UMLS:C0043167 - FACTA Search

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Query: UMLS:C0043167 (pertussis)
19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adenosine Ri receptors and inhibitory guanine-nucleotide-regulatory components were solubilized from rat cerebral-cortical membranes with sodium cholate. (-)-N6-Phenylisopropyl[2,8-3H]adenosine [( 3H]PIA) binds with high affinity to the soluble receptors, which retain the pharmacological specificity of adenosine Ri receptors observed in membranes. The binding is regulated by bivalent cations and guanine nucleotides. Bivalent cations increase [3H]PIA binding by increasing both the affinity and the apparent number of receptors. Guanine nucleotides decrease agonist binding by increasing the dissociation of the ligand-receptor complex. Adenosine agonists stabilize the high-affinity form of the soluble receptor. The hydrodynamic properties of the adenosine receptor were determined with cholate extracts of membranes that were treated with [3H]PIA. Sucrose-gradient-centrifugation analysis indicates that the receptor has a sedimentation coefficient of 7.7 S. The receptor is eluted from Sepharose 6B columns with an apparent Stokes radius of 7.2 nm. Labelling of either sucrose-gradient or gel-filtration-column fractions with pertussis toxin and [32P]-NAD+ reveals that both the 41,000- and 39,000-Mr substrates overlap with the receptor activity. These studies suggest that the high-affinity adenosine-receptor-binding activity in the cholate extract represents a stable R1-N complex.
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PMID:Hydrodynamic properties of adenosine Ri receptors solubilized from rat cerebral-cortical membranes. 343 74

Adenosine, via interaction with A1 adenosine receptors, increases insulin sensitivity and inhibits lipolysis in adipocytes. To investigate regulation of this system, adipocytes were incubated for up to 72 h with the nonmetabolizable adenosine receptor agonist, N6-phenylisopropyl adenosine (PIA). Adenosine receptors were measured by the binding of 125I-hydroxyphenylisopropyl adenosine to membranes. PIA down-regulated adenosine receptors, decreasing the number of binding sites with no change in affinity. Adipocytes were incubated for 48 h without or with 100 nM PIA to down-regulate the A1 receptors by approximately 60%. The cells were washed, and lipolysis and glucose transport were assessed. The ability of PIA to inhibit lipolysis was markedly attenuated in the down-regulated cells. Furthermore, the EC50 of insulin was increased approximately 3-fold in the PIA-treated cells. 125I-Insulin binding to the PIA-treated cells was unchanged, demonstrating that the decreased insulin sensitivity is not due to decreased insulin receptor binding. Pertussis toxin catalyzed ADP-ribosylation of a 41-kDa protein thought to be the alpha-subunit of Gi. This 41-kDa protein was decreased in membranes from cells treated with PIA, with a maximal 50% loss. This suggests that Gi is down-regulated and that loss of both the A1 adenosine receptor and Gi are involved in the metabolic changes observed after PIA treatment.
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PMID:Adenosine receptor down-regulation and insulin resistance following prolonged incubation of adipocytes with an A1 adenosine receptor agonist. 368 Feb 21

Several reports from our laboratory have suggested the involvement of the brain adenosinergic system in ethanol-induced motor incoordination (EIMI). This study is an extension of the previous work and pertains to the evaluation of the role of the striatal adenosine in EIMI in male Sprague-Dawley rats. Using the motor incoordination induced by 1.5 g/kg of ethanol (ip) as a test response, the possible behavioral interactions between ethanol and adenosine agonists and antagonists in the striatum were investigated. Intrastriatal (IST) administration of adenosine A1-, A1 = A2-, and As-selective agonists, R(-)N6-(2-phenylisopropyl)adenosine (R-PIA), 5'-N-ethylcarboxamido-adenosine (NECA), and 5'-(N-cyclopropyl)-carboxamidoadenosine, respectively, significantly and dose-dependently accentuated EIMI when evaluated by rotorod test, suggesting the striatal adenosinergic modulation of EIMI. No significant change in normal motor coordination was noted, even when the highest IST doses of adenosine agonists were followed by saline instead of ethanol, suggesting that the observed behavioral interactions of these drugs were selective to ethanol. Hippocampus, which is known not to be involved in the normal motor functions, was selected as a control brain area because of the presence of high density of adenosine receptors, as well as the high levels of adenosine. Intrahippocampal NECA failed to alter EIMI, indicating the specific role of striatal and not hippocampal adenosinergic system in the modulation of EIMI. The potentiating effects of adenosine agonists N6-cyclohexyladenosine (CHA) and CGS-21680 on EIMI were blocked by adenosine A1- and A2-selective antagonists, 8-cyclopentyl-1,3-dipropylxanthine and 3,7-dimethyl-1-propargylxanthine, respectively, suggesting the participation of specific adenosine receptors in this functional interaction. A role for the adenosine A1 receptor in the striatal adenosinergic modulation of EIMI was favored based on the rank-order potency of adenosine agonists. IST pretreatment with pertussis toxin (PT), but not with PT beta-oligomer, nearly completely eliminated the accentuation of EIMI by CHA, further supporting the favored role of adenosine A1 receptors in EIMI. Histological and IST [3H]R-PIA distribution data confirmed that the observed behavioral effects were caused by exclusive striatal distribution of intrastriatally microinjected drugs. Data obtained suggested modulation of acute EIMI by striatal adenosine receptor-mediated mechanism(s) and the coupling of these adenosine receptor to the PT-sensitive Gi protein.
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PMID:Possible role of striatal adenosine in the modulation of acute ethanol-induced motor incoordination in rats. 748 36

The identity and role of G proteins in coupling adenosine receptors to effectors have been studied to a limited degree. We have identified the G proteins whose GTPase activity is stimulated by adenosine receptor agonists in neuronal membranes. (R)-Phenylisopropyladenosine, 2-chloroadenosine, and N-ethylcarboxamideadenosine produced a concentration-dependent stimulation of GTPase. At 10(-5) M, the increase above basal GTPase in frontal cortex was 25 +/- 4, 20 +/- 3, and 8 +/- 1%, respectively, and in the cerebellum 55 +/- 2, 41 +/- 4, and 22 +/- 2%, respectively. The effects of (R)-phenylisopropyladenosine and 2-chloroadenosine were inhibited by (1) A1 antagonists (76-96% reduction), (2) pretreatment with pertussis toxin (90-100% reduction), and (3) antibodies raised against the alpha-subunit of Gi and G(o) (55-57% reduction by each), suggesting that A1 receptors interact equally with Gi and G(o). (R)-Phenylisopropyladenosine increased the binding of a nonhydrolyzable analogue of GTP to membranes in a pertussis toxin-sensitive manner, indicative of activation of Gi or G(o). Previously, (+/-)-Bay K 8644 enhanced GTP hydrolysis by G(o) but not Gi. Now we report a profound synergistic stimulation of GTPase in the presence of (R)-phenylisopropyladenosine and (+/-)-Bay K 8644 (10(-7) to 10(-5) M). (+/-)-Bay K 8644 had no effect on nucleotide exchange and, thus, cannot activate G(o). It appears that a positive cooperative stimulation of G(o) occurs when it is first activated by A1 receptors and subsequently interacts with the L-type Ca2+ channel.
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PMID:Adenosine A1 agonists and the Ca2+ channel agonist bay K 8644 produce a synergistic stimulation of the GTPase activity of Go in rat frontal cortical membranes. 753 3

1. Adenosine is known to stimulate capillary outgrowth and endothelial cell proliferation, but the underlying mechanism has not been identified. In order to identify the receptor subtype involved, the effects of adenosine receptor agonists and antagonists on human umbilical vein endothelial cell (HUVEC) proliferation were investigated. 2. Raising intracellular adenosine levels by use of the adenosine transport inhibitor, 4-nitrobenzylthioinosine (NBMPR) did not affect cell growth. This observation suggests that stimulation of an extracellular adenosine receptor generates the mitogenic signal. 3. In the presence of adenosine deaminase (ADA), which was used to remove adenosine present in the culture medium, the adenosine receptor agonists N-ethylcarboxamidoadenosine (NECA, non-selective) and CGS21680 (A2A-receptor-selective) stimulated [3H]-thymidine incorporation with a half-maximum effect at about 10 nM, while N6-cyclopentyladenosine (CPA, A1-selective) was about 100 fold less potent. The adenosine receptor antagonist, xanthine amine congener (XAC) produced a concentration-dependent decrease in endothelial cell proliferation with a half-maximum effect at about 10 nM. Hence, stimulation of an endothelial A2A-adenosine receptor seems responsible for the mitogenic signal. 4. In the presence of ADA, isoprenaline is also able to stimulate [3H]-thymidine incorporation with a half maximal effect of about 3 nM, an effect, which is reversed by the highly beta 2-selective antagonist, ICI 118,551. In the absence of ADA, isoprenaline exerts only a minor stimulatory effect. Combination of A2A adenosine and beta 2-adrenoceptor agonists did not further enhance [3H]-thymidine incorporation when compared to the sole addition of each agonist. We therefore conclude that both receptors stimulate endothelial cell proliferation via a common signal transduction pathway. 5. Both receptors are coupled to stimulation of adenylyl cyclase via the stimulatory G protein G8.However, direct activation of downstream effectors in the cyclic AMP-signalling cascade (G8 with cholera toxin, adenylyl cyclase with forskolin, protein kinase A with 8Br-cyclic AMP) not only failed to mimic the action of receptor-activation, but even reduced cell proliferation.6. Similarly, pertussis toxin-treatment which inactivated the Gi 2 protein present in HUVEC and thus inhibited cell proliferation per se, did not impair the ability of A2A-receptor agonists to stimulate cell proliferation. This suggests that the A2A-adenosine and beta2-adrenoceptor-mediated stimulation of endothelial cell proliferation occurs via a mechanism that is independent of G8 and Gi.
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PMID:Stimulation of human umbilical vein endothelial cell proliferation by A2-adenosine and beta 2-adrenoceptors. 759 25

The hormonal responsiveness profile of the cortical collecting duct varies from one species to another. To identify the hormones and agonists that modulate the functions of this tubule segment in the human species, we generated a cell line (HCD) immortalized by SV40 virus. The tubular origin of this cell line was assessed by the expression of collecting duct-specific antigens and the ability of vasopressin to increase by nine-fold cAMP synthesis. Glucagon and adenosine stimulated cAMP synthesis, and atrial natriuretic peptide stimulated cGMP synthesis in a concentration-dependent manner. Bradykinin, adenosine and angiotensin increased intracellular calcium concentration ([Ca2+]i). Because adenosine can regulate tubular functions, we examined its role on glucagon-induced cAMP synthesis. Using adenosine analogs, we demonstrated that HCT cells both expressed adenosine type-2 (A2) receptors which stimulated cAMP production, and adenosine type-1 (A1) receptors linked to [Ca2+]i increase which inhibited glucagon-stimulated cAMP synthesis. The inhibitory effect was abolished by pertussis toxin, and was neither due to [Ca2+]i increase nor to protein kinase C activation, which indicated that some A1 adenosine receptors were directly negatively coupled to adenylyl cyclase. These results suggest that adenosine can modify human cortical collecting duct functions in opposite ways according to the adenosine receptor activated.
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PMID:Role of adenosine on glucagon-induced cAMP in a human cortical collecting duct cell line. 763 60

The present study examines the effects of 12-O-tetradecanoylphorbol-13-acetate (TPA) on agonist-regulated 3',5'-cyclic adenosine monophosphate (cAMP) formation and cAMP-mediated effects in cultured Sertoli cells from immature rats. Concentration-dependent stimulation of cAMP levels by follicle-stimulating hormone (FSH) was inhibited dramatically by the coaddition of 100 nmol/l TPA, which exerted a similar inhibition of glucagon- and isoproterenol-stimulated cAMP production. These results show that protein kinase C (PKC) activation by TPA attenuates Gs-protein-mediated agonist activation of cAMP production. (-)-N6(R)-Phenylisopropyladenosine (L-PIA), an A1-adenosine receptor agonist, inhibited cAMP stimulation by FSH in a concentration-dependent manner. When L-PIA was added in increasing concentrations simultaneously with 100 nmol/l TPA, the L-PIA still inhibited FSH-stimulated cAMP production in a concentration-dependent manner. In the presence of TPA, the half-inhibitory concentration (IC50) for L-PIA inhibition of cAMP formation was reduced by more than one order of magnitude, indicating that PKC activation by TPA increases the sensitivity of Sertoli cells to Gi-protein-mediated agonist inhibition of cAMP production. The inhibitory effects of TPA on FSH-stimulated cAMP production were still observed when cAMP phosphodiesterase activity was inhibited by 1 mmol/l methylisobutylxanthine or when the activity of G alpha i-protein was eliminated by pretreatment with 100 micrograms/l pertussis toxin. Taken together, the results indicate that PKC activation inhibits agonist-dependent stimulation of cAMP production by phosphorylation of components common to all the activating agonists used, and not via stimulation of G(i)-protein activity or degradation of cAMP by cAMP phosphodiesterase activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Protein kinase C activation and positive and negative agonist regulation of 3',5'-cyclic adenosine monophosphate levels in cultured rat Sertoli cells. 768 9

Vascular smooth muscle has been reported to contain the A1 subtype of adenosine receptors, but the existence of such receptor(s) in coronary smooth muscle has not been established. In the present study, the 3H-labeled A1-selective antagonist [3H]8-cyclopentyl-1,3-dipropylxanthine ([3H]DPCPX) was used to demonstrate the specific binding in porcine coronary artery smooth muscle membranes. The binding was saturable with a Bmax of 6.43 +/- 1.02 fmol/mg protein. Scatchard analysis of the binding data provided a single binding site with a Kd of 0.21 +/- 0.025 nmol/L. In the competition experiments, adenosine receptor agonists and antagonists showed the following order of potency (nmol/L): S-N6-(2-endonorbornyl)adenosine (S-ENBA) 0.11 = R(-)-N6-phenylisopropyladenosine 0.32 > DPCPX 3.2 = xanthine amine congener 2.4 = N6-cyclopentyladenosine 2.67 > 5'-(N-ethylcarboxamido)-adenosine 7.35 >> 2-[p-(2-carboxyethyl)-phenethyl-amino]-5'-(N-ethylcarboxamido)- adenosine 1000 > theophylline 83,000. This order of potency fits the criteria for the A1 adenosine receptor. S-ENBA, a highly selective A1 receptor agonist, was used to investigate the effect on isoproterenol-mediated vasorelaxation and cAMP accumulation. S-ENBA (0.1 to 10 nmol/L) dose-dependently shifted the isoproterenol-mediated (10(-8) to 10(-5) mol/L) vasorelaxation to the right in vascular rings. S-ENBA (10 nmol/L) inhibited the basal cAMP levels by 36% and attenuated the isoproterenol (10(-5) mol/L)-stimulated cAMP by 25% in the coronary rings. These inhibitory effects of S-ENBA on isoproterenol-mediated cAMP-accumulation and vasorelaxation were abolished by pertussis toxin (100 ng/mL, overnight) treatment of the arteries.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Binding of A1 adenosine receptor ligand [3H]8-cyclopentyl-1,3-dipropylxanthine in coronary smooth muscle. 778 77

The production of hydrogen peroxide (H2O2) as an essential process for iodide organification is a key reaction in TSH-induced thyroid hormone synthesis. Here we characterize the signal transduction pathway involved in TSH-induced H2O2 production in FRTL-5 thyroid cells. At higher than 1 nM TSH, N6-(L-2-phenylisopropyl)adenosine (PIA), an adenosine receptor agonist having, by itself, no influence on H2O2 generation, potentiated this TSH action, whereas the TSH increase and PIA addition reduced cAMP accumulation. RO 20-1724, a phosphodiesterase inhibitor, amplified the TSH-induced cAMP accumulation, but did not change H2O2 generation in the whole range of TSH used. Ca(2+)-mobilizing agonists, GTP and ATP, also induced H2O2 production without stimulating cAMP accumulation. Chelation of intracellular Ca2+ markedly inhibited the TSH action, but intracellular Ca2+ increases by either thapsigargin or ionomycin mimicking it. All of the findings show the participation of Ca2+, but not cAMP, in the action of TSH. Desensitization of protein kinase-C (PKC) did not influence the receptor-mediated H2O2 production, suggesting the reduced importance of PKC activation compared to Ca2+ signaling to the reaction. A rise in intracellular Ca2+ independent of receptor activation also induced H2O2 production as well as arachidonate release, and both were potentiated by PIA. In addition, inhibitors of phospholipase-A2 and the arachidonate metabolic pathway depressed H2O2 generation, suggesting the participation of an arachidonate cascade in the Ca(2+)-dependent H2O2 production. Lipoxygenase inhibitors depressed the Ca2+ action without influencing arachidonate release, suggesting the involvement of a lipoxygenase product(s) of arachidonate in the Ca(2+)-signaling mechanism. In conclusion, in FRTL-5 cells, TSH-induced H2O2 production is mediated not by cAMP, but by the phospholipase-C/Ca2+ cascade, possibly followed by the Ca(2+)-dependent phospholipase-A2/arachidonate cascade. PIA amplifies TSH-induced H2O2 production at the steps of phospholipase-C and phospholipase-A2 activation in a pertussis toxin-sensitive manner.
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PMID:Thyrotropin-induced hydrogen peroxide production in FRTL-5 thyroid cells is mediated not by adenosine 3',5'-monophosphate, but by Ca2+ signaling followed by phospholipase-A2 activation and potentiated by an adenosine derivative. 782 20

Adenosine exerts pronounced biological effects in the heart cell. The role of multiple adenosine receptor subtypes in regulating the heart cell function is not known. Ventricular cells cultured from chick embryos 14 days in ovo were used to study a novel feature of heart cell regulation by the stimulatory adenosine receptors. The inhibitory adenosine A1 receptor pathway was first inactivated by pertussis toxin treatment of the cultures, and the effects of adenosine agonists and antagonists on the heart cell contractile amplitude, measured via an opticovideo motion detection system, and on the modulation of cAMP level were determined. Adenosine and N-ethyladenosine-5'-uronic acid (NECA), capable of activating both the adenosine A2a and A2b receptors, caused a greater increase in the contractile amplitude than did the A2a-selective agonist 2-[4-(2-carboxythyl)phenylethylamino]-5'-N-ethylcarboxamidoa denosine (CGS21680). NECA caused a biphasic increase in cAMP, which became monophasic in the presence of the A2a receptor-selective antagonist 8-(3-chlorostyryl)caffeine, whereas the CGS21680-induced cAMP response was monophasic. Blocking with 8-(3-chlorostyryl)caffeine abolished most of the CGS21680-elicited contractile or cAMP response while attenuating only part of the adenosine- or NECA-stimulated responses. Blocking with the A2b-selective antagonists 1,3-diethyl-8-phenylxanthine or alloxazine caused a more pronounced inhibititon of the contractile or cAMP response by adenosine or NECA than by CGS21680. Affinity of the A2a receptor was 60-fold higher than that of the A2b receptor. These data demonstrate that a functional A2b receptor is expressed on the heart cell and is capable of mediating augmentation of cardiac myocyte contractility and that adenosine A2a and A2b receptors, with greatly different affinity, coexist and are coupled to the same functional responses. Taken together, the data suggest a novel feature of heart cell regulation, where the high-affinity A2a receptor can play an important modulatory role in the presence of a low level of adenosine, whereas the low-affinity A2b receptor becomes functionally important when the adenosine level is high.
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PMID:Adenosine A2a and A2b receptors in cultured fetal chick heart cells. High- and low-affinity coupling to stimulation of myocyte contractility and cAMP accumulation. 783 35

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