共查询到20条相似文献,搜索用时 31 毫秒
1.
Shigeki Shibata Akihiko Himeno Kazuto Shigematsu Keisuke Tsutsumi Yasuko Sakurai-Yamashita Kimihiro Yamashita 《Cellular and molecular neurobiology》1997,17(1):89-100
1. We used the quantitative receptor autoradiographic method plus 125I-endothelin-1 (125I-ET-1), BQ-123, a specific antagonist for the endothelin ETA receptor, and sarafotoxin S6c, a selective agonist for the ETB receptor to investigate the ET receptor in the rat pituitary gland.2. The method revealed that the BQ-123-sensitive ETA receptor was present predominantly in the anterior lobe and Rathke's pouch.3. The posterior lobe contained BQ-123-sensitive ETA and sarafotoxin S6c-sensitive ETB receptors, in almost the same proportion. There was no significant 125I-ET-1 binding to the intermediate lobe.4. Knowledge of the heterogeneous distribution of ET receptor subtypes in the pituitary gland supplies information that will be pertinent to physiological investigations of the gland. 相似文献
2.
Martina Wendel Anna Petzold Roland Koslowski Michael Kasper Antje Augstein Lilla Knels Jörg-Uwe Bleyl Thea Koch 《Histochemistry and cell biology》2000,122(5):507-517
Pulmonary fibrosis is characterized by excessive extracellular matrix deposition with concomitant loss of gas exchange units, and endothelin-1 (ET-1) has been implicated in its pathogenesis. Increased levels of ET-1 from tissues and bronchoalveolar lavage have been reported in patients with pulmonary fibrosis and in animal models after intratracheal bleomycin. We characterized the cellular distribution of alveolar ET receptors by immunohistochemistry in bleomycin-induced pulmonary fibrosis in the rat and determined the regulation by bleomycin of ET receptor mRNA expression in isolated alveolar macrophages and rat lung fibroblasts. We found significant increases in the numbers of fibroblasts and macrophages at day 7 compared to day 28 and control animals. ETB receptor immunoreactivity was observed on fibroblasts and invading monocytes. Isolated fibroblasts expressed both ETA and ETB receptor mRNA, and ETA receptor mRNA was upregulated by bleomycin. Isolated resident alveolar macrophages expressed neither ETA nor ETB receptor mRNA which were also not induced by bleomycin. We conclude that, while ETB receptor stimulation of fibroblasts and monocytes recruited during bleomycin-induced lung injury exerts antagonistic effects on fibroblast collagen synthesis, the observed increase in the number of fibroblasts in vivo and upregulation of fibroblast ETA receptor mRNA by bleomycin in vitro point to a predominance of the profibrotic effects of ET receptor engagement. 相似文献
3.
4.
Kuruvilla L Nair RR Umashankar PR Lal AV Kartha CC 《Cell biochemistry and biophysics》2007,47(1):65-72
Given that vascular endothelial cells play an important role in the modulation of vascular structure and function, we hypothesized
that endocardial endothelial cells (EECs) may have a modulator role in regulating the cardiac interstitial cells. Endocardial
endothelial cells were isolated from freshly collected pig hearts and cardiac fibroblasts were isolated from 3- to 4-d-old
Wistar rats. Fibroblasts were cultured in the presence or absence of conditioned medium from EECs. Proliferation of cardiac
fibroblasts was measured by the incorporation of [3H]-Thymidine and collagen synthesis was assayed by the incorporation of [3H]-proline. To determine the involvement of signaling mediators, in separate experiments, cardiac fibroblasts were incubated
with BQ123 (selective ETA receptor antagonist), PD142893 (nonselective ETA/ETB receptor antagonist), Bis-indolylmaleimide (PKC inhibitor), PD 098059 (MEK inhibitor), or neutralizing anti-transforming
growth factor (TGF)-β-antibody. Endocardial endothelium-derived factors endothelin (ET)-1, TGF-β, and Angiotensin (Ang)-II
in the conditioned medium were assayed by enzyme-linked immunosorbent assay using commercially available kits. We report here
evidence that suggest that endocardial endothelial cells stimulate both proliferation and collagen synthesis of cardiac fibroblasts.
The response seems to be mediated by endothelin through its ETA receptor.
Our results also indicate that protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) pathways are essential for
the EEC-induced proliferation of cardiac fibroblasts. 相似文献
5.
Endothelin-3 (ET-3) elicited a concentration-dependent positive inotropic effect on rabbit papillary muscle, the maximal response being approximately 65% of the maximal response to isoproterenol. ET-1 induced a positive inotropic effect over the concentration range below 10–9 M, at which ET-3 did not produce a positive inotropic effect, but the maximal response to ET-1 was equivalent to or slightly lower than that of ET-3. The nonselective ET receptor antagonist PD 145065 effectively antagonized the positive inotropic effect of ET-3 in a concentration-dependent manner and abolished it at 10–5 M. PD 145065 decreased the positive inotropic effect induced by ET 1 at lower concentrations (< 10–9 M) but it did not affect the main portion of the concentration-response curve for the positive inotropic effect, i.e., the effect induced by high concentrations (> 10–9 M) of ET-1. PD 145065 antagonized also the positive inotropic effect of sarafotoxin S6c. PD 145065 inhibited the specific binding of [125I]ET-1 and of [125I]ET-3 with a high- and a low-affinity site for competition. ETB selective ligands, RES-701-1 and sarafotoxin S6c, displaced [125Iuc]ET-3 with high affinity but they scarcely affected the [1251]ET-1 binding. These findings indicate that different subtypes of the ET receptor are responsible for the induction of the positive inotropic effect of ET-3 and ET-1. ET receptors involved in the production of the positive inotropic effect in the rabbit ventricular myocardium have pharmacological characteristics that are different from those of conventional ET receptors originally classified based on the pharmacological findings in noncardiac tissues. The positive inotropic effect of ET-3 in the rabbit ventricular muscle may be mediated predominantly by ETA1 receptors that are susceptible to PD 145065 as well as BQ-123 and FR139317, and partially mediated by ETB receptors that are inhibitable with RES-701-1. ETA2 receptors that are resistant to ETA selective as well as nonselective antagonists may mainly be responsible for the positive inotropic effect of ET-1 in the rabbit ventricular muscle. 相似文献
6.
Background
Cigarette smoking is a strong cardiovascular risk factor and endothelin (ET) receptors are related to coronary artery diseases. The present study established an in vivo secondhand smoke (SHS) exposure model and investigated the hypothesis that cigarette smoke induces ET receptor upregulation in rat coronary arteries and its possible underlying mechanisms.Methodology/Principal Findings
Rats were exposed to SHS for 200 min daily for 8 weeks. The coronary arteries were isolated and examined. The vasoconstriction was studied by a sensitive myograph. The expression of mRNA and protein for receptors was examined by real-time PCR, Western blot and immunofluorescence. Compared to fresh air exposure, SHS increased contractile responses mediated by endothelin type A (ETA) and type B (ETB) receptors in coronary arteries. In parallel, the expression of mRNA and protein for ETA and ETB receptors of smoke exposed rats were higher than that of animals exposed to fresh air, suggesting that SHS upregulates ETA and ETB receptors in coronary arteries in vivo. Immunofluorescence staining showed that the enhanced receptor expression was localized to the smooth muscle cells of coronary arteries. The protein levels of phosphorylated (p)-Raf-1 and p-ERK1/2 in smoke exposed rats were significantly higher than in control rats, demonstrating that SHS induces the activation of the Raf/ERK/MAPK pathway. Treatment with Raf-1 inhibitor GW5074 suppressed SHS-induced enhanced contraction mediated by ETA receptors, and inhibited the elevated mRNA and protein levels of ETA and ETB receptors caused by SHS. The results of correlation and regression analysis showed that phosphorylation of Raf and ERK1/2 were independent determinants to affect protein expression of ETB and ETA receptors.Conclusions/Significance
Cigarette smoke upregulates ETB and ETA receptors in rat coronary artery, which is associated with the activation of the Raf/ERK/MAPK pathway. 相似文献7.
8.
Rafael Sobrano Fais Rafael Menezes da Costa Allan Carvalho Mendes Fabíola Mestriner Simon Gabriel Comerma-Steffensen Rita C. Tostes Ulf Simonsen Fernando Silva Carneiro 《Journal of cellular and molecular medicine》2023,27(1):1-14
In the present study, we hypothesized that endothelin (ET) receptors (ETA and ETB) stimulation, through increased calcium and ROS formation, leads to Nucleotide Oligomerization Domain-Like Receptor Family, Pyrin Domain Containing 3 (NLRP3) activation. Intracavernosal pressure (ICP/MAP) was measured in C57BL/6 (WT) mice. Functional and immunoblotting assays were performed in corpora cavernosa (CC) strips from WT, NLRP3−/− and caspase−/− mice in the presence of ET-1 (100 nM) and vehicle, MCC950, tiron, BAPTA AM, BQ123, or BQ788. ET-1 reduced the ICP/MAP in WT mice, and MCC950 prevented the ET-1 effect. ET-1 decreased CC ACh-, sodium nitroprusside (SNP)-induced relaxation, and increased caspase-1 expression. BQ123 an ETA receptor antagonist reversed the effect. The ETB receptor antagonist BQ788 also reversed ET-1 inhibition of ACh and SNP relaxation. Additionally, tiron, BAPTA AM, and NLRP3 genetic deletion prevented the ET-1-induced loss of ACh and SNP relaxation. Moreover, BQ123 diminished CC caspase-1 expression, while BQ788 increased caspase-1 and IL-1β levels in a concentration-dependent manner (100 nM–10 μM). Furthermore, tiron and BAPTA AM prevented ET-1-induced increase in caspase-1. In addition, BAPTA AM blocked ET-1-induced ROS generation. In conclusion, ET-1-induced erectile dysfunction depends on ETA- and ETB-mediated activation of NLRP3 in mouse CC via Ca2+-dependent ROS generation. 相似文献
9.
Harada N Himeno A Shigematsu K Sumikawa K Niwa M 《Cellular and molecular neurobiology》2002,22(2):207-226
1. Interaction in the recognition of endothelin-1 (ET-1), a typical bivalent ET receptor-ligand, between ETA and ETB receptors was investigated in the rat anterior pituitary gland, using our quantitative receptor autoradiographic method with tissue sections preserving the cell-membrane structure and ET receptor-related compounds.2. In saturation binding studies with increasing concentrations (0.77–200 pM) of 125I-ET-1 (nonselective bivalent radioligand), 125I-ET-1 binding to the rat anterior pituitary gland was saturable and single with a K
D of 71 pM and a B
max of 120 fmol mg–1. When 1.0 M BQ-123 (ETA antagonist) was added to the incubation buffer, binding parameters were 8.3 pM of K
D and 8.0 fmol mg–1 of B
max, whereas 10 nM sarafotoxin S6c (ETB agonist) exerted little change in these binding parameters (K
D, 72 pM; B
max, 110 fmol mg–1).3. Competition binding studies with a fixed amount (3.8 pM) of 125I-ET-1 revealed that when 1.0 M BQ-123 was present in the incubation buffer, ETB receptor-related compounds such as sarafotoxin S6c, ET-3, IRL1620 (ETB agonist), and BQ-788 (ETB antagonist) competitively inhibited 125I-ET-1 binding with K
is of 140, 18, 350 pM, and 14 nM, respectively, however, these compounds were not significant competitors for 125I-ET-1 binding in the case of absence of BQ-123.4. In cold-ligand saturation studies with a fixed amount (390 pM) of 125I-IRL 1620 (ETB radioligand), IRL1620 bound to a single population of the ETB receptor, and no change was observed in binding characteristics in the presence of 1.0 M BQ-123. 125I-IRL1620 binding was competitively inhibited by ET-1 and ET-3 in the absence of BQ-123, with K
is of 20 and 29 pM, respectively, the affinities being much the same as those of 29 nM, in the presence of 1.0 M BQ-123.5. Two nonbivalent ETA antagonists, BQ-123 and PD151242, were highly sensitive and full competitors for 125I-ET-1 binding (5.0 pM), in the presence of 10 nM sarafotoxin S6c.6. Taken together with the present finding that mRNAs encoding the rat ETA and the ETB receptors are expressed in the anterior pituitary gland, we tentatively conclude that although there are ETA and ETB receptors with a functional binding capability for ET receptor-ligands, the ETB receptor does not independently recognize ET-1 without the aid of the ETA receptor. If this thesis is tenable, then ET-1 can bridge between the two receptors to form an ETA–ETB receptor heterodimer. 相似文献
10.
《Life sciences》1997,61(25):PL397-PL401
The injection of endothelin-1 (ET-1) (2 pmol) into the dorsolateral periaqueductal gray area (PAG) of mice produces antinociceptive effect as underscored by increases in the latency time for the reaction to a hot plate. Pretreatment of the PAG area with bosentan (10 nmol) (a mixed ETA/ETB receptor antagonist), FR 139317 (5 nmol) (ETA receptor selective antagonist) or BQ-788 (5 nmol) (ETB receptor selective antagonist) greatly reduced the antinociceptive effect induced by ET-1. Therefore, ET-1 induces antinociceptive effects via both ETA/ETB receptors. In addition, since ET-antagonists lowered per se the control reaction time of the mice when administered alone to the PAG area, we would suggest that endogenous ET-1 acting within the PAG area contributes to the suppression of pain. 相似文献
11.
Juan CC Chang LW Huang SW Chang CL Lee CY Chien Y Hsu YP Ho PH Chen YC Ho LT 《Obesity (Silver Spring, Md.)》2006,14(3):398-404
Objective : To explore the role of endothelin‐1 (ET‐1) on lipid metabolism, we examined the effect of ET‐1 on lipolysis in rat adipocytes. Research Methods and Procedure : Adipocytes isolated from male Sprague‐Dawley rats, weighing 400 to 450 grams, were incubated in Krebs‐Ringer buffer with or without 10?7 M ET‐1 for various times or with various concentrations of ET‐1 for 4 hours; then glycerol release into the incubation medium was measured. In addition, selective ETAR and ETBR blockers were used to identify the ET receptor subtype involved. We also explored the involvement of cyclic adenosine monophosphate (cAMP) in ET‐1‐stimulated lipolysis using an adenylyl cyclase inhibitor and by measuring changes in intracellular cAMP levels in response to ET‐1 treatment. To further explore the underlying mechanism of ET‐1 action, we examined the involvement of the extracellular signal‐regulated kinase (ERK)‐mediated pathways. Results : Our results showed that ET‐1 caused lipolysis in rat adipocytes in a time‐ and dose‐dependent manner. BQ610, a selective ETAR blocker, blocked this effect. The adenylyl cyclase inhibitor, 2′, 5′‐dideoxyadenosine, had no effect on ET‐1‐stimulated lipolysis. ET‐1 did not induce an increase in intracellular cAMP levels. In addition, ET‐1‐induced lipolysis was blocked by inhibition of ERK activation using PD98059. Coincubation of cells with ET‐1 and insulin suppressed ET‐1‐stimulated lipolysis. Discussion : These findings show that ET‐1 stimulates lipolysis in rat adipocytes through the ETAR and activation of the ERK pathway. The underlying mechanism is cAMP‐independent. However, this non‐conventional lipolytic effect of ET‐1 is inhibited by the anti‐lipolytic effect of insulin. 相似文献
12.
《Cellular signalling》2014,26(12):2885-2895
The endothelin-1 (ET-1)/endothelin A receptor (ETAR, a G protein-coupled receptor) axis confers pleiotropic effects on both tumor cells and the tumor microenvironment, modulating chemo-resistance and other tumor-associated processes by activating Gαq- and β-arrestin-mediated pathways. While the precise mechanisms by which these effects occur remain to be elucidated, interference with ETAR signaling has emerged as a promising antitumor strategy in many cancers including ovarian cancer (OC). However, current clinical approaches using ETAR antagonists in the absence of a detailed knowledge of downstream signaling have resulted in multiple adverse side effects and limited therapeutic efficacy. To maximize the safety and efficacy of ETAR-targeted OC therapy, we investigated the role of other G protein subunits such as Gαs in the ETAR-mediated ovarian oncogenic signaling. In HEY (human metastatic OC) cells where the ET-1/ETAR axis is well-characterized, Gαs signaling inhibits ETAR-mediated OC cell migration, wound healing, proliferation and colony formation on soft agar while inducing OC cell apoptosis. Mechanistically, ET-1/ETAR is coupled to Gαs/cAMP signaling in the same ovarian carcinoma-derived cell line. Gαs/cAMP/PKA activation inhibits ETAR-mediated β-arrestin activation of angiogenic/metastatic Calcrl and Icam2 expression. Consistent with our findings, Gαs overexpression is associated with improved survival in OC patients in the analysis of the Cancer Genome Atlas data. In conclusion, our results indicate a novel function for Gαs signaling in ET-1/ETAR-mediated OC oncogenesis and may provide a rationale for a biased signaling mechanism, which selectively activates Gαs-coupled tumor suppressive pathways while blocking Gαq-/β-arrestin-mediated oncogenic pathways, to improve the targeting of the ETAR axis in OC. 相似文献
13.
Rafael Sobrano Fais Rafael Menezes da Costa Allan Carvalho Mendes Fabíola Mestriner Simon Gabriel ComermaSteffensen Rita C. Tostes Ulf Simonsen Fernando Silva Carneiro 《Journal of cellular and molecular medicine》2023,27(1):1
In the present study, we hypothesized that endothelin (ET) receptors (ETA and ETB) stimulation, through increased calcium and ROS formation, leads to Nucleotide Oligomerization Domain‐Like Receptor Family, Pyrin Domain Containing 3 (NLRP3) activation. Intracavernosal pressure (ICP/MAP) was measured in C57BL/6 (WT) mice. Functional and immunoblotting assays were performed in corpora cavernosa (CC) strips from WT, NLRP3−/− and caspase−/− mice in the presence of ET‐1 (100 nM) and vehicle, MCC950, tiron, BAPTA AM, BQ123, or BQ788. ET‐1 reduced the ICP/MAP in WT mice, and MCC950 prevented the ET‐1 effect. ET‐1 decreased CC ACh‐, sodium nitroprusside (SNP)‐induced relaxation, and increased caspase‐1 expression. BQ123 an ETA receptor antagonist reversed the effect. The ETB receptor antagonist BQ788 also reversed ET‐1 inhibition of ACh and SNP relaxation. Additionally, tiron, BAPTA AM, and NLRP3 genetic deletion prevented the ET‐1‐induced loss of ACh and SNP relaxation. Moreover, BQ123 diminished CC caspase‐1 expression, while BQ788 increased caspase‐1 and IL‐1β levels in a concentration‐dependent manner (100 nM–10 μM). Furthermore, tiron and BAPTA AM prevented ET‐1‐induced increase in caspase‐1. In addition, BAPTA AM blocked ET‐1‐induced ROS generation. In conclusion, ET‐1‐induced erectile dysfunction depends on ETA‐ and ETB‐mediated activation of NLRP3 in mouse CC via Ca2+‐dependent ROS generation. 相似文献
14.
Endothelin-1 (ET-1) induces contraction of vascular smooth muscle through binding to endothelin type A receptor (ETAR). COS-7 cells stably expressing high levels of the ETAR were established (designated COS-7(ETAR)). The COS-7(ETAR) cell bound [125I]ET-1 with a Kd of 932 ± 161 pM and a Bmax of 74 ± 13 fmol/2 × 105 cells. [125I]ET-1 binding was inhibited by ET-1 and the ETAR antagonist BQ-610, but not by the endothelin type B receptor (ETBR) antagonist BQ-788. In clones expressing two ETAR mutants containing D46N or R53Q substitutions in the first extracellular domain of the receptor, [125I]ET-1 binding activity was dramatically reduced. This suggests that these single amino acid substitutions alter the three-dimensional structure of the ligand-binding domain of the ETAR. Using COS-7(ETAR) cell, we showed that Ca2+ or Mg2+ was essential for ET-1 binding to the ETAR and that ET-1 treatment induced postreceptor signaling, that is, intracellular accumulation of cyclic AMP (cAMP) and Ca2+ mobilization. The COS-7(ETAR) established in this study will be a useful tool for screening ET-1 antagonists for treating hypertension. 相似文献
15.
《Peptides》2017
Endothelin (ET)-1 is an important peptide in cancer progression stimulating cellular proliferation, tumor angiogenesis and metastasis. ET-1 binds with high affinity to the ETA receptor (R) and ETBR on cancer cells. High levels of tumor ET-1 and ETAR are associated with poor survival of lung cancer patients. Here the effects of ET-1 on epidermal growth factor (EGF)R and HER2 transactivation were investigated using non-small cell lung cancer (NSCLC) cells. ETAR mRNA was present in all 10 NSCLC cell lines examined. Addition of ET-1 to NCI-H838 or H1975 cells increased EGFR, HER2 and ERK tyrosine phosphorylation within 2 min. The increase in EGFR and HER2 transactivation caused by ET-1 addition to NSCLC cells was inhibited by lapatinib (EGFR and HER2 tyrosine kinase inhibitor (TKI)), gefitinib (EGFR TKI), ZD4054 or BQ-123 (ETAR antagonist), GM6001 (matrix metalloprotease inhibitor), PP2 (Src inhibitor) or Tiron (superoxide scavenger). ET-1 addition to NSCLC cells increased cytosolic Ca2+ and reactive oxygen species. ET-1 increased NSCLC clonal growth, whereas BQ123, ZD4054, lapatinib or gefitinib inhibited proliferation. The results indicate that ET-1 may regulate NSCLC cellular proliferation in an EGFR- and HER2-dependent manner. 相似文献
16.
Florian G?rtner Thorsten Seidel Uwe Schulz Jan Gummert Hendrik Milting 《The Journal of biological chemistry》2013,288(45):32138-32148
Endothelin receptor A (ETA), a G protein-coupled receptor, mediates endothelin signaling, which is regulated by GRK2. Three Ser and seven Thr residues recently proven to be phosphoacceptor sites are located in the C-terminal extremity (CTE) of the receptor following its palmitoylation site. We created various phosphorylation-deficient ETA mutants. The phospholipase C activity of mutant receptors in HEK-293 cells was analyzed during continuous endothelin stimulation to investigate the impact of phosphorylation sites on ETA desensitization. Total deletion of phosphoacceptor sites in the CTE affected proper receptor regulation. However, proximal and distal phosphoacceptor sites both turned out to be sufficient to induce WT-like desensitization. Overexpression of the Gαq coupling-deficient mutant GRK2-D110A suppressed ETA-WT signaling but failed to decrease phospholipase C activity mediated by the phosphorylation-deficient mutant ETA-6PD. In contrast, GRK2-WT acted on both receptors, whereas the kinase-inactive mutant GRK2-D110A/K220R failed to inhibit signaling of ETA-WT and ETA-6PD. This demonstrates that ETA desensitization involves at least two autonomous GRK2-mediated components: 1) a phosphorylation-independent signal decrease mediated by blocking of Gαq and 2) a mechanism involving phosphorylation of Ser and Thr residues in the CTE of the receptor in a redundant fashion, able to incorporate either proximal or distal phosphoacceptor sites. High level transfection of GRK2 variants influenced signaling of ETA-WT and ETA-6PD and hints at an additional phosphorylation-independent regulatory mechanism. Furthermore, internalization of mRuby-tagged receptors was observed with ETA-WT and the phosphorylation-deficient mutant ETA-14PD (lacking 14 phosphoacceptor sites) and turned out to be based on a phosphorylation-independent mechanism. 相似文献
17.
In the developing heart, cardiomyocytes undergo terminal differentiation during a critical window around birth. Hypoxia is a major stress to preterm infants, yet its effect on the development and maturation of the heart remains unknown. We tested the hypothesis in a rat model that newborn anoxia accelerates cardiomyocyte terminal differentiation and results in reduced cardiomyocyte endowment in the developing heart via an endothelin-1-dependent mechanism. Newborn rats were exposed to anoxia twice daily from postnatal day 1 to 3, and hearts were isolated and studied at postnatal day 4 (P4), 7 (P7), and 14 (P14). Anoxia significantly increased HIF-1α protein expression and pre-proET-1 mRNA abundance in P4 neonatal hearts. Cardiomyocyte proliferation was significantly decreased by anoxia in P4 and P7, resulting in a significant reduction of cardiomyocyte number per heart weight in the P14 neonates. Furthermore, the expression of cyclin D2 was significantly decreased due to anoxia, while p27 expression was increased. Anoxia has no significant effect on cardiomyocyte binucleation or myocyte size. Consistently, prenatal hypoxia significantly decreased cardiomyocyte proliferation but had no effect on binucleation in the fetal heart. Newborn administration of PD156707, an ETA-receptor antagonist, significantly increased cardiomyocyte proliferation at P4 and cell size at P7, resulting in an increase in the heart to body weight ratio in P7 neonates. In addition, PD156707 abrogated the anoxia-mediated effects. The results suggest that hypoxia and anoxia via activation of endothelin-1 at the critical window of heart development inhibits cardiomyocyte proliferation and decreases myocyte endowment in the developing heart, which may negatively impact cardiac function later in life. 相似文献
18.
O'Tierney PF Angelis E Tse MY Pang JJ Adams MA Pang SC 《Molecular and cellular biochemistry》2005,275(1-2):57-66
We have previously shown that the partial disruption of the gene for atrial natriuretic peptide (ANP) results in a salt-sensitive phenotype. The present study examined the possibility that alterations in either the ANP natriuretic pathway or endothelin (ET) system in the kidney of the salt-challenged ANP +/− mouse was responsible for its salt-sensitive phenotype. Plasma ANP levels and renal cGMP activity were increased in response to a salt load in both ANP +/+ and +/− mice. However, the mRNA expression of proANP was found to be increased only in the ANP +/− kidney along with its guanylyl cyclase-linked receptor, NPRA; the upregulation of NPRA mRNA was limited to the renal medulla. This suggests that the renal ANP pathway remains capable of responding to a salt load in the ANP +/− animal, but may be compensating for other dysfunctional pathways. We also report a significant increase in renal ET-1 mRNA and ETA receptor protein expression in medulla and cortex of the salt-treated, ANP +/− mouse, but not its wild-type counterpart. In fact, ETA expression decreased in the renal cortex of the ANP +/+ salt-treated animal. The ETB receptor expression was not affected by diet in either genotype. We hypothesize that the salt-sensitive hypertension in the ANP +/− mouse is exacerbated, and possibly driven by the vasoconstrictive effects resulting from an upregulated ET-1/ETA pathway. 相似文献
19.
Nikhil Khadtare Ralph Stephani Vijaya Korlipara 《Bioorganic & medicinal chemistry letters》2017,27(11):2281-2285
The endothelin axis and in particular the two receptor subtypes, ETA and ETB, are under investigation for the treatment of various diseases such as pulmonary arterial hypertension, fibrosis, renal failure and cancer. Previous work in our lab has shown that 1,3,6-trisubstituted-4-oxo-1,4-dihydroquinoline-2-carboxylic acid derivatives exhibit noteworthy endothelin receptor antagonist activity. A series of analogues with modifications centered around position 6 of the heterocyclic quinolone core and replacement of the aryl carboxylic acid group with an isosteric tetrazole ring was designed and synthesized to further optimize the structure activity relationship. The endothelin receptor antagonist activity was determined by in vitro Förster resonance energy transfer (FRET) using GeneBLAzer® assay technology. The most potent member of this series exhibited ETA receptor antagonist activity in the subnanomolar range with an IC50 value of 0.8 nM, and was 1000-fold selective for the ETA receptor compared to the ETB receptor. Its activity and selectivity profile resembles that of the most recently approved drug, macitentan. 相似文献
20.
Marcel Lindemann Sonja Hinz Winnie Deuther-Conrad Vigneshwaran Namasivayam Sladjana Dukic-Stefanovic Rodrigo Teodoro Magali Toussaint Mathias Kranz Cathleen Juhl Jörg Steinbach Peter Brust Christa E. Müller Barbara Wenzel 《Bioorganic & medicinal chemistry》2018,26(16):4650-4663
On the basis of a pyrazine core structure, three new adenosine A2B receptor ligands (7a–c) were synthesized containing a 2-fluoropyridine moiety suitable for 18F-labeling. Compound 7a was docked into a homology model of the A2B receptor based on X-ray structures of the related A2A receptor, and its interactions with the adenosine binding site were rationalized. Binding affinity data were determined at the four human adenosine receptor subtypes. Despite a rather low selectivity regarding the A1 receptor, 7a was radiolabeled as the most suitable candidate (Ki(A2B)?=?4.24?nM) in order to perform in vivo studies in mice with the aim to estimate fundamental pharmacokinetic characteristics of the compound class. Organ distribution studies and a single PET study demonstrated brain uptake of [18F]7a with a standardized uptake value (SUV) of ≈1 at 5?min post injection followed by a fast wash out. Metabolism studies of [18F]7a in mice revealed the formation of a blood–brain barrier penetrable radiometabolite, which could be structurally identified. The results of this study provide an important basis for the design of new derivatives with improved binding properties and metabolic stability in vivo. 相似文献