receptor expression, which was significantly prevented by ATG (saline vs. ATG: 2.80 ± 0.37 vs. 0.95 ±0.27, p<0.05; n=3-4/group). ATG treatment in hyperoxic females also decreased the cortical expressionof ET-1 and ETA receptor. No changes in cortical inflammation or glomerular morphology were observed.Further preliminary results showed that hyperoxia led to a 4-fold increase in splenic ET-1 expression insaline-treated mice, and a 7-fold increase in mice treated with ATG. These results demonstrate sexdifferences in the effects of hyperoxia and ATG treatment in the renal ET-1 system and highlight ATG asa possible therapeutic target to attenuate hyperoxia-induced kidney damage. Funded by NIHK01HL145324 and UAB Diabetes Research Center Pilot Project grant to CDM.

scholarly journals ETB2 receptor subtype stimulation relaxes the iris sphincter muscle

2009 ◽  
pp. 835-842
Author(s):  
A Rocha-Sousa ◽  
J Saraiva ◽  
M Amaral ◽  
P Alves-Faria ◽  
F Falcão-Reis ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Receptor Subtype ◽  
Sphincter Muscle ◽  
Receptor Stimulation ◽  
Eta Receptor ◽  
Etb Receptor ◽  
Rabbit Iris Sphincter ◽  
Eta Receptor Antagonist ◽  
Rabbit Iris ◽  
Iris Sphincter

Effects of ETB receptor stimulation and its subcellular pathways were evaluated in carbachol pre-contracted rabbit iris sphincter muscles (n=51). ETB stimulation with sarafotoxin (SRTX-c; 10-10-10-6 M) was tested in the absence (n=7) or presence of 10-5 M of: BQ-788 (ETB2 receptor antagonist; n=6), L-NA (NOS inhibitor; n=7) or indomethacin (cyclooxygenase inhibitor; n=10). Effects of ETB stimulation by endothelin-1 (ET-1; 10-10– 10-7 M) in the presence of an ETA receptor antagonist (BQ-123; 10-5 M; n=7) and of ETB1 stimulation by IRL-1620 (10-10–10-7 M; n=7) were also tested. Finally, the effects of SRTX-c (10-9–10-7 M) in electric field stimulation (EFS) contraction were evaluated (n=7). ETB receptor stimulation by SRTX-c or ET-1 in presence of BQ-123 promoted a concentration-dependent relaxation of the rabbit iris sphincter muscle by 10.8±2.0 % and 9.4±1.8 %, respectively. This effect was blocked by BQ-788 (-2.3±2.0 %), L-NA (4.5±2.3 %) or indomethacin (2.3±2.9 %). Selective ETB1 stimulation by IRL-1620 did not relax the iris sphincter muscle (0.9±5.4 %). EFS elicited contraction was not altered by SRTX-c. In conclusion, ETB receptor stimulation relaxes the carbachol precontracted iris sphincter muscle, an effect that is mediated by the ETB2 receptor subtype, through NO and the release of prostaglandins.

scholarly journals The interaction between protein kinase A and progesterone on basal and inflammation-induced myometrial oxytocin receptor expression

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0239937
Author(s):  
Angela Yulia ◽  
Alice J. Varley ◽  
Natasha Singh ◽  
Kaiyu Lei ◽  
Rachel M. Tribe ◽  
...  
Keyword(s):  
Preterm Labour ◽  
Elective Caesarean Section ◽  
Oxytocin Receptor ◽  
Receptor Expression ◽  
Mrna Levels ◽  
Myometrial Cells ◽  
Protein Levels ◽  
Repressive Effect ◽  
Effector System ◽  
Cyclase Activator

Our previous work has shown myometrial PKA activity declines in term and twin-preterm labour in association with an increase in the expression of the oxytocin receptor (OTR). Here we investigate the action of cAMP/PKA in basal conditions, with the addition of progesterone (P4) and/or IL-1β to understand how cAMP/PKA acts to maintain pregnancy and whether the combination of cAMP and P4 would be a viable therapeutic combination for the prevention of preterm labour (PTL). Further, given that we have previously found that cAMP enhances P4 action we wanted to test the hypothesis that changes in the cAMP effector system are responsible for the functional withdrawal of myometrial P4 action. Myometrial cells were grown from biopsies obtained from women at the time of elective Caesarean section before the onset of labour. The addition of forskolin, an adenylyl cyclase activator, repressed basal OTR mRNA levels at all doses and P4 only enhanced this effect at its highest dose. Forskolin repressed the IL-1β-induced increase in OTR mRNA and protein levels in a PKA-dependent fashion and repressed IL-1β-activation and nuclear transfer of NFκB and AP-1. P4 had similar effects and the combination P4 and forskolin had greater effects on OTR and NFκB than forskolin alone. While PKA knockdown had no effect on the ability of P4 to repress IL-1β-induced OTR expression it reversed the repressive effect of the combination of P4 and forskolin and resulted in a greater increase than observed with IL-1β alone. These studies suggest that cAMP acts via PKA to repress inflammation-driven OTR expression, but that when PKA activity is reduced, the combination of cAMP and P4 actually enhances the OTR response to inflammation, promoting the onset of labour and suggesting that changes in the cAMP effector system can induce a functional P4 withdrawal.

Regulation of P2X7nucleotide receptor function in human monocytes by extracellular ions and receptor density

2001 ◽  
Vol 280 (4) ◽  
pp. C943-C953 ◽  
Author(s):  
Lalitha Gudipaty ◽  
Benjamin D. Humphreys ◽  
Gary Buell ◽  
George R. Dubyak
Keyword(s):  
Cell Surface ◽  
Human Blood ◽  
Pore Formation ◽  
Cell Types ◽  
Receptor Activation ◽  
Receptor Expression ◽  
Receptor Protein ◽  
Receptor Subtype ◽  
Mrna Levels ◽  
Blood Monocytes

P2X receptors function as ATP-gated cation channels. The P2X7receptor subtype is distinguished from other P2X family members by a very low affinity for extracellular ATP (millimolar EC50) and its ability to trigger induction of nonselective pores on repeated or prolonged stimulation. Previous studies have indicated that certain P2X7receptor-positive cell types, such as human blood monocytes and murine thymocytes, lack this pore-forming response. In the present study we compared pore formation in response to P2X7receptor activation in human blood monocytes with that in macrophages derived from these monocytes by in vitro tissue culture. ATP induced nonselective pores in macrophages but not in freshly isolated monocytes when both cell types were identically stimulated in standard NaCl-based salines. However, ion substitution studies revealed that replacement of extracellular Na+and Cl−with K+and nonhalide anions strongly facilitated ATP-dependent pore formation in monocytes. These ionic conditions also resulted in increased agonist affinity, such that 30–100 μM ATP was sufficient for activation of nonselective pores by P2X7receptors. Comparison of P2X7receptor expression in blood monocytes with that in macrophages indicated no differences in steady-state receptor mRNA levels but significant increases (up to 10-fold) in the amount of immunoreactive P2X7receptor protein at the cell surface of macrophages. Thus ability of ATP to activate nonselective pores in cells that natively express P2X7receptors can be modulated by receptor subunit density at the cell surface and ambient levels of extracellular Na+and Cl−. These mechanisms may prevent adventitious P2X7receptor activation in monocytes until these proinflammatory leukocytes migrate to extravascular sites of tissue damage.

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