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1.
AimsAngiotensin-(1-9) [Ang-(1-9)] and Ang-(1-7) are cleaved by Ang converting enzyme 2 forming Ang I and Ang II, respectively, and the truncated Angs play a role in regulating atrial natriuretic peptide (ANP) secretion. Previously, we found that Ang-(1-7) stimulates ANP secretion via the Mas receptor. However, the effect of Ang-(1-9) on ANP secretion is still unknown. The aim of the present study is to determine whether Ang-(1-9) stimulates ANP secretion and to characterize the signaling pathway involved in stimulating secretion. Main methodsWe examined the effects of Ang-(1-9) on ANP secretion and atrial contractility with and without inhibitors in isolated perfused atria. Key findingsAng-(1-9) stimulated ANP secretion and concentration without change in atrial contractility. Ang-(1-9)-induced-ANP secretion was increased from 5% to 60% by 3 μM Ang-(1-9) during the low-stretch state of the atrium. This stimulatory effect of Ang-(1-9) on ANP secretion was attenuated by pretreatment with an Ang II type 2 receptor (AT 2R) antagonist but not by AT 1R or Mas receptor antagonist. In addition, pretreatment with inhibitors of phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt), nitric oxide synthase (NOS) and soluble guanylyl cyclase (sGC) blocked Ang-(1-9)-induced ANP secretion. In the high-stretch atrial state, Ang-(1-9)-induced ANP secretion was increased more than in the low-stretch state following addition of 1 μM Ang-(1-9) (from 108% to 170%). In an in vivo experiment, acute infusion of Ang-(1-9) increased plasma ANP level without altering arterial blood pressure. This effect was attenuated by pretreatment with AT 2R antagonist but not by Mas receptor antagonist. SignificanceThese results suggest that Ang-(1-9) stimulates ANP secretion via the AT 2R-PI3K-Akt-NO-cGMP pathway. 相似文献
2.
Antagonism of the adenosine A 2A receptor affords a possible treatment of Parkinson’s disease. In the course of investigating pyrazolo[4,3- e]-1,2,4-triazolo[1,5- c]pyrimidine A 2A antagonists, we prepared [1,2,4]-triazolo[4,3- c]pyrimidin-3-ones with potent and selective (vs A 1) A 2A antagonist activity. Structure-activity relationships are described for this series. 相似文献
3.
Rapid phosphoester hydrolysis of endogenous purine and pyrimidine nucleotides has challenged the characterization of the role of P2 receptors in physiology and pathology. Nucleotide phosphoester stabilization has been pursued on a number of medicinal chemistry fronts. We investigated the in vitro and in vivo stability and pharmacokinetics of prototypical nucleotide P2Y1 receptor (P2Y1R) agonists and antagonists. These included the riboside nucleotide agonist 2-methylthio-ADP and antagonist MRS2179, as well as agonist MRS2365 and antagonist MRS2500 containing constrained (N)-methanocarba rings, which were previously reported to form nucleotides that are more slowly hydrolyzed at the α-phosphoester compared with the ribosides. In vitro incubations in mouse and human plasma and blood demonstrated the rapid hydrolysis of these compounds to nucleoside metabolites. This metabolism was inhibited by EDTA to chelate divalent cations required by ectonucleotidases for nucleotide hydrolysis. This rapid hydrolysis was confirmed in vivo in mouse pharmacokinetic studies that demonstrate that MRS2365 is a prodrug of the nucleoside metabolite AST-004 (MRS4322). Furthermore, we demonstrate that the nucleoside metabolites of MRS2365 and 2-methylthio-ADP are adenosine receptor (AR) agonists, notably at A3 and A1ARs. In vivo efficacy of MRS2365 in murine models of traumatic brain injury and stroke can be attributed to AR activation by its nucleoside metabolite AST-004, rather than P2Y1R activation. This research suggests the importance of reevaluation of previous in vitro and in vivo research of P2YRs and P2XRs as there is a potential that the pharmacology attributed to nucleotide agonists is due to AR activation by active nucleoside metabolites. 相似文献
4.
The highly potent but modestly selective N-(2-amino-4-methoxy-benzothiazol-7-yl)- N-ethyl-acetamide derivative 2 was selected as the starting point for the design of novel selective A 2B antagonists, due to its excellent potency, and good drug-like properties. A series of compounds containing nonaromatic amides or ureas of five- or six-membered rings, and also bearing an m-trifluoromethyl-phenyl group (shown to impart superior potency) was prepared and evaluated for their selectivity against the A 2A and A 1 receptors. This work resulted in the identification of compound 30, with excellent potency and high selectivity against both A 2A and A 1 receptors. 相似文献
5.
Chronic granulomatous disease (CGD) is caused by defects in the NADPH oxidase complex and is characterized by an increased susceptibility to infection. Other significant complications of CGD include autoimmunity and non-infectious hyperinflammatory disorders. We show that a gp91 phox deficiency leads to the development of phenotypically altered T lymphocytes in mice and that this abnormal, hyperactive phenotype can be modulated by activation of the adenosine A 2A receptor. T cells isolated from CGD mice produce significantly higher levels of the pro-inflammatory cytokines IFN-γ, IL-2, TNF-α, IL-4 and IL-13 than do WT cells after TCR-mediated activation; treatment with the selective adenosine A 2A receptor agonist, CGS21680, potently inhibits this response. Additionally, the over exuberant inflammatory response elicited by thioglycollate challenge in gp91 phox deficient mice is attenuated by CGS21680. These data suggest that treatment with A 2AR agonists may be an effective therapy by which to regulate the immune system hyperactivity that results from a gp91 phox deficiency. 相似文献
6.
The role of the adenosine A 3 receptor in hematopoiesis was studied using adenosine A 3 receptor knockout (A 3AR KO) mice. Hematological parameters of peripheral blood and femoral bone marrow of irradiated and untreated A 3AR KO mice and their wild-type (WT) counterparts were investigated. Irradiation of the mice served as a defined hematopoiesis-damaging means enabling us to evaluate contingent differences in the pattern of experimentally induced hematopoietic suppression between the A 3AR KO mice and WT mice. Defects were observed in the counts and/or functional parameters of blood cells in the A 3AR KO mice. These defects include statistically significantly lower values of blood neutrophil and monocyte counts, as well as those of mean erythrocyte volume, mean erythrocyte hemoglobin, blood platelet counts, mean platelet volume, and plateletcrit, and can be considered to bear evidence of the lack of a positive role played by the adenosine A 3 receptor in the hematopoietic system. Statistically significantly increased values of the bone marrow parameters studied in A 3AR KO mice (femoral bone marrow cellularity, granulocyte/macrophage progenitor cells, and erythrocyte progenitor cells) can probably be explained by compensatory mechanisms attempting to offset the disorders in the function of blood elements in these mice. The pattern of the radiation-induced hematopoietic suppression was very similar in A 3AR KO mice and their WT counterparts. 相似文献
7.
In recent studies performed in our laboratory we have shown that acute administration of (-)-linalool, the natural occurring enantiomer in essential oils, possesses anti-inflammatory, antihyperalgesic and antinociceptive effects in different animal models. The antihyperalgesic and antinociceptive effects of (-)-linalool have been ascribed to its capacity in stimulating the opioidergic, cholinergic and dopaminergic systems, as well as to its interaction with K+ channels, or to its local anaesthetic activity and/or to the negative modulation of glutamate transmission. Activation of A1 or A2A receptors has been shown to induce antinociceptive effects, and the possible involvement of adenosine in (-)-linalool antinociceptive effect, has not been elucidated yet. Therefore, in the present study, we have investigated the effects of 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), a selective adenosine A1 receptor antagonist and the effects of 3,7-dimethyl-1-propargilxanthine (DMPX), a selective adenosine A2A receptor antagonist on the antinociception of (-)-linalool in mice, measured in the hot-plate test. Both DPCPX (0.1 mg/kg; i.p.) and DMPX (0.1 mg/kg; i.p.) pre-treatment significantly depressed the antinociceptive effect of (-)-linalool at the highest doses tested. These findings demonstrated that the effect of (-)-linalool on pain responses is, at least partially, mediated by the activity of adenosine A1 and A2A receptors. 相似文献
8.
Adenosine A 2A receptor (A 2AR) is a G protein-coupled receptor enriched in the striatum for which an increased expression has been demonstrated in certain neurological diseases. Interestingly, previous in vitro studies demonstrated that A 2AR expression levels are reduced after treatment with S-adenosyl-L-methionine (SAM), a methyl donor molecule involved in the methylation of important biological structures such as DNA, proteins, and lipids. However, the in vivo effects of SAM treatment on A 2AR expression are still obscure. Here, we demonstrated that 2 weeks of SAM treatment produced a significant reduction in the rat striatal A 2AR messenger RNA (mRNA) and protein content as well as A 2AR-mediated signaling. Furthermore, when the content of 5-methylcytosine levels in the 5′UTR region of ADORA2A was analyzed, this was significantly increased in the striatum of SAM-treated animals; thus, an unambiguous correlation between SAM-mediated methylation and striatal A 2AR expression could be established. Overall, we concluded that striatal A 2AR functionality can be controlled by SAM treatment, an issue that might be relevant for the management of these neurological conditions that course with increased A 2AR expression. 相似文献
11.
Angiotensin II (Ang II) type 1 receptor (AT 1R) mediates the major cardiovascular effects of Ang II. However, the effects mediated via AT 2R are still controversial. The aim of the present study is to define the effect of AT 2R agonist CGP42112A (CGP) on high stretch-induced ANP secretion and its mechanism using in vitro and in vivo experiments. CGP (0.01, 0.1 and 1 μM) stimulated high stretch-induced ANP secretion and concentration from isolated perfused rat atria. However, atrial contractility and the translocation of extracellular fluid did not change. The augmented effect of CGP (0.1 μM) on high stretch-induced ANP secretion was attenuated by the pretreatment with AT 2R antagonist or inhibitor for phosphoinositol 3-kinase (PI3K), nitric oxide (NO), soluble guanylyl cyclase (sGC), or protein kinase G (PKG). However, antagonist for AT 1R or Mas receptor did not influence CGP-induced ANP secretion. In vivo study, acute infusion of CGP for 10 min increased plasma ANP level without blood pressure change. In renal hypertensive rat atria, AT 2R mRNA and protein levels were up-regulated and the response of plasma ANP level to CGP infusion in renal hypertensive rats augmented. The pretreatment with AT 2R antagonist for 10 min followed by CGP infusion attenuated an increased plasma ANP level induced by CGP. However, pretreatment with AT 1R or Mas receptor antagonist unaffected CGP-induced increase in plasma ANP level. Therefore, we suggest that AT 2R agonist CGP stimulates high stretch-induced ANP secretion through PI3K/NO/sGC/PKG pathway and these effects are augmented in renal hypertensive rats. 相似文献
12.
Nociceptin (N/OFQ) is a novel heptadecapeptide with an amino acid sequence similar to that of endogenous opioid peptide dynorphin A. Dynorphin have been reported to increase the secretion of atrial natriuretic peptide (ANP) via selective activation of kappa-opioid receptor in cultured atrial cardiocytes. The present study was designed to investigate the direct effect of N/OFQ on the ANP secretion in cultured neonatal rat cardiac myocytes via N/OFQ receptor (NOP) activation. The secretion of ANP from cultured neonatal cardiac myocytes was increased in terms of incubation time. N/OFQ, at a dose of 0.3, 1, 3, and 10 microM, caused increases in ANP secretion in a dose-dependent manner. The N/OFQ-induced ANP secretion was completely antagonized by antagonists of NOP, 1 microM each of [Phe1 (CH2-NH) Gly2] nociceptin (1-13)-NH2 ([FG]N/OFQ(1-13)NH2) or naloxone benzoylhydrazone. In contrast, naloxone (1 microM), the non-selective opioid receptor antagonist, did not alter ANP response to N/OFQ. N/OFQ at 3 microM inhibited basal and forskolin-stimulated cAMP production, which was partially antagonized with the pretreatment of [FG]N/OFQ(1-13)NH2. An increase in ANP secretion by N/OFQ was also partially blocked by the pretreatment of forskolin. Homologous competition studies in neonatal cardiomyocyte membranes revealed the presence of two distinct sites. The high affinity site (10.9 +/- 1.6 nM) was far less abundant than the low affinity site. Therefore, these results suggest that N/OFQ causes an increase in ANP secretion in cultured neonatal cardiac myocytes by decreasing cAMP through its binding sites. 相似文献
13.
Limonene is a major aromatic compound in essential oils extracted from citrus rind. The application of limonene, especially in aromatherapy, has expanded significantly, but its potential effects on cellular metabolism have been elusive. We found that limonene directly binds to the adenosine A 2A receptor, which may induce sedative effects. Results from an in vitro radioligand binding assay showed that limonene exhibits selective affinity to A 2A receptors. In addition, limonene increased cytosolic cAMP concentration and induced activation of protein kinase A and phosphorylation of cAMP-response element-binding protein in Chinese hamster ovary cells transfected with the human adenosine A 2A receptor gene. Limonene also increased cytosolic calcium concentration, which can be achieved by the activation of adenosine A 2A receptors. These findings suggest that limonene can act as a ligand and an agonist for adenosine A 2A receptors. 相似文献
14.
The synthesis of an important set of 3-furfurylxanthine derivatives is described. Binding affinities were determined for rat A 1 and human A 2A, A 2B and A 3 receptors. Several of the 3-furfuryl-7-methylxanthine derivatives showed moderate-to-high affinity at human A 2B receptors, the most active compound ( 10d) having a Ki of 7.4 nM for hA 2B receptors, with selectivities over rA 1 and hA 2A receptors up to 14-fold and 11-fold, respectively. Affinities for hA 3 receptors were very low for all members of the set. 相似文献
15.
The conformation of a constrained peptide mimicking the putative first intracellular domain (iLP1) of thromboxane A(2) receptor (TP) was determined by (1)H 2D NMR spectroscopy. Through completed assignments of TOCSY, DQF-COSY, and NOESY spectra, a NMR structure of the peptide showed a beta-turn in residues 56-59 and a short helical structure in the residues 63-66. It suggests that residues 63-66 may be part of the second transmembrane domain (TM), and that Arg60, in an exposed position on the outer surface of the loop, may be involved in signaling through charge contact with Gq protein. The sequence alignment of Lys residue in the same position of other prostanoid receptors mediates different G protein couplings, suggesting that the chemical properties of Arg and Lys may also affect the receptor signaling activity. These hypotheses were supported by mutagenesis studies, in which the mutant of Arg60Leu completely lost activity in increasing intracellular calcium level through Gq coupling, and the mutant of Arg60Lys retained only about 35% signaling activity. The difference between the side chain functions of Lys and Arg in effecting the signaling was discussed. 相似文献
16.
SCH 58261 is a reported adenosine A 2A receptor antagonist, which is active in rat in vivo models of Parkinson’s Disease upon ip administration. However, it has poor selectivity versus the A 1 receptor and does not demonstrate oral activity. We report the design and synthesis of biaryl and heteroaryl analogs of SCH 58261 which improve the A 2A receptor binding selectivity as well as the pharmacokinetic properties of SCH 58261. In particular, the quinoline 25 has excellent A 2A receptor in vitro binding affinity and selectivity, sustained rat plasma levels upon oral dosing, and is active orally in a rat behavioral assay. 相似文献
17.
D 1- and D 2-types of dopamine receptors are located separately in direct and indirect pathway striatal projection neurons (dSPNs and iSPNs). In comparison, adenosine A 1-type receptors are located in both neuron classes, and adenosine A 2A-type receptors show a preferential expression in iSPNs. Due to their importance for neuronal excitability, Ca 2+-currents have been used as final effectors to see the function of signaling cascades associated with different G protein-coupled receptors. For example, among many other actions, D 1-type receptors increase, while D 2-type receptors decrease neuronal excitability by either enhancing or reducing, respectively, Ca V1 Ca 2+-currents. These actions occur separately in dSPNs and iSPNs. In the case of purinergic signaling, the actions of A 1- and A 2A-receptors have not been compared observing their actions on Ca 2+-channels of SPNs as final effectors. Our hypotheses are that modulation of Ca 2+-currents by A 1-receptors occurs in both dSPNs and iSPNs. In contrast, iSPNs would exhibit modulation by both A 1- and A 2A-receptors. We demonstrate that A 1-type receptors reduced Ca 2+-currents in all SPNs tested. However, A 2A-type receptors enhanced Ca 2+-currents only in half tested neurons. Intriguingly, to observe the actions of A 2A-type receptors, occupation of A 1-type receptors had to occur first. However, A 1-receptors decreased Ca V2 Ca 2+-currents, while A 2A-type receptors enhanced current through Ca V1 channels. Because these channels have opposing actions on cell discharge, these differences explain in part why iSPNs may be more excitable than dSPNs. It is demonstrated that intrinsic voltage-gated currents expressed in SPNs are effectors of purinergic signaling that therefore play a role in excitability. 相似文献
18.
The molecular mechanism of membrane-associated reactions induced by auxin was investigated in membranes isolated from cultured cells of soybean ( Glycine max L.). Auxins increased the activity of phospholipase A 2 in microsomes isolated from suspensioncultured soybean cells. The reaction was measured as the accumulation of radioactive lysophosphatidylcholine hydrolyzed from radioactive phosphatidylcholine in membranes which had been prelabelled with [ 14-C]choline in vivo. Stimulation by auxin was detectable after 1 min and was auxin-specific in that weak auxins had little effect. Auxin concentrations as low as 2·10 –8 M and up to 2·10 +3 M -naphthaleneacetic acid already stimulated the phospholipase A 2 activity. Guanosine and adenosine diphosphate at 100 M, if applied during homogenization of cells, completely abolished the stimulation of phospholipase A 2 by auxin and, when applied after homogenization, had no effect. Guanosine and adenosine 5-O-thiotriphosphate, uridine 5-diphosphate, and uridine 5-triphosphate, all at 100 M, had no effect in either treatment, suggesting that only nucleotides entrapped in the vesicles could exert an effect. The effect of auxin on phospholipase A 2 had an optimum at pH 5.5 and was abolished completely by an antibody against the membrane-associated auxin-binding protein from maize coleoptiles, applied after homogenization. This antibody recognized a 22-kDa polypeptide in highly purified plasma membranes from cultured soybean cells. This suggests a receptor function for this auxin-binding protein and a role for a cytosolic nucleotide-binding protein in the activation of phospholipase A 2 by auxin. It is concluded that phospholipase A 2 has a function in plant signal transduction.Abbreviations ABP
auxin-binding protein
- ATP S
adenosine 5-O-thiotriphosphate
- 2,4-D
2,4-dichlorophenoxyacetic acid
- GTP S
guanosine 5-O-(thiotriphosphate)
- IgG
immunoglobulin G
- LPC
lysophosphatidylcholine;
-
-NAA
, -naphthaleneacetic acid
- PLA 2
phospholipase A 2
We cordially acknowledge the gift of anti-ABP antibody by D. Klämbt and the help by H. Ordowski (both Botanisches Institut, Universität Bonn) with the immunoblotting experiments. This work was supported by the Deutsche Forschungsgemeinschaft. 相似文献
19.
The clinical management of neuroendocrine tumours is complex. Such tumours are highly vascular suggesting tumour-related angiogenesis. Adenosine, released during cellular stress, damage and hypoxia, is a major regulator of angiogenesis. Herein, we describe the expression and function of adenosine receptors (A(1), A(2A), A(2B) and A(3)) in neuroendocrine tumours. Expression of adenosine receptors was investigated in archival human neuroendocrine tumour sections and in two human tumour cell lines, BON-1 (pancreatic) and KRJ-I (intestinal). Their function, with respect to growth and chromogranin A secretion was carried out in vitro. Immunocytochemical data showed that A(2A) and A(2B) receptors were strongly expressed in 15/15 and 13/18 archival tumour sections. Staining for A(1) (4/18) and A(3) (6/18) receptors was either very weak or absent. In vitro data showed that adenosine stimulated a three- to fourfold increase in cAMP levels in BON-1 and KRJ-1 cells. The non-selective adenosine receptor agonist (adenosine-5'N-ethylcarboxamide, NECA) and the A(2A)R agonist (CGS21680) stimulated cell proliferation by up to 20-40% which was attenuated by A(2B) (PSB603 and MRS1754) and A(2A) (SCH442416) receptor selective antagonists but not by the A(1) receptor antagonist (PSB36). Adenosine and NECA stimulated a twofold increase in chromogranin A secretion in BON-1 cells. Our data suggest that neuroendocrine tumours predominantly express A(2A) and A(2B) adenosine receptors; their activation leads to increased proliferation and secretion of chromogranin A. Targeting adenosine signal pathways, specifically inhibition of A(2) receptors, may thus be a useful addition to the therapeutic management of neuroendocrine tumours. 相似文献
20.
SCH 58261 is a reported adenosine A 2A receptor antagonist which is active in rat in vivo models of Parkinson’s Disease upon ip administration. However, it has poor selectivity versus the A 1 receptor and does not demonstrate oral activity. Quinoline analogs have improved upon the selectivity and pharmacokinetics of SCH 58261, but were difficult to handle due to poor aqueous solubility. We report the design and synthesis of fused heterocyclic analogs of SCH 58261 with aqueous solubility as well as improved A 2A receptor binding selectivity and pharmacokinetic properties. In particular, the tetrahydronaphthyridine 4s has excellent A 2A receptor in vitro binding affinity and selectivity, is active orally in a rat in vivo model of Parkinson’s Disease, and has aqueous solubility of 100 μM at physiological pH. 相似文献
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