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Sample records for beta-adrenergic antagonists

  1. Beta-adrenergic antagonists during general anesthesia reduced postoperative pain: a systematic review and a meta-analysis of randomized controlled trials.

    Science.gov (United States)

    Härkänen, Lasse; Halonen, Jari; Selander, Tuomas; Kokki, Hannu

    2015-12-01

    We have performed a systematic literature review and a meta-analysis investigating the effect of beta-adrenergic antagonist on perioperative pain in randomized clinical trials (RCTs). The search included the CENTRAL, CINAHL, EMBASE, and MEDLINE databases (from inception to 10 February 2015). From the retrieved full texts, we hand-searched the references and PubMed related citations. A total of 11 RCTs consisting data of 701 adult patients were eligible for this systematic review. Esmolol was evaluated in ten trials and propranolol in one. Esmolol decreased the need for rescue analgesics by 32-50%; p esmolol-treated patients: 52-57 vs. 23-34%, p < 0.05. Adverse effects were rarely reported, and as reported were mostly cardiovascular alterations. In conclusion, intra-operative beta-adrenergic antagonists' administration may decrease postoperative pain and analgesic consumption when given as an adjuvant to general anesthesia. PMID:26160590

  2. Indobufen interacts with the sulphonylurea, glipizide, but not with the beta-adrenergic receptor antagonists, propranolol and atenolol.

    OpenAIRE

    Elvander-Ståhl, E; Melander, A; Wåhlin-Boll, E

    1984-01-01

    This study assessed the possible interactions of the cyclooxygenase inhibitor indobufen with one sulphonylurea, glipizide, and with two beta-adrenoceptor antagonists, one of which is extensively metabolised already in the first passage through the liver (propranolol) while the other essentially escapes biotransformation (atenolol). Indobufen was first given as a single 200 mg dose and then for a 5 day period in a dosage of 200 mg twice daily, to six healthy volunteers. Glipizide (5 mg), propr...

  3. An investigation into the receptor-regulating effects of the acute administration of opioid agonists and an antagonist on beta adrenergic receptors in the rat cerebral cortex

    International Nuclear Information System (INIS)

    Past and current research indicated that biochemical deviations which might be involved in the etiology and pathophysiology of depression, included abnormalities or imbalances in the noradrenergic, serotonergic, hormonal and possibly in the endogenous opioid, dopaminergic, histaminergic, cholinergic and trace amine systems. In order to investigate a possible link between the noradrenergic system and opioids, it was decided to test the acute effects of opioid administration on cortical beta adrenoceptor numbers and affinity. As these receptors have been most consistently downregulated by antidepressant treatment, they may be involved in the mechanism of antidepressant action of these agents. It was decided to investigate beta adrenoceptor-regulatory effects of opioid treatment. Naloxone was tested alone, with a view to suppressing any possible endogenous opioid influences upon beta receptor status and revealing an effect which would possibly be the opposite of that brought about by the administration of opioid agonists. Naloxone was administered together with morphine to demonstrate that any beta receptor up- or downregulation which might be measured, had indeed been opioid-receptor mediated. It was found that the acute administration of four different mu opioid agonists, naloxone and naloxone plus morphine, did not cause any statistically significant alterations in cortical beta adrenergic receptor numbers or affinity in the rat. A radioactive ligand, the beta adrenoceptor-labelling compound referred to as DHA (L-dihydroalprenolol HCI) was used in this study

  4. A beta-adrenergic antagonist reduces traumatic memories and PTSD symptoms in female but not in male patients after cardiac surgery

    NARCIS (Netherlands)

    Krauseneck, T.; Padberg, F.; Roozendaal, B.; Grathwohl, M.; Weis, F.; Hauer, D.; Kaufmann, I.; Schmoeckel, M.; Schelling, G.

    2010-01-01

    Background. Epinephrine enhances emotional memory whereas P-adrenoceptor antagonists (beta-blockers, BBs) impair it. However, the effects of BB administration on memory are sex dependent. Therefore, we predicted differential effects of epinephrine and the BB metoprolol given to male and female patie

  5. Beta adrenergic receptors in human cavernous tissue

    International Nuclear Information System (INIS)

    Beta adrenergic receptor binding was performed with 125I iodocyanopindolol on human cavernous tissue membrane fractions from normal tissue and transsexual procedures obtained postoperatively, as well as from postmortem sources. Isotherm binding studies on normal fresh tissues indicated that the receptor density was 9.1 fmoles/mg. with a KD of 23 pM. Tissue stored at room temperature for 4 to 6 hours, then at 4C in saline solution for 19 to 20 hours before freezing showed no significant changes in receptor density or affinity, and provided evidence for the stability of postmortem tissue obtained within the same time period. Beta receptor density of 2 cavernous preparations from transsexual procedures was not significantly different from normal control tissues, and showed that high concentrations of estrogen received by these patients had no effect on beta adrenergic receptor density. Displacement of 125iodocyanopindolol by 5 beta adrenergic agents demonstrated that 1-propranolol had the greatest affinity followed by ICI 118,551, zinterol, metoprolol and practolol. When the results of these displacement studies were subjected to Scatfit, non- linear regression line analysis, a single binding site was described. Based on the relative potency of the selective beta adrenergic agents it appears that these receptors were of the beta 2 subtype

  6. Beta adrenergic receptors in human cavernous tissue

    Energy Technology Data Exchange (ETDEWEB)

    Dhabuwala, C.B.; Ramakrishna, C.V.; Anderson, G.F.

    1985-04-01

    Beta adrenergic receptor binding was performed with /sup 125/I iodocyanopindolol on human cavernous tissue membrane fractions from normal tissue and transsexual procedures obtained postoperatively, as well as from postmortem sources. Isotherm binding studies on normal fresh tissues indicated that the receptor density was 9.1 fmoles/mg. with a KD of 23 pM. Tissue stored at room temperature for 4 to 6 hours, then at 4C in saline solution for 19 to 20 hours before freezing showed no significant changes in receptor density or affinity, and provided evidence for the stability of postmortem tissue obtained within the same time period. Beta receptor density of 2 cavernous preparations from transsexual procedures was not significantly different from normal control tissues, and showed that high concentrations of estrogen received by these patients had no effect on beta adrenergic receptor density. Displacement of /sup 125/iodocyanopindolol by 5 beta adrenergic agents demonstrated that 1-propranolol had the greatest affinity followed by ICI 118,551, zinterol, metoprolol and practolol. When the results of these displacement studies were subjected to Scatfit, non- linear regression line analysis, a single binding site was described. Based on the relative potency of the selective beta adrenergic agents it appears that these receptors were of the beta 2 subtype.

  7. Human myometrial adrenergic receptors: identification of the beta-adrenergic receptor by [3H]dihydroalprenolol binding

    International Nuclear Information System (INIS)

    The radioactive beta-adrenergic antagonist [3H] dihydroalprenolol (DHA) binds to particulate preparations of human myometrium in a manner compatible with binding to the beta-adrenergic receptor. The binding of DHA is rapid (attaining equilibrium in 12 minutes), readily reversible (half time = 16 minutes), high affinity (K/sub D/ = 0.50 nM), low capacity (Bmax = 70 fmoles/mg of protein), and stereoselective ([-]-propranolol is 100 times as potent as [+] -propranolol in inhibiting DHA binding). Adrenergic agonists competed for DHA binding sites in a manner compatible with beta-adrenergic interactions and mirrored β2 pharmacologic potencies: isoproterenol > epinephrine >> norepinephrine. Studies in which zinterol, a β2-adrenergic agonist, competed for DHA binding sites in human myometrial particulate indicated that at least 87% of the beta-adrenergic receptors present are β2-adrenergic receptors. Binding of DHA to human myometrial beta-adrenergic receptors provides a tool which may be used in the examination of gonadal hormonal modification of adrenergic response in human uterus as well as in the analysis of beta-adrenergic agents as potentially useful tocolytic agents

  8. Beta adrenergic receptors in pigmented ciliary processes.

    OpenAIRE

    Trope, G. E.; Clark, B.

    1982-01-01

    Beta adrenergic receptors from membrane fragments of pigmented sheep eyes were studied and characterised by ligand binding techniques after the removal of melanin. In a representative experiment the beta max (total number of beta receptors) was 394.9 fmol/mg protein. The receptor affinity (Ka) was 440 pM. The potency series of drugs to displace 125I-HYP from the receptors was timolol = (-) propranolol greater than (+) propranolol greater than salbutamol greater than practolol. beta 1 Recepto...

  9. Effects of halothane on the human beta-adrenergic receptor of lymphocyte membranes

    International Nuclear Information System (INIS)

    The effects of halothane on beta-adrenergic receptor antagonist interaction were studied using the membranes of human lymphocytes as a model. Membrane preparations of lymphocytes were obtained from blood samples withdrawn from seven healthy young volunteers. Beta-receptor studies were performed using (-)125I iodocyanopindolol (125ICP) binding. Non-specific binding was determined in the presence of (-)isoproterenol. Beta-receptor density (Bmax) and the dissociation constant (KD) for 125ICP were determined from saturation curves. Beta-receptor affinity for agonists evaluated by the IC50 (the concentration of isoproterenol required to inhibit 50% of specific 125ICP binding) and the dissociation constant (KL) for isoproterenol was established from competition curves. The effect of halothane 1%, in an air oxygen mixture (oxygen fraction: 0.3) administered by tonometry during ligand membrane incubation, on beta-adrenergic receptor, was compared to that of control experiments not exposed to halothane. Halothane produced a moderate but significant decrease of Bmax (-10%) and a significant increase in non-specific binding (+30%), while KD, IC50, and KL were unchanged. The authors conclude that halothane, in vitro, decreases beta-adrenergic receptor density. This effect could be mediated by an alteration of the receptor in the membrane due to action of halothane on the lipid phase of the membrane

  10. Characterization of beta-adrenergic receptors in dispersed rat testicular interstitial cells

    Energy Technology Data Exchange (ETDEWEB)

    Poyet, P.; Labrie, F.

    1987-01-01

    Recent studies have shown that beta-adrenergic agents stimulate steroidogenesis and cyclic AMP formation in mouse Leydig cells in culture. To obtain information about the possible presence and the characteristics of a beta-adrenergic receptor in rat testicular interstitial cells, the potent beta-adrenergic antagonist (/sup 125/I)cyanopindolol (CYP) was used as ligand. Interstitial cells prepared by collagenase dispersion from rat testis were incubated with the ligand for 2 h at room temperature. (/sup 125/I)cyanopindolol binds to a single class of high affinity sites at an apparent KD value of 15 pM. A number of sites of 6,600 sites/cell is measured when 0.1 microM (-) propranolol is used to determine non-specific binding. The order of potency of a series of agonists competing for (/sup 125/I)cyanopindolol binding is consistent with the interaction of a beta 2-subtype receptor: zinterol greater than (-) isoproterenol greater than (-) epinephrine = salbutamol much greater than (-) norepinephrine. In addition, it was observed that the potency of a large series of specific beta 1 and beta 2 synthetic compounds for displacing (/sup 125/I)cyanopindolol in rat interstitial cells is similar to the potency observed for these compounds in a typical beta 2-adrenergic tissue, the rat lung. For example, the potency of zinterol, a specific beta 2-adrenergic agonist, is 10 times higher in interstitial cells and lung than in rat heart, a typical beta 1-adrenergic tissue. Inversely, practolol, a typical beta 1-antagonist, is about 50 times more potent in rat heart than in interstitial cells and lung.

  11. Determination of beta-adrenergic receptor blocking pharmaceuticals in united states wastewater effluent

    Energy Technology Data Exchange (ETDEWEB)

    Huggett, D.B.; Khan, I.A.; Foran, C.M.; Schlenk, D

    2003-02-01

    This is the first report of beta-adrenergic receptor antagonist pharmaceuticals in United States wastewater effluent. - Beta adrenergic receptor antagonists ({beta}-Blockers) are frequently prescribed medications in the United States and have been identified in European municipal wastewater effluent, however no studies to date have investigated these compounds in United States wastewater effluent. Municipal wastewater effluent was collected from treatment facilities in Mississippi, Texas, and New York to investigate the occurrence of metoprolol, nadolol, and propranolol. Propranolol was identified in all wastewater samples analyzed (n=34) at concentrations {<=}1.9 {mu}g/l. Metoprolol and nadolol were identified in {>=}71% of the samples with concentrations of metoprolol {<=}1.2 {mu}g/l and nadolol {<=}0.36 {mu}g/l. Time course studies at both Mississippi plants and the Texas plant indicate that concentrations of propranolol, metoprolol, and nadolol remain relatively constant at each sampling period. This study indicates that {beta}-Blockers are present in United States wastewater effluent in the ng/l to {mu}g/l range.

  12. Determination of beta-adrenergic receptor blocking pharmaceuticals in united states wastewater effluent

    International Nuclear Information System (INIS)

    This is the first report of beta-adrenergic receptor antagonist pharmaceuticals in United States wastewater effluent. - Beta adrenergic receptor antagonists (β-Blockers) are frequently prescribed medications in the United States and have been identified in European municipal wastewater effluent, however no studies to date have investigated these compounds in United States wastewater effluent. Municipal wastewater effluent was collected from treatment facilities in Mississippi, Texas, and New York to investigate the occurrence of metoprolol, nadolol, and propranolol. Propranolol was identified in all wastewater samples analyzed (n=34) at concentrations ≤1.9 μg/l. Metoprolol and nadolol were identified in ≥71% of the samples with concentrations of metoprolol ≤1.2 μg/l and nadolol ≤0.36 μg/l. Time course studies at both Mississippi plants and the Texas plant indicate that concentrations of propranolol, metoprolol, and nadolol remain relatively constant at each sampling period. This study indicates that β-Blockers are present in United States wastewater effluent in the ng/l to μg/l range

  13. Expression of inwardly rectifying potassium channels (GIRKs and beta-adrenergic regulation of breast cancer cell lines

    Directory of Open Access Journals (Sweden)

    Cakir Yavuz

    2004-12-01

    Full Text Available Abstract Background Previous research has indicated that at various organ sites there is a subset of adenocarcinomas that is regulated by beta-adrenergic and arachidonic acid-mediated signal transduction pathways. We wished to determine if this regulation exists in breast adenocarcinomas. Expression of mRNA that encodes a G-protein coupled inwardly rectifying potassium channel (GIRK1 has been shown in tissue samples from approximately 40% of primary human breast cancers. Previously, GIRK channels have been associated with beta-adrenergic signaling. Methods Breast cancer cell lines were screened for GIRK channels by RT-PCR. Cell cultures of breast cancer cells were treated with beta-adrenergic agonists and antagonists, and changes in gene expression were determined by both relative competitive and real time PCR. Potassium flux was determined by flow cytometry and cell signaling was determined by western blotting. Results Breast cancer cell lines MCF-7, MDA-MB-361 MDA-MB 453, and ZR-75-1 expressed mRNA for the GIRK1 channel, while MDA-MB-468 and MDA-MB-435S did not. GIRK4 was expressed in all six breast cancer cell lines, and GIRK2 was expressed in all but ZR-75-1 and MDA-MB-435. Exposure of MDA-MB-453 cells for 6 days to the beta-blocker propranolol (1 μM increased the GIRK1 mRNA levels and decreased beta2-adrenergic mRNA levels, while treatment for 30 minutes daily for 7 days had no effect. Exposure to a beta-adrenergic agonist and antagonist for 24 hours had no effect on gene expression. The beta adrenergic agonist, formoterol hemifumarate, led to increases in K+ flux into MDA-MB-453 cells, and this increase was inhibited by the GIRK channel inhibitor clozapine. The tobacco carcinogen 4-(methylnitrosamino-1-(3-pyridyl-1-butanone (NNK, a high affinity agonist for beta-adrenergic receptors stimulated activation of Erk 1/2 in MDA-MB-453 cells. Conclusions Our data suggests β-adrenergic receptors and GIRK channels may play a role in breast cancer.

  14. Coregulation of calcium channels and beta-adrenergic receptors in cultured chick embryo ventricular cells

    International Nuclear Information System (INIS)

    To examine mechanisms whereby the abundance of functional Ca channels may be regulated in excitable tissue, Ca channel number was estimated by binding of the dihydropyridine (DHP) antagonist 3H (+)PN200-110 to monolayers of intact myocytes from chick embryo ventricle. Beta adrenergic receptor properties were studied in cultured myocytes using [3H]CGP12177, an antagonist ligand. Physiological correlates for alterations in DHP binding site number included 45Ca uptake and contractile response to (+)BAYk 8644, a specific L-type Ca channel activator. All binding and physiological determinations were performed in similar intact cell preparations under identical conditions. 4-h exposure to 1 microM isoproterenol reduced cell surface beta-adrenergic receptor number from 44 +/- 3 to 17 +/- 2 fmol/mg (P less than 0.05); DHP binding sites declined in number from 113 +/- 25 to 73 +/- 30 fmol/mg (P less than 0.03). When protein kinase A was activated by a non-receptor-dependent mechanism, DHP binding declined similarly to 68% of control. Exposure to diltiazem, a Ca channel antagonist, for 18-24 h had no effect on number of DHP binding sites. After 4-h isoproterenol exposure, 45Ca uptake stimulated by BAYk 8644 declined from 3.3 +/- 0.2 nmol/mg to 2.9 +/- 0.3 nmol/mg (P less than 0.01) and BAYk 8644-stimulated increase in amplitude of contraction declined from 168 +/- 7 to 134 +/- 11% (P = 0.02). Thus, elevation of [cAMP] in myocytes is associated with a time-dependent decline in Ca channel abundance as estimated by DHP binding and a decline in physiological responses that are in part dependent on abundance of Ca channels. Binding of a directly acting Ca channel antagonist for 18-24 h does not modulate the number of DHP binding sites

  15. Beta-adrenergic agonists as additive in beef cattle

    OpenAIRE

    Marcelo Vedovatto; Camila Celeste Brandão Ferreira Ítavo; João Artêmio Marin Beltrame; Ricardo Carneiro Brumatti; Gumercindo Loriano Franco

    2014-01-01

    The agonists receptor beta-adrenergic (β-AA) are present in virtually all types of mammalian cells and are stimulated by catecholamines (epinephrine and norepinephrine) produced by the organism itself. The β-AA agonists are synthetic substances with similar structure to these amines. When provided in the diet they alter the body composition of animals, affecting the distribution of nutrients toward to protein deposition, and decreasing lipogenesis. Although the mechanisms of action are not fu...

  16. Dopaminergic and beta-adrenergic effects on gastric antral motility

    DEFF Research Database (Denmark)

    Bech, K; Hovendal, C P; Gottrup, F;

    1984-01-01

    bethanechol or pentagastrin inducing motor activity patterns as in the phase III of the MMC and the digestive state respectively. The stimulated antral motility was dose-dependently inhibited by dopamine. The effect was significantly blocked by specifically acting dopaminergic blockers, while alpha- and beta......-adrenergic blockers were without any significant effects. Dose-response experiments with bethanechol and dopamine showed inhibition of a non-competitive type. Isoprenaline was used alone and in conjunction with selective blockade of beta 1- and beta 2-receptors during infusion of bethanechol which induces a pattern...... similar to phase III in the migrating myoelectric complex. The stimulated antral motility was dose-dependently inhibited by isoprenaline. The effect could be significantly blocked by propranolol (beta 1 + beta 2-adrenoceptor blocker) and by using in conjunction the beta 1-adrenoceptor blocker practolol...

  17. Expression of mammalian beta-adrenergic receptors in Xenopus laevis oocytes

    International Nuclear Information System (INIS)

    Xenopus laevis oocytes are a useful transcription and expression system for DNA and RNA, respectively. Total cellular RNA was extracted from mouse lymphoma S49 cells and poly(A)+mRNA prepared by affinity chromatography of RNA on oligo(dT) cellulose. The membranes of S49 cells contain beta-adrenergic receptors that display pharmacological characteristics of beta2-subtype. Xenopus laevis oocytes were injected with 50 ng of mRNA/oocyte. Expression of beta-adrenergic receptors in oocytes incubated for 30 hr after microinjection was assessed in membranes by radioligand binding using [3H] dihydroalprenolol. The injected oocytes displayed 0.34 fmol receptor/oocyte as compared to 0.02 fmol receptor/oocyte in the control oocytes. The affinity of beta-adrenergic receptors in injected oocytes for this radioligand was 2 nM, a value similar to the affinity of beta-adrenergic receptors for DHA in S49 cell membranes. The potency of beta-adrenergic agonists in competing for DHA binding to oocytes membranes was isoproterenol > epinephrine > norepineprine, indicating that the expressed beta-adrenergic receptors were of the beta2-subtype. The K/sub I/ of these agonists for the beta-adrenergic receptor in oocyte membranes was 0.03, 0.15 and 1.2 μM, respectively. The role of post-translational modification in dictating receptor subtype is analyzed using mRNA of beta1- as well as beta2-adrenergic receptors

  18. Beta-adrenergic receptors on murine lymphocytes: density varies with cell maturity and lymphocyte subtype and is decreased after antigen administration

    International Nuclear Information System (INIS)

    beta-Adrenergic receptors were assayed on intact, viable, murine splenocytes and thymocytes using the labeled adrenergic antagonists [3H]-dihydroalprenolol l-[ring propyl-3H(N)] ([3H]DHA) and 4-(3-t-butylamino-2-hydroxypropoxy)-[5,7-3H]benzimidazol-2-one ([3H]CGP 12177). The sites detected by [3H]DHA did not always possess the characteristics of beta-adrenergic receptors and were demonstrated to be stereospecific only after the addition of the binding assay. Populations of cells from C57Bl/6 inbred and CF1 outbred mice were compared. Purified T cells from C57Bl/6 mice had fewer receptors than did either whole spleen or B cells. Thymocytes from either strain had significantly fewer receptors than did the other lymphocyte populations. However, mature medullary thymocytes purified from C57Bl/6 mice had higher numbers of receptors per cell which were comparable to those of the splenic T cell. Radiation-resistant splenocytes recovered from CF1 mice 24 hr after 700 rad of irradiation possessed greatly increased numbers of receptors per cell. Immunization with sheep red blood cells caused a significant reduction in the density of receptors on splenocytes from C57Bl/6 mice. The wide variations observed in the density of beta-adrenergic receptors, possibly related to cell maturity or state of activation, seem to provide opportunities for differential modulation of cell functions by either endogenous or exogenous adrenergic agents

  19. Modulation of. beta. -adrenergic response in rat brain astrocytes by serum and hormones

    Energy Technology Data Exchange (ETDEWEB)

    Wu, D.K.; Morrison, R.S.; de Vellis, J.

    1985-01-01

    Purified astrocyte cultures from neonatal rat cerebrum respond to isoproterenol, a ..beta..-adrenergic agonist, with a transient rise in cAMP production. This astroglial property was regulated by serum, a chemically defined medium (serum-free medium plus hydrocortisone, putrescine, prostaglandin F/sub 2/, insulin, and fibroblast growth factor) and epidermal growth factor. Compared to astrocytes grown in serum-supplemented medium, astrocytes grown in the chemically defined medium were nonresponsive to isoproterenol stimulation, and this difference did not appear to be due to selection of a subpopulation of cells by either medium. The data suggest that a decreased ..beta..-adrenergic receptor number and an increased degradation of cAMP may account for the reduced response to ..beta..-adrenergic stimulation. The nonresponsive state of astrocytes in the defined medium was reversible when the medium was replaced with serum-supplemented medium. An active substance(s) in serum was responsible for restoring the responsiveness of astrocytes. Each of the five components of the defined medium had little effect by itself; however, together they acted synergistically to desensitize astrocytes to ..beta..-adrenergic stimulation. On the other hand, epidermal growth factor, a potent mitogen for astrocytes, was very competent by itself in reducing the cAMP response of astrocytes to ..beta..-adrenergic stimulation. Thus purified astrocytes grown in the chemically defined medium appear to be a good model for the study of hormonal interactions and of serum factors which may modulate the ..beta..-adrenergic response.

  20. Maintained cerebral metabolic ratio during exercise in patients with beta-adrenergic blockade

    DEFF Research Database (Denmark)

    Gam, Christiane M B; Rasmussen, Peter; Secher, Niels H;

    2009-01-01

    BACKGROUND: Decreased cerebral metabolic ratio (CMR) [molar uptake of O(2) versus molar uptake of (glucose + (1/2) lactate)] during exercise is attenuated by intravenous administration of the non-selective beta-adrenergic receptor antagonist propranolol. We evaluated to what extent cirrhotic...... patients in oral treatment with propranolol are able to mobilize brain non-oxidative carbohydrate metabolism. METHODS: Incremental cycle ergometry to exhaustion (86 +/- 4.2 W; mean +/- SD) was performed in eight cirrhotic patients instrumented with a catheter in the brachial artery and one retrograde...... and during exercise, respectively. During exercise the glucose a-v diff of 0.46 +/- 0.06 mM remained at a level similar to rest (0.54 +/- 0.03 mM) and at exhaustion the CMR was not significantly changed (5.8 +/- 1.1 versus 6.0 +/- 0.6). In controls, CMR decreased from 5.6 +/- 0.9 at rest to 3.4 +/- 0.7 (P

  1. Ontogeny of alpha- and beta-adrenergic anorexia in rats.

    Science.gov (United States)

    Lora-Vilchis, M C; Chambert, G; Rodriguez-Zendejas, A M; Soto-Mora, L M; Russek, M; Epstein, A N

    1988-12-01

    The anorectic action of alpha- (phenylephrine) and beta- (isoproterenol) adrenergic agonists was studied in mildly deprived neonatal, weanling, prepubescent, and adult rats. Intraperitoneal phenylephrine produced a reduction of food intake at all ages but with reduced potency and with a maximum of 50% in neonates. Contrary to intramuscular epinephrine that has no effect on feeding at any age, intramuscular phenylephrine was as effective as intraperitoneal in neonates, probably because it is not as rapidly destroyed in tissues as epinephrine. However, in weanlings and adults intramuscular phenylephrine was much less anorectic than intraperitoneal, suggesting that this effect is exerted via the liver. Isoproterenol did not reduce milk intake at any age before adulthood. Lactate had no effect on milk intake before the age of 40 days. Thus catecholamine anorexia is a purely alpha-adrenergic effect in young rats and appears before the metabolic effect of lactate. beta-Adrenergic anorexia, on the other hand, can be obtained only after puberty, suggesting that the mechanism mediating it matures after the preparatory action of the sexual hormones. PMID:2849323

  2. Beta-adrenergic agonists as additive in beef cattle

    Directory of Open Access Journals (Sweden)

    Marcelo Vedovatto

    2014-10-01

    Full Text Available The agonists receptor beta-adrenergic (β-AA are present in virtually all types of mammalian cells and are stimulated by catecholamines (epinephrine and norepinephrine produced by the organism itself. The β-AA agonists are synthetic substances with similar structure to these amines. When provided in the diet they alter the body composition of animals, affecting the distribution of nutrients toward to protein deposition, and decreasing lipogenesis. Although the mechanisms of action are not fully understood, these may cause morphological and physiological changes such as increased blood flow decrease in plasma insulin, decreased lipogenesis, and muscle hypertrophy mainly in type II fibers. We also observed changes in motility and secretions grastointestinal tract, beyond the direct influence on the rumen bacteria, altering the digestibility of the diet. The β-AA agonists released in some countries for use in beef cattle are ractopamine hydrochloride and zilpaterol hydrochloride. According to literature data, the inclusion of these additives in the diet of feedlot cattle has been associated with an increase infeed efficiency with the increase in daily weight gain and with equal or lower feed intake. Carcass characteristics improvement was verified in carcass weight, and increased loin eye area, but with the possibility to decrease the subcutaneous fat thickness and marbling. Reviews in sensory panel of meat from animals consuming β-AA agonists showed decreased tenderness and juiciness. Thus β-AA improve performance and carcass characteristics, but more studies are needed to confirm whether they have negative influence on the organoleptic characteristics of the meat.

  3. Effects of beta-adrenergic blocking agents on specific binding of [3H]D-Ala2-Met5-enkephalinamide and [3H]naloxone.

    OpenAIRE

    Takayama, Haruhiko; Ogawa,Norio; Asanuma, Masato; Hirata, Hiroshi; Ogura,Toshio; Ota,Zensuke

    1991-01-01

    To gain further insight into the central nervous system (CNS)-action of beta-adrenergic blocking agents (beta-blockers), we examined the effects of various kinds of beta-blockers on opioid receptors (Op-Rs) using radiolabeled receptor assay (RRA). We demonstrated that beta-blockers are competitively bound to Op-Rs in the CNS. Sodium index of beta-blockers in [3H]naloxone binding study indicated that beta-blockers had the mixed agonist-antagonist activity of opiates. The relative potency of be...

  4. Targeting of beta adrenergic receptors results in therapeutic efficacy against models of hemangioendothelioma and angiosarcoma.

    Directory of Open Access Journals (Sweden)

    Jessica M Stiles

    Full Text Available Therapeutic targeting of the beta-adrenergic receptors has recently shown remarkable efficacy in the treatment of benign vascular tumors such as infantile hemangiomas. As infantile hemangiomas are reported to express high levels of beta adrenergic receptors, we examined the expression of these receptors on more aggressive vascular tumors such as hemangioendotheliomas and angiosarcomas, revealing beta 1, 2, and 3 receptors were indeed present and therefore aggressive vascular tumors may similarly show increased susceptibility to the inhibitory effects of beta blockade. Using a panel of hemangioendothelioma and angiosarcoma cell lines, we demonstrate that beta adrenergic inhibition blocks cell proliferation and induces apoptosis in a dose dependent manner. Beta blockade is selective for vascular tumor cells over normal endothelial cells and synergistically effective when combined with standard chemotherapeutic or cytotoxic agents. We demonstrate that inhibition of beta adrenergic signaling induces large scale changes in the global gene expression patterns of vascular tumors, including alterations in the expression of established cell cycle and apoptotic regulators. Using in vivo tumor models we demonstrate that beta blockade shows remarkable efficacy as a single agent in reducing the growth of angiosarcoma tumors. In summary, these experiments demonstrate the selective cytotoxicity and tumor suppressive ability of beta adrenergic inhibition on malignant vascular tumors and have laid the groundwork for a promising treatment of angiosarcomas in humans.

  5. Alpha and beta adrenergic effects on metabolism in contracting, perfused muscle

    DEFF Research Database (Denmark)

    Richter, Erik; Ruderman, N B; Galbo, H

    1982-01-01

    The role of alpha- and beta-adrenergic receptor stimulation for the effect of epinephrine on muscle glycogenolysis, glucose- and oxygen uptake and muscle performance was studied in the perfused rat hindquarter at rest and during electrical stimulation (60 contractions/min). Adrenergic stimulation...... was obtained by epinephrine in a physiological concentration (2.4 X 10(-8) M) and alpha- and beta-adrenergic blockade by 10(-5) M phentolamine and propranolol, respectively. Epinephrine enhanced net glycogenolysis during contractions most markedly in slow-twitch red fibers. In these fibers the effect...... stimulation of alpha-adrenergic receptors and had a positive inotropic effect during contractions which was abolished by alpha- as well as by beta-adrenergic blockade. The results indicate that epinephrine has profound effects on contracting muscle, and that these effects are elicited through different...

  6. Beta-Adrenergic Receptor Expression in Muscle Cells

    Science.gov (United States)

    Young, Ronald B.; Bridge, K.; Vaughn, J. R.

    1999-01-01

    beta-adrenergic receptor (bAR) agonists presumably exert their physiological action on skeletal muscle cells through the bAR. Since the signal generated by the bAR is cyclic AMP (cAMP), experiments were initiated in primary chicken muscle cell cultures to determine if artificial elevation of intracellular cAMP by treatment with forskolin would alter the population of bAR expressed on the surface of muscle cells. Chicken skeletal muscle cells after 7 days in culture were employed for the experiments because muscle cells have attained a steady state with respect to muscle protein metabolism at this stage. Cells were treated with 0-10 uM forskolin for a total of three days. At the end of the 1, 2, and 3 day treatment intervals, the concentration of cAMP and the bAR population were measured. Receptor population was measured in intact muscle cell cultures as the difference between total binding of [H-3]CGP-12177 and non-specific binding of [H-3]CGP-12177 in the presence of 1 uM propranolol. Intracellular cAMP concentration was measured by radioimmunoassay. The concentration of cAMP in forskolin-treated cells increased up to 10-fold in a dose dependent manner. Increasing concentrations of forskolin also led to an increase in (beta)AR population, with a maximum increase of approximately 50% at 10 uM. This increase in (beta)AR population was apparent after only 1 day of treatment, and the pattern of increase was maintained for all 3 days of the treatment period. Thus, increasing the intracellular concentration of cAMP leads to up-regulation of (beta)AR population. Clenbuterol and isoproterenol gave similar effects on bAR population. The effect of forskolin on the quantity and apparent synthesis rate of the heavy chain of myosin (mhc) were also investigated. A maximum increase of 50% in the quantity of mhc was observed at 0.2 UM forskolin, but higher concentrations of forskolin reduced the quantity of mhc back to control levels.

  7. Beta-adrenergic modulation of tremor and corticomuscular coherence in humans.

    Directory of Open Access Journals (Sweden)

    Mark R Baker

    Full Text Available Coherence between the bioelectric activity of sensorimotor cortex and contralateral muscles can be observed around 20 Hz. By contrast, physiological tremor has a dominant frequency around 10 Hz. Although tremor has multiple sources, it is partly central in origin, reflecting a component of motoneuron discharge at this frequency. The motoneuron response to ~20 Hz descending input could be altered by non-linear interactions with ~10 Hz motoneuron firing. We investigated this further in eight healthy human subjects by testing the effects of the beta-adrenergic agents propranolol (non-selective β-antagonist and salbutamol (β(2-agonist, which are known to alter the size of physiological tremor. Corticomuscular coherence was assessed during an auxotonic precision grip task; tremor was quantified using accelerometry during index finger extension. Experiments with propranolol used a double-blind, placebo-controlled crossover design. A single oral dose of propranolol (40 mg significantly increased beta band (15.3-32.2 Hz corticomuscular coherence compared with placebo, but reduced tremor in the 6.2-11.9 Hz range. Salbutamol (2.5 mg was administered by inhalation. Whilst salbutamol significantly increased tremor amplitude as expected, it did not change corticomuscular coherence. The opposite direction of the effects of propranolol on corticomuscular coherence and tremor, and the fact that salbutamol enhances tremor but does not affect coherence, implies that the magnitude of corticomuscular coherence is little influenced by non-linear interactions with 10 Hz oscillations in motoneurons or the periphery. Instead, we suggest that propranolol and salbutamol may affect both tremor and corticomuscular coherence partly via a central site of action.

  8. Characterization of beta-adrenergic receptors and adenylate cyclase activity in rat brown fat

    International Nuclear Information System (INIS)

    Catecholamines stimulate thermogenesis in rat brown fat through a mechanism which involves binding to the beta-adrenergic receptor (BAR), stimulation of adenylate cyclase (AC) and culminating with uncoupling of mitochondrial respiration from ATP synthesis. The authors characterized BAR, AC and cytochrome (cyt) c oxidase in CDF (F-344) interscapular brown fat. Scatchard analysis of [125]Iodopindolol binding yields a straight line consistent with a single class of antagonist binding sites with 41.8 +/- 12.0 fmol BAR/mg protein and a K/sub d/ of 118 +/- 15 pM. Binding was both specific and stereospecific. Competition with 1-propranolol (K/sub d/ = 6.7 nM) was 15 times more potent than d-propranolol (K/sub d/ = 103 nM). Competition with isoproterenol (K/sub d/ = 79 nM) was 10 times more potent than epinephrine (K/sub d/ = 820 nM) which was 35 times more potent than norepinephrine (K/sub d/ = 2.9 x 10-5 M) suggesting predominate beta2-type BAR. Cyt c oxidase activity was assessed in brown fat mitochrondrial preparations. The ratio of BAR to cyt c activity was 959 +/- 275 nmol BAR/mol cyc c/min. Isoproterenol (0.1 mM) stimulated AC activity was 24 times GTP (0.1 mM) stimulated AC (98.5 vs 40.7 pmol cAMP/min/mg). NaF-stimulated AC was nine times basal activity (90.5 vs 11.3 pmol cAMP/min/mg). These data demonstrate the presence of a beta-2-type BAR coupled to adenylate cyclase in rat brown fat

  9. Characterization of beta-adrenergic receptors and adenylate cyclase activity in rat brown fat

    Energy Technology Data Exchange (ETDEWEB)

    Baresi, L.A.; Morley, J.E.; Scarpace, P.J.

    1986-03-01

    Catecholamines stimulate thermogenesis in rat brown fat through a mechanism which involves binding to the beta-adrenergic receptor (BAR), stimulation of adenylate cyclase (AC) and culminating with uncoupling of mitochondrial respiration from ATP synthesis. The authors characterized BAR, AC and cytochrome (cyt) c oxidase in CDF (F-344) interscapular brown fat. Scatchard analysis of (/sup 125/)Iodopindolol binding yields a straight line consistent with a single class of antagonist binding sites with 41.8 +/- 12.0 fmol BAR/mg protein and a K/sub d/ of 118 +/- 15 pM. Binding was both specific and stereospecific. Competition with 1-propranolol (K/sub d/ = 6.7 nM) was 15 times more potent than d-propranolol (K/sub d/ = 103 nM). Competition with isoproterenol (K/sub d/ = 79 nM) was 10 times more potent than epinephrine (K/sub d/ = 820 nM) which was 35 times more potent than norepinephrine (K/sub d/ = 2.9 x 10/sup -5/ M) suggesting predominate beta/sub 2/-type BAR. Cyt c oxidase activity was assessed in brown fat mitochrondrial preparations. The ratio of BAR to cyt c activity was 959 +/- 275 nmol BAR/mol cyc c/min. Isoproterenol (0.1 mM) stimulated AC activity was 24 times GTP (0.1 mM) stimulated AC (98.5 vs 40.7 pmol cAMP/min/mg). NaF-stimulated AC was nine times basal activity (90.5 vs 11.3 pmol cAMP/min/mg). These data demonstrate the presence of a beta-/sub 2/-type BAR coupled to adenylate cyclase in rat brown fat.

  10. Beta-Adrenergic signaling in rat heart is similarly affected by continuous and intermittent normobaric hypoxia

    Czech Academy of Sciences Publication Activity Database

    Hahnová, K.; Kašparová, D.; Žurmanová, J.; Neckář, Jan; Kolář, František; Novotný, J.

    2016-01-01

    Roč. 35, č. 2 (2016), s. 165-173. ISSN 0231-5882 R&D Projects: GA ČR(CZ) GAP303/12/1162 Institutional support: RVO:67985823 Keywords : rat myocardium * chronic hypoxia * beta-adrenergic receptors * adenylyl cyclase Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery Impact factor: 1.173, year: 2014

  11. Substrate utilization and thermogenic responses to beta-adrenergic stimulation in obese subjects with NIDDM

    NARCIS (Netherlands)

    Blaak, E E; Saris, W H; Wolffenbuttel, B H

    1999-01-01

    OBJECTIVE: This study intended to investigate disturbances in beta-adrenergically-mediated substrate utilization and thermogenesis in obese subjects with mild non insulin-dependent diabetes mellitus (NIDDM). DESIGN: Following a baseline period of 30 min, the beta-agonist isoproterenol (ISO) was admi

  12. Iontophoretic {beta}-adrenergic stimulation of human sweat glands: possible assay for cystic fibrosis transmembrane conductance regulator activity in vivo.

    OpenAIRE

    Shamsuddin, A. K. M.; Reddy, M. M.; Quinton, P. M.

    2008-01-01

    With the advent of numerous candidate drugs for therapy in cystic fibrosis (CF), there is an urgent need for easily interpretable assays for testing their therapeutic value. Defects in the cystic fibrosis transmembrane conductance regulator (CFTR) abolished beta-adrenergic but not cholinergic sweating in CF. Therefore, the beta-adrenergic response of the sweat gland may serve both as an in vivo diagnostic tool for CF and as a quantitative assay for testing the efficacy of new drugs designed t...

  13. The roles of beta-adrenergic receptors in tumorigenesis and the possible use of beta-adrenergic blockers for cancer treatment: possible genetic and cell-signaling mechanisms

    International Nuclear Information System (INIS)

    Cancer is the leading cause of death in the USA, and the incidence of cancer increases dramatically with age. Beta-adrenergic blockers appear to have a beneficial clinical effect in cancer patients. In this paper, we review the evidence of an association between β-adrenergic blockade and cancer. Genetic studies have provided the opportunity to determine which proteins link β-adrenergic blockade to cancer pathology. In particular, this link involves the major histocompatibility complex class II molecules, the renin–angiotensin system, transcription factor nuclear factor-kappa-light-chain-enhancer of activated B cells, poly(ADP-ribose) polymerase-1, vascular endothelial growth factor, and the reduced form of nicotinamide adenine dinucleotide phosphate oxidase. Beta-adrenergic blockers also exert anticancer effects through non-genomic factors, including matrix metalloproteinase, mitogen-activated protein kinase pathways, prostaglandins, cyclooxygenase-2, oxidative stress, and nitric oxide synthase. In conclusion, β-adrenergic blockade may play a beneficial role in cancer treatment. Additional investigations that examine β-adrenergic blockers as cancer therapeutics are required to further elucidate this role

  14. Influence of beta adrenergic blockade on effects of physical training in patients with ischaemic heart disease.

    OpenAIRE

    L. Vanhees; Fagard, R.; Amery, A

    1982-01-01

    Reduction in heart rate during submaximal exercise is often used to judge the progress of patients with ischaemic heart disease in the course of a physical training programme. Some patients, however, are treated with beta adrenergic blocking drugs and it remains controversial if chronic beta blockade influences the effects of training and if heart rate remains a useful guide in the evaluation of the state of training of these patients. Male postinfarction patients, 15 treated with and 15 with...

  15. {beta}-adrenergic receptor density and adenylate cyclase activity in lead-exposed rat brain after cessation of lead exposure

    Energy Technology Data Exchange (ETDEWEB)

    Chang, Huoy-Rou [I-Shou University, Department of Biomedical Engineering, Dashu Shiang, Kaohsiung County (Taiwan); Tsao, Der-An [Fooyin University of Technology, Department of Medical Technology (Taiwan); Yu, Hsin-Su [Taiwan University, Department of Dermatology, College of Medicine (Taiwan); Ho, Chi-Kung [Kaohsiung Medical University, Occupational Medicine (Taiwan); Kaohsiung Medical University, Graduate Institute of Medicine, Research Center for Occupational Disease (Taiwan)

    2005-01-01

    To understanding the reversible or irreversible harm to the {beta}-adrenergic system in the brain of lead-exposed rats, this study sets up an animal model to estimate the change in the sympathetic nervous system of brain after lead exposure was withdrawn. We address the following topics in this study: (a) the relationship between withdrawal time of lead exposure and brain {beta}-adrenergic receptor, blood lead level, and brain lead level in lead-exposed rats after lead exposure was stopped; and (b) the relationship between lead level and {beta}-adrenergic receptor and cyclic AMP (c-AMP) in brain. Wistar rats were chronically fed with 2% lead acetate and water for 2 months. Radioligand binding was assayed by a method that fulfilled strict criteria of {beta}-adrenergic receptor using the ligand [{sup 125}I]iodocyanopindolol. The levels of lead were determined by electrothermal atomic absorption spectrometry. The c-AMP level was determined by radioimmunoassay. The results showed a close relationship between decreasing lead levels and increasing numbers of brain {beta}-adrenergic receptors and brain adenylate cyclase activity after lead exposure was withdrawn. The effect of lead exposure on the {beta}-adrenergic system of the brain is a partly reversible condition. (orig.)

  16. Concanavalin a increases beta-adrenergic and glucocorticoid receptors in porcine splenocytes

    International Nuclear Information System (INIS)

    We identified specific glucocorticoid and beta-adrenergic receptors on porcine splenocytes. There are 2000 to 4000 glucocorticoid receptors per cell with a K /SUB D/ of 2 to 4 nM and 1000 beta-adrenergic receptors with a K /SUB D/ of 0.3 to 0.6 nM. When splenocytes were incubated with concanavalin A (Con A), there was an approximate 2-fold increase in both gluococorticoid and beta-adrenergic receptors with no change in binding affinity. Incubation of splenocytes with cortisol as low as 40 nM (13 ng/ml) inhibited proliferation in response to Con A. This inhibitory effect of cortisol was not due to cytotoxic effects of glucocorticoids. At maximal physiologic concentrations (400 nM; 135 ng/ml), cortisol caused reductions in Con A activation of thymocytes and peripheral blood mononuclear cells. When eight wk old pigs were restrained, there was an increase in plasma cortisol, atrophy of thymus and reduction in skin test responses to phytohemagglutinin. On the basis of the data, we suggest that physiologic concentrations of stress asociated hormones affect functional activities of porcine lymphoid cells. Since activated splenocytes display increased numbers of receptors for these hormones, perhaps glucocorticoids or catecholamines normally function in vivo to suppress clonal expansion of antigen activated and autoreactive T lymphocytes

  17. Electrical Stimulation Decreases Coupling Efficiency Between Beta-Adrenergic Receptors and Cyclic AMP Production in Cultured Muscle Cells

    Science.gov (United States)

    Young, R. B.; Bridge, K. Y.

    1999-01-01

    Electrical stimulation of skeletal muscle cells in culture is an effective way to simulate the effects of muscle contraction and its effects on gene expression in muscle cells. Expression of the beta-adrenergic receptor and its coupling to cyclic AMP synthesis are important components of the signaling system that controls muscle atrophy and hypertrophy, and the goal of this project was to determine if electrical stimulation altered the beta-adrenergic response in muscle cells. Chicken skeletal muscle cells that had been grown for seven days in culture were subjected to electrical stimulation for an additional two days at a pulse frequency of 0.5 pulses/sec and a pulse duration of 200 msec. At the end of this two-day stimulation period, beta-adrenergic receptor population was measured by the binding of tritium-labeled CGP-12177 to muscle cells, and coupling to cAMP synthesis was measured by Radioimmunoassay (RIA) after treating the cells for 10 min with the potent (beta)AR agonist, isoproterenol. The number of beta adrenergic receptors and the basal levels of intracellular cyclic AMP were not affected by electrical stimulation. However, the ability of these cells to synthesize cyclic AMP was reduced by approximately 50%. Thus, an enhanced level of contraction reduces the coupling efficiency of beta-adrenergic receptors for cyclic AMP production.

  18. Differences in affinity of cardiac beta-adrenergic receptors for [3H]dihydroalprenolol

    International Nuclear Information System (INIS)

    We performed quantitative light microscopic autoradiography of [3H]dihydroalprenolol (DHA) binding to frozen sections of canine myocardium to test the hypothesis that there are differences in the density or affinity of beta-adrenergic receptors on various tissue compartments. In one study, with concentrations of [3H]DHA from 0.34 to 5.1 nM, specific binding to cardiac myocytes was saturable, whereas nonspecific binding was linear with ligand concentration. Arterioles had more specific grain counts than muscle cells (P less than 0.0001), and Scatchard analysis showed that the arterioles had a much higher affinity for [3H]DHA than myocytes. In a second study with lower concentrations of [3H]DHA (0.19-1.98 nM), binding to the arterioles saturated, whereas binding to the cardiac myocytes did not. Specific binding to arterioles was significantly higher (P less than 0.0001) than binding to myocytes at all concentrations of [3H]DHA. The dissociation constants for the subendocardial and subepicardial myocytes were 1.57 and 1.71 nM, respectively, while the dissociation constant for the arterioles was 0.26 nM. The maximum number of binding sites was 911 grains/0.9 X 10(-2) mm2 for subepicardial myocytes, 936 for subendocardial myocytes, and 986 for arterioles. The large nerves accompanying an epicardial artery also demonstrated specific [3H]DHA binding. Thus this study has demonstrated major differences in the distribution and affinity of beta-adrenergic receptors, which may help to explain various physiological responses to beta-adrenergic stimulation

  19. Low sodium diet corrects the defect in lymphocyte beta-adrenergic responsiveness in hypertensive subjects.

    OpenAIRE

    Feldman, R D; Lawton, W J; McArdle, W L

    1987-01-01

    To determine the role of dietary sodium intake in the reduction in beta-adrenergic sensitivity in hypertension, lymphocyte beta-receptors from 8 borderline hypertensive and 16 normotensive subjects were studied after 5 d on a high sodium diet (400 meq/d) and also following a low sodium diet (10 meq/d). During the high sodium diet, lymphocyte beta-receptor-stimulated adenylate cyclase activity, expressed as the relative increase over basal levels stimulated by the beta-agonist isoproterenol, w...

  20. beta-adrenergic effects on carbohydrate metabolism in the unweighted rat soleus muscle

    Science.gov (United States)

    Kirby, Christopher R.; Tischler, Marc E.

    1990-01-01

    The effect of unweighting on the response of the soleus-muscle carbohydrate metabolism to a beta-adrenergic agonist (isoproterenol) was investigated in rats that were subjected to three days of tail-cast suspension. It was found that isoproterenol promoted glycogen degradation in soleus from suspended rats to a higher degree than in weighted soleus from control rats, and had no effect in unweighted digitorum longus. However, isoproterenol did not have a greater inhibitory effect on the net uptake of tritium-labeled 2-deoxy-glucose by the unweighted soleus and that isoproterenol inhibited hexose phosphorylation less in the unweighted than in the control muscle.

  1. Distribution of beta-adrenergic receptors in failing human myocardium. Implications for mechanisms of down-regulation

    International Nuclear Information System (INIS)

    The density of beta-adrenergic receptors is reduced in crude membranes prepared from failing human myocardium. We used quantitative autoradiography of radioligand binding sites in intact tissue slices to determine whether the total tissue content of receptors is reduced and to characterize the transmural distribution of receptors in cardiac myocytes and the coronary vasculature in hearts obtained from nine cardiac transplant patients with severe congestive failure. Binding of [125Iodo]cyanopindolol to transmural slices of human myocardium was rapid, saturable, stereoselective, and displaceable by agonists and antagonists with an appropriate rank order of potency. Binding isotherms in four normal and nine failing ventricles showed a significant reduction in the total tissue content of beta-receptors in failing myocardium (38.3 +/- 2.0 fmol/mg protein) compared with normal tissue (52.4 +/- 1.7 fmol/mg protein, p = 0.038). In the normal ventricles, the greatest receptor density was observed autoradiographically in myocytic regions of the subendocardium. Receptor density of the coronary arterioles was approximately 70% of that in adjacent myocytic regions. The density of binding sites in both myocytic regions and arterioles was diminished in all regions of the failing ventricles, but down-regulation was due primarily to a selective reduction of beta-receptors of subendocardial myocytes (63 +/- 5% of subepicardial receptor density vs. 115 +/- 6% in controls, p less than 0.0001). These observations indicate that down-regulation occurs nonuniformly in the transmural distribution and thus is likely not related simply to elevated circulating catecholamine levels

  2. Severe hyperkalemia as a complication of timolol, a topically applied beta-adrenergic antagonist

    International Nuclear Information System (INIS)

    Severe hyperkalemia occurred in a patient with radiation pneumonitis and glaucoma shortly after beginning prednisone therapy. There was no evidence of renal failure, diabetes, acidosis, increased potassium intake, or significant tissue trauma. Medications having adverse effects on potassium metabolism were considered, and the patient's use of timolol maleate eyedrops was discontinued. His serum potassium level normalized despite continuation of the prednisone therapy. He became hyperkalemic on rechallenge with timolol and normokalemic following its withdrawal. This case indicates that the potential for beta-blocker-induced hyperkalemia exists even with topical appreciation

  3. Severe hyperkalemia as a complication of timolol, a topically applied beta-adrenergic antagonist

    Energy Technology Data Exchange (ETDEWEB)

    Swenson, E.R.

    1986-06-01

    Severe hyperkalemia occurred in a patient with radiation pneumonitis and glaucoma shortly after beginning prednisone therapy. There was no evidence of renal failure, diabetes, acidosis, increased potassium intake, or significant tissue trauma. Medications having adverse effects on potassium metabolism were considered, and the patient's use of timolol maleate eyedrops was discontinued. His serum potassium level normalized despite continuation of the prednisone therapy. He became hyperkalemic on rechallenge with timolol and normokalemic following its withdrawal. This case indicates that the potential for beta-blocker-induced hyperkalemia exists even with topical appreciation.

  4. PET measures of pre- and post-synaptic cardiac beta adrenergic function

    Energy Technology Data Exchange (ETDEWEB)

    Link, Jeanne M.; Stratton, John R.; Levy, Wayne; Poole, Jeanne E.; Shoner, Steven C.; Stuetzle, Werner; Caldwell, James H. E-mail: jcald@u.washington.edu

    2003-11-01

    Positron Emission Tomography was used to measure global and regional cardiac {beta}-adrenergic function in 19 normal subjects and 9 congestive heart failure patients. [{sup 11}C]-meta-hydroxyephedrine was used to image norepinephrine transporter function as an indicator of pre-synaptic function and [{sup 11}C]-CGP12177 was used to measure cell surface {beta}-receptor density as an indicator of post-synaptic function. Pre-synaptic, but not post-synaptic, function was significantly different between normals and CHF patients. Pre-synaptic function was well matched to post-synaptic function in the normal hearts but significantly different and poorly matched in the CHF patients studied. This imaging technique can help us understand regional sympathetic function in cardiac disease.

  5. Synthesis of the sup 11 C-labelled. beta. -adrenergic receptor ligands atenolol, metoprolol and propanolol

    Energy Technology Data Exchange (ETDEWEB)

    Antoni, G.; Ulin, J.; Laangstroem, B. (Uppsala Univ. (Sweden). Dept. of Organic Chemistry)

    1989-01-01

    The {sup 11}C-labelled {beta}-adrenergic receptor ligands atenolol 1, metoprolol 2 and propranolol 3 have been synthesized by an N-alkylation reaction using (2-{sup 11}C)isopropyl iodide. The labelled isopropyl iodide was prepared in a one-pot reactor system from ({sup 11}C)carbon dioxide and obtained in 40% radiochemical yield within 14 min reaction time. The total reaction times for compounds 1-3, counted from the start of the isopropyl iodide synthesis and including purification were 45-55 min. The products were obtained in 5-15% radiochemical yields and with radiochemical purities higher than 98%. The specific activity ranged from 0.4 to 4 GBq/{mu}mol. In a typical experiment starting with 4 GBq around 75 MBq of product was obtained. (author).

  6. Effect of alpha and beta adrenergic blockade on epinephrine induced pulmonary insufficiency.

    Science.gov (United States)

    Berk, J L; Hagen, J F; Koo, R

    1976-04-01

    Recent studies demonstrated that epinephrine causes significant pulmonary A-V shunting. This study reports the effect of alpha and beta adrenergic blockade on this shunting. Sixty-three anesthetized mongrel dogs were ventilated with a mechanical respirator. Measurements of (1) the pulmonary shunt, (2) cardiac output, (3) mean pulmonary artery, pulmonary capillary wedge and systemic pressures, and (4) pulmonary and systemic vascular resistances were obtained at 5, 15 and 30 minute intervals during the first hour and hourly for 5 hours. Fifteen dogs received no treatment. All others received epinephrine hydrochloride, 2 mug/kg/min for 5 hours. Ten received epinephrine only. Ten were pretreated with propranolol hydrochloride, 250 mug/kg, 12 with phenoxybenzamine, 1 mg/kg, and 16 with phenoxybenzamine and propranolol. Propranolol significantly decreased the epinephrine induced pulmonary shunt at all times and was the most effective drug. Phenoxybenzamine decreased the early shunting, but less than propranolol, and did not decrease the late shunting. Blockade with propranolol and phenoxybenzamine was less effective than propranolol alone. Based on the observed hemodynamic changes it was suggested that beta blockade is effective in reducing epinephrine induced pulmonary insufficiency by favorably altering the flow and distribution of pulmonary blood flow which in turn decreases epinephrine induced ventilation-perfusion inequalities and capillary hypertension both of which result in shunting. Conversely phenoxybenzamine has an unfavorable effect on the pulmonary flow. These studies support previous work in animals and man which showed that beta adrenergic stimulation is important in the pathogenesis of pulmonary insufficiency. Because the amounts of epinephrine used produce blood levels observed in critical illness, these studies add support to a relationship between the increased catecholamine stimulation of critical illness and the associated and often unexplained

  7. Glucose-induced thermogenesis in patients with small cell lung carcinoma. The effect of acute beta-adrenergic inhibition

    DEFF Research Database (Denmark)

    Simonsen, L; Bülow, J; Tuxen, C; Christensen, N J

    1994-01-01

    was measured by the open circuit ventilated hood system. Forearm blood flow was measured by venous occlusion strain-gauge plethysmography. The uptake of oxygen in the forearm was calculated as the product of the forearm blood flow and the difference in arteriovenous oxygen concentration. The glucose......-induced forearm oxygen uptake in the period 60-120 min following the glucose load was significantly reduced after beta-adrenergic inhibition from 103 +/- 28 mumol 100 g-1 60 min-1 to 29 +/- 29 mumol 100 g-1 60 min-1 (P <0.05). The noreadrenaline concentration in the arterial blood was not increased in the......Seven patients with histologically verified small cell lung carcinoma were given an oral glucose load of 75 g on two occasions to examine the effect of glucose on whole body and forearm thermogenesis with and without acute beta-adrenergic inhibition with propranolol. Whole body energy expenditure...

  8. Food restriction prevents an age-associated increase in rat liver beta-adrenergic receptors

    Energy Technology Data Exchange (ETDEWEB)

    Dax, E.M.; Ingram, D.K.; Partilla, J.S.; Gregerman, R.I.

    1989-05-01

    In male Wistar rats fed ad libitum (24% protein, 4.5 Kcal/gm), the (/sup 125/I)iodopindolol binding capacity of the beta-adrenergic receptors in liver of 24-month-old animals is 3-4 times greater than that of 6-month-old counterparts. In rats fed the same diet, on alternate days from weaning, the receptor capacity did not increase significantly between 6 and 24 months (10.20 +/- 0.55 vs 9.20 +/- 0.72 fmol/mg) or between 24 and 30 months. This was not due to acute dietary deprivation, as rats food-restricted for only 2 weeks, at 23.5 months of age, also showed elevated receptor capacities compared to 6-month-old ad libitum fed animals. Moreover, intermittent feeding produced no significant effects among 6-month-old animals, whether restricted since weaning or for two weeks prior to sacrifice. Many biochemical parameters that decrease with aging in rats fed ad libitum are prevented by dietary restriction. Our results demonstrate that a reproducible biochemical process that increases with aging is also prevented with dietary restriction. The age-related, liver beta-receptor increase may be a potentially reliable marker for studying biochemical perturbations that modify life span.

  9. Effects of beta-adrenergic blockade on ventilation and gas exchange during incremental exercise.

    Science.gov (United States)

    Dodd, S; Powers, S; O'Malley, N; Brooks, E; Sommers, H

    1988-08-01

    Controversy exists concerning the effects of acute beta-adrenergic blockade on ventilation during exercise. Hence, the purpose of this study was to determine the effects of acute beta blockade on ventilation and gas exchange during incremental exercise. Nine male subjects underwent incremental exercise on a cycle ergometer (30 W.min-1) to exhaustion, with one trial being performed 60 min after the subject ingested propranolol hydrochloride (Inderal 1 mg.kg-1 BW) while the second test served as control. The treatment order was counterbalanced to preclude any ordering effect on the results, and 1 week separated the tests. Ventilation and gas exchange were monitored by open circuit techniques. No difference (p greater than 0.05) existed in VE, % Hb sat, VCO2, ventilatory threshold, and VE/VCO2 between treatments at the same exercise stage. VO2max was lowered from 3.82 to 3.26 l.min-1 (p less than 0.05) and HRmax was reduced from 190 to 150 bpm (p less than 0.05) as a result of beta blockade. These data suggested that acute beta blockade had no effect on exercise ventilation, but decreased HRmax at comparable work rates. In addition, VO2max and exercise time to exhaustion were hindered, probably due to beta blockade limitation of HRmax, and, thus, oxygen transport. PMID:3178619

  10. Food restriction prevents an age-associated increase in rat liver beta-adrenergic receptors

    International Nuclear Information System (INIS)

    In male Wistar rats fed ad libitum (24% protein, 4.5 Kcal/gm), the [125I]iodopindolol binding capacity of the beta-adrenergic receptors in liver of 24-month-old animals is 3-4 times greater than that of 6-month-old counterparts. In rats fed the same diet, on alternate days from weaning, the receptor capacity did not increase significantly between 6 and 24 months (10.20 +/- 0.55 vs 9.20 +/- 0.72 fmol/mg) or between 24 and 30 months. This was not due to acute dietary deprivation, as rats food-restricted for only 2 weeks, at 23.5 months of age, also showed elevated receptor capacities compared to 6-month-old ad libitum fed animals. Moreover, intermittent feeding produced no significant effects among 6-month-old animals, whether restricted since weaning or for two weeks prior to sacrifice. Many biochemical parameters that decrease with aging in rats fed ad libitum are prevented by dietary restriction. Our results demonstrate that a reproducible biochemical process that increases with aging is also prevented with dietary restriction. The age-related, liver beta-receptor increase may be a potentially reliable marker for studying biochemical perturbations that modify life span

  11. Glucocorticoids and beta-adrenergic-receptor agonists: their combined effect on fetal rabbit lung surfactant.

    Science.gov (United States)

    Ekelund, L; Enhorning, G

    1985-08-15

    In a previous study on pregnant rabbits (Am J Obstet Gynecol 1983; 147:437) we found that a prolonged infusion of the beta 2-adrenergic-receptor agonist terbutaline would first cause a release of fetal pulmonary surfactant, so that more was available in the airways. However, the airway fluid then contained less surfactant, indicating a depletion of stores. Since terbutaline is often used in high doses as a tocolytic agent, surfactant depletion could be a serious side effect. With further studies on rabbits, we wanted to test the hypothesis that with an accelerated surfactant synthesis, achieved with glucocorticoids, the increased release, evoked with the terbutaline, would never cause a depletion of the surfactant stores. Our results supported this hypothesis. Betamethasone, administered to the pregnant doe on the twenty-sixth and twenty-seventh days of gestation, 0.1 mg/kg, increased compliance of the fetal lungs, and more phospholipid phosphorus could be lavaged from the airways. These effects were further increased when, following steroid administration, the doe was infused with terbutaline. Depletion of the surfactant stores was never seen when betamethasone was given prior to the beta-adrenergic-receptor agonist. PMID:3839627

  12. Characterization of phosphorylated beta-adrenergic receptors from desensitized turkey erythrocytes

    Energy Technology Data Exchange (ETDEWEB)

    Rebar, R.; Crooke, S.T.; Stadel, J.M.

    1986-05-01

    Catecholamine-induced desensitization of turkey erythrocyte (TE) adenylate cyclase results in a 40-50 percent decrease in agonist stimulated cyclase activity. Desensitization is accompanied by decreased mobility on SDS-PAGE of beta-adrenergic receptor (BAR) proteins photoaffinity labeled with (/sup 125/I)-p-azidobenzylcarazolol compared to control. Using a low crosslinked gel, the M/sub r/ = 42,000 band of BAR from desensitized TE was further resolved into a doublet compared to a single M/sub r/ = 38,000 band for control. The formation of the doublet appears to correlate with the amount of adenylate cyclase desensitization. Preincubating TE for 20 hr at 37/sup 0/C with /sup 32/P-/sub i/ labels BAR. /sup 32/P-BAR was partially purified by affinity chromatography over alprenolol-Sepharose. Limited digest peptide maps of /sup 32/P-BAR using papain identified a unique peptide (M/sub r/ = 2800) from BAR of desensitized TE which was absent in control. This unique /sup 32/P-peptide was found only in the upper band of the doublet of BAR from desensitized TE. These data indicate that BAR is not uniformly phosphorylated following agonist-induced desensitization of TE and identify a peptide of BAR which is a site of phosphorylation correlating with desensitization of TE adenylate cyclase.

  13. Studies of the stimulation and desensitization of beta adrenergic receptors in the human lymphocyte

    International Nuclear Information System (INIS)

    Lymphocytes, were employed in radioligand binding studies of beta-adrenergic receptor density and affinity for agonists and in studies of isoproterenol stimulated adenylate cyclase activity. Studies of isoproterenol stimulation of adenylate cyclase activity demonstrated a role for extracellular calcium ions but not for extracellular magnesium ions in this process. Responses were diminished by chelation or by removal of extracellular calcium, as well as by lanthanum ion which competes with calcium for membrane binding sites. Initial studies using 3H-dihydroalprenolol (3H-DHA) indicated that 40% of cell surface beta receptors are lost during exposure of lymphocytes to isoproterenol and that the remaining receptors have a reduced affinity for beta agonists. Results from studies with 125iodocyanopindolol (125ICYP) are consistent with the view that beta receptors lost from the cell surface during isoproterenol treatment are present in a internal compartment of the cell. In mild asthmatic patients receiving a three week regimen of oral terbutaline a 40% reduction in the total receptor population was observed, suggesting that degradation of internalized receptors had occurred

  14. [The association between beta-adrenergic receptor gene polymorphisms and personality traits].

    Science.gov (United States)

    Numajiri, Maki; Aoki, Jun; Nishizawa, Daisuke; Kasai, Shinya; Ogai, Yasukazu; Ikeda, Kazutaka; Iwahashi, Kazuhiko

    2012-08-01

    The relationship between the polymorphisms (SNPs) of the beta-adrenergic receptor (beta-AR) gene and personality assessed by TCI (Temperament and Character Inventory), was studied among 192 healthy Japanese subjects (121 male subjects and 71 female subjects). In this study, the statistical analyses were performed overall and separately for each sex. As a result, it was shown that there were significant relationships between SD (self-directedness) and 49Ser/Gly (rs1801252) in ADRB1, P (persistence) and 389Arg/Gly (rs1801253) in ADRB1, and ST (self-transcendence) and 27Gln/Glu (rs1042714) in ADRB2 overall. Among the male subjects, there were further significant relationships between ST and 49Ser/Gly in ADRB1, NS (novelty-seeking), HA (harm avoidance) and P and 389Arg/Gly in ADRB1, and P and 64Arg/Trp(rsrs4994) in ADRB3. Among the female subjects, there were also significant relationships between SD and 49Ser/Gly in ADRB1, and C (cooperativeness) and 389Arg/Gly in ADRB1. Thus it was shown that there were correlations between beta-AR gene polymorphisms and several subscales of TCI. PMID:23012891

  15. Cardiovascular response to beta-adrenergic blockade or activation in 23 inbred mouse strains.

    Directory of Open Access Journals (Sweden)

    Corinne Berthonneche

    Full Text Available We report the characterisation of 27 cardiovascular-related traits in 23 inbred mouse strains. Mice were phenotyped either in response to chronic administration of a single dose of the beta-adrenergic receptor blocker atenolol or under a low and a high dose of the beta-agonist isoproterenol and compared to baseline condition. The robustness of our data is supported by high trait heritabilities (typically H(2>0.7 and significant correlations of trait values measured in baseline condition with independent multistrain datasets of the Mouse Phenome Database. We then focused on the drug-, dose-, and strain-specific responses to beta-stimulation and beta-blockade of a selection of traits including heart rate, systolic blood pressure, cardiac weight indices, ECG parameters and body weight. Because of the wealth of data accumulated, we applied integrative analyses such as comprehensive bi-clustering to investigate the structure of the response across the different phenotypes, strains and experimental conditions. Information extracted from these analyses is discussed in terms of novelty and biological implications. For example, we observe that traits related to ventricular weight in most strains respond only to the high dose of isoproterenol, while heart rate and atrial weight are already affected by the low dose. Finally, we observe little concordance between strain similarity based on the phenotypes and genotypic relatedness computed from genomic SNP profiles. This indicates that cardiovascular phenotypes are unlikely to segregate according to global phylogeny, but rather be governed by smaller, local differences in the genetic architecture of the various strains.

  16. Hypoxia and glucose independently regulate the beta-adrenergic receptor-adenylate cyclase system in cardiac myocytes.

    OpenAIRE

    Rocha-Singh, K J; Honbo, N Y; Karliner, J S

    1991-01-01

    We explored the effects of two components of ischemia, hypoxia and glucose deprivation, on the beta-adrenergic receptor (beta AR)-adenylate cyclase system in a model of hypoxic injury in cultured neonatal rat ventricular myocytes. After 2 h of hypoxia in the presence of 5 mM glucose, cell surface beta AR density (3H-CGP-12177) decreased from 54.8 +/- 8.4 to 39 +/- 6.3 (SE) fmol/mg protein (n = 10, P less than 0.025), while cytosolic beta AR density (125I-iodocyanopindolol [ICYP]) increased by...

  17. Catecholamine-induced desensitization of adenylate cyclase coupled. beta. -adrenergic receptors in turkey erythrocytes: evidence for a two-step mechanism

    Energy Technology Data Exchange (ETDEWEB)

    Stadel, J.M.; Rebar, R.; Crooke, S.T.

    1987-09-08

    Preincubation of turkey erythrocytes with isoproterenol is associated with (1) 50-60% attenuation of agonist-stimulated adenylate cyclase activity, (2) altered mobility of the ..beta..-adrenergic receptor on sodium dodecyl sulfate-polyacrylamide gels, and (3) increased phosphorylation of the ..beta..-adrenergic receptor. Using a low-cross-linked polyacrylamide gel, the ..beta..-adrenergic receptor protein from isoproterenol-desensitized cells, labeled with /sup 32/P or with the photoaffinity label /sup 125/I-(p-azidobenzyl)carazolol, can be resolved into a doublet (M/sub r/ similarly ordered 37,000 and M/sub r/ similarly ordered 41,000) as compared to a single M/sub r/ similarly ordered 37,000 ..beta..-adrenergic receptor protein from control erythrocytes. The appearance of the doublet was dependent on the concentration of agonist used to desensitize the cells. Incubation of erythrocytes with dibutyryl-cAMP did not promote formation of the doublet but decreased agonist-stimulated adenylate cyclase activity 40-50%. Limited-digestion peptide maps of /sup 32/P-labeled ..beta..-adrenergic receptors using papain revealed a unique phosphopeptide in the larger molecular weight band (M/sub r/ similarly ordered 41,000) of the doublet from the agonist-desensitized preparation that was absent in the peptide maps of the smaller band (M/sub r/ similarly ordered 37,000), as well as control or dibutyryl-cAMP-desensitized receptor. These data provide evidence that maximal agonist-induced desensitization of adenylate cyclase coupled ..beta..-adrenergic receptors in turkey erythrocytes occurs by a two-step mechanism.

  18. Effects of two beta-adrenergic agonists on finishing performance, carcass characteristics, and meat quality of feedlot steers.

    Science.gov (United States)

    Avendaño-Reyes, L; Torres-Rodríguez, V; Meraz-Murillo, F J; Pérez-Linares, C; Figueroa-Saavedra, F; Robinson, P H

    2006-12-01

    The impact of using 2 beta-adrenergic agonists in feedlot cattle fed finishing diets was evaluated using 54 steers (45 crossbred Charolais and 9 Brangus) initially weighing 424 +/- 26.6 kg in a randomized complete block design with 3 treatments and 6 blocks (i.e., 18 pens with 3 steers per pen). Response variables were feedlot performance, carcass characteristics, and meat quality. Treatments were 1) control (no supplement added); 2) zilpaterol hydrochloride (ZH; 60 mg.steer(-1).d(-1)); and 3) ractopamine hydrochloride (RH; 300 mg.steer(-1).d(-1)). The beta-agonists were added to the diets during the final 33 d of the experiment. The groups of steers fed ZH or RH improved (P Meat from the ZH- (P = 0.0007) and RH- (P = 0.0267) supplemented steers had greater shear force values than control steers (ZH = 5.11; RH = 4.83; control = 4.39 kg/cm(2)). Variables related to meat color indicated that both beta-agonists led to a similar redness of the LM area related to the control group. In general, feedlot performance was greatly enhanced by beta-adrenergic agonists, and meat tenderness from treated animals was classified as intermediate. Furthermore, meat color was not altered by beta-agonist supplementation. PMID:17093218

  19. Reduced number of alpha- and beta-adrenergic receptors in the myocardium of rats exposed to tobacco smoke

    Energy Technology Data Exchange (ETDEWEB)

    Larue, D.; Kato, G.

    1981-04-09

    The concentration of alpha- and beta-adrenergic receptors--as measured by specific (/sup 3/H)WB-4101 and (-)-(/sup 3/H)dihydroalprenolol binding--was diminished by 60% below control values in the hearts of rats exposed to tobacco smoke. These changes in receptor numbers took place almost immediately after tobacco smoke exposure and were rapidly reversible after termination of the exposure. The dissociation constant, KD, for (/sup 3/H)WB-4101 was identical in exposed (KD . 0.34 +/- 0.09 nM) and control (KD . 0.35 +/- 0.07 nM) hearts but was significantly different in the case of (-)-(3H)dihydroalprenolol binding (exposed, KD . 2.83 +/- 0.30 mM vs. control KD . 5.22 +/- 0.61 nM). For beta-receptor binding there was no significant difference between exposed and control animals in the Ki values for (-)-epinephrine, (-)-norepinephrine, (-)-alprenolol, (+/-)-propranolol or timolol. (-)-Isoproterenol, however, was found to bind with lower affinity in exposed compared with control hearts. For alpha-receptor binding there was no significant difference between control and 'smoked' animals in the Ki values for (-)-epinephrine, (-0)-norepinephrine or phentolamine. The decrease in alpha- and beta-adrenergic receptor concentration may be related to the phenomenon of receptor desensitization resulting from a release of catecholamines in rats exposed to tobacco smoke.

  20. Beta-adrenergic receptors support attention to extinction learning that occurs in the absence, but not the presence, of a context change

    Directory of Open Access Journals (Sweden)

    Marion Emma André

    2015-05-01

    Full Text Available The noradrenergic (NA-system is an important regulator of cognitive function. It contributes to extinction learning(EL, and in disorders where EL is impaired NA-dysfunction has been postulated. We explored whether NA acting on beta-adrenergic-receptors (β-AR, regulates EL that depends on context, but is not fear-associated. We assessed behaviour in an ‘AAA’ or ‘ABA’ paradigm: rats were trained for 3 days in a T-maze(context-A to learn that a reward is consistently found in the goal arm, despite low reward probability. This was followed on day 4 by EL(unrewarded, whereby in the ABA-paradigm, EL was reinforced by a context change (B, and in the AAA-paradigm, no context change occurred. On day 5, re-exposure to the A-context (unrewarded occurred. Typically, in control ‘AAA’ animals EL occurred on day 4 that progressed further on day 5. In control ‘ABA’ animals, EL also occurred on day 4, followed by renewal of the previously learned (A behavior on day 5, that was followed (in day 5 by extinction of this behavior, as the animals realised that no food reward would be given.Treatment with the β-AR-antagonist, propranolol, prior to EL on day 4, impaired EL in the AAA-paradigm. In the ‘ABA’ paradigm, antagonist treatment on day 4, had no effect on extinction that was reinforced by a context change (B. Furthermore, β-AR-antagonism prior to renewal testing (on day 5 in the ABA-paradigm, resulted in normal renewal behavior, although subsequent extinction of responses during day 5 was prevented by the antagonist. Thus, under both treatment conditions, β-AR-antagonism prevented extinction of the behavior learned in the ‘A’ context.β-AR-blockade during an overt context change did not prevent EL, whereas β-AR were required for EL in an unchanging context. These data suggest that β-AR may support EL by reinforcing attention towards relevant changes in the previously learned experience, and that this process supports extinction

  1. Association between Selective Beta-adrenergic Drugs and Blood Pressure Elevation: Data Mining of the Japanese Adverse Drug Event Report (JADER) Database.

    Science.gov (United States)

    Ohyama, Katsuhiro; Inoue, Michiko

    2016-01-01

    Selective beta-adrenergic drugs are used clinically to treat various diseases. Because of imperfect receptor selectivity, beta-adrenergic drugs cause some adverse drug events by stimulating other adrenergic receptors. To examine the association between selective beta-adrenergic drugs and blood pressure elevation, we reviewed the Japanese Adverse Drug Event Reports (JADERs) submitted to the Japan Pharmaceuticals and Medical Devices Agency. We used the Medical Dictionary for Regulatory Activities (MedDRA) Preferred Terms extracted from Standardized MedDRA queries for hypertension to identify events related to blood pressure elevation. Spontaneous adverse event reports from April 2004 through May 2015 in JADERs, a data mining algorithm, and the reporting odds ratio (ROR) were used for quantitative signal detection, and assessed by the case/non-case method. Safety signals are considered significant if the ROR estimates and lower bound of the 95% confidence interval (CI) exceed 1. A total of 2021 reports were included in this study. Among the nine drugs examined, significant signals were found, based on the 95%CI for salbutamol (ROR: 9.94, 95%CI: 3.09-31.93) and mirabegron (ROR: 7.52, 95%CI: 4.89-11.55). The results of this study indicate that some selective beta-adrenergic drugs are associated with blood pressure elevation. Considering the frequency of their indications, attention should be paid to their use in elderly patients to avoid adverse events. PMID:27374969

  2. Temporal patterns of electrical remodeling in canine ventricular hypertrophy: Focus on I-Ks downregulation and blunted beta-adrenergic activation

    NARCIS (Netherlands)

    M. Stengl; C. Ramakers; D.W. Donker; A. Nabar; A.V. Rybin; R.L.H.M.G. Spatjens; T. van der Nagel; W.K.W.H. Wodzig; K.R. Sipido; G. Antoons; A.F.M. Moorman; M.A. Vos; P.G.A. Volders

    2006-01-01

    Objectives: Electrical remodeling in cardiac hypertrophy often involves the downregulation of K+ currents, including beta-adrenergic (beta-A)-sensitive I-Ks. Temporal patterns of ion-channel downregulation are poorly resolved. In dogs with complete atrioventricular block (AVB), we examined (1) the t

  3. Effect of beta-adrenergic blockade on elevated arterial compliance and low systemic vascular resistance in cirrhosis

    DEFF Research Database (Denmark)

    Møller, S; Bendtsen, F; Henriksen, Jens Henrik Sahl

    2001-01-01

    beta-blockers, but the effect of this treatment on arterial compliance has not been investigated. The aim of the present study was therefore to assess the effects of propranolol on the arterial compliance of patients with cirrhosis. METHODS: Twenty patients with cirrhosis underwent a haemodynamic......) of 17.8 mmHg, and responded to beta-blocker treatment with a significant reduction in the HVPG (-16%; P < 0.001). Arterial compliance was elevated (1.27 versus controls 1.01 ml/mmHg; P < 0.001), but remained almost unchanged during beta-adrenergic blockade (1.27 versus 1.29 ml/mmHg, +2%, ns), whereas...... beta-blockers increases small vessel (arteriolar) vascular tone towards the normal level, but does not affect the elevated compliance of the larger arteries in patients with cirrhosis....

  4. Effect of beta-adrenergic blockade on elevated arterial compliance and low systemic vascular resistance in cirrhosis

    DEFF Research Database (Denmark)

    Møller, Søren; Bendtsen, Flemming; Henriksen, Jens Henrik

    2001-01-01

    beta-blockers, but the effect of this treatment on arterial compliance has not been investigated. The aim of the present study was therefore to assess the effects of propranolol on the arterial compliance of patients with cirrhosis. METHODS: Twenty patients with cirrhosis underwent a haemodynamic......) of 17.8 mmHg, and responded to beta-blocker treatment with a significant reduction in the HVPG (-16%; P < 0.001). Arterial compliance was elevated (1.27 versus controls 1.01 ml/mmHg; P < 0.001), but remained almost unchanged during beta-adrenergic blockade (1.27 versus 1.29 ml/mmHg, +2%, ns), whereas......BACKGROUND: Patients with cirrhosis exhibit a characteristic hyperdynamic circulation with increased cardiac output and heart rate and reduced systemic vascular resistance. The compliance of the arterial tree has recently been reported to be increased in these patients, who are often treated with...

  5. Beta-Adrenergic Receptors and Isoproterenol-stimulated Potassium Transport in Erythrocytes from Normal and Hypothyroid Turkeys: QUANTITATIVE RELATION BETWEEN RECEPTOR OCCUPANCY AND PHYSIOLOGIC RESPONSIVENESS

    OpenAIRE

    Furukawa, Haruyasu; Loeb, John N.; Bilezikian, John P.

    1980-01-01

    We have previously reported that in hypothyroid turkeys the number of beta-adrenergic receptors in intact erythrocytes is reduced by ∼50% without any changes in the affinity of the receptor for the agonist, isoproterenol. In view of the physiological action of the catecholamines to stimulate bidirectional ion fluxes in these cells, we have now examined the possibility that the decrease in beta receptor number might be associated with concomitant changes in catecholamine-dependent potassium io...

  6. Pet measurements of postsynaptic muscarinic and beta adrenergic receptors in the heart

    International Nuclear Information System (INIS)

    There is ample evidence from both experimental and clinical studies that changes in β-adrenergic and muscarinic receptor density can be associated with such cardiac diseases as congestive heart failure, myocardial ischemia and infarction, cardiomyopathy, diabetes, or thyroid-induced muscle disease. Changes in B-adrenergic density also have been shown in the denervated transplanted heart. These alterations of cardiac receptors have been demonstrated in vitro on homogenates from samples collected mainly during surgery or post mortem. Recent developments of Positron Emission Tomography (PET) techniques and of radioligands suitable for cardiac receptor binding studies in vivo have made possible both the imaging and the measurement of receptor density. From these studies, important information is now available concerning physiologic and pathologic conditions, as well as alterations induced by treatment. For the investigation of myocardial B-adrenergic receptors we have used [11C] CGP 12177, a potent hydrophilic antagonist of the 3-adrenergic receptor. The quantification of myocardial muscarinic receptors in vivo has been obtained with [11C] MQNB, a nonmetabolized hydrophilic antagonist of the muscarinic receptor. Receptor density and affinity have been measured by a kinetic, nonequilibrium approach in an experimental protocol that provides sufficient data to determine values for all parameters from a single experiment

  7. Developmental Changes is Expression of Beta-Adrenergic Receptors in Cultures of C2C12 Skeletal Muscle Cells

    Science.gov (United States)

    Young, Ronald B.; Bridge, K. Y.; Vaughn, J. R.

    2000-01-01

    beta-Adrenergic receptor (bAR) agonists have been reported to modulate growth in several mammalian and avian species, and bAR agonists presumably exert their physiological action on skeletal muscle cells through this receptor. Because of the importance of bAR regulation on muscle protein metabolism in muscle cells, the objectives of this study were to determine the developmental expression pattern of the bAR population in C2C12 skeletal muscle cells, and to analyze changes in both the quantity and isoform expression of the major muscle protein, myosin. The number of bAR in mononucleated C2C12 cells was approximately 8,000 bAR per cell, which is comparable with the population reported in several other nonmuscle cell types. However, the bar population increased after myoblast fusion to greater than 50,000 bAR per muscle cell equivalent. The reasons for this apparent over-expression of bAR in C2C12 cells is not known. The quantity of myosin also increased after C2C12 myoblast fusion, but the quantity of myosin was less than that reported in primary muscle cell cultures. Finally, at least five different isoforms of myosin heavy chain could be resolved in C2C12 cells, and three of these exhibited either increased or decreased developmental regulation relative to the others. Thus, C2C12 myoblasts undergo developmental regulation of bAR population and myosin heavy chain isoform expression.

  8. Effect of beta-ADrenergic Agonist on Cyclic AMP Synthesis in Chicken Skeletal Muscle Cells in Culture

    Science.gov (United States)

    Young, R. B.; Bridge, K. Y.; Rose, M. Franklin (Technical Monitor)

    2000-01-01

    Several beta-adrenergic receptor (bAR) agonists are known to cause hypertrophy of skeletal muscle tissue. Because it seems logical that these agonists exert their action on muscle through stimulation of cAMP synthesis, five bAR agonists encompassing a range in activity from strong to weak were evaluated for their ability to stimulate cAMP accumulation in embryonic chicken skeletal muscle cells in culture. Two strong agonists (epinephrine and isoproterenol), one moderate agonist (albuterol), and two weak agonists known to cause hypertrophy in animals (clenbuterol and cimaterol) were studied. Dose response curves were determined over six orders of magnitude in concentration for each agonist, and values were determined for their maximum stimulation of cAMP synthesis rate (Bmax) and the agonist concentration at which 50% stimulation of cAMP synthesis (EC50) occurred. Bmax values decreased in the following order: isoproterenol, epinephrine, albuterol, cimaterol, clenbuterol. Cimaterol and clenbuterol at their Bmax levels were approximately 15-fold weaker than isoproterenol in stimulating the rate of cAMP synthesis. In addition, the EC50 values for isoproterenol, cimaterol, clenbuterol, epinephrine, and albuterol were 360 nM, 630 nM, 900 nM, 2,470 nM, and 3,650 nM, respectively. Finally, dose response curves show that the concentrations of cimaterol and clenbuterol in culture media at concentrations known to cause significant muscle hypertrophy in animals had no detectable effect on stimulation of CAMP accumulation in chicken skeletal muscle cells.

  9. Activation of Cyclic AMP Synthesis by Full and Partial Beta-Adrenergic Receptor Agonists in Chicken Skeletal Muscle Cells

    Science.gov (United States)

    Young, R. B.; Bridge, K. Y.

    2003-01-01

    Several beta-adrenergic receptor (bAR) agonists are known to cause hypertrophy of skeletal muscle tissue. Accordingly, five bAR agonists encompassing a range in activity from strong to weak were evaluated for their ability to stimulate CAMP accumulation in embryonic chicken skeletal muscle cells in culture. Two strong agonists (epinephrine and isoproterenol), one moderate agonist (albuterol), and two weak agonists known to cause hypertrophy in animals (clenbuterol and cimaterol) were studied. Dose response curves were determined over six orders of magnitude in concentration for each agonist, and values were determined for their maximum stimulation of CAMP synthesis rate (Bmax) and the agonist concentration at which 50% stimulation of CAMP synthesis (EC50) occurred. Bmax values decreased in the following order: isoproterenol, epinephrine, albuterol, cimaterol, clenbuterol. Cimaterol and clenbuterol at their Bmax concentrations were approximately 15-fold weaker than isoproterenol in stimulating the rate of CAMP synthesis. When cimaterol and clenbuterol were added to culture media at concentrations known to cause significant muscle hypertrophy in animals, there was no detectable effect on stimulation of CAMP synthesis. Finally, these same levels of cimaterol and clenbuterol did not antagonize the stimulation of CAMP by either epinephrine or isoproterenol.

  10. New beta-adrenergic agonists used illicitly as growth promoters in animal breeding: chemical and pharmacodynamic studies.

    Science.gov (United States)

    Mazzanti, Gabriela; Daniele, Claudia; Boatto, Gianpiero; Manca, Giuliana; Brambilla, Gianfranco; Loizzo, Alberto

    2003-05-01

    Clenbuterol and beta-adrenergic receptor agonist drugs are illegally used as growth promoters in animal production. Pharmacologically active residues in edible tissues led to intoxication outbreaks in several countries. Pressure of official controls pulsed synthesis of new compounds to escape analytical procedures. We report two new compounds named 'A' and 'G4', found in feeding stuffs. Chemical structure was studied through nuclear magnetic resonance-imaging and infrared spectroscopy, and beta(1)- and beta(2)-adrenergic activity was evaluated on isolated guinea-pig atrium and trachea in comparison with clenbuterol. Both compounds share with clenbuterol an halogenated aromatic ring with a primary amino group. Main modifications consisted of substitution of secondary amino group with an alkyl chain in compound A and substitution of the ter-butyl group with a benzene ring in compound G4. In guinea-pig trachea these compounds showed myorelaxant potency lower than clenbuterol (EC(50) was 43.8 nM for clenbuterol, 11700 nM for compound A, 2140 nM for G4). On the contrary, in the guinea-pig atrium (heart-beat rate stimulant effect) the compounds were more potent than clenbuterol (EC(50) was 15.2 nM for clenbuterol, 3.4 nM for compound A, 2.8 nM for G4). These pharmacodynamic properties, and stronger lipophilic properties shown by the two compounds may result in increased cardiovascular risk for consumers of illicitly treated animals. PMID:12699899

  11. Road transportation affects blood hormone levels and lymphocyte glucocorticoid and beta-adrenergic receptor concentrations in calves.

    Science.gov (United States)

    Odore, R; D'Angelo, A; Badino, P; Bellino, C; Pagliasso, S; Re, G

    2004-11-01

    The effect of transportation on blood cortisol and catecholamine levels, lymphocyte glucocorticoid receptor (GR) and beta-adrenergic receptor (beta-AR) concentrations was investigated in calves. Blood samples were collected from 24 six-month-old calves before departure (T(0)), on arrival (T(1)), and at 24 h (T(2)) and one week (T(3)) after arrival. Animals were loaded and transported about 950 km, from the Midy-Pyrenes region (Cahors, France) to the Piedmont region (Italy), over a total of 14 h. Serum cortisol levels and plasma catecholamines (adrenaline, noradrenaline) were determined by radioimmunoassay. Lymphocyte GRs and beta-ARs were measured through binding assays. A significant (P < 0.05) increase in cortisol and catecholamine concentrations was observed immediately after transport. The increase in hormone levels at time T(1) was negatively correlated with lymphocyte GR and beta-AR concentrations. At times T(2) and T(3), blood cortisol and catecholamine levels and lymphocyte GRs and beta-ARs returned to normal. The results demonstrate the activation of the hypothalamic-pituitary-adrenal axis and the catecholaminergic system in long-term transported calves. However, these systems returned to normal within 24 h after the end of transport. PMID:15501147

  12. Cellular effects of beta-adrenergic and of cAMP stimulation on potassium transport in rat alveolar epithelium.

    Science.gov (United States)

    Saumon, G; Basset, G; Bouchonnet, F; Crone, C

    1989-07-01

    Alveolar fluid absorption is greatly enhanced by cAMP and by beta-adrenergic agonists via an increase in Na+ transport. Little is known about K+ homeostasis under these circumstances. We studied K+ transport across alveolar epithelium in isolated perfused rat lungs stimulated either by dibutyryl-cAMP or isoproterenol. K+ fluxes and the apparent permeability of 86Rb across the epithelium (alveoli to plasma) were interpreted according to a model involving two types of cells, B and L, distinguished by the location of Na+-K+-ATPases (basal and luminal). Water is considered to be absorbed by B cells in a solute-coupled process energized by a basolateral Na+-K+-ATPase that is stimulated by isoproterenol and cAMP. K+ transport out of the alveoli is due to the activity of a Na+-K+-ATPase located in the apical membrane of L cells. In the present study net transport rate of K+ was -0.5 +/- 0.15 nmol/s, n = 20 (out of alveoli) in control conditions. When the epithelium was stimulated by dibutyryl-cAMP (10(-4) mol/l) net absorption of K+ reversed to net 'secretion' into alveoli (3.2 +/- 0.31 nmol/s), fluid absorption was not stimulated. K+ 'secretion' was abolished by apical Ba2+, indicating it was due to opening of apical K+ channels. Basolateral ouabain reversed net K+ 'secretion' to net absorption indicating that K+ entry into alveoli was dependent on activity of B cell basolateral Na+-K+-ATPase (masking simultaneous K+ removal by apical L cell Na+-K+-pump). When larger concentrations of dibutyryl-cAMP (10(-3) mol/l) or when isoproterenol were used to stimulate the epithelium there was a tripling of fluid absorption.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2571117

  13. Ultrastructural characterization of noradrenergic- and beta-adrenergic receptor-containing profiles in the lateral nucleus of the amygdala

    Directory of Open Access Journals (Sweden)

    Claudia Farb

    2010-10-01

    Full Text Available Norepinephrine (NE is thought to play a key role in fear and anxiety, but its role in amygdala-dependent Pavlovian fear conditioning, a major model for understanding the neural basis of fear, is poorly understood. The lateral nucleus of the amygdala (LA is a critical brain region for fear learning and regulating the effects of stress on memory. To understand better the cellular mechanisms of NE and its adrenergic receptors in the LA, we used antibodies directed against dopamine beta-hydroxylase (DβH, the synthetic enzyme for NE, or against two different isoforms of the beta-adrenergic receptors (βARs, one that predominately recognizes neurons (βAR 248 and the other astrocytes (βAR 404, to characterize the microenvironments of DβH and βAR. By electron microscopy, most DβH terminals did not make synapses, but when they did, they formed both asymmetric and symmetric synapses. By light microscopy, βARs were present in both neurons and astrocytes. Confocal microscopy revealed that both excitatory and inhibitory neurons express βAR248. By electron microscopy, βAR 248 was present in neuronal cell bodies, dendritic shafts and spines, and some axon terminals and astrocytes. When in dendrites and spines, βAR 248 was frequently concentrated along plasma membranes and at post-synaptic densities of asymmetric (excitatory synapses. βAR 404 was expressed predominately in astrocytic cell bodies and processes. These astrocytic processes were frequently interposed between unlabeled terminals or ensheathed asymmetric synapses. Our findings provide a morphological basis for understanding ways in which NE may modulate transmission by acting via synaptic or non-synaptic mechanisms in the LA.

  14. Alpha- and beta-adrenergic-receptor systems in bronchial asthma and in subjects without asthma: reduced mononuclear cell beta-receptors in bronchial asthma.

    Science.gov (United States)

    Sato, T; Bewtra, A K; Hopp, R J; Nair, N; Townley, R G

    1990-12-01

    We assessed the adrenergic-receptor system in individuals with bronchial hyperreactivity, beta-Adrenergic receptors on mononuclear cell membranes, alpha-adrenergic receptors on platelet membranes, and the cAMP response in these cell types to different stimuli, including platelet-activating factor (PAF), were determined. Studies were assessed in 10 subjects with mild asthma, six methacholine-sensitive subjects without asthma, and 10 normal subjects. The density and affinity of beta-receptors and alpha-receptors were determined by Scatchard analysis. Our findings were that (1) subjects with asthma had a significantly lower density of beta-receptors compared to normal subjects, (2) subjects with asthma had a significantly lower cAMP response to isoproterenol stimulation compared to the two other groups, (3) in subjects without asthma. PAF decreased the basal cAMP level and significantly inhibited the response to isoproterenol stimulation, (4) there was no difference in density and affinity of platelet alpha-receptors or in platelet cAMP responses to stimulation by alpha-agonists among these three groups, and (5) neither cAMP response or beta-receptor density on mononuclear cells were significantly correlated with pulmonary-function tests (FEV/FVC times 100), sensitivity to methacholine, or cold-air inhalation. These results suggest that patients with asthma may have a lower isoproterenol cAMP response and decreased density of beta-adrenergic receptors on mononuclear cells in the absence of beta-agonist therapy. It is speculated that release of PAF and other mediators secondary to allergen exposure, even in the absence of overt attacks of asthma, may inhibit the response to endogenous or exogenous beta-adrenergic agonists. PMID:2175758

  15. Beta-Adrenergic Receptor Population is Up-Regulated in Chicken Skeletal Muscle Cells Treated with Forskolin

    Science.gov (United States)

    Bridge, K. Y.; Young, R. B.; Vaughn, J. R.

    1998-01-01

    Skeletal muscle hypertrophy is promoted by in vivo administration of beta-adrenergic receptor (betaAR) agonists. These compounds presumably exert their physiological action through the betaAR, and alterations in the population of betaAR could potentially change the ability of the cell to respond to the betaAR agonists. Since the intracellular chemical signal generated by the betaAR is cyclic AMP (cAMP), experiments were initiated in primary chicken muscle cell cultures to determine if artificial elevation of intracellular cAMP by treatment with forskolin would alter the population of functional betaAR expressed on the surface of muscle cells. Chicken skeletal muscle cells after 7 days in culture were employed for the experiments because muscle cells have attained a steady state with respect to muscle protein metabolism at this stage. Cells were treated with 0-10 microM forskolin for a total of three days. At the end of the 1, 2, and 3 day treatment intervals, the concentration of cAMP and the betaAR population were measured. Receptor population was measured in intact muscle cell cultures as the difference between total binding of [H-3]CGP-12177 and non-specific binding of [H-3]CGP-12177 in the presence of 1 microM propranolol. Intracellular cAMP concentration was measured by radioimmunoassay. The concentration of cAMP in forskolin-treated cells increased up to 10-fold in a dose dependent manner. Increasing concentrations of forskolin also led to an increase in betaAR population, with a maximum increase of approximately 50% at 10 microM. This increase in PAR population was apparent after only 1 day of treatment, and the pattern of increase was maintained for all 3 days of the treatment period. Thus, increasing the intracellular concentration of cAMP leads to up-regulation of betaAR population. The effect of forskolin on the quantity and apparent synthesis rate of the heavy chain of myosin (mhc) were also investigated. A maximum increase of 50% in the quantity of mhc

  16. Memory Enhancement Induced by Post-Training Intrabasolateral Amygdala Infusions of [beta]-Adrenergic or Muscarinic Agonists Requires Activation of Dopamine Receptors: Involvement of Right, but Not Left, Basolateral Amygdala

    Science.gov (United States)

    LaLumiere, Ryan T.; McGaugh, James L.

    2005-01-01

    Previous findings indicate that the noradrenergic, dopaminergic, and cholinergic innervations of the basolateral amygdala (BLA) modulate memory consolidation. The current study investigated whether memory enhancement induced by post-training intra-BLA infusions of a [beta]-adrenergic or muscarinic cholinergic agonist requires concurrent activation…

  17. Autoradiographic quantitation of. beta. -adrenergic receptors on neural cells in primary cultures. 1. Pharmacological studies of (/sup 125/I)pindolol binding of individual astroglial cells

    Energy Technology Data Exchange (ETDEWEB)

    Burgess, S.K.; McCarthy, K.D. (North Carolina Univ., Chapel Hill (USA). School of Medicine)

    1985-05-27

    The current investigation was undertaken to determine whether the binding of (/sup 125/I)pindolol (*IPIN) to immunocytochemically stained cultured cells, as measured by quantitative autoradiography, would fulfill the usual pharmacological criteria for specific ..beta..-adrenergic receptor binding. *IPIN binding experiments were carried out on individual astroglia obtained from neonatal rat cerebral cortex and grown as primary cultures on polylysine-coated glass slides. Autoradiographic silver grains on cells which stained for the intracellular astroglial marker, glial fibrillary acidic protein (GFAP), were quantified by a microcomputer-based video digitizing system. This study is a demonstration of receptor binding parameters derived from single cells in a known population, and represents a novel approach to the problem of assessing cell-type specific receptors on neural cells in mixed primary cultures.

  18. Effect of Increased Cyclic AMP Concentration on Muscle Protein Synthesis and Beta-Adrenergic Receptor Expression in Chicken Skeletal Muscle Cells in Culture

    Science.gov (United States)

    Young, R. B.; Vaughn, J. R.; Bridge, K. Y.; Smith, C. K.

    1998-01-01

    Analogies of epinephrine are known to cause hypertrophy of skeletal muscle when fed to animals. These compounds presumably exert their physiological action through interaction with the P-adrenergic receptor. Since the intracellular signal generated by the Beta-adrenergic receptor is cyclic AMP (cAMP), experiments were initiated in cell culture to determine if artificial elevation of cAMP by treatment with forskolin would alter muscle protein metabolism and P-adrenergic receptor expression. Chicken skeletal muscle cells after 7 days in culture were treated with 0.2-30 micrometers forskolin for a total of three days. At the end of the treatment period, both the concentration of cAMP and the quantity of myosin heavy chain (MHC) were measured. Concentration of cAMP in forskolin-treated cells increased up to 10-fold in a dose dependent manner. In contrast, the quantity of MHC was increased approximately 50% above control cells at 0.2 micrometers forskolin, but exhibited a gradual decline at higher levels of forskolin so that the quantity of MHC in cells treated with 30 micrometers forskolin was not significantly different from controls. Curiously, the intracellular concentration of cAMP which elicited the maximum increase in the quantity of MHC was only 40% higher than cAMP concentration in control cells.

  19. Exercise induced changes in lymphocyte beta adrenergic receptors correlate with peak exercise heart rates in healthy trained and sedentary human subjects

    International Nuclear Information System (INIS)

    Lymphocyte beta adrenergic receptors (lymph BAR) increase after maximal multistage treadmill exercise (TME) presumably by externalization from intracellular vesicles. Nine healthy subjects underwent symptom limited TME by the Bruce protocol. Heart rate was measured at the end of each 3 minute stage. Plasma norepinephrine (NE), plasma epinephrine (EPI) and lymph BAR were measured at rest and at peak exercise. Catecholamines were determined by high performance liquid chromatography. Lymph BAR were measured by separating cells from 25cc of whole blood across a Ficoll-Hypaque density gradient and incubating membrane preparations with 7 dilutions of I125 cyanopindolol in the presence or absence of 1μM(-) propranolol in a total assay volume of 450 μl. BAR was standardized to Lowry-Peterson protein at rest and exercise. The relationship of maximum heart rate versus peak plasma NE, EPI and lymph BAR was analyzed by linear regression. The following conclusions were reached: (1) there is a significant correlation between exercise induced changes in lymph BAR and peak heart rate; (2) this relationship does not exist between peak plasma NE or EPI and peak heart rate

  20. Exercise induced changes in lymphocyte beta adrenergic receptors correlate with peak exercise heart rates in healthy trained and sedentary human subjects

    Energy Technology Data Exchange (ETDEWEB)

    Eisinger, M.; Engelmeier, R.; Glisson, S.; Scanlon, P.

    1986-03-05

    Lymphocyte beta adrenergic receptors (lymph BAR) increase after maximal multistage treadmill exercise (TME) presumably by externalization from intracellular vesicles. Nine healthy subjects underwent symptom limited TME by the Bruce protocol. Heart rate was measured at the end of each 3 minute stage. Plasma norepinephrine (NE), plasma epinephrine (EPI) and lymph BAR were measured at rest and at peak exercise. Catecholamines were determined by high performance liquid chromatography. Lymph BAR were measured by separating cells from 25cc of whole blood across a Ficoll-Hypaque density gradient and incubating membrane preparations with 7 dilutions of I/sup 125/ cyanopindolol in the presence or absence of 1..mu..M(-) propranolol in a total assay volume of 450 ..mu..l. BAR was standardized to Lowry-Peterson protein at rest and exercise. The relationship of maximum heart rate versus peak plasma NE, EPI and lymph BAR was analyzed by linear regression. The following conclusions were reached: (1) there is a significant correlation between exercise induced changes in lymph BAR and peak heart rate; (2) this relationship does not exist between peak plasma NE or EPI and peak heart rate.

  1. Incidence of sudden cardiac death associated with coronary artery occlusion in dogs with hypertension and left ventricular hypertrophy is reduced by chronic beta-adrenergic blockade.

    Science.gov (United States)

    Dellsperger, K C; Martins, J B; Clothier, J L; Marcus, M L

    1990-09-01

    Because beta-adrenergic blockade has as one of its many effects altered electrophysiological abnormalities after dogs with left ventricular hypertrophy have been subjected to coronary occlusion, we tested the hypothesis that metoprolol (200-400 mg/day) would reduce mortality rates in dogs with one-kidney, one clip left ventricular hypertrophy while a similar reduction in arterial pressure with enalapril (20-40 mg/day) would not. Dogs with left ventricular hypertrophy were given metoprolol or enalapril for 5-7 days before a 3-hour coronary occlusion. Infarct size and risk area were measured with triphenyltetrazolium chloride stain and barium angiography, respectively. For control (n = 15), left ventricular hypertrophy (n = 17), left ventricular hypertrophy plus metoprolol (n = 12), and left ventricular hypertrophy plus enalapril (n = 15) groups, mean arterial pressure, ratio of infarct size to risk area, and dogs experiencing sudden death were 110 +/- 4, 142 +/- 4, 121 +/- 7, and 120 +/- 3 mm Hg; 44 +/- 5%, 65 +/- 5%, 44 +/- 7%, and 30 +/- 4%; and 27%, 65%, 17%, and 53%, respectively. Thus, the excessive increase in early mortality occurring when dogs with hypertension and left ventricular hypertrophy undergo coronary occlusion is interrupted with beta-blockade, possibly via electrophysiological effects rather than by changes in arterial pressure or infarct size. PMID:1975521

  2. Calcium-linked increase in coupled cAMP synthesis and hydrolysis is an early event in cholinergic and. beta. -adrenergic stimulation of parotid secretion

    Energy Technology Data Exchange (ETDEWEB)

    Deeg, M.A.; Graeff, R.M.; Walseth, T.F.; Goldberg, N.D. (Univ. of Minnesota, Minneapolis (USA))

    1988-11-01

    The dynamics and compartmental characteristics of cAMP metabolism were examined by {sup 18}O labeling of cellular adenine nucleotide {alpha} phosphoryls in rat parotid gland stimulated to secrete with {beta}-adrenergic and cholinergic agents. The secretory response occurred in association with a rapidly increased rate of cAMP hydrolysis apparently coordinated with an equivalent increase in the rate of cAMP synthesis, since the cellular concentration of cAMP remained unchanged. The magnitude of this metabolic response was equivalent to the metabolism of 10-75 times the cellular content of cAMP within the first minute of stimulation. This increased metabolic rate occurred only during the early (1-3 min) period of stimulation, in what appeared to be an exclusive cellular compartment distinguished by a unique distribution of {sup 18}O among adenine nucleotide {alpha} phosphoryls. This {sup 18}O distribution contrasted with that produced by forskolin, which increased cellular cAMP concentration and elicited only a delayed response missing the early secretory component. The early acceleration of cAMP metabolism appeared linked to a stimulus-induced increase in intracellular Ca{sup 2+} concentration, since the Ca{sup 2+} ionophore ionomycin produced the same metabolic response in association with secretion. These observations suggest that cAMP metabolism is involved in stimulus-secretion coupling by a Ca{sup 2+}-linked mechanism different from that in which cAMP plays the role of a second messenger.

  3. Effect of electrical stimulation on beta-adrenergic receptor population and cyclic amp production in chicken and rat skeletal muscle cell cultures

    Science.gov (United States)

    Young, R. B.; Bridge, K. Y.; Strietzel, C. J.

    2000-01-01

    Expression of the beta-adrenergic receptor (betaAR) and its coupling to cyclic AMP (cAMP) synthesis are important components of the signaling system that controls muscle atrophy and hypertrophy, and the goal of this study was to determine if electrical stimulation in a pattern simulating slow muscle contraction would alter the betaAR response in primary cultures of avian and mammalian skeletal muscle cells. Specifically, chicken skeletal muscle cells and rat skeletal muscle cells that had been grown for 7 d in culture were subjected to electrical stimulation for an additional 2 d at a pulse frequency of 0.5 pulses/sec and a pulse duration of 200 msec. In chicken skeletal muscle cells, the betaAR population was not significantly affected by electrical stimulation; however, the ability of these cells to synthesize cyclic AMP was reduced by approximately one-half. In contrast, the betaAR population in rat muscle cells was increased slightly but not significantly by electrical stimulation, and the ability of these cells to synthesize cyclic AMP was increased by almost twofold. The basal levels of intracellular cyclic AMP in neither rat muscle cells nor chicken muscle cells were affected by electrical stimulation.

  4. The beta-adrenergic blocker carvedilol restores L-type calcium current in a myocardial infarction model of rabbit

    Institute of Scientific and Technical Information of China (English)

    LI Xia; HUANG Cong-xin; JIANG Hong; CAO Feng; WANG Teng

    2005-01-01

    Background Carvedilol, an antagonist of α1- and β-adrenergic receptors, has shown efficacy in reducing all-cause death and arrhythmia death for ischemic heart disease and congestive heart failure in several large-scale trials. It has been found to prevent ventricular remodeling, and recently was reported to reverse down-regulation of Na+ channel in a chronic heart failure model. This study was conducted to investigate whether carvedilol could reverse the ion remodeling in a myocardial infarction model of rabbit.Methods After the procedure of coronary ligation, animals were randomized to placebo or carvedilol treatment (5 mg/kg). Action potentials, L-type calcium current (Ica L) and the effect of isoproterenol stimulation on Ica L were measured using whole-cell patch method. Evaluation of the expression of calcium channel subunits was carried out by RT-PCR and Western blot. Results The results indicate that mean peak Ica L densities (pA/pF) at +10 mV was reduced in postinfarction myocytes (5.33±0.45, n=25) compared to sham myocytes (6.52±0.21, n=20). Treatment of myocardial infarction rabbits with carvedilol could restore it partially (5.91±0.39, n=20, P<0.05). However, steady-state activation parameters were similar in three groups. With stimulation by isoproterenol (1 μmol/L) Ica L increased in all three groups, but the increase was smaller in postinfarction myocytes. mRNA levels of calcium channel subunit CaA1 gene was decreased but CaB2a, CaB2b and CaB3 mRNA levels did not change after MI. Corresponding change in CaA1 protein was also observed. Conclusions The results demonstrate that carvedilol restores Ica L density and reverse the downregulation of CaA1 postinfarction.

  5. The second Lilly Prize Lecture, University of Newcastle, July 1977. beta-Adrenergic receptor blockade in hypertension, past, present and future.

    Science.gov (United States)

    Prichard, B N

    1978-01-01

    All beta-adrenoceptor blocking drugs that have been described share the common property of being competitive inhibitors. They differ in their associated properties, the presence or absence of cardioselectivity, membrane stabilizing activity, and partial agonist activity. Recently some beta-adrenoceptor blocking drugs have been reported which also possess alpha-adrenoceptor blocking activity. The associated properties have been used as a basis for classifying beta-adrenoceptor blocking drugs (Fitzgerald, 1969, 1972). The presence or absence of cardioselectivity is most useful for dividing beta-adrenoceptor blocking drugs. The non-selective drugs (Division I) can be further divided according to the presence or absence of intrinsic sympathomimetic activity (ISA) and membrane stabilizing activity (Fitzgerald's groups I-IV). Group I possess both membrane activity and ISA, e.g. alprenolol, oxprenolol, group II just membrane action, e.g. propanolol, group III ISA but no membrane action, e.g. pindolol. Fitzgerald placed pindolol in group I but should be placed in group III as it possesses a high degree of beta-adrenoceptor blocking potency in relation to its membrane activity (Prichard, 1974). Finally drugs in group IV have neither ISA nor membrane action, e.g. sotalol, timolol. The cardioselective drugs (Division II) can be similarly sub-divided into groups I-IV according to the presence or absence of ISA or membrane action (Fitzgerald grouped all these together as group V). Lastly there are new beta-adrenergic receptor blocking drugs which in addition have alpha- adrenergic receptor blocking properties (Division III). PMID:26370

  6. Effect of Electrical Stimulation on Beta-Adrenergic Receptor Population and Coupling Efficiency in Chicken and Rat Skeleton Muscle Cell Cultures

    Science.gov (United States)

    Young, Ronald B.; Bridge, Kristin Y.; Strietzel, Catherine J.

    1999-01-01

    Expression of the beta-adrenergic receptor (bAR) and its coupling to cyclic AMP (cAMP) synthesis are important components of the signaling system that controls muscle atrophy and hypertrophy, and the goal of this study was to determine if electrical stimulation in a pattern simulating slow muscle contraction would alter the bAR response in primary cultures of avian and mammalian skeletal muscle cells. Specifically, chicken skeletal muscle cells and rat skeletal muscle cells that had been grown for seven days in culture were subjected to electrical stimulation for an additional two days at a pulse frequency of 0.5 pulses/sec and a pulse duration of 200 msec. In chicken skeletal muscle cells, the bAR population was not significantly affected by electrical stimulation; however, the ability of these cells to synthesize cyclic AMP was reduced by approximately one-half. Thus, in chicken muscle cells an enhanced level of contraction reduced the coupling efficiency of bAR for cyclic AMP production by approximately 55% compared to controls. In contrast, the bAR population in rat muscle cells was increased by approximately 25% by electrical stimulation, and the ability of these cells to synthesize cyclic AMP was also increased by almost two-fold. Thus, in rat muscle cells an enhanced level of contraction increased the coupling efficiency of bAR for cyclic AMP production by approximately 50% compared to controls. The basal levels of intracellular cyclic AMP in both rat muscle cells and chicken muscle cells were not affected by electrical stimulation.

  7. Beta-adrenergic stimulation of cFOS via protein kinase A is mediated by cAMP regulatory element binding protein (CREB)-dependent and tissue-specific CREB-independent mechanisms in corticotrope cells.

    Science.gov (United States)

    Boutillier, A L; Barthel, F; Roberts, J L; Loeffler, J P

    1992-11-25

    Catecholamines stimulate proopiomelanocortin (POMC) gene expression in corticotrope cells, but the molecular mechanisms of these effects are not known. While beta-adrenergic receptors stimulate the protein kinase A (PKA) system, the POMC promoter does not have classical cAMP-response elements (CREs). Therefore, we investigated the induction of the c-fos protooncogen, previously shown to increase POMC transcription in AtT20 cells. In this corticotrope-derived cell line, we show that activation of beta-receptors with isoprenaline (Iso) induces a transient rise in c-fos mRNA levels. Gel mobility shift assays with a labeled AP1 consensus sequence (TGACTCA) showed induction of specific binding activity after Iso treatment. Cotransfection experiments with dominant inhibitory PKA mutants and reporter genes containing c-fos promoter sequences showed that c-fos induction by Iso is entirely dependent on a functional PKA activity. Furthermore, we show that beta-receptor induction of c-fos in corticotrophs is mediated by at least two distinct cAMP-responsive sequences. cAMP regulatory element binding (CREB)-dependent induction is observed on the CRE located at -60 bp on the c-fos promoter. A region located in the vicinity of the dyad symetry element (-290) is also found to mediate tissue-specific cAMP induction. Transcriptional activation by this site, although sensitive to PKA antagonism, is not blocked by CREB mutants. PMID:1331087

  8. Drug-induced regulation of 1,4-dihydropyridine Ca sup 2+ channel antagonist binding sites in the brain and heart

    Energy Technology Data Exchange (ETDEWEB)

    Ramkumar, V.

    1987-01-01

    The ability of drugs to regulate the voltage-sensitive Ca{sup 2+} channels were assessed by determining the bind of ({sup 3}H)dihydropyridine Ca{sup 2+} channel antagonists in the heart and brain following administration of these drugs to rats and mice. Mice and rats implanted with morphine pellets for 3 days showed an increase in dihydropyridine binding sites in the brain, compared to non-treated or placebo treated controls. No increase in dihydropyridine binding sites was observed in the heart. The significance of the increase in binding to physical dependence on morphine is implied from the findings that pretreatment with Ca{sup 2+} channel antagonist drugs led to an attenuation of naloxone-precipitated withdrawal signs in both dependent rats and mice. Administration of other drugs, known to depress the CNS, was undertaken to determine whether the changes observed with morphine was a nonspecific response of the brain to depressant drugs. Prolonged administration of reserpine to rats resulted in no changes in dihydropyridine binding sites in the brain, even though the {beta}-adrenergic receptors in this tissue are upregulated. However, reserpine decreased the density of ({sup 3}H)nimodipine binding sites in the heart of this is accompanied by concomitant increases in {beta}-adrenergic receptors.

  9. A dose–response study of the effects of pre-test administration of beta-adrenergic receptor antagonist propranolol on the learning of active place avoidance, a spatial cognition task, in rats

    Czech Academy of Sciences Publication Activity Database

    Stuchlík, Aleš; Petrásek, Tomáš; Valeš, Karel

    2009-01-01

    Roč. 200, č. 1 (2009), s. 144-149. ISSN 0166-4328 R&D Projects: GA ČR(CZ) GA309/07/0341; GA ČR(CZ) GA309/09/0286 Institutional research plan: CEZ:AV0Z50110509 Keywords : propranolol * learning * spatial memory Subject RIV: FH - Neurology Impact factor: 3.220, year: 2009

  10. Human fat cell alpha-2 adrenoceptors. I. Functional exploration and pharmacological definition with selected alpha-2 agonists and antagonists

    International Nuclear Information System (INIS)

    This study was undertaken to investigate more fully the pharmacological characteristics of the human fat cell alpha-2 adrenoceptor. Biological assays were performed on intact isolated fat cells while radioligand binding studies were carried out with [3H]yohimbine in membranes. These pharmacological studies brought: (1) a critical definition of the limits of the experimental conditions required for the exploration of alpha-2 adrenergic responsiveness on human fat cells and membranes; (2) an improvement in the pharmacological definition of the human fat cell postsynaptic alpha-2 adrenoceptor. Among alpha-2 agonists, UK-14,304 was the most potent and the relative order of potency was: UK-14,304 greater than p-aminoclonidine greater than clonidine = B-HT 920 greater than rilmenidine. For alpha-2 antagonists, the potency order was: yohimbine greater than idazoxan greater than SK ampersand F-86,466 much greater than benextramine; (3) a description of the impact of benextramine (irreversible alpha-1/alpha-2 antagonist) on human fat cell alpha-2 adrenergic receptors and on human fat cell function; the drug inactivates the alpha-2 adrenergic receptors with a minor impact on beta adrenergic receptors and without noticeable alterations of fat cell function as assessed by preservation of beta adrenergic and Al-adenosine receptor-mediated lipolytic responses; and (4) a definition of the relationship existing between alpha-2 adrenergic receptor occupancy, inhibition of adenylate cyclase activity and antilipolysis with full and partial agonists. The existence of a receptor reserve must be taken into account when evaluating alpha-2 adrenergic receptor distribution and regulation of human fat cells

  11. Exposure to cAMP and beta-adrenergic stimulation recruits Ca(V)3 T-type channels in rat chromaffin cells through Epac cAMP-receptor proteins.

    Science.gov (United States)

    Novara, M; Baldelli, P; Cavallari, D; Carabelli, V; Giancippoli, A; Carbone, E

    2004-07-15

    T-type channels are expressed weakly or not at all in adult rat chromaffin cells (RCCs) and there is contrasting evidence as to whether they play a functional role in catecholamine secretion. Here we show that 3-5 days after application of pCPT-cAMP, most RCCs grown in serum-free medium expressed a high density of low-voltage-activated T-type channels without altering the expression and characteristics of high-voltage-activated channels. The density of cAMP-recruited T-type channels increased with time and displayed the typical biophysical and pharmacological properties of low-voltage-activated Ca(2+) channels: (1) steep voltage-dependent activation from -50 mV in 10 mm Ca(2+), (2) slow deactivation but fast and complete inactivation, (3) full inactivation following short conditioning prepulses to -30 mV, (4) effective block of Ca(2+) influx with 50 microM Ni(2+), (5) comparable permeability to Ca(2+) and Ba(2+), and (6) insensitivity to common Ca(2+) channel antagonists. The action of exogenous pCPT-cAMP (200 microM) was prevented by the protein synthesis inhibitor anisomycin and mimicked in most cells by exposure to forskolin and 1-methyl-3-isobutylxanthine (IBMX) or isoprenaline. The protein kinase A (PKA) inhibitor H89 (0.3 microM) and the competitive antagonist of cAMP binding to PKA, Rp-cAMPS, had weak or no effect on the action of pCPT-cAMP. In line with this, the selective Epac agonist 8CPT-2Me-cAMP nicely mimicked the action of pCPT-cAMP and isoprenaline, suggesting the existence of a dominant Epac-dependent recruitment of T-type channels in RCCs that may originate from the activation of beta-adrenoceptors. Stimulation of beta-adrenoceptors occurs autocrinally in RCCs and thus, the neosynthesis of low-voltage-activated channels may represent a new form of 'chromaffin cell plasticity', which contributes, by lowering the threshold of action potential firing, to increasing cell excitability and secretory activity during sustained sympathetic stimulation and

  12. GABAB antagonists

    DEFF Research Database (Denmark)

    Frydenvang, Karla Andrea; Hansen, J J; Krogsgaard-Larsen, P;

    1994-01-01

    Phaclofen, which is the phosphonic acid analogue of the GABAB agonist (RS)-3-(4-chlorophenyl)-4-aminobutyric acid (baclofen), is a GABAB antagonist. As part of our studies on the structural requirements for activation and blockade of GABAB receptors, we have resolved phaclofen using chiral...... chromatographic techniques. The absolute stereochemistry of (-)-(R)-phaclofen was established by X-ray crystallographic analysis. (-)-(R)-Phaclofen was shown to inhibit the binding of [3H]-(R)-baclofen to GABAB receptor sites on rat cerebellar membranes (IC50 = 76 +/- 13 microM), whereas (+)-(S)-phaclofen was...... inactive in this binding assay (IC50 > 1000 microM). (-)-(R)-Phaclofen (200 microM) was equipotent with (RS)-phaclofen (400 microM) in antagonizing the action of baclofen in rat cerebral cortical slices, while (+)-(S)-phaclofen (200 microM) was inactive. The structural similarity of the agonist (R)-baclofen...

  13. ACTH Antagonists

    Science.gov (United States)

    Clark, Adrian John; Forfar, Rachel; Hussain, Mashal; Jerman, Jeff; McIver, Ed; Taylor, Debra; Chan, Li

    2016-01-01

    Adrenocorticotropin (ACTH) acts via a highly selective receptor that is a member of the melanocortin receptor subfamily of type 1 G protein-coupled receptors. The ACTH receptor, also known as the melanocortin 2 receptor (MC2R), is unusual in that it is absolutely dependent on a small accessory protein, melanocortin receptor accessory protein (MRAP) for cell surface expression and function. ACTH is the only known naturally occurring agonist for this receptor. This lack of redundancy and high degree of ligand specificity suggests that antagonism of this receptor could provide a useful therapeutic aid and a potential investigational tool. Clinical situations in which this could be useful include (1) Cushing’s disease and ectopic ACTH syndrome – especially while preparing for definitive treatment of a causative tumor, or in refractory cases, or (2) congenital adrenal hyperplasia – as an adjunct to glucocorticoid replacement. A case for antagonism in other clinical situations in which there is ACTH excess can also be made. In this article, we will explore the scientific and clinical case for an ACTH antagonist, and will review the evidence for existing and recently described peptides and modified peptides in this role. PMID:27547198

  14. Calcium channel antagonist and beta-blocker overdose: antidotes and adjunct therapies.

    Science.gov (United States)

    Graudins, Andis; Lee, Hwee Min; Druda, Dino

    2016-03-01

    Management of cardiovascular instability resulting from calcium channel antagonist (CCB) or beta-adrenergic receptor antagonist (BB) poisoning follows similar principles. Significant myocardial depression, bradycardia and hypotension result in both cases. CCBs can also produce vasodilatory shock. Additionally, CCBs, such as verapamil and diltiazem, are commonly ingested in sustained-release formulations. This can also be the case for some BBs. Peak toxicity can be delayed by several hours. Provision of early gastrointestinal decontamination with activated charcoal and whole-bowel irrigation might mitigate this. Treatment of shock requires a multimodal approach to inotropic therapy that can be guided by echocardiographic or invasive haemodynamic assessment of myocardial function. High-dose insulin euglycaemia is commonly recommended as a first-line treatment in these poisonings, to improve myocardial contractility, and should be instituted early when myocardial dysfunction is suspected. Catecholamine infusions are complementary to this therapy for both inotropic and chronotropic support. Catecholamine vasopressors and vasopressin are used in the treatment of vasodilatory shock. Optimizing serum calcium concentration can confer some benefit to improving myocardial function and vascular tone after CCB poisoning. High-dose glucagon infusions have provided moderate chronotropic and inotropic benefits in BB poisoning. Phosphodiesterase inhibitors and levosimendan have positive inotropic effects but also produce peripheral vasodilation, which can limit blood pressure improvement. In cases of severe cardiogenic shock and/or cardiac arrest post-poisoning, extracorporeal cardiac assist devices have resulted in successful recovery. Other treatments used in refractory hypotension include intravenous lipid emulsion for lipophilic CCB and BB poisoning and methylene blue for refractory vasodilatory shock. PMID:26344579

  15. [Metabolism of beta-adrenergic substances. Therapeutic implications].

    Science.gov (United States)

    Brès, J; Clauzel, A M; Pistre, M C; Rachmat, H; Bressolle, F

    1985-01-01

    The metabolism of the main beta-adrenoceptor stimulants which are not catechol derivatives involves conjugation with glucuronic or sulphuric acids in several animal species and conjugation with sulphuric acid in man. These drugs are not metabolized by MAO like isoproterenol or by COMT like the catechol derivatives: isoproterenol, trimetoquinol, hexoprenaline and rimiterol. Sulphate conjugation, in man, increases with the number of hydroxy groups. For salbutamol, pirbuterol, terbutaline and fenoterol, about 30%, 30%, 15% and 10% are respectively present in plasma as the unchanged active compound. Clenbuterol, a new specific beta 2-adrenoceptor stimulant, is a 4-amino-3,5 dichloro-benzene derivative and cannot be conjugated. It is cleared from the body mainly by the renal route (43% of the administered dose) and has eight minor metabolites, identical in several animal species and in man. Tulobuterol with no hydroxy substitute does not undergo conjugation, but is metabolized to 4-hydroxy tulobuterol. This metabolite is shown to be eight times more potent than tulobuterol. Metabolism depends greatly upon the route of administration: intravenous, subcutaneous, oral, by aerosol or instillation into the bronchial tree. Conjugation or COMT inactivation can take place in the gut wall (terbutaline), in lungs (isoproterenol, terbutaline, rimiterol) or by hepatic first-pass. These processes decrease the amount of drug reaching the blood and the receptor sites. Metabolism in the lung is important for ibuterol (terbutaline diisobutyrate), which is more lipophilic than terbutaline and spreads throughout tissues where it is hydrolyzed to active terbutaline. Biotransformations are determined by environmental or genetic factors and by the associated therapy and can change dramatically from one patient to another (interindividual variability) or for the same patient by multiple dosing (intra-individual variability). These differences in the rates of the metabolism can explain, partly, the differences observed in the response to beta-adrenoceptor stimulants by responder or non-responder patients. Decision about a therapeutic dosage regiment involves the choice of the drug, of the route of administration and of the dose. This choice is made on the basis of the dose/response relationship. In the kinetic approach, pharmacokinetic data obtained after a single dose facilitate the development of an appropriate dosage regimen. PMID:2865990

  16. Beta-Adrenergic gene therapy for cardiovascular disease

    Directory of Open Access Journals (Sweden)

    Koch Walter J

    2000-10-01

    Full Text Available Abstract Gene therapy using in vivo recombinant adenovirus-mediated gene transfer is an effective technique that offers great potential to improve existing drug treatments for the complex cardiovascular diseases of heart failure and vascular smooth muscle intimal hyperplasia. Cardiac-specific adenovirus-mediated transfer of the carboxyl-terminus of the β-adrenergic receptor kinase (βARKct, acting as a Gβγ-β-adrenergic receptor kinase (βARK1 inhibitor, improves basal and agonist-induced cardiac performance in both normal and failing rabbit hearts. In addition, βARKct adenovirus infection of vascular smooth muscle is capable of significantly diminishing neointimal proliferation after angioplasty. Therefore, further investigation is warranted to determine whether inhibition of βARK1 activity and sequestration of Gβγ via an adenovirus that encodes the βARKct transgene might be a useful clinical tool for the treatment of cardiovascular pathologies.

  17. Illegal use of beta-adrenergic agonists: European Community.

    Science.gov (United States)

    Kuiper, H A; Noordam, M Y; van Dooren-Flipsen, M M; Schilt, R; Roos, A H

    1998-01-01

    The use of veterinary medicinal products within the European Community is governed by a series of directives and regulations that describe the requirements for safety, quality, and efficacy of these products. Veterinary therapeutic use of beta-agonists has only been approved in the case of clenbuterol for bronchodilatation in horses and calves and for tocolysis in cows. No beta-agonists have been permitted in the European Community for growth-promoting purposes in farm animals. Surveillance for the presence of residues of veterinary agents in food-producing animals and meat is regulated by the Directive 86/469/EEC containing specific guidelines for sampling procedures on farms and in slaughterhouses. The level and frequency of sampling is dependent on the category of compounds and animal species. When positive samples have been identified (above certain action levels), sampling intensity is increased. Results of monitoring programs in EU member states during 1992 and 1993 for the occurrence of residues of beta-agonists in food-producing animals vary substantially with respect to the percentages of positive samples, ranging from 0 to 7%. The variability is partly explained by differences in sampling strategies, detection methods, and action levels applied. Identification of the proper matrices for sampling and detection of beta-agonists is important. In the case of clenbuterol, hair and choroid retinal tissue are appropriate tissues because clenbuterol accumulates in these matrices. A clear decrease in the use of clenbuterol in cattle has been observed in The Netherlands, Germany, Northern Ireland, and Spanish Basque Country over the last 3 yr. This is partly due to intensified surveillance activities at farms and slaughterhouses by governmental agencies and production sector organizations. There are data on human intoxication following consumption of liver or meat from cattle treated with beta-agonists. At the concentrations of clenbuterol measured in contaminated liver and meat samples, pharmacological effects may be expected in humans after consuming 100 to 200 g of product. The use of highly active beta-agonists as growth promoters is not appropriate because of the potential hazard for human and animal health, as was recently concluded at the scientific Conference on Growth Promotion in Meat Production (Nov. 1995, Brussels). PMID:9464899

  18. Characterization of potent and selective antagonists at postsynaptic 5-HT1A receptors in a series of N4-substituted arylpiperazines.

    Science.gov (United States)

    Peglion, J L; Canton, H; Bervoets, K; Audinot, V; Brocco, M; Gobert, A; Le Marouille-Girardon, S; Millan, M J

    1995-09-29

    Benzocycloalkyl and benzocycloalkenyl moities linked, directly or via an alkyl chain, to oxygen-bearing heteroarylpiperazines were synthesized, in an attempt to obtain potent and selective antagonists at postsynaptic 5-HT1A receptors. From the numerous arylpiperazines described in the literature, 1-(2,3-dihydro-1,4-benzodioxin-5-yl)piperazine (3a) was chosen as a model of an arylpiperazine in view of its selectivity for 5-HT1A receptors versus alpha 1-, alpha 2-, and beta-adrenergic receptors, as well as dopamine D1 and D2 receptors. Two other closely-related arylpiperazines, 1-(1,5-benzodioxepin-6-yl)piperazine (3b) and 1-(benzofuran-7-yl)piperazine (3c), were also examined in this study. All compounds showed high affinity at 5-HT1A sites (8.10 pKis 10-fold selectivity in vitro for 5-HT1A versus alpha 1-adrenergic receptors. Compound 14 displayed an optimal compromise between potency (pKi = 8.75), marked antagonist activity, and selectivity toward alpha 1-adrenergic (81-fold) and dopamine D2 (195-fold) receptors. These characteristics clearly distinguish 14 from previously-reported ligands such as the postsynaptic 5-HT1A antagonist BMY 7378 and the weak partial agonist NAN 190 which, in contrast to the compounds of this series, belong to the well-exemplified class of imido derivatives of (o-methoxyphenyl)piperazines. The availability of 14 (S 15535) should facilitate the further elucidation of the functional role and potential therapeutic significance of 5-HT1A receptors. PMID:7562940

  19. Effects and mechanism of different adrenergic receptor antagonists on left ventricular hypertrophy subsequent to coarctation of abdominal aorta in rats

    Institute of Scientific and Technical Information of China (English)

    HU Qin; LI Long-gui; ZHANG Yun

    2004-01-01

    To study the changes of a collagen-binding protein (Colligin) and myosin heavy chain isoform (α/β-MHC) gene and protein in left ventricular hypertrophy subsequent to coarctation of abdominal aorta in rats and the ef-fects of three kinds of adrenergic receptor blockers: Carvedilol (CAR), Metoprolol (MET) and Terazosin (TER) on these changes, and to elucidate the effects and new mechanism of CAR on left ventricular hypearophy regression. Methods: A model of hypertrophy induced by coarctation of abdominal aorta(CAA) was used in this study. Thirty two male istar rats were divided randomly into four groups 4 weeks after CAA operation: CAA, CAR, MET and TER.emodynamics, ventric-ular remodeling parameters, expressions of Colligin and α/β-MHC mRNA, protein expressions of Collagen Ⅰ /Ⅲ and Colligin were investigated in the four groups and sham operation group. Results: Left ventricle hypertrophy was observed clearly 16 weeks after operation. The ratio of α/β-MHC mRNA decreased, while expressions of Collagen Ⅰ/Ⅲ proteins and Colligin mRNA/protein increased( P < 0.05). CAR could ameliorate left ventricle hypertrophy prior to MET and TER. CAR could also change the expressions of α/β-MHC, Collagen Ⅰ/Ⅲ and Colligin in both gene and protein levels ( P < 0.05), while MET and TER have no effect on them ( P > 0.05). Conclusion: The effects of CAR on extracellular matrix proteins and MHC isoform shift regression of left ventricle may be due to antiproliferative or antioxidative mechanism, which was indepen-dent of beta-adrenergic receptor antagonist.

  20. A Foldable Antagonistic Actuator

    OpenAIRE

    Shintake, Jun; Rosset, Samuel; Schubert, Bryan Edward; Floreano, Dario; Shea, Herbert

    2015-01-01

    We report on an actuator based on dielectric elastomers that is capable of antagonistic actuation and passive folding. This actuator enables foldability in robots with simple structures. Unlike other antagonistic dielectric elastomer devices, our concept uses elastic hinges to allow the folding of the structure, which also provides an additional design parameter. To validate the actuator concept through a specific application test, a foldable elevon actuator with outline size of 70 mm × 130 m...

  1. Selective orexin receptor antagonists.

    Science.gov (United States)

    Lebold, Terry P; Bonaventure, Pascal; Shireman, Brock T

    2013-09-01

    The orexin, or hypocretin, neuropeptides (orexin-A and orexin-B) are produced on neurons in the hypothalamus which project to key areas of the brain that control sleep-wake states, modulation of food intake, panic, anxiety, emotion, reward and addictive behaviors. These neuropeptides exert their effects on a pair of G-protein coupled receptors termed the orexin-1 (OX1) and orexin-2 (OX2) receptors. Emerging biology suggests the involvement of these receptors in psychiatric disorders as they are thought to play a key role in the regulation of multiple systems. This review is intended to highlight key selective OX1 or OX2 small-molecule antagonists. PMID:23891187

  2. Immediate post-defeat infusions of the noradrenergic receptor antagonist propranolol impair the consolidation of conditioned defeat in male Syrian hamsters.

    Science.gov (United States)

    Gray, Cloe Luckett; Krebs-Kraft, Desiree L; Solomon, Matia B; Norvelle, Alisa; Parent, Marise B; Huhman, Kim L

    2015-12-01

    Social defeat occurs when an animal is attacked and subjugated by an aggressive conspecific. Following social defeat, male Syrian hamsters fail to display species-typical territorial aggression and instead exhibit submissive or defensive behaviors even when in the presence of a non-aggressive intruder. We have termed this phenomenon conditioned defeat (CD). The mechanisms underlying CD are not fully understood, but data from our lab suggest that at least some of the mechanisms are similar to those that mediate classical fear conditioning. The goal of the present experiment was to test the hypothesis that noradrenergic signaling promotes the consolidation of CD, as in classical fear conditioning, by determining whether CD is disrupted by post-training blockade of noradrenergic activity. In Experiment 1, we determined whether systemic infusions of the noradrenergic receptor antagonist propranolol (0, 1.0, 10, or 20mg/kg) given immediately after a 15 min defeat by a resident aggressor would impair CD tested 48 h later. Hamsters that were given immediate post-training infusions of propranolol (1.0, but not 10 or 20mg/kg) showed significantly less submissive behavior than did those given vehicle infusions supporting the hypothesis that there is noradrenergic modulation of the consolidation of a social defeat experience. In Experiment 2, we demonstrated that propranolol (1.0mg/kg) given immediately, but not 4 or 24h, after defeat impaired CD tested 48 h after defeat indicating that the window within which the memory for social defeat is susceptible to beta-adrenergic modulation is temporary. In Experiment 3, we examined whether central blockade of noradrenergic receptors could recapitulate the effect of systemic injections by giving an intracerebroventricular infusion of propranolol immediately after defeat and examining the effect on CD 24h later. Centrally administered propranolol (20 μg/3 μl but not 2 μg/3 μl) was also effective in dose-dependently reducing

  3. Excitatory amino acid receptor antagonists

    DEFF Research Database (Denmark)

    Johansen, T N; Frydenvang, Karla Andrea; Ebert, B;

    1997-01-01

    We have previously shown that (RS)-2-amino-2-(5-tert-butyl-3-hydroxyisoxazol-4-yl)acetic acid (ATAA) is an antagonist at N-methyl-D-aspartic acid (NMDA) and (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) receptors. We have now resolved ATAA via diastereomeric salt formation...

  4. Simultaneous stimulation of GABA and beta adrenergic receptors stabilizes isotypes of activated adenylyl cyclase heterocomplex

    Directory of Open Access Journals (Sweden)

    Robichon Alain

    2004-06-01

    Full Text Available Abstract Background We investigated how the synthesis of cAMP, stimulated by isoproterenol acting through β-adrenoreceptors and Gs, is strongly amplified by simultaneous incubation with baclofen. Baclofen is an agonist of δ-aminobutyric acid type B receptors [GABAB], known to inhibit adenylyl cyclase via Gi. Because these agents have opposite effects on cAMP levels, the unexpected increase in cAMP synthesis when they are applied simultaneously has been intensively investigated. From previous reports, it appears that cyclase type II contributes most significantly to this phenomenon. Results We found that simultaneous application of isoproterenol and baclofen specifically influences the association/dissociation of molecules involved in the induction and termination of cyclase activity. Beta/gamma from [GABA]B receptor-coupled Gi has a higher affinity for adenylyl cyclase isoform(s when these isoforms are co-associated with Gs. Our data also suggest that, when beta/gamma and Gαs are associated with adenylyl cyclase isoform(s, beta/gamma from [GABA]B receptor-coupled Gi retards the GTPase activity of Gαs from adrenergic receptor. These reciprocal regulations of subunits of the adenylyl cyclase complex might be responsible for the drastic increase of cAMP synthesis in response to the simultaneous signals. Conclusions Simultaneous signals arriving at a particular synapse converge on molecular detectors of coincidence and trigger specific biochemical events. We hypothesize that this phenomenon comes from the complex molecular architectures involved, including scaffolding proteins that make reciprocal interactions between associated molecules possible. The biochemistry of simultaneous signaling is addressed as a key to synaptic function.

  5. Cerebral oxygenation decreases during exercise in humans with beta-adrenergic blockade

    DEFF Research Database (Denmark)

    Seifert, T.; Rasmussen, P.; Secher, Niels H.;

    2009-01-01

    AIM: Beta-blockers reduce exercise capacity by attenuated increase in cardiac output, but it remains unknown whether performance also relates to attenuated cerebral oxygenation. METHODS: Acting as their own controls, eight healthy subjects performed a continuous incremental cycle test to exhaustion...... with or without administration of the non-selective beta-blocker propranolol. Changes in cerebral blood flow velocity were measured with transcranial Doppler ultrasound and those in cerebral oxygenation were evaluated using near-infrared spectroscopy and the calculated cerebral mitochondrial oxygen...

  6. Oxidation of nutrients in bull calves treated with beta-adrenergic agonists

    DEFF Research Database (Denmark)

    Chwalibog, André; Jensen, K; Thorbek, G

    1996-01-01

    Oxidation of protein (OXP), carbohydrate (OXCHO) and fat (OXF) was investigated with 12 growing bulls treated with beta-agonist (L-644, 969) during two 6 weeks trials (Section A and B) at a mean live weight of 195 and 335 kg. Heat production and nutrient oxidation was calculated from gas exchange......, with CO2 reduced for CO2 from fermentation processes, and nitrogen excretion in urine. The beta-agonist had no effect on the level of rumen fermentation as indicated by the same methane production for control and treated animals. Heat Production (HE, RQx) increased by the treatment of beta......-agonist corresponding to the increment in the protein retention. OXP/HE,RQx was reduced to about 10% in treated animals, indicating that in order to supply amino acids for an increased protein deposition oxidation of protein is decreased. OXF/HE,RQx were markedly higher in treated animals, but as indicated by the same...

  7. Mapping genetic variants associated with beta-adrenergic responses in inbred mice.

    Directory of Open Access Journals (Sweden)

    Micha Hersch

    Full Text Available β-blockers and β-agonists are primarily used to treat cardiovascular diseases. Inter-individual variability in response to both drug classes is well recognized, yet the identity and relative contribution of the genetic players involved are poorly understood. This work is the first genome-wide association study (GWAS addressing the values and susceptibility of cardiovascular-related traits to a selective β(1-blocker, Atenolol (ate, and a β-agonist, Isoproterenol (iso. The phenotypic dataset consisted of 27 highly heritable traits, each measured across 22 inbred mouse strains and four pharmacological conditions. The genotypic panel comprised 79922 informative SNPs of the mouse HapMap resource. Associations were mapped by Efficient Mixed Model Association (EMMA, a method that corrects for the population structure and genetic relatedness of the various strains. A total of 205 separate genome-wide scans were analyzed. The most significant hits include three candidate loci related to cardiac and body weight, three loci for electrocardiographic (ECG values, two loci for the susceptibility of atrial weight index to iso, four loci for the susceptibility of systolic blood pressure (SBP to perturbations of the β-adrenergic system, and one locus for the responsiveness of QTc (p<10(-8. An additional 60 loci were suggestive for one or the other of the 27 traits, while 46 others were suggestive for one or the other drug effects (p<10(-6. Most hits tagged unexpected regions, yet at least two loci for the susceptibility of SBP to β-adrenergic drugs pointed at members of the hypothalamic-pituitary-thyroid axis. Loci for cardiac-related traits were preferentially enriched in genes expressed in the heart, while 23% of the testable loci were replicated with datasets of the Mouse Phenome Database (MPD. Altogether these data and validation tests indicate that the mapped loci are relevant to the traits and responses studied.

  8. Is there a problem with inhaled long-acting beta-adrenergic agonists?

    Science.gov (United States)

    Nelson, Harold S

    2006-01-01

    Short-acting beta(2)-agonists are effective in relieving acute symptoms of asthma and in the short-term prevention of symptoms from stimuli, such as exercise. They are ineffective when used on a regular schedule to improve asthma control. Long-acting beta(2)-agonists, on the other hand, provide sustained bronchodilation and improve asthma control. Regular use of long-acting beta(2)-agonists is not associated with significant tolerance to their bronchodilator action, impairment in the response to albuterol, decreased baseline pulmonary function, increased response to methacholine, or increased risk of adverse cardiac events. Case-control studies do not suggest an increased risk for death or intensive care unit admissions with use of long-acting beta(2)-agonists. In prospective studies in which there has been an increase in asthma deaths or serious asthma exacerbations, this increased risk has not been observed in subjects using inhaled corticosteroids. Where increased deaths have occurred in relation to either short- or long-acting beta(2)-agonists, the events have not occurred equally throughout the exposed population. This suggests that these outcomes were not a direct toxic effect of the drugs and increases the possibility that they resulted from an interaction between relief of symptoms by beta(2)-agonists and delay in seeking medical care. PMID:16387577

  9. Cardiac function in patients with early cirrhosis during maximal beta-adrenergic drive

    DEFF Research Database (Denmark)

    Krag, Aleksander; Bendtsen, Flemming; Dahl, Emilie Kristine;

    2014-01-01

    BACKGROUND AND AIM: Cardiac dysfunction in patients with early cirrhosis is debated. We investigated potential cardiac dysfunction by assessing left ventricular systolic performance during a dobutamine stress test in patients with early cirrhosis. PATIENTS AND METHODS: Nineteen patients with Child......: Patients with cirrhosis and controls had an equal stress response, the heart rate and ejection fraction increased similarly and maximal heart rate was reached in all. At rest CO was higher in Child B patients than controls. During maximal stress, Child B patients had higher CO (10.6±2.7 vs. 8.0±1.8 L...... ventricle mass increased by 5.6 gram per model for end stage liver disease (MELD) point. MELD score correlated with the end diastolic and systolic volume, CO, and stroke volume at rest and at stress (all p<0.05). CONCLUSION: In patients with early cirrhosis the chronotropoic and inotropic response to...

  10. Peptide YY antagonizes beta-adrenergic-stimulated release of insulin in dogs

    International Nuclear Information System (INIS)

    Peptide YY (PYY) and neuropeptide Y (NPY) are peptides of 36 amino acids that share structural homologies with pancreatic polypeptide (PP). PP is predominantly found in the endocrine pancreas. PYY is primarily found in mucosal endocrine cells of the distal ileum, colon, and rectum, whereas NPY is found in both the peripheral and central nervous system. Previous studies indicate that these peptides can interact with the autonomic nervous system. The objective of the present experiments was to study the effect of PYY on neurally stimulated insulin release in conscious dogs. Intravenous administration of PYY (100, 200, and 400 pmol·kg-1 ·h-1) reduced 2-DG-stimulated insulin release in a dose-dependent manner (P <0.05) without affecting plasma glucose levels. Administration of NPY, but not PP, reduced 2-DG-stimulated release of insulin. The inhibitory action of PYY on 2-DG-stimulated insulin release persisted in the presence of atropine or phentolamine treatment; however, hexamethonium alone or phentolamine plus propranolol treatment blocked the inhibitory action of PYY. Release of insulin stimulated by the β-agonist isoproterenol was also inhibited by PYY. These results indicate that PYY can inhibit autonomic neurotransmission by a mechanism that may involve ganglionic or postganglionic inhibition of β-adrenergic stimulation. The findings suggest a role for PYY and NPY in the autonomic regulation of insulin release

  11. Beta-adrenergic receptor sensitivity, autonomic balance and serotonergic activity in practitioners of Transcendental Meditation

    Energy Technology Data Exchange (ETDEWEB)

    Hill, D.A.

    1989-01-01

    The aim of this thesis was to investigate the acute autonomic effects of the Transcendental Meditation Program (TM) and resolve the conflict arising from discrepant neurochemical and psychophysiological data. Three experimental investigations were performed. The first examined beta{sub 2}-adrenergic receptors (AR's) on peripheral blood lymphocytes, via (I{sup 125})iodocyanopindolol binding, in 10 male mediating and 10 age matched non-meditating control subjects, to test the hypothesis that the long-term practice of TM and the TM Sidhi Program (TMSP) reduces end organ sensitivity to adrenergic agonists. The second investigated respiratory sinus arrhythmia (an indirect measure of cardiac Parasympathetic Nervous System tone), and skin resistance (a measure of Sympathetic Nervous System tone) during periods of spontaneous respiratory apneusis, a phenomenon occurring during TM that is known to mark the subjective experience of transcending. The third was within subject investigation of the acute effects of the TMSP on 5-hydroxytryptamine (5-HT) activity. Platelet 5-HT was assayed by high pressure liquid chromatography with electrochemical detection, plasma prolactin (PL) and lutenizing hormone (LH) by radioimmunoassay, tryptophan by spectrofluorimetry, and alpha-1-acid glycoprotein (AGP, a modulator of 5-HT uptake) by radial immunodiffusion assay.

  12. Metabolic consequences of beta-adrenergic receptor blockade for the acutely ischemic dog myocardium

    International Nuclear Information System (INIS)

    In an experimental study in 50 dogs the myocardial uptake of free fatty acids (FFAs) after beta-blockade was determined using radioiodinated heptadecanoic acid as a metabolic tracer. All 4 beta-blockers used (metoprolol, timolol, propranolol and pindolol) lowered the uptake of FFAs in the normal canine heart. Uptake of FFAs was also diminished after coronary artery occlusion per se, but administration of beta-blockers exerted little additional influence on the uptake of FFAs. This observation was qualitatively parallelled by the uptake of 201Tl in concomitant experiments. Plasma FFA levels were increased by pindolol (non-selective with intrinsic sympathomimetic activity), not changed by metoprolol (a cardioselective betablocking agent) and lowered by timolol and propranolol (both non-selective compounds). The extent of ischemic tissue, as reflected by uptake of iodoheptadecanoic acid and 201Tl, was diminished by metoprolol but not by other beta-blockers. Regional distribution of both tracers, as shown in the endo-epicardial uptake ratios, was hardly influenced by beta-blockade, except for a small increase of 201Tl uptake in non-occluded endocardium. Uptake of 201Tl as well as of iodoheptadecanoic acid in the ischemic area was increased by metoprolol, timolol and propranolol and decreased by pindolol. We conclude that beta-blocking agents confer different effects on myocardial uptake and metabolism of FFAs which might possibly be related to their different inherent properties. (orig.)

  13. Metabolic consequences of beta-adrenergic receptor blockade for the acutely ischemic dog myocardium

    Energy Technology Data Exchange (ETDEWEB)

    Westera, G.; Hollander, W. den; Wall, E.E. van der; Eenige, M.J. van; Scholtalbers, S.; Visser, F.C.; Roos, J.P.

    1984-02-01

    In an experimental study in 50 dogs the myocardial uptake of free fatty acids (FFAs) after beta-blockade was determined using radioiodinated heptadecanoic acid as a metabolic tracer. All 4 beta-blockers used (metoprolol, timolol, propranolol and pindolol) lowered the uptake of FFAs in the normal canine heart. Uptake of FFAs was also diminished after coronary artery occlusion per se, but administration of beta-blockers exerted little additional influence on the uptake of FFAs. This observation was qualitatively parallelled by the uptake of /sup 201/Tl in concomitant experiments. Plasma FFA levels were increased by pindolol (non-selective with intrinsic sympathomimetic activity), not changed by metoprolol (a cardioselective betablocking agent) and lowered by timolol and propranolol (both non-selective compounds). The extent of ischemic tissue, as reflected by uptake of iodoheptadecanoic acid and /sup 201/Tl, was diminished by metoprolol but not by other beta-blockers. Regional distribution of both tracers, as shown in the endo-epicardial uptake ratios, was hardly influenced by beta-blockade, except for a small increase of /sup 201/Tl uptake in non-occluded endocardium. Uptake of /sup 201/Tl as well as of iodoheptadecanoic acid in the ischemic area was increased by metoprolol, timolol and propranolol and decreased by pindolol. We conclude that beta-blocking agents confer different effects on myocardial uptake and metabolism of FFAs which might possibly be related to their different inherent properties.

  14. Beta-adrenergic receptor sensitivity, autonomic balance and serotonergic activity in practitioners of Transcendental Meditation

    International Nuclear Information System (INIS)

    The aim of this thesis was to investigate the acute autonomic effects of the Transcendental Meditation Program (TM) and resolve the conflict arising from discrepant neurochemical and psychophysiological data. Three experimental investigations were performed. The first examined beta2-adrenergic receptors (AR's) on peripheral blood lymphocytes, via [I125]iodocyanopindolol binding, in 10 male mediating and 10 age matched non-meditating control subjects, to test the hypothesis that the long-term practice of TM and the TM Sidhi Program (TMSP) reduces end organ sensitivity to adrenergic agonists. The second investigated respiratory sinus arrhythmia (an indirect measure of cardiac Parasympathetic Nervous System tone), and skin resistance (a measure of Sympathetic Nervous System tone) during periods of spontaneous respiratory apneusis, a phenomenon occurring during TM that is known to mark the subjective experience of transcending. The third was within subject investigation of the acute effects of the TMSP on 5-hydroxytryptamine (5-HT) activity. Platelet 5-HT was assayed by high pressure liquid chromatography with electrochemical detection, plasma prolactin (PL) and lutenizing hormone (LH) by radioimmunoassay, tryptophan by spectrofluorimetry, and alpha-1-acid glycoprotein (AGP, a modulator of 5-HT uptake) by radial immunodiffusion assay

  15. Effective use of TNF antagonists

    OpenAIRE

    Yocum, David

    2004-01-01

    Tumor necrosis factor (TNF) antagonists are biologic response modifiers that have significantly improved functional outcomes in patients with rheumatoid arthritis (RA). RA is a progressive disease in which structural joint damage can continue to develop even in the face of symptomatic relief. Before the introduction of biologic agents, the management of RA involved the use of disease-modifying antirheumatic drugs (DMARDs) early in the course of disease. This focus on early treatment, combined...

  16. Endothelin receptors and their antagonists.

    Science.gov (United States)

    Maguire, Janet J; Davenport, Anthony P

    2015-03-01

    All three members of the endothelin (ET) family of peptides, ET-1, ET-2, and ET-3, are expressed in the human kidney, with ET-1 being the predominant isoform. ET-1 and ET-2 bind to two G-protein-coupled receptors, ETA and ETB, whereas at physiological concentrations ET-3 has little affinity for the ET(A) receptor. The human kidney is unusual among the peripheral organs in expressing a high density of ET(B). The renal vascular endothelium only expresses the ET(B) subtype and ET-1 acts in an autocrine or paracrine manner to release vasodilators. Endothelial ETB in kidney, as well as liver and lungs, also has a critical role in scavenging ET-1 from the plasma. The third major function is ET-1 activation of ET(B) in in the nephron to reduce salt and water re-absorption. In contrast, ET(A) predominate on smooth muscle, causing vasoconstriction and mediating many of the pathophysiological actions of ET-1. The role of the two receptors has been delineated using highly selective ET(A) (BQ123, TAK-044) and ET(B) (BQ788) peptide antagonists. Nonpeptide antagonists, bosentan, macitentan, and ambrisentan, that are either mixed ET(A)/ET(B) antagonists or display ET(A) selectivity, have been approved for clinical use but to date are limited to pulmonary hypertension. Ambrisentan is in clinical trials in patients with type 2 diabetic nephropathy. This review summarizes ET-receptor antagonism in the human kidney, and considers the relative merits of selective versus nonselective antagonism in renal disease. PMID:25966344

  17. Antianginal Actions of Beta-Adrenoceptor Antagonists

    OpenAIRE

    O'Rourke, Stephen T.

    2007-01-01

    Angina pectoris is usually the first clinical sign of underlying myocardial ischemia, which results from an imbalance between oxygen supply and oxygen demand in the heart. This report describes the pharmacology of β-adrenoceptor antagonists as it relates to the treatment of angina. The β-adrenoceptor antagonists are widely used in long-term maintenance therapy to prevent acute ischemic episodes in patients with chronic stable angina. Beta-adrenoceptor antagonists competitively inhibit the bin...

  18. Client Perceptions of Two Antagonist Programs.

    Science.gov (United States)

    Capone, Thomas A.; And Others

    1980-01-01

    Reports results of a questionnaire administered to participants in an antagonist drug outpatient clinic and an antagonist drug work-release program to obtain awareness of acceptance of the program participants. Naltrexone patients recommended an alternative method of administering the drug and changing the money system to award deserving inmates…

  19. Antagonistic formation motion of cooperative agents

    Institute of Scientific and Technical Information of China (English)

    卢婉婷; 代明香; 薛方正

    2015-01-01

    This paper investigates a new formation motion problem of a class of first-order multi-agent systems with antagonis-tic interactions. A distributed formation control algorithm is proposed for each agent to realize the antagonistic formation motion. A sufficient condition is derived to ensure that all agents make an antagonistic formation motion in a distributed manner. It is shown that all agents can be spontaneously divided into several groups, and agents in the same group collab-orate while agents in different groups compete. Finally, a numerical simulation is included to demonstrate our theoretical results.

  20. Cytokine antagonists and their potential therapeutic use

    OpenAIRE

    Debets, Reno; Savelkoul, Huub

    1994-01-01

    textabstractNew and exciting developments in the understanding of the interaction between cytokines and their receptors, and the clinical application of cytokine antagonists, were discussed at a recent meeting. Here, Reno Debets and Huub Savelkoul revisit this progress.

  1. High-affinity neuropeptide Y receptor antagonists.

    OpenAIRE

    Daniels, A J; Matthews, J. E.; Slepetis, R J; Jansen, M; Viveros, O. H.; Tadepalli, A.; Harrington, W; Heyer, D; Landavazo, A; Leban, J J

    1995-01-01

    Neuropeptide Y (NPY) is one of the most abundant peptide transmitters in the mammalian brain. In the periphery it is costored and coreleased with norepinephrine from sympathetic nerve terminals. However, the physiological functions of this peptide remain unclear because of the absence of specific high-affinity receptor antagonists. Three potent NPY receptor antagonists were synthesized and tested for their biological activity in in vitro, ex vivo, and in vivo functional assays. We describe he...

  2. Benzodiazepine receptor antagonists for hepatic encephalopathy

    DEFF Research Database (Denmark)

    Als-Nielsen, B; Gluud, L L; Gluud, C

    2004-01-01

    Hepatic encephalopathy may be associated with accumulation of substances that bind to a receptor-complex in the brain resulting in neural inhibition. Benzodiazepine receptor antagonists may have a beneficial effect on patients with hepatic encephalopathy.......Hepatic encephalopathy may be associated with accumulation of substances that bind to a receptor-complex in the brain resulting in neural inhibition. Benzodiazepine receptor antagonists may have a beneficial effect on patients with hepatic encephalopathy....

  3. GABAA receptor partial agonists and antagonists

    DEFF Research Database (Denmark)

    Krall, Jacob; Balle, Thomas; Krogsgaard-Larsen, Niels;

    2015-01-01

    A high degree of structural heterogeneity of the GABAA receptors (GABAARs) has been revealed and is reflected in multiple receptor subtypes. The subunit composition of GABAAR subtypes is believed to determine their localization relative to the synapses and adapt their functional properties to the...... antagonists have been essential in defining the tonic current but both remaining issues concerning the GABAARs involved and the therapeutic possibilities of modulating tonic inhibition underline the need for GABAAR antagonists with improved selectivity....

  4. Histamine-2 Receptor Antagonists and Semen Quality.

    Science.gov (United States)

    Banihani, Saleem A

    2016-01-01

    Histamine-2 receptor antagonists are a class of drugs used to treat the acid-related gastrointestinal diseases such as ulcer and gastro-oesophageal reflux disease. Although such drugs, especially ranitidine and famotidine, are still widely used, their effects on semen quality, and hence on male infertility, is still unclear. This MiniReview systematically addresses and summarizes the effect of histamine-2 receptor antagonists (cimetidine, ranitidine, nizatidine and famotidine) on semen quality, particularly, on sperm function. Cimetidine appears to have adverse effects on semen quality. While the effects of ranitidine and nizatidine on semen quality are still controversial, famotidine does not appear to change semen quality. Therefore, additional studies will be required to clarify whether histamine-2 receptor-independent effects of these drugs play a role in semen quality as well as further clinical studies including direct comparison of the histamine-2 receptor antagonists. PMID:26176290

  5. Auxin-Oxylipin Crosstalk: Relationship of Antagonists

    Institute of Scientific and Technical Information of China (English)

    Maik Hoffmann; Mathias Hentrich; Stephan Pollmann

    2011-01-01

    Phytohormones regulate a wide array of developmental processes throughout the life cycle of plants. Herein, the various plant hormones may interact additively, synergistically, or antagonistically. By their cooperation they create a delicate regulatory network whose net output largely depends on the action of specific phytohormone combinations rather than on the independent activities of separate hormones. While most classical studies of plant hormonal control have focused mainly on the action of single hormones or on the synergistic interaction of hormones in regulating various developmental processes, recent work is beginning to shed light on the crosstalk of nominally antagonistic plant hormones, such as gibberellins and auxins with oxylipins or abscisic acid. In this review, we summarize our current understanding of how two of the first sight antagonistic plant hormones, i.e. auxins and oxylipins,interact in controlling plant responses and development.

  6. Oxazolidinones as novel human CCR8 antagonists.

    Science.gov (United States)

    Jin, Jian; Wang, Yonghui; Wang, Feng; Kerns, Jeffery K; Vinader, Victoria M; Hancock, Ashley P; Lindon, Matthew J; Stevenson, Graeme I; Morrow, Dwight M; Rao, Parvathi; Nguyen, Cuc; Barrett, Victoria J; Browning, Chris; Hartmann, Guido; Andrew, David P; Sarau, Henry M; Foley, James J; Jurewicz, Anthony J; Fornwald, James A; Harker, Andy J; Moore, Michael L; Rivero, Ralph A; Belmonte, Kristen E; Connor, Helen E

    2007-03-15

    High-throughput screening of the corporate compound collection led to the discovery of a novel series of N-substituted-5-aryl-oxazolidinones as potent human CCR8 antagonists. The synthesis, structure-activity relationships, and optimization of the series that led to the identification of SB-649701 (1a), are described. PMID:17267215

  7. Azines as histamine H4 receptor antagonists.

    Science.gov (United States)

    Lazewska, Dorota; Kiec-Kononowicz, Katarzyna

    2012-01-01

    Since 2000, when the histamine H4 receptor (H4R) was cloned, it has constituted an interesting target for drug development. Pharmacological studies suggest the potential utility of histamine H4R antagonists/inverse agonists in the treatment of inflammatory diseases, e.g. allergic rhinitis, asthma, atopic dermatitis, colitis, or pruritus. The first H4R ligands were non-selective compounds, but intensive chemical and pharmacological work has led to the discovery of highly potent and selective H4R antagonists (e.g. JNJ7777120, CZC-13788, PF-2988403, A-940894, A-987306). The first compound (UR-63325) has finally entered into clinical studies for the treatment of allergic respiratory diseases (completing the phase I ascending dose trial) and has been found to be safe and well tolerated. The number of scientific publications and patent applications in the H4 field is increasing annually. Among the diverse chemical structures of the H4R antagonists described a 2-aminopyrimidine scaffold is repeatedly found. This review looked at recent advances in the search for H4R antagonists as reflected in patent applications/patents and peer-reviewed publications over the last two years. The work concerns azines (mono-, di-, triazines) and their fused analogues. The chemistry and pharmacology has been described. PMID:22202103

  8. Genetic factors influencing pyrimidine-antagonist chemotherapy

    NARCIS (Netherlands)

    Maring, JG; Groen, HJM; Wachters, FM; Uges, DRA; de Vries, EGE

    2005-01-01

    Pyrimidine antagonists, for example, 5-fluorouracil (5-FU), cytarabine (ara-C) and gemcitabine (dFdC), are widely used in chemotherapy regimes for colorectal, breast, head and neck, non-small-cell lung cancer, pancreatic cancer and leukaemias. Extensive metabolism is a prerequisite for conversion of

  9. Vasopressin receptor antagonists: Characteristics and clinical role.

    Science.gov (United States)

    Rondon-Berrios, Helbert; Berl, Tomas

    2016-03-01

    Hyponatremia, the most common electrolyte disorder in hospitalized patients is associated with increased risk of mortality even when mild and apparently asymptomatic. Likewise morbidity manifested as attention deficits, gait disturbances, falls, fractures, and osteoporosis is more prevalent in hyponatremic subjects. Hyponatremia also generates a significant financial burden. Therefore, it is important to explore approaches that effectively and safely treat hyponatremia. Currently available strategies are physiologically sound and affordable but lack evidence from clinical trials and are limited by variable efficacy, slow response, and/or poor compliance. The recent emergence of vasopressin receptor antagonists provides a class of drugs that target the primary pathophysiological mechanism, namely vasopressin mediated impairment of free water excretion. This review summarizes the historical development, pharmacology, clinical trials supporting efficacy and safety, shortcomings, as well as practical suggestions for the use of vasopressin receptor antagonists. PMID:27156765

  10. Bicycloorthocarboxylate convulsants. Potent GABAA receptor antagonists

    International Nuclear Information System (INIS)

    4-t-Butyl-1-(4-bromophenyl)-bicycloorthocarboxylate antagonizes gamma-aminobutyric acid (GABA)-mediated relaxation at a functional insect nerve-muscle synapse, mimicking the action of picrotoxinin, suggesting that it causes GABA antagonism through blockade of the chloride ionophore. It is also a potent GABAA receptor antagonist, inhibiting the binding of [35S]t-butyl-bicyclophosphorothionate ([35S]TBPS) to EDTA/water-dialyzed human brain P2 membranes. Structure-activity relationships of 74 1,4-bis-substituted bicycloorthocarboxylates, mostly new compounds, reveal that for high potency as a GABAA receptor antagonist the optimal 4-substituent is a C4 to C6 branched chain alkyl or cycloalkyl group (e.g., t-butyl, s-butyl, or cyclohexyl) and the optimal 1-substituent is a phenyl moiety with one or more electron-withdrawing groups (e.g., 4-cyano, 4-bromo, 4-chloro, 3,4-dichloro, or pentafluoro). Bicycloorthocarboxylate inhibitors of [35S]TBPS binding with IC50 values of 5-10 nM exceed by several-fold the potency of any GABAA receptor antagonist previously reported. The 4-t-butyl-1-(4-azidophenyl) analog, synthesized as a candidate photoaffinity label, gives an IC50 of 315 nM. The potency of bicycloorthocarboxylates for decreasing [35S]TBPS binding generally correlates with their toxicity, i.e., compounds without inhibitory activity in this brain receptor assay are of low toxicity on intraperitoneal administration to mice, and the analogs most potent as inhibitors are generally those most toxic to mice (e.g., IC50 of 5 nM and LD50 of 0.06 mg/kg for 4-t-butyl-1-(4-cyanophenyl)-bicycloorthocarboxylate). The effects of phenyl substituents on the potency of the orthobenzoates as GABAA receptor antagonists are similar to those on toxicity

  11. Antagonistic parent-offspring co-adaptation.

    Directory of Open Access Journals (Sweden)

    Mathias Kölliker

    Full Text Available BACKGROUND: In species across taxa, offspring have means to influence parental investment (PI. PI thus evolves as an interacting phenotype and indirect genetic effects may strongly affect the co-evolutionary dynamics of offspring and parental behaviors. Evolutionary theory focused on explaining how exaggerated offspring solicitation can be understood as resolution of parent-offspring conflict, but the evolutionary origin and diversification of different forms of family interactions remains unclear. METHODOLOGY/PRINCIPAL FINDINGS: In contrast to previous theory that largely uses a static approach to predict how "offspring individuals" and "parental individuals" should interact given conflict over PI, we present a dynamic theoretical framework of antagonistic selection on the PI individuals obtain/take as offspring and the PI they provide as parents to maximize individual lifetime reproductive success; we analyze a deterministic and a stochastic version of this dynamic framework. We show that a zone for equivalent co-adaptation outcomes exists in which stable levels of PI can evolve and be maintained despite fast strategy transitions and ongoing co-evolutionary dynamics. Under antagonistic co-adaptation, cost-free solicitation can evolve as an adaptation to emerging preferences in parents. CONCLUSIONS/SIGNIFICANCE: We show that antagonistic selection across the offspring and parental life-stage of individuals favors co-adapted offspring and parental behavior within a zone of equivalent outcomes. This antagonistic parent-offspring co-adaptation does not require solicitation to be costly, allows for rapid divergence and evolutionary novelty and potentially explains the origin and diversification of the observed provisioning forms in family life.

  12. Aminopyrimidine derivatives as adenosine antagonists / Janke Kleynhans

    OpenAIRE

    Kleynhans, Janke

    2013-01-01

    Aims of this project - The aim of this study was to design and synthesise novel 2-aminopyrimidine derivatives as potential adenosine A1 and A2A receptor antagonists. Background and rationale - Parkinson’s disease is the second most common neurodegenerative disorder (after Alzheimer’s disease) and is characterised by the selective death of the dopaminergic neurons of the nigro-striatal pathway. Distinctive motor symptoms include bradykinesia, muscle rigidity and tremor, while non-m...

  13. Antagonistic neural networks underlying differentiated leadership roles

    OpenAIRE

    Boyatzis, Richard E.; Rochford, Kylie; Jack, Anthony I.

    2014-01-01

    The emergence of two distinct leadership roles, the task leader and the socio-emotional leader, has been documented in the leadership literature since the 1950s. Recent research in neuroscience suggests that the division between task-oriented and socio-emotional-oriented roles derives from a fundamental feature of our neurobiology: an antagonistic relationship between two large-scale cortical networks – the task-positive network (TPN) and the default mode network (DMN). Neural activity in TPN...

  14. Tribulus Terrestris (l Protects Heart and Liver from Beta Adrenergic-Stimulated Cardiotoxicity: Biochemical and Histological study in Wistar Rats

    Directory of Open Access Journals (Sweden)

    S. B Mahammad Rahmathulla

    2013-03-01

    Full Text Available Acute myocardial infarction is a wearisome risk inherent in all major surgeries. Preoperative evaluation has been directed mainly to assess its risk because it carries with it a very high mortality. Living donor liver transplantation has been subject to inquiry not only because of the morbidity risk but also because of the mortality risk it carries to the live donor. The present study investigates the protective effects of Tribulus terrestris Fruit aqueous Extract (TTFAEt in myocardially infarcted rats. The oral administration of TTFAEt to rats for 40 days afforded good protection against isoproterenol-induced alterations in cardiac levels of lipid peroxidation (LPO as well as the activities of antioxidant enzymes like Superoxide dismutase (SOD, Catalase (CAT, glutathione peroxidase (GPx, Glutathione-S-transferase (GST. Antioxidants can prevent reactive oxygen species-mediated damage and thus may have potential application in the prevention and cure of chronic diseases. Myocardial infarction produces a significant abnormal liver functioning. Liver tissue marker enzymes injury like alanine aminotransferase (ALT, aspartate aminotransferase (AST and lactate dehydrogenase (LDH. The protective effect of TTFAEt was further supported by the reversal of isoproterenol-induced histological changes in the liver. The results suggest that TTFAEt protect the heart and circulatory system and also hepatoprotective and thereby maintain the near normal architecture of liver tissues.

  15. Association of beta-adrenergic receptor polymorphisms and mortality in carvedilol-treated chronic heart-failure patients

    DEFF Research Database (Denmark)

    Petersen, Morten; Andersen, Jon T; Hjelvang, Brian R;

    2011-01-01

    patients benefit from ß-adrenoceptor blocker treatment, and stratifying patients to different ß-adrenoceptor blockers by the use of pharmacogenomics might be of great value in improving HF therapy. • Previous studies have shown that the two single nucleotide polymorphisms (SNPs) ADRB1 Arg389Gly and ADRB2...... carvedilol response was seen with respect to survival over a median follow-up period of 6.7 years. • This genotype combination did not show a stratified metoprolol response. AIM Pharmacogenetics can be used as a tool for stratified pharmacological therapy in cardiovascular medicine. We investigated whether a...

  16. Does calcium channel blockade and beta-adrenergic blockade affect platelet function and fibrinolysis to a varying degree?

    DEFF Research Database (Denmark)

    Fornitz, Gitte Gleerup; Mehlsen, J; Winther, K

    1995-01-01

    The effects of isradipine and atenolol on platelet function and fibrinolytic activity were studied in 10 male patients with mild untreated hypertension. After a 2-week placebo run-in period, the volunteers were randomized to either isradipine 2.5 mg twice daily or atenolol 100 mg daily for a 6-mo...

  17. Post-Retrieval [beta]-Adrenergic Receptor Blockade: Effects on Extinction and Reconsolidation of Cocaine-Cue Memories

    Science.gov (United States)

    Fricks-Gleason, Ashley N.; Marshall, John F.

    2008-01-01

    Contexts and discrete cues associated with drug-taking are often responsible for relapse among addicts. Animal models have shown that interference with the reconsolidation of drug-cue memories can reduce seeking of drugs or drug-paired stimuli. One such model is conditioned place preference (CPP) in which an animal is trained to associate a…

  18. Tribulus Terrestris (l) Protects Heart and Liver from Beta Adrenergic-Stimulated Cardiotoxicity: Biochemical and Histological study in Wistar Rats

    OpenAIRE

    S. B Mahammad Rahmathulla; K. V Sailaja; Kodidhela Lakshmi Devi

    2013-01-01

    Acute myocardial infarction is a wearisome risk inherent in all major surgeries. Preoperative evaluation has been directed mainly to assess its risk because it carries with it a very high mortality. Living donor liver transplantation has been subject to inquiry not only because of the morbidity risk but also because of the mortality risk it carries to the live donor. The present study investigates the protective effects of Tribulus terrestris Fruit aqueous Extract (TTFAEt) in myocardially inf...

  19. Effect of cardiopulmonary bypass on beta adrenergic receptor-adenylate cyclase system on surfaces of peripheral lymphocytes.

    Science.gov (United States)

    Luo, A; Tian, Y; Jin, S

    2000-01-01

    The experimental results showed that the level of CAMP, the ratio of cAPM to cGMP, IL-2R expression and IL-2 production in vitro in lymphocytes immediate and 2 weeks after cardiopulmonary bypass (CPB) were significantly lower than those before anesthetics in the patients undergoing cardiac surgery with CPB. These findings suggested that CPB could cause serious damage to adrenergic beta receptor-adenylate cyclase system on circulating lymphocytes surfaces, which might be one of the mechanisms resulting in immunosuppression after open heart surgery with CPB. PMID:12845765

  20. Corticosterone time-dependently modulates {beta}-adrenergic effects on long-term potentiation in the hippocampal dentate gyrus.

    NARCIS (Netherlands)

    Z. Pu; H. Krugers; M. Joëls

    2007-01-01

    Previous experiments in the hippocampal CA1 area have shown that corticosterone can facilitate long-term potentiation (LTP) in a rapid non-genomic fashion, while the same hormone suppresses LTP that is induced several hours after hormone application. Here, we elaborated on this finding by examining

  1. Physiopathology of beta-adrenergic dysfunction and role of MRP4 during aging, diabetes mellitus and metabolic syndrom

    OpenAIRE

    Carillion, Aude

    2015-01-01

    The studies presented in this report looked for a better understanding of the altered response to stimulation of the β-adrenergic receptors in several physiopathological contexts. The first study confirms the alteration of the β-adrenergic response at the cardiomyocyte level in the senescent cardiomyopathy. The role of MRP4 (multidrug resistance associated protein 4) in the reduced inotropic response to isoproterenol is emphasized. The second study evaluates the response to β-adrenoceptors st...

  2. Medicinal chemistry of competitive kainate receptor antagonists.

    Science.gov (United States)

    Larsen, Ann M; Bunch, Lennart

    2011-02-16

    Kainic acid (KA) receptors belong to the group of ionotropic glutamate receptors and are expressed throughout in the central nervous system (CNS). The KA receptors have been shown to be involved in neurophysiological functions such as mossy fiber long-term potentiation (LTP) and synaptic plasticity and are thus potential therapeutic targets in CNS diseases such as schizophrenia, major depression, neuropathic pain and epilepsy. Extensive effort has been made to develop subtype-selective KA receptor antagonists in order to elucidate the physiological function of each of the five subunits known (GluK1-5). However, to date only selective antagonists for the GluK1 subunit have been discovered, which underlines the strong need for continued research in this area. The present review describes the structure-activity relationship and pharmacological profile for 10 chemically distinct classes of KA receptor antagonists comprising, in all, 45 compounds. To the medicinal chemist this information will serve as reference guidance as well as an inspiration for future effort in this field. PMID:22778857

  3. From the Cover: Glutamate antagonists limit tumor growth

    Science.gov (United States)

    Rzeski, Wojciech; Turski, Lechoslaw; Ikonomidou, Chrysanthy

    2001-05-01

    Neuronal progenitors and tumor cells possess propensity to proliferate and to migrate. Glutamate regulates proliferation and migration of neurons during development, but it is not known whether it influences proliferation and migration of tumor cells. We demonstrate that glutamate antagonists inhibit proliferation of human tumor cells. Colon adenocarcinoma, astrocytoma, and breast and lung carcinoma cells were most sensitive to the antiproliferative effect of the N-methyl-D-aspartate antagonist dizocilpine, whereas breast and lung carcinoma, colon adenocarcinoma, and neuroblastoma cells responded most favorably to the -amino-3-hydroxy-5-methyl-4-isoxazole-propionate antagonist GYKI52466. The antiproliferative effect of glutamate antagonists was Ca2+ dependent and resulted from decreased cell division and increased cell death. Morphological alterations induced by glutamate antagonists in tumor cells consisted of reduced membrane ruffling and pseudopodial protrusions. Furthermore, glutamate antagonists decreased motility and invasive growth of tumor cells. These findings suggest anticancer potential of glutamate antagonists.

  4. Adrenergic effects on secretion of amylase from the rat salivary glands

    DEFF Research Database (Denmark)

    Poulsen, Steen Seier; Nexø, Ebba

    1988-01-01

    The present study was undertaken to investigate the effect of adrenergic agents on secretion of amylase from the salivary glands in vivo. Saliva was collected from the distal oesophagus in conscious rats. Adrenaline increased the concentration of amylase in saliva and serum significantly. The...... result of infusion of alpha- and beta-adrenergic antagonists as well as noradrenaline and isoproterenol showed that secretion of salivary amylase is predominantly mediated by stimulation of beta-adrenergic receptors, especially of the beta 1-subtype. Investigation of the isoenzyme pattern in saliva...

  5. Leptin regulates bone formation via the sympathetic nervous system

    Science.gov (United States)

    Takeda, Shu; Elefteriou, Florent; Levasseur, Regis; Liu, Xiuyun; Zhao, Liping; Parker, Keith L.; Armstrong, Dawna; Ducy, Patricia; Karsenty, Gerard

    2002-01-01

    We previously showed that leptin inhibits bone formation by an undefined mechanism. Here, we show that hypothalamic leptin-dependent antiosteogenic and anorexigenic networks differ, and that the peripheral mediators of leptin antiosteogenic function appear to be neuronal. Neuropeptides mediating leptin anorexigenic function do not affect bone formation. Leptin deficiency results in low sympathetic tone, and genetic or pharmacological ablation of adrenergic signaling leads to a leptin-resistant high bone mass. beta-adrenergic receptors on osteoblasts regulate their proliferation, and a beta-adrenergic agonist decreases bone mass in leptin-deficient and wild-type mice while a beta-adrenergic antagonist increases bone mass in wild-type and ovariectomized mice. None of these manipulations affects body weight. This study demonstrates a leptin-dependent neuronal regulation of bone formation with potential therapeutic implications for osteoporosis.

  6. Intrahippocampal Infusions of Anisomycin Produce Amnesia: Contribution of Increased Release of Norepinephrine, Dopamine, and Acetylcholine

    Science.gov (United States)

    Qi, Zhenghan; Gold, Paul E.

    2009-01-01

    Intra-amygdala injections of anisomycin produce large increases in the release of norepinephrine (NE), dopamine (DA), and serotonin in the amygdala. Pretreatment with intra-amygdala injections of the beta-adrenergic receptor antagonist propranolol attenuates anisomycin-induced amnesia without reversing the inhibition of protein synthesis, and…

  7. Comparison of hemodynamic responses to dexmedetomidine versus esmolol in patients undergoing beating heart surgery

    OpenAIRE

    Mohamed Abdel Rahman Salem M.D,* Mostafa Elhamamsy M.D

    2001-01-01

    adrenergic agonists decrease sympathetic tone with ensuing attenuation of neuroendocrine and hemodynamic responses to anesthesia and surgery. Also, administration of beta -adrenergic antagonists contributes to prophylaxis against hypertension, tachycardia and myocardial ischemia and myocardial protection during cardiac surgery. The effects of dexmedetomidine (DEX), a highly specific alpha -adrenergic agonist, on these responses have not yet been fully reported in patients undergoing cardiac s...

  8. Implementation of a fluorescence-based screening assay identifies histamine H3 receptor antagonists clobenpropit and iodophenpropit as subunit-selective N-methyl-D-aspartate receptor antagonists

    DEFF Research Database (Denmark)

    Hansen, Kasper Bø; Mullasseril, Praseeda; Dawit, Sara; Kurtkaya, Natalie L; Yuan, Hongjie; Vance, Katie M; Orr, Anna G; Kvist, Trine; Ogden, Kevin K; Le, Phuong; Vellano, Kimberly M; Lewis, Iestyn; Kurtkaya, Serdar; Du, Yuhong; Qui, Min; Murphy, T J; Snyder, James P; Bräuner-Osborne, Hans; Traynelis, Stephen F

    2010-01-01

    NMDA receptor function, including the histamine H3 receptor antagonists clobenpropit and iodophenpropit, as well as the vanilloid receptor transient receptor potential cation channel, subfamily V, member 1 (TRPV1) antagonist capsazepine. These compounds are noncompetitive antagonists and the histamine...

  9. Antagonistic coevolution between quantitative and Mendelian traits.

    Science.gov (United States)

    Yamamichi, Masato; Ellner, Stephen P

    2016-03-30

    Coevolution is relentlessly creating and maintaining biodiversity and therefore has been a central topic in evolutionary biology. Previous theoretical studies have mostly considered coevolution between genetically symmetric traits (i.e. coevolution between two continuous quantitative traits or two discrete Mendelian traits). However, recent empirical evidence indicates that coevolution can occur between genetically asymmetric traits (e.g. between quantitative and Mendelian traits). We examine consequences of antagonistic coevolution mediated by a quantitative predator trait and a Mendelian prey trait, such that predation is more intense with decreased phenotypic distance between their traits (phenotype matching). This antagonistic coevolution produces a complex pattern of bifurcations with bistability (initial state dependence) in a two-dimensional model for trait coevolution. Furthermore, with eco-evolutionary dynamics (so that the trait evolution affects predator-prey population dynamics), we find that coevolution can cause rich dynamics including anti-phase cycles, in-phase cycles, chaotic dynamics and deterministic predator extinction. Predator extinction is more likely to occur when the prey trait exhibits complete dominance rather than semidominance and when the predator trait evolves very rapidly. Our study illustrates how recognizing the genetic architectures of interacting ecological traits can be essential for understanding the population and evolutionary dynamics of coevolving species. PMID:27009218

  10. Sexually antagonistic selection in human male homosexuality.

    Science.gov (United States)

    Camperio Ciani, Andrea; Cermelli, Paolo; Zanzotto, Giovanni

    2008-01-01

    Several lines of evidence indicate the existence of genetic factors influencing male homosexuality and bisexuality. In spite of its relatively low frequency, the stable permanence in all human populations of this apparently detrimental trait constitutes a puzzling 'Darwinian paradox'. Furthermore, several studies have pointed out relevant asymmetries in the distribution of both male homosexuality and of female fecundity in the parental lines of homosexual vs. heterosexual males. A number of hypotheses have attempted to give an evolutionary explanation for the long-standing persistence of this trait, and for its asymmetric distribution in family lines; however a satisfactory understanding of the population genetics of male homosexuality is lacking at present. We perform a systematic mathematical analysis of the propagation and equilibrium of the putative genetic factors for male homosexuality in the population, based on the selection equation for one or two diallelic loci and Bayesian statistics for pedigree investigation. We show that only the two-locus genetic model with at least one locus on the X chromosome, and in which gene expression is sexually antagonistic (increasing female fitness but decreasing male fitness), accounts for all known empirical data. Our results help clarify the basic evolutionary dynamics of male homosexuality, establishing this as a clearly ascertained sexually antagonistic human trait. PMID:18560521

  11. Sexually antagonistic selection in human male homosexuality.

    Directory of Open Access Journals (Sweden)

    Andrea Camperio Ciani

    Full Text Available Several lines of evidence indicate the existence of genetic factors influencing male homosexuality and bisexuality. In spite of its relatively low frequency, the stable permanence in all human populations of this apparently detrimental trait constitutes a puzzling 'Darwinian paradox'. Furthermore, several studies have pointed out relevant asymmetries in the distribution of both male homosexuality and of female fecundity in the parental lines of homosexual vs. heterosexual males. A number of hypotheses have attempted to give an evolutionary explanation for the long-standing persistence of this trait, and for its asymmetric distribution in family lines; however a satisfactory understanding of the population genetics of male homosexuality is lacking at present. We perform a systematic mathematical analysis of the propagation and equilibrium of the putative genetic factors for male homosexuality in the population, based on the selection equation for one or two diallelic loci and Bayesian statistics for pedigree investigation. We show that only the two-locus genetic model with at least one locus on the X chromosome, and in which gene expression is sexually antagonistic (increasing female fitness but decreasing male fitness, accounts for all known empirical data. Our results help clarify the basic evolutionary dynamics of male homosexuality, establishing this as a clearly ascertained sexually antagonistic human trait.

  12. Mechanisms of immune regulation by norepinephrine and cholera toxin

    Energy Technology Data Exchange (ETDEWEB)

    Campbell, K.S.

    1988-01-01

    Norepinephrine has previously been demonstrated by this laboratory to potentiate the in vitro T-dependent antibody response through the stimulation of {beta}-adrenergic receptors. The role of {beta}-adrenergic receptor subtypes in norepinephrine-induced potentiation of the antibody responses was examined with selective {beta}-adrenergic antagonists. The antagonists were metoprolol ({beta}{sub 1}-selective), ICI 118-551 ({beta}{sub 2}-selective), and propranolol ({beta}-non-selective). Both propranolol and ICI 118-551 blocked norepinephrine-induced potentiation of the antibody response, but metoprolol was ineffective. Receptor binding competition of antagonists with the radioligant, ({sup 3}H)CGP-12177 was examined and results were analyzed with the computer program, LIGAND. Competition by ICI 118-551 identified 75% {beta}{sub 2}- and 25% {beta}{sub 1}-adrenergic receptors on splenic mononuclear cells. Enriched T lymphocytes exhibited 75% {beta}{sub 2}-adrenergic receptors, while enriched B lymphocytes contained 90% {beta}{sub 2}-adrenergic receptors as identified by ICI 118-551. Greater than twice as many total receptors were identified on B lymphocytes than T lymphocytes. A T cell lymphoma contained about 60% {beta}{sub 2}-receptors, while 100% were {beta}{sub 2} receptors on a B cell lymphoma, as assessed by ICI 118-551. Results support a heterogeneous {beta}-adrenergic receptor population on T lymphocytes and a more homogeneous {beta}{sub 2}-population on B lymphocytes.

  13. Corticospinal control of antagonistic muscles in the cat.

    Science.gov (United States)

    Ethier, Christian; Brizzi, Laurent; Giguère, Dominic; Capaday, Charles

    2007-09-01

    We recently suggested that movement-related inter-joint muscle synergies are recruited by selected excitation and selected release from inhibition of cortical points. Here we asked whether a similar cortical mechanism operates in the functional linking of antagonistic muscles. To this end experiments were done on ketamine-anesthetized cats. Intracortical microstimulation (ICMS) and intramuscular electromyographic recordings were used to find and characterize wrist, elbow and shoulder antagonistic motor cortical points. Simultaneous ICMS applied at two cortical points, each evoking activity in one of a pair of antagonistic muscles, produced co-contraction of antagonistic muscle pairs. However, we found an obvious asymmetry in the strength of reciprocal inhibition; it was always significantly stronger on physiological extensors than flexors. Following intravenous injection of a single bolus of strychnine, a cortical point at which only a physiological flexor was previously activated also elicited simultaneous activation of its antagonist. This demonstrates that antagonistic corticospinal neurons are closely grouped, or intermingled. To test whether releasing a cortical point from inhibition allows it to be functionally linked with an antagonistic cortical point, one of three GABA(A) receptor antagonists, bicuculline, gabazine or picrotoxin, was injected iontophoretically at one cortical point while stimulation was applied to an antagonistic cortical point. This coupling always resulted in co-contraction of the represented antagonistic muscles. Thus, antagonistic motor cortical points are linked by excitatory intracortical connections held in check by local GABAergic inhibition, with reciprocal inhibition occurring at the spinal level. Importantly, the asymmetry of cortically mediated reciprocal inhibition would appear significantly to bias muscle maps obtained by ICMS in favor of physiological flexors. PMID:17880397

  14. The Attractiveness of Opposites: Agonists and Antagonists.

    LENUS (Irish Health Repository)

    O'Brien, Tony

    2015-02-02

    ABSTRACT Opioid-induced bowel dysfunction, of which constipation is the most common aspect, is a major limiting factor in the use of opioids for pain management. The availability of an oral, long-acting formulation of oxycodone and naloxone represents a highly significant development in pain management. The combination of an opioid analgesic with an opioid antagonist offers reliable pain control with a significant reduction in the burden of opioid-induced constipation. This report is adapted from paineurope 2014; Issue 3, ©Haymarket Medical Publications Ltd, and is presented with permission. paineurope is provided as a service to pain management by Mundipharma International, LTD and is distributed free of charge to healthcare professionals in Europe. Archival issues can be accessed via the website: http:\\/\\/www.paineurope.com at which European health professionals can register online to receive copies of the quarterly publication.

  15. Mutually-antagonistic interactions in baseball networks

    Science.gov (United States)

    Saavedra, Serguei; Powers, Scott; McCotter, Trent; Porter, Mason A.; Mucha, Peter J.

    2010-03-01

    We formulate the head-to-head matchups between Major League Baseball pitchers and batters from 1954 to 2008 as a bipartite network of mutually-antagonistic interactions. We consider both the full network and single-season networks, which exhibit structural changes over time. We find interesting structure in the networks and examine their sensitivity to baseball’s rule changes. We then study a biased random walk on the matchup networks as a simple and transparent way to (1) compare the performance of players who competed under different conditions and (2) include information about which particular players a given player has faced. We find that a player’s position in the network does not correlate with his placement in the random walker ranking. However, network position does have a substantial effect on the robustness of ranking placement to changes in head-to-head matchups.

  16. Mutually-Antagonistic Interactions in Baseball Networks

    CERN Document Server

    Saavedra, Serguei; McCotter, Trent; Porter, Mason A; Mucha, Peter J

    2009-01-01

    We formulate the head-to-head matchups between Major League Baseball pitchers and batters from 1954 to 2008 as a bipartite network of mutually-antagonistic interactions. We consider both the full network and single-season networks, which exhibit interesting structural changes over time. We also find that these networks exhibit a significant network structure that is sensitive to baseball's rule changes. We then study a biased random walk on the matchup networks as a simple and transparent way to compare the performance of players who competed under different conditions. We find that a player's position in the network does not correlate with his success in the random walker ranking but instead has a substantial effect on its sensitivity to changes in his own aggregate performance.

  17. Antagonistic activity of marine sponges associated Actinobacteria

    Institute of Scientific and Technical Information of China (English)

    Selvakumar Dharmaraj; Dhevendaran Kandasamy

    2016-01-01

    Objective: To focus on the isolation and preliminary characterization of marine sponges associated Actinobacteria particularly Streptomyces species and also their antagonistic activities against bacterial and fungal pathogens. Methods: The sponges were collected from Kovalam and Vizhinjam port of south-west coast of Kerala, India. Isolation of strains was carried out from sponge extracts using international Streptomyces project media. For preliminary identification of the strains, morphological (mycelial colouration, soluble pigments, melanoid pigmentation, spore morphology), nutritional uptake (carbon utilisation, amonoacids influence, sodium chloride tolerance), physiological (pH, temperature) and chemotaxonomical characterization were done. Antimicrobial studies were also carried out for the selected strains. Results: With the help of the spicule structures, the collected marine sponges were identified as Callyspongia diffusa, Mycale mytilorum, Tedania anhelans and Dysidea fragilis. Nearly 94 strains were primarily isolated from these sponges and further they were sub-cultured using international Streptomyces project media. The strains exhibited different mycelial colouration (aerial and substrate), soluble and melanoid pigmentations. The strains possessed three types of sporophore morphology namely rectus flexibilis, spiral and retinaculiaperti. Among the 94 isolates, seven exhibited antibacterial and antifungal activities with maximal zone of inhibition of 30 mm. The nutritional, physiological and chemotaxonomical characteristic study helped in the conventional identification of the seven strains and they all suggest that the strains to be grouped under the genus Streptomyces. Conclusions: The present study clearly helps in the preliminary identification of the isolates associated with marine sponges. Antagonistic activities prove the production of antimicrobial metabolites against the pathogens. Marine sponges associated Streptomyces are universally well

  18. Serotonin 2A receptor antagonists for treatment of schizophrenia

    DEFF Research Database (Denmark)

    Ebdrup, Bjørn Hylsebeck; Rasmussen, Hans; Arnt, Jørn; Glenthøj, Birte Yding

    2011-01-01

    receptor antagonists is evaluated. Moreover, the investigational pipeline of major pharmaceutical companies is examined and an Internet search conducted to identify other pharmaceutical companies investigating 5-HT2A receptor antagonists for the treatment of schizophrenia. Expert opinion: 5-HT2A receptor...

  19. DEFICIENCY OF INTERLEUKIN-1 RECEPTOR ANTAGONIST RESPONSIVE TO ANAKINRA

    OpenAIRE

    SCHNELLBACHER, CHARLOTTE; CIOCCA, GIOVANNA; MENENDEZ, ROXANNA; Aksentijevich, Ivona; Goldbach-Mansky, Raphaela; DUARTE, ANAM.; RIVAS-CHACON, RAFAEL

    2012-01-01

    We describe a 3-month-old infant who presented to our institution with interleukin (IL)-1 receptor antagonist deficiency (DIRA), which consists of neutrophilic pustular dermatosis, periostitis, aseptic multifocal osteomyelitis, and persistently high acutephase reactants. Skin findings promptly improved upon initiation of treatment with anakinra (recombinant human IL-1 receptor antagonist), and the bony lesions and systemic inflammation resolved with continued therapy.

  20. Antagonistic and Bargaining Games in Optimal Marketing Decisions

    Science.gov (United States)

    Lipovetsky, S.

    2007-01-01

    Game theory approaches to find optimal marketing decisions are considered. Antagonistic games with and without complete information, and non-antagonistic games techniques are applied to paired comparison, ranking, or rating data for a firm and its competitors in the market. Mix strategy, equilibrium in bi-matrix games, bargaining models with…

  1. Pros and cons of vitamin K antagonists and non-vitamin K antagonist oral anticoagulants.

    Science.gov (United States)

    Riva, Nicoletta; Ageno, Walter

    2015-03-01

    Anticoagulant treatment can be currently instituted with two different classes of drugs: the vitamin K antagonists (VKAs) and the newer, "novel" or non-vitamin K antagonist oral anticoagulant drugs (NOACs). The NOACs have several practical advantages over VKAs, such as the rapid onset/offset of action, the lower potential for food and drug interactions, and the predictable anticoagulant response. However, the VKAs currently have a broader spectrum of indications, a standardized monitoring test, and established reversal strategies. The NOACs emerged as alternative options for the prevention and treatment of venous thromboembolism and for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Nevertheless, there remain some populations for whom the VKAs remain the most appropriate anticoagulant drug. This article discusses the advantages and disadvantages of VKAs and NOACs. PMID:25703519

  2. Pharmacokinetic interactions with calcium channel antagonists (Part I).

    Science.gov (United States)

    Schlanz, K D; Myre, S A; Bottorff, M B

    1991-11-01

    Calcium channel antagonists are a diverse class of drugs widely used in combination with other therapeutic agents. The potential exists for many clinically significant pharmacokinetic interactions between these and other concurrently administered drugs. The mechanisms of calcium channel antagonist-induced changes in drug metabolism include altered hepatic blood flow and impaired hepatic enzyme metabolising activity. Increases in serum concentrations and/or reductions in clearance have been reported for several drugs used with a number of calcium channel antagonists. A number of reports and studies of calcium channel antagonist interactions have yielded contradictory results and the clinical significance of pharmacokinetic changes seen with these agents is ill-defined. The first part of this article deals with interactions between calcium antagonists and marker compounds, theophylline, midazolam, lithium, doxorubicin, oral hypoglycaemics and cardiac drugs. PMID:1773549

  3. Adrenergic Modulation of Pancreatic Glucagon Secretion in Man

    Science.gov (United States)

    Gerich, John E.; Langlois, Maurice; Noacco, Claudio; Schneider, Victor; Forsham, Peter H.

    1974-01-01

    In order to characterize the influence of the adrenergic system on pancreatic glucagon secretion in man, changes in basal glucagon secretion during infusions of pure alpha and beta adrenergic agonists and their specific antagonists were studied. During infusion of isoproterenol (3 μg/min), a beta adrenergic agonist, plasma glucagon rose from a mean (±SE) basal level of 104±10 to 171±15 pg/ml, P < 0.0002. Concomitant infusion of propranolol (80 μg/min), a beta adrenergic antagonist, prevented the effects of isoproterenol, although propranolol itself had no effect on basal glucagon secretion. During infusion of methoxamine (0.5 mg/min), an alpha adrenergic agonist, plasma glucagon declined from a mean basal level of 122±15 to 75±17 pg/ml, P < 0.001. Infusion of phentolamine (0.5 mg/min), an alpha adrenergic antagonist, caused a rise in plasma glucagon from a mean basal level of 118±16 to 175±21 pg/ml, P < 0.0001. Concomitant infusion of methoxamine with phentolamine caused a reversal of the effects of phentolamine. The present studies thus confirm that catecholamines affect glucagon secretion in man and demonstrate that the pancreatic alpha cell possesses both alpha and beta adrenergic receptors. Beta adrenergic stimulation augments basal glucagon secretion, while alpha adrenergic stimulation diminishes basal glucagon secretion. Furthermore, since infusion of phentolamine, an alpha adrenergic antagonist, resulted in an elevation of basal plasma glucagon levels, there appears to be an inhibitory alpha adrenergic tone governing basal glucagon secretion. The above findings suggest that catecholamines may influence glucose homeostasis in man through their effects on both pancreatic alpha and beta cell function. Images PMID:4825234

  4. Antagonistic neural networks underlying differentiated leadership roles.

    Science.gov (United States)

    Boyatzis, Richard E; Rochford, Kylie; Jack, Anthony I

    2014-01-01

    The emergence of two distinct leadership roles, the task leader and the socio-emotional leader, has been documented in the leadership literature since the 1950s. Recent research in neuroscience suggests that the division between task-oriented and socio-emotional-oriented roles derives from a fundamental feature of our neurobiology: an antagonistic relationship between two large-scale cortical networks - the task-positive network (TPN) and the default mode network (DMN). Neural activity in TPN tends to inhibit activity in the DMN, and vice versa. The TPN is important for problem solving, focusing of attention, making decisions, and control of action. The DMN plays a central role in emotional self-awareness, social cognition, and ethical decision making. It is also strongly linked to creativity and openness to new ideas. Because activation of the TPN tends to suppress activity in the DMN, an over-emphasis on task-oriented leadership may prove deleterious to social and emotional aspects of leadership. Similarly, an overemphasis on the DMN would result in difficulty focusing attention, making decisions, and solving known problems. In this paper, we will review major streams of theory and research on leadership roles in the context of recent findings from neuroscience and psychology. We conclude by suggesting that emerging research challenges the assumption that role differentiation is both natural and necessary, in particular when openness to new ideas, people, emotions, and ethical concerns are important to success. PMID:24624074

  5. Antagonistic Neural Networks Underlying Differentiated Leadership Roles

    Directory of Open Access Journals (Sweden)

    Richard Eleftherios Boyatzis

    2014-03-01

    Full Text Available The emergence of two distinct leadership roles, the task leader and the socio-emotional leader, has been documented in the leadership literature since the 1950’s. Recent research in neuroscience suggests that the division between task oriented and socio-emotional oriented roles derives from a fundamental feature of our neurobiology: an antagonistic relationship between two large-scale cortical networks -- the Task Positive Network (TPN and the Default Mode Network (DMN. Neural activity in TPN tends to inhibit activity in the DMN, and vice versa. The TPN is important for problem solving, focusing of attention, making decisions, and control of action. The DMN plays a central role in emotional self-awareness, social cognition, and ethical decision making. It is also strongly linked to creativity and openness to new ideas. Because activation of the TPN tends to suppress activity in the DMN, an over-emphasis on task oriented leadership may prove deleterious to social and emotional aspects of leadership. Similarly, an overemphasis on the DMN would result in difficulty focusing attention, making decisions and solving known problems. In this paper, we will review major streams of theory and research on leadership roles in the context of recent findings from neuroscience and psychology. We conclude by suggesting that emerging research challenges the assumption that role differentiation is both natural and necessary, in particular when openness to new ideas, people, emotions, and ethical concerns are important to success.

  6. Endothelin receptor antagonists in pulmonary arterial hypertension.

    Science.gov (United States)

    Dupuis, J; Hoeper, M M

    2008-02-01

    The endothelin (ET) system, especially ET-1 and the ET(A) and ET(B) receptors, has been implicated in the pathogenesis of pulmonary arterial hypertension (PAH). Together with prostanoids and phosphodiesterase 5 inhibitors, ET receptor antagonists have become mainstays in the current treatment of PAH. Three substances are currently available for the treatment of PAH. One of these substances, bosentan, blocks both ET(A) and ET(B) receptors, whereas the two other compounds, sitaxsentan and ambrisentan, are more selective blockers of the ET(A) receptor. There is ongoing debate as to whether selective or nonselective ET receptor blockade is advantageous in the setting of PAH, although there is no clear evidence that receptor selectivity is relevant with regard to the clinical effects of these drugs. For the time being, other features, such as safety profiles and the potential for pharmacokinetic interactions with other drugs used in the treatment of PAH, may be more important than selectivity or nonselectivity when selecting treatments for individual patients. PMID:18238950

  7. Multiple Targeting Approaches on Histamine H3 Receptor Antagonists

    Directory of Open Access Journals (Sweden)

    Mohammad eKhanfar

    2016-05-01

    Full Text Available With the very recent market approval of pitolisant (Wakix®, the interest in clinical applications of novel multifunctional histamine H3 receptor antagonists has clearly increased. Since histamine H3 receptor antagonists in clinical development have been tested for a variety of different indications, the combination of pharmacological properties in one molecule for improved pharmacological effects and reduced unwanted side-effects is rationally based on the increasing knowledge on the complex neurotransmitter regulations. The polypharmacological approaches on histamine H3 receptor antagonists on different G-protein coupled receptors, transporters, enzymes as well as on NO-signaling mechanism are described, supported with some lead structures.

  8. The muscarinic antagonists scopolamine and atropine are competitive antagonists at 5-HT3 receptors.

    Science.gov (United States)

    Lochner, Martin; Thompson, Andrew J

    2016-09-01

    Scopolamine is a high affinity muscarinic antagonist that is used for the prevention of post-operative nausea and vomiting. 5-HT3 receptor antagonists are used for the same purpose and are structurally related to scopolamine. To examine whether 5-HT3 receptors are affected by scopolamine we examined the effects of this drug on the electrophysiological and ligand binding properties of 5-HT3A receptors expressed in Xenopus oocytes and HEK293 cells, respectively. 5-HT3 receptor-responses were reversibly inhibited by scopolamine with an IC50 of 2.09 μM. Competitive antagonism was shown by Schild plot (pA2 = 5.02) and by competition with the 5-HT3 receptor antagonists [(3)H]granisetron (Ki = 6.76 μM) and G-FL (Ki = 4.90 μM). The related molecule, atropine, similarly inhibited 5-HT evoked responses in oocytes with an IC50 of 1.74 μM, and competed with G-FL with a Ki of 7.94 μM. The reverse experiment revealed that granisetron also competitively bound to muscarinic receptors (Ki = 6.5 μM). In behavioural studies scopolamine is used to block muscarinic receptors and induce a cognitive deficit, and centrally administered concentrations can exceed the IC50 values found here. It is therefore possible that 5-HT3 receptors are also inhibited. Studies that utilise higher concentrations of scopolamine should be mindful of these potential off-target effects. PMID:27108935

  9. Vasodilatory mechanisms of beta receptor blockade.

    OpenAIRE

    Rath, Géraldine; Balligand, Jean-Luc; Dessy, Chantal

    2012-01-01

    Beta-blockers are widely prescribed for the treatment of a variety of cardiovascular pathologies. Compared to traditional beta-adrenergic antagonists, beta-blockers of the new generation exhibit ancillary properties such as vasodilation through different mechanisms. This translates into a more favorable hemodynamic profile. The relative affinities of beta-adrenoreceptor antagonists towards the three beta-adrenoreceptor isotypes matter for predicting their functional impact on vasomotor contro...

  10. Secondary prevention with calcium antagonists after acute myocardial infarction

    DEFF Research Database (Denmark)

    Hansen, J F

    1992-01-01

    Experimental studies have demonstrated that the 3 calcium antagonists nifedipine, diltiazem, and verapamil have a comparable effect in the prevention of myocardial damage during ischaemia. Secondary prevention trials after acute myocardial infarction, which aimed at improving survival and...

  11. TRPV1 Antagonists and Chronic Pain: Beyond Thermal Perception

    OpenAIRE

    Brandt, Michael R.; Beyer, Chad E; Stahl, Stephen M.

    2012-01-01

    In the last decade, considerable evidence as accumulated to support the development of Transient Receptor Potential Vanilloid 1 (TRPV1) antagonists for the treatment of various chronic pain conditions. Whereas there is a widely accepted rationale for the development of TRPV1 antagonists for the treatment of various inflammatory pain conditions, their development for indications of chronic pain, where conditions of tactical, mechanical and spontaneous pain predominate, is less clear. Preclinic...

  12. Bradykinin antagonists modified with dipeptide mimetic beta-turn inducers.

    Science.gov (United States)

    Alcaro, Maria C; Vinci, Valerio; D'Ursi, Anna M; Scrima, Mario; Chelli, Mario; Giuliani, Sandro; Meini, Stefania; Di Giacomo, Marcello; Colombo, Lino; Papini, Anna Maria

    2006-05-01

    Bradykinin (BK) is involved in a wide variety of pathophysiological processes. Potent BK peptide antagonists can be developed introducing constrained unnatural amino acids, necessary to force the secondary structure of the molecule. In this paper, we report a structure-activity relationship study of two peptide analogues of the potent B2 antagonist HOE 140 by replacing the D-Tic-Oic dipeptide with conformationally constrained dipeptide mimetic beta-turn inducers. PMID:16504505

  13. The Apolipoprotein E Antagonistic Pleiotropy Hypothesis: Review and Recommendations

    OpenAIRE

    Tuminello, Elizabeth R.; S Duke Han

    2011-01-01

    Research on apolipoprotein E (APOE) has consistently revealed a relationship between the gene's ε 4 allele and risk for development of Alzheimer's disease (AD). However, research with younger populations of ε 4 carriers has suggested that the APOE ε 4 allele may in fact be beneficial in earlier ages and may only confer risk of cognitive decline later in life. Accordingly, we and others have proposed that APOE may represent an example of antagonistic pleiotropy. Antagonistic pleiotropy is an e...

  14. Deficiency of interleukin-1 receptor antagonist responsive to anakinra.

    Science.gov (United States)

    Schnellbacher, Charlotte; Ciocca, Giovanna; Menendez, Roxanna; Aksentijevich, Ivona; Goldbach-Mansky, Raphaela; Duarte, Ana M; Rivas-Chacon, Rafael

    2013-01-01

    We describe a 3-month-old infant who presented to our institution with interleukin (IL)-1 receptor antagonist deficiency (DIRA), which consists of neutrophilic pustular dermatosis, periostitis, aseptic multifocal osteomyelitis, and persistently high acute-phase reactants. Skin findings promptly improved upon initiation of treatment with anakinra (recombinant human IL-1 receptor antagonist), and the bony lesions and systemic inflammation resolved with continued therapy. PMID:22471702

  15. Interleukin-2 receptor antagonists as induction therapy after heart transplantation

    DEFF Research Database (Denmark)

    Møller, Christian H; Gustafsson, Finn; Gluud, Christian;

    2008-01-01

    About half of the transplantation centers use induction therapy after heart transplantation. Interleukin-2 receptor antagonists (IL-2Ras) are used increasingly for induction therapy. We conducted a systematic review of randomized trials assessing IL-2Ras.......About half of the transplantation centers use induction therapy after heart transplantation. Interleukin-2 receptor antagonists (IL-2Ras) are used increasingly for induction therapy. We conducted a systematic review of randomized trials assessing IL-2Ras....

  16. Control of heart rate during thermoregulation in the heliothermic lizard Pogona barbata: importance of cholinergic and adrenergic mechanisms.

    Science.gov (United States)

    Seebacher, F; Franklin, C E

    2001-12-01

    During thermoregulation in the bearded dragon Pogona barbata, heart rate when heating is significantly faster than when cooling at any given body temperature (heart rate hysteresis), resulting in faster rates of heating than cooling. However, the mechanisms that control heart rate during heating and cooling are unknown. The aim of this study was to test the hypothesis that changes in cholinergic and adrenergic tone on the heart are responsible for the heart rate hysteresis during heating and cooling in P. barbata. Heating and cooling trials were conducted before and after the administration of atropine, a muscarinic antagonist, and sotalol, a beta-adrenergic antagonist. Cholinergic and beta-adrenergic blockade did not abolish the heart rate hysteresis, as the heart rate during heating was significantly faster than during cooling in all cases. Adrenergic tone was extremely high (92.3 %) at the commencement of heating, and decreased to 30.7 % at the end of the cooling period. Moreover, in four lizards there was an instantaneous drop in heart rate (up to 15 beats min(-1)) as the heat source was switched off, and this drop in heart rate coincided with either a drop in beta-adrenergic tone or an increase in cholinergic tone. Rates of heating were significantly faster during the cholinergic blockade, and least with a combined cholinergic and beta-adrenergic blockade. The results showed that cholinergic and beta-adrenergic systems are not the only control mechanisms acting on the heart during heating and cooling, but they do have a significant effect on heart rate and on rates of heating and cooling. PMID:11815660

  17. Biocontrol of Some Tomato Disease Using Some Antagonistic Microorganisms

    Directory of Open Access Journals (Sweden)

    Ilham M. El–Rafai

    2003-01-01

    Full Text Available Four biocontrol�agents, namely : Trichoderma harzianum, T. hamatum, Bacillus subtilis and Pseudomonas fluorescens, have been tested for their potential antagonism for controlling fusarium wilt, verticillium wilt and early blight diseases of tomato. In vitro studies showed that culture filtrates of all antagonistic organisms significantly decrease the spore germination and germ tube-length of the tested pathogens, F. oxysporum f. sp. lycopersici, Verticillium dahliae and Alternaria solani. The linear growth and sporulation of the concerned pathogens were also inhibited the degree of inhibition was varied according to the tested antagonistic filtrate. In vivo studies, three treatments were applied; inoculation of the soil with antagonist period to sowing, soaking tomato seeds in the filtrate of the tested antagonist before sowing and coating of tomato seeds with spores of the antagonist before planting. Soil inoculation and seed coating with T. hamatum spores completely controlled the concerned diseases and improved the yield. However, P. fluorescens seed coating controlled the early blight disease and improved the tomato growth as well. Concerning the chemical assessment, T. hamatum soil inoculation and seed coating treatments gave the highest increase for chlorophyll a, b and cartenoids. Also the same treatments showed the highest increase of phenolic compounds (free and conjugated and the lowest percentage for sugars content of tomato leaves infected with the concerned pathogens.

  18. First Irish birth following IVF therapy using antagonist protocol.

    LENUS (Irish Health Repository)

    Mocanu, E V

    2012-02-01

    BACKGROUND: During in vitro fertilization (IVF), the prevention of a premature LH surge was traditionally achieved using a gonadotrophin releasing hormone agonist (GnRH-a), and more recently, a GnRH antagonist. AIMS: We report a case of a 37 year old treated using the GnRH antagonist in a second completed cycle of IVF. METHODS: IVF was performed for primary infertility of 5-year duration due to frozen pelvis secondary to endometriosis. RESULTS: Following controlled ovarian hyperstimulation, oocyte recovery and fertilization, cleavage and transfer of two zygotes, a pregnancy established. A twin gestation was diagnosed at 7-weeks scan and pregnancy ended with the delivery of twin girls by emergency caesarean section. CONCLUSION: This is a first report of a delivery following IVF using the antagonist protocol in Ireland. Such therapy is patient friendly and its use should be introduced on a larger scale in clinical practice.

  19. ANTAGONISTIC BACTERIA AGAINST SCHIZOPHYLLUM COMMUNE FR. IN PENINSULAR MALAYSIA

    Directory of Open Access Journals (Sweden)

    ANTARJO DIKIN

    2006-01-01

    Full Text Available Schizophyllum commune Fr., is one of the important fungi, causes brown germ and seed rot of oil palm. Biodiversity of antagonistic bacteria from oil palm plantations in Peninsular Malaysia is expected to support in development of biopesticide. Isolation with liquid assay and screening antagonistic bacteria using dual culture assay were carried out in the bioexploration. A total of 265 bacterial isolates from plant parts of oil palm screened 52 antagonistic bacterial isolates against 5. commune. Bacterial isolates were identified by using Biolog* Identification System i.e. Bacillus macroccanus, B. thermoglucosidasius, Burkholderia cepacia, B. gladioli, B. multivorans, B pyrrocinia, B. spinosa, Corynebacterium agropyri, C. misitidis, Enterobacter aerogenes, Microbacterium testaceum, Pseudomonas aeruginosa, P. citronellolis, Rhodococcus rhodochrous, Serratia ficaria, Serratia sp., S. marcescens, Staphylococcus sciuri, Sternotrophomonas maltophilia.

  20. Oxytocin antagonists for the management of preterm birth: a review.

    Science.gov (United States)

    Usta, Ihab M; Khalil, Ali; Nassar, Anwar H

    2011-06-01

    Preterm birth, the leading cause of neonatal morbidity and mortality, is estimated at incidence of 12.7% of all births, which has not decreased over the last four decades despite intensive antenatal care programs aimed at high-risk groups, the widespread use of tocolytics, and a series of other preventive and therapeutic interventions. Oxytocin antagonists, namely atosiban, represent an appealing choice that seems to be effective with apparently fewer side effects than the traditional tocolytics. This article reviews the available literature on the pharmacokinetics, mode of administration, and clinical utility of oxytocin antagonists for acute and maintenance tocolysis with special emphasis on its safety profile. PMID:21170825

  1. Discovery of small molecule antagonists of TRPV1.

    Science.gov (United States)

    Rami, Harshad K; Thompson, Mervyn; Wyman, Paul; Jerman, Jeffrey C; Egerton, Julie; Brough, Stephen; Stevens, Alexander J; Randall, Andrew D; Smart, Darren; Gunthorpe, Martin J; Davis, John B

    2004-07-16

    Small molecule antagonists of the vanilloid receptor 1 (TRPV1, also known as VR1) are disclosed. Ureas such as 5 (SB-452533) were used to explore the structure activity relationship with several potent analogues identified. Pharmacological studies using electrophysiological and FLIPR Ca(2+) based assays showed compound 5 was an antagonist versus capsaicin, noxious heat and acid mediated activation of TRPV1. Study of a quaternary salt of 5 supports a mode of action in which compounds from this series cause inhibition via an extracellularly accessible binding site on the TRPV1 receptor. PMID:15203132

  2. Pharmacokinetic interactions with calcium channel antagonists (Part II).

    Science.gov (United States)

    Schlanz, K D; Myre, S A; Bottorff, M B

    1991-12-01

    Since calcium channel antagonists are a diverse class of drugs frequently administered in combination with other agents, the potential for clinically significant pharmacokinetic drug interactions exists. These interactions occur most frequently via altered hepatic blood flow and impaired hepatic enzyme activity. Part I of the article, which appeared in the previous issue of the Journal, dealt with interactions between calcium antagonists and marker compounds, theophylline, midazolam, lithium, doxorubicin, oral hypoglycaemics and cardiac drugs. Part II examines interactions with cyclosporin, anaesthetics, carbamazepine and cardiovascular agents. PMID:1782739

  3. Voltage-Gated Calcium Channel Antagonists and Traumatic Brain Injury

    Directory of Open Access Journals (Sweden)

    Bruce Lyeth

    2013-06-01

    Full Text Available Traumatic brain injury (TBI is a leading cause of death and disability in the United States. Despite more than 30 years of research, no pharmacological agents have been identified that improve neurological function following TBI. However, several lines of research described in this review provide support for further development of voltage gated calcium channel (VGCC antagonists as potential therapeutic agents. Following TBI, neurons and astrocytes experience a rapid and sometimes enduring increase in intracellular calcium ([Ca2+]i. These fluxes in [Ca2+]i drive not only apoptotic and necrotic cell death, but also can lead to long-term cell dysfunction in surviving cells. In a limited number of in vitro experiments, both L-type and N-type VGCC antagonists successfully reduced calcium loads as well as neuronal and astrocytic cell death following mechanical injury. In rodent models of TBI, administration of VGCC antagonists reduced cell death and improved cognitive function. It is clear that there is a critical need to find effective therapeutics and rational drug delivery strategies for the management and treatment of TBI, and we believe that further investigation of VGCC antagonists should be pursued before ruling out the possibility of successful translation to the clinic.

  4. Neuroprotection by NMDA receptor antagonists in a variety of neuropathologies.

    Science.gov (United States)

    Palmer, G C

    2001-09-01

    Because of adverse reactions, early efforts to introduce high affinity competitive or use-dependent NMDA receptor antagonists into patients suffering from stroke, head trauma or epilepsy met with failure. Later it was discovered that both low affinity use-dependent NMDA receptor antagonists and compounds with selective affinity for the NR2B receptor subunit met the criteria for safe administration into patients. Furthermore, these low affinity antagonists exhibit significant mechanistic differences from their higher affinity counterparts. Success of the latter is attested to the ability of the following low affinity compounds to be marketed: 1) Cough suppressant-dextromethorphan (available for decades); 2) Parkinson's disease--amantadine, memantine and budipine; 3) Dementia--memantine; and 4) Epilepsy--felbamate. Moreover, Phase III clinical trials are ongoing with remacemide for epilepsy and Huntington's disease and head trauma for HU-211. A host of compounds are or were under evaluation for the possible treatment of stroke, head trauma, hyperalgesia and various neurodegenerative disorders. Despite the fact that other drugs with associated NMDA receptor mechanisms have reached clinical status, this review focuses only on those competitive and use-dependent NMDA receptor antagonists that reached clinical trails. The ensuing discussions link the in vivo pharmacological investigations that led to the success/mistakes/ failures for eventual testing of promising compounds in the clinic. PMID:11554551

  5. Synthesis and evaluation of 18F-labeled PPARγ antagonists

    International Nuclear Information System (INIS)

    Introduction: Peroxisome proliferator-activated receptor gamma (PPARγ) transcriptionally modulates fat metabolism and also plays a role in pathological conditions such as cancer, neurodegenerative disease and inflammation. PPARγ imaging agents are potential tools for investigating these diseases. Methods: Four analogs of GW9662, a PPARγ antagonist, with different fluorine-containing substituents at the para-position of the aniline ring were synthesized and evaluated using two different receptor binding assays for measuring PPARγ affinity. Micro-positron emission tomography (PET) imaging studies were performed in a transgenic mouse model having a heart-specific overexpression of PPARγ. Results: All four analogs were found to have binding affinities that were comparable to or better than the reference antagonist, GW9662, using a scintillation proximity assay (SPA). However, only the chloro-based analogs (compounds 3 and 4) had activity in a whole-cell assay measuring activation of the PPARγ/retinoid X receptor complex. The microPET imaging studies in an MHC-PPARγ transgenic mouse model showed high uptake and PPARγ-specific binding for the irreversible antagonist [18F]3, whereas the corresponding reversible methoxy analog ([18F]5) displayed only nonspecific uptake in heart. Conclusions: The results of this preliminary study show that the irreversible antagonist [18F]3 may represent a novel strategy for imaging PPARγ in vivo with PET.

  6. Characterization of a novel non-steroidal glucocorticoid receptor antagonist

    Energy Technology Data Exchange (ETDEWEB)

    Li, Qun-Yi; Zhang, Meng [The National Center for Drug Screening, Shanghai (China); State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai (China); Hallis, Tina M.; DeRosier, Therese A. [Cell Systems Division, Invitrogen, Madison, WI (United States); Yue, Jian-Min; Ye, Yang [State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai (China); Mais, Dale E. [The National Center for Drug Screening, Shanghai (China); MPI Research, Mattawan, MI (United States); Wang, Ming-Wei, E-mail: wangmw@mail.shcnc.ac.cn [The National Center for Drug Screening, Shanghai (China); State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai (China)

    2010-01-15

    Selective antagonists of the glucocorticoid receptor (GR) are desirable for the treatment of hypercortisolemia associated with Cushing's syndrome, psychic depression, obesity, diabetes, neurodegenerative diseases, and glaucoma. NC3327, a non-steroidal small molecule with potent binding affinity to GR (K{sub i} = 13.2 nM), was identified in a high-throughput screening effort. As a full GR antagonist, NC3327 greatly inhibits the dexamethasone (Dex) induction of marker genes involved in hepatic gluconeogenesis, but has a minimal effect on matrix metalloproteinase 9 (MMP-9), a GR responsive pro-inflammatory gene. Interestingly, the compound recruits neither coactivators nor corepressors to the GR complex but competes with glucocorticoids for the interaction between GR and a coactivator peptide. Moreover, NC3327 does not trigger GR nuclear translocation, but significantly blocks Dex-induced GR transportation to the nucleus, and thus appears to be a 'competitive' GR antagonist. Therefore, the non-steroidal compound, NC3327, may represent a new class of GR antagonists as potential therapeutics for a variety of cortisol-related endocrine disorders.

  7. Characterization of a novel non-steroidal glucocorticoid receptor antagonist

    International Nuclear Information System (INIS)

    Selective antagonists of the glucocorticoid receptor (GR) are desirable for the treatment of hypercortisolemia associated with Cushing's syndrome, psychic depression, obesity, diabetes, neurodegenerative diseases, and glaucoma. NC3327, a non-steroidal small molecule with potent binding affinity to GR (Ki = 13.2 nM), was identified in a high-throughput screening effort. As a full GR antagonist, NC3327 greatly inhibits the dexamethasone (Dex) induction of marker genes involved in hepatic gluconeogenesis, but has a minimal effect on matrix metalloproteinase 9 (MMP-9), a GR responsive pro-inflammatory gene. Interestingly, the compound recruits neither coactivators nor corepressors to the GR complex but competes with glucocorticoids for the interaction between GR and a coactivator peptide. Moreover, NC3327 does not trigger GR nuclear translocation, but significantly blocks Dex-induced GR transportation to the nucleus, and thus appears to be a 'competitive' GR antagonist. Therefore, the non-steroidal compound, NC3327, may represent a new class of GR antagonists as potential therapeutics for a variety of cortisol-related endocrine disorders.

  8. Reversal strategies for vitamin K antagonists in acute intracerebral hemorrhage

    NARCIS (Netherlands)

    Parry-Jones, Adrian R.; Di Napoli, Mario; Goldstein, Joshua N.; Schreuder, Floris H B M; Tetri, Sami; Tatlisumak, Turgut; Yan, Bernard; Van Nieuwenhuizen, Koen M.; Dequatre-Ponchelle, Nelly; Lee-Archer, Matthew; Horstmann, Solveig; Wilson, Duncan; Pomero, Fulvio; Masotti, Luca; Lerpiniere, Christine; Godoy, Daniel Agustin; Cohen, Abigail S.; Houben, Rik; Al-Shahi Salman, Rustam; Pennati, Paolo; Fenoglio, Luigi; Werring, David; Veltkamp, Roland; Wood, Edith; Dewey, Helen M.; Cordonnier, Charlotte; Klijn, Catharina J M; Meligeni, Fabrizio; Davis, Stephen M.; Huhtakangas, Juha; Staals, Julie; Rosand, Jonathan; Meretoja, Atte

    2015-01-01

    Objective There is little evidence to guide treatment strategies for intracerebral hemorrhage on vitamin K antagonists (VKA-ICH). Treatments utilized in clinical practice include fresh frozen plasma (FFP) and prothrombin complex concentrate (PCC). Our aim was to compare case fatality with different

  9. Reversal strategies for vitamin K antagonists in acute intracerebral hemorrhage

    NARCIS (Netherlands)

    Parry-Jones, A.R.; Napoli, M. Di; Goldstein, J.N.; Schreuder, F.H.; Tetri, S.; Tatlisumak, T.; Yan, B.; Nieuwenhuizen, K.M.; Dequatre-Ponchelle, N.; Lee-Archer, M.; Horstmann, S.; Wilson, D.; Pomero, F.; Masotti, L.; Lerpiniere, C.; Godoy, D.A.; Cohen, A.S.; Houben, R.; Al-Shahi Salman, R.; Pennati, P.; Fenoglio, L.; Werring, D.; Veltkamp, R.; Wood, E.; Dewey, H.M.; Cordonnier, C.; Klijn, C.J.M.; Meligeni, F.; Davis, S.M.; Huhtakangas, J.; Staals, J.; Rosand, J.; Meretoja, A.

    2015-01-01

    OBJECTIVE: There is little evidence to guide treatment strategies for intracerebral hemorrhage on vitamin K antagonists (VKA-ICH). Treatments utilized in clinical practice include fresh frozen plasma (FFP) and prothrombin complex concentrate (PCC). Our aim was to compare case fatality with different

  10. Epiminocyclohepta[b]indole analogs as 5-HT6 antagonists

    DEFF Research Database (Denmark)

    Henderson, Alan J; Guzzo, Peter R; Ghosh, Animesh; Kaur, Jagjit; Koo, Jia-Man; Nacro, Kassoum; Panduga, Shailaja; Pathak, Rashmi; Shimpukade, Bharat; Tan, Valentina; Xiang, Kai; Wierschke, Jonathan D; Isherwood, Matthew L

    2012-01-01

    A new series of epiminocyclohepta[b]indoles with potent 5-HT(6) antagonist activity were discovered and optimized using in vitro protocols. One compound from this series was progressed to advanced pharmacokinetic (PK) studies followed by 5-HT(6) receptor occupancy studies. The compound was found to...

  11. About the use of antagonistic bacteria and fungi

    OpenAIRE

    Tilcher, R.; Schmidt, C.; Lorenz, D.; Wolf, G. A.

    2002-01-01

    Microorganisms isolated from the phylloplane of vine and cereal plants inhibiting different phytopathogenic fungi were tested as biological control agents against Plasmopara viticola (downy mildew of grapevine). Based on screening in vitro against Phytophthora infestans, P. parasitica, Pythium ultimum, Botrytis cinerea 62 bacterial isolates were selected for tests with Plasmopara viticola.. Antifungal bacterial strains were assayed for antagonistic activity towards the grapevine dieback fungu...

  12. Medium-Induced Antagonistic Behavior in Staphylococcus Aureus.

    Science.gov (United States)

    Benathen, Isaiah A.

    1992-01-01

    Antagonism is the production of substances by microorganisms that inhibit or prevent the growth of other bacteria. This paper demonstrates the antagonistic behavior of gram-positive coccus on the B. subtilis and Enterococcus faecalis gram-positive microorganisms, showing that the process of antagonism is sometimes dependent on the nutritional…

  13. Precycle Estradiol in Synchronization and Scheduling of Antagonist Cycles.

    Science.gov (United States)

    Saple, Shilpa; Agrawal, Mukesh; Kawar, Simi

    2016-08-01

    Antagonist cycles have an inherent issue of lack of flexibility. As a result where batching of cycles is desired, it is not the preferred protocol in ART cycles. There is also the limitation of ovarian response in antagonist cycle due to the size heterogenesities of antral follicles at the start of stimulation. Among the different options available, use of estrogen in the luteal phase of the preceding cycle has definitely shown benefits with regard to better control of cycle as well as synchronization of follicles available for stimulation. The article gives a detailed analysis of the different options available for timing the egg collection in antagonist cycles, the advantages and drawbacks, and the method of use of estrogen. Whereas in the majority of the trials where estrogen pretreatment was used, the goal of scheduling of egg collection was definitely achieved, increased duration and dose of gonadotropin stimulation were required. There was definite advantage of higher oocyte yield in these cycles. The possibility of premature LH rise later during stimulation and subsequent poor implantation in these cycles has to be further evaluated. Nevertheless, batching of patient friendly antagonist cycles can be effectively possible by use of precycle estrogen treatment. PMID:27382226

  14. Possible site of action of CGRP antagonists in migraine

    DEFF Research Database (Denmark)

    Tfelt-Hansen, Peer; Olesen, Jes

    2011-01-01

    The calcitonin gene-related peptide (CGRP) receptor antagonists olcegepant and telcagepant are very potent drugs. Both are effective in migraine but in doses much higher than would be predicted from receptor binding and other in vitro results. This could perhaps suggest an effect of CGRP antagoni...

  15. How Hybrid Organizations Turn Antagonistic Assets into Complementarities

    DEFF Research Database (Denmark)

    Hockerts, Kai

    2015-01-01

    explicit social missions through business-inspired earned-income strategies, with the express goal of creating market disequilibria. This article demonstrates the challenges hybrids face and outlines how to overcome them by identifying hidden complementarities and creating new ones, by eliminating the need...... for complementarities, and by creating demands for antagonistic assets, or by using partnerships....

  16. Accumulation of Deleterious Mutations Near Sexually Antagonistic Genes.

    Science.gov (United States)

    Connallon, Tim; Jordan, Crispin Y

    2016-01-01

    Mutation generates a steady supply of genetic variation that, while occasionally useful for adaptation, is more often deleterious for fitness. Recent research has emphasized that the fitness effects of mutations often differ between the sexes, leading to important evolutionary consequences for the maintenance of genetic variation and long-term population viability. Some forms of sex-specific selection-i.e., stronger purifying selection in males than females-can help purge a population's load of female-harming mutations and promote population growth. Other scenarios-e.g., sexually antagonistic selection, in which mutations that harm females are beneficial for males-inflate genetic loads and potentially dampen population viability. Evolutionary processes of sexual antagonism and purifying selection are likely to impact the evolutionary dynamics of different loci within a genome, yet theory has mostly ignored the potential for interactions between such loci to jointly shape the evolutionary genetic basis of female and male fitness variation. Here, we show that sexually antagonistic selection at a locus tends to elevate the frequencies of deleterious alleles at tightly linked loci that evolve under purifying selection. Moreover, haplotypes that segregate for different sexually antagonistic alleles accumulate different types of deleterious mutations. Haplotypes that carry female-benefit sexually antagonistic alleles preferentially accumulate mutations that are primarily male harming, whereas male-benefit haplotypes accumulate mutations that are primarily female harming. The theory predicts that sexually antagonistic selection should shape the genomic organization of genetic variation that differentially impacts female and male fitness, and contribute to sexual dimorphism in the genetic basis of fitness variation. PMID:27226163

  17. Mineralocorticoid receptor antagonists: emerging roles in cardiovascular medicine

    Directory of Open Access Journals (Sweden)

    Funder JW

    2013-10-01

    Full Text Available John W FunderPrince Henry's Institute, Clayton, Victoria, AustraliaAbstract: Spironolactone was first developed over 50 years ago as a potent mineralocorticoid receptor (MR antagonist with undesirable side effects; it was followed a decade ago by eplerenone, which is less potent but much more MR-specific. From a marginal role as a potassium-sparing diuretic, spironolactone was shown to be an extraordinarily effective adjunctive agent in the treatment of progressive heart failure, as was eplerenone in subsequent heart failure trials. Neither acts as an aldosterone antagonist in the heart as the cardiac MR are occupied by cortisol, which becomes an aldosterone mimic in conditions of tissue damage. The accepted term “MR antagonist”, (as opposed to “aldosterone antagonist” or, worse, “aldosterone blocker”, should be retained, despite the demonstration that they act not to deny agonist access but as inverse agonists. The prevalence of primary aldosteronism is now recognized as accounting for about 10% of hypertension, with recent evidence suggesting that this figure may be considerably higher: in over two thirds of cases of primary aldosteronism therapy including MR antagonists is standard of care. MR antagonists are safe and vasoprotective in uncomplicated essential hypertension, even in diabetics, and at low doses they also specifically lower blood pressure in patients with so-called resistant hypertension. Nowhere are more than 1% of patients with primary aldosteronism ever diagnosed and specifically treated. Given the higher risk profile in patients with primary aldosteronism than that of age, sex, and blood pressure matched essential hypertension, on public health grounds alone the guidelines for first-line treatment of all hypertension should mandate inclusion of a low-dose MR antagonist.Keywords: spironolactone, eplerenone, primary aldosteronism, public health, inverse agonists

  18. Insight into 144 patients with ocular vascular events during VEGF antagonist injections

    DEFF Research Database (Denmark)

    Mansour, Ahmad M; Shahin, Maha; Kofoed, Peter K;

    2012-01-01

    To record ocular vascular events following injections of vascular endothelium growth factor (VEGF) antagonists.......To record ocular vascular events following injections of vascular endothelium growth factor (VEGF) antagonists....

  19. DIHYDROPYRIDINE CALCIUM ANTAGONISTS: DATA OF EVIDENCE BASED MEDICINE AND RECOM-MENDATIONS ON PRACTICAL USE

    Directory of Open Access Journals (Sweden)

    S. Y. Martsevich

    2015-12-01

    Full Text Available The classification of calcium antagonists is presented. There were considered the results of large randomized trials, which were devoted to study of influence of dihydropyridine calcium antagonists on the risk of cardiovascular complications. The place of dihydropyridine calcium antagonists in modern recommendations on treatment of arterial hypertension and ischemic heart disease is defined. The clinical importance of differences between various presentations of dihy-dropyridine calcium antagonists is stressed.

  20. Oral mineralocorticoid antagonists for recalcitrant central serous chorioretinopathy

    Directory of Open Access Journals (Sweden)

    Chin EK

    2015-08-01

    Full Text Available Eric K Chin, David RP Almeida, C Nathaniel Roybal, Philip I Niles, Karen M Gehrs, Elliott H Sohn, H Culver Boldt, Stephen R Russell, James C FolkDepartment of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, IA, USAPurpose: To evaluate the effect and tolerance of oral mineralocorticoid antagonists, eplerenone and/or spironolactone, in recalcitrant central serous chorioretinopathy.Methods: Retrospective consecutive observational case series. Primary outcome measures included central macular thickness (CMT, µm, macular volume (MV, mm3, Snellen visual acuity, and prior treatment failures. Secondary outcomes included duration of treatment, treatment dosage, and systemic side effects.Results: A total of 120 patients with central serous chorioretinopathy were reviewed, of which 29 patients were treated with one or more mineralocorticoid antagonists. The average age of patients was 58.4 years. Sixteen patients (69.6% were recalcitrant to other interventions prior to treatment with oral mineralocorticoid antagonists, with an average washout period of 15.3 months. The average duration of mineralocorticoid antagonist treatment was 3.9±2.3 months. Twelve patients (52.2% showed decreased CMT and MV, six patients (26.1% had increase in both, and five patients (21.7% had negligible changes. The mean decrease in CMT of all patients was 42.4 µm (range, -136 to 255 µm: 100.7 µm among treatment-naïve patients, and 16.9 µm among recalcitrant patients. The mean decrease in MV of all patients was 0.20 mm3 (range, -2.33 to 2.90 mm3: 0.6 mm3 among treatment-naïve patients, and 0.0 mm3 among recalcitrant patients. Median visual acuity at the start of therapy was 20/30 (range, 20/20–20/250, and at final follow-up it was 20/40 (range, 20/20–20/125. Nine patients (39.1% experienced systemic side effects, of which three patients (13.0% were unable to continue therapy.Conclusion: Mineralocorticoid antagonist treatment had a positive treatment

  1. Nociceptive Effects of Locally Treated Metoprolol

    Directory of Open Access Journals (Sweden)

    Nursima Cukadar

    2015-06-01

    Results: Metoprolol, an antagonist, significantly decreased the thermal latency and mechanical thresholds with dose and time dependent manner. However, dobutamine, an agonist, enhanced the latency and thresholds dose and time dependent. Conclusions: This results suggest that in contrast to dobutamine, locally treated metoprolol may cause hyperalgesic and allodynic actions. In addition, our results can demonstrate that peripheral beta-adrenergic receptors can play important roles in nociceptive process. [Cukurova Med J 2015; 40(2.000: 258-266

  2. Nociceptive Effects of Locally Treated Metoprolol

    OpenAIRE

    Nursima Cukadar; Furkan Baran; Kadir Ercan Ozsoy; Fatih B. Uyanik; Tuba Surer; Tufan Mert; Yasemin Gunes

    2015-01-01

    Purpose: Beta (beta-)-adrenergic receptor antagonists, such as metoprolol, are often used to avoid circulatory complications during anesthesia for their antihypertensive and anti-tachycardia effects in patients with cardiovascular diseases. Although a few previous studies have been reported to exert antinociceptive and anesthetic effects of these drugs, knowledge about their action mechanisms in nociceptive process including pain perception is limited. This study therefore designed to identif...

  3. Effect of Propranolol on Functional Connectivity in Autism Spectrum Disorder—A Pilot Study

    OpenAIRE

    Narayanan, Ananth; White, Catherine A.; Saklayen, Sanjida; Scaduto, Mary J.; Carpenter, Allen L.; Abduljalil, Amir; Schmalbrock, Petra; Beversdorf, David Q.

    2010-01-01

    A decrease in interaction between brain regions is observed in individuals with autism spectrum disorder (ASD), which is believed to be related to restricted neural network access in ASD. Propranolol, a beta-adrenergic antagonist, has revealed benefit during performance of tasks involving flexibility of access to networks, a benefit also seen in ASD. Our goal was to determine the effect of propranolol on functional connectivity in ASD during a verbal decision making task as compared to nadolo...

  4. Are peripheral opioid antagonists the solution to opioid side effects?

    LENUS (Irish Health Repository)

    Bates, John J

    2012-02-03

    Opioid medication is the mainstay of therapy for severe acute and chronic pain. Unfortunately, the side effects of these medications can affect patient comfort and safety, thus limiting their proven therapeutic potential. Whereas the main analgesic effects of opioids are centrally mediated, many of the common side effects are mediated via peripheral receptors. Novel peripheral opioid antagonists have been recently introduced that can block the peripheral actions of opioids without affecting centrally mediated analgesia. We review the clinical and experimental evidence of their efficacy in ameliorating opioid side effects and consider what further information might be useful in defining their role. IMPLICATIONS: The major analgesic effects of opioid medication are mediated within the brain and spinal cord. Many of the side effects of opioids are caused by activation of receptors outside these areas. Recently developed peripherally restricted opioid antagonists have the ability to block many opioid side effects without affecting analgesia.

  5. Lead optimization studies of cinnamic amide EP2 antagonists.

    Science.gov (United States)

    Ganesh, Thota; Jiang, Jianxiong; Yang, Myung-Soon; Dingledine, Ray

    2014-05-22

    Prostanoid receptor EP2 can play a proinflammatory role, exacerbating disease pathology in a variety of central nervous system and peripheral diseases. A highly selective EP2 antagonist could be useful as a drug to mitigate the inflammatory consequences of EP2 activation. We recently identified a cinnamic amide class of EP2 antagonists. The lead compound in this class (5d) displays anti-inflammatory and neuroprotective actions. However, this compound exhibited moderate selectivity to EP2 over the DP1 prostanoid receptor (∼10-fold) and low aqueous solubility. We now report compounds that display up to 180-fold selectivity against DP1 and up to 9-fold higher aqueous solubility than our previous lead. The newly developed compounds also display higher selectivity against EP4 and IP receptors and a comparable plasma pharmacokinetics. Thus, these compounds are useful for proof of concept studies in a variety of models where EP2 activation is playing a deleterious role. PMID:24773616

  6. Interleukin-1-receptor antagonist in type 2 diabetes mellitus

    DEFF Research Database (Denmark)

    Larsen, Claus M; Faulenbach, Mirjam; Vaag, Allan;

    2007-01-01

    proliferation, and apoptosis. METHODS: In this double-blind, parallel-group trial involving 70 patients with type 2 diabetes, we randomly assigned 34 patients to receive 100 mg of anakinra (a recombinant human interleukin-1-receptor antagonist) subcutaneously once daily for 13 weeks and 36 patients to receive......BACKGROUND: The expression of interleukin-1-receptor antagonist is reduced in pancreatic islets of patients with type 2 diabetes mellitus, and high glucose concentrations induce the production of interleukin-1beta in human pancreatic beta cells, leading to impaired insulin secretion, decreased cell...... (P=0.03); C-peptide secretion was enhanced (P=0.05), and there were reductions in the ratio of proinsulin to insulin (P=0.005) and in levels of interleukin-6 (P<0.001) and C-reactive protein (P=0.002). Insulin resistance, insulin-regulated gene expression in skeletal muscle, serum adipokine levels...

  7. Antagonistic otolith-visual units in cat vestibular nuclei

    Science.gov (United States)

    Daunton, Nancy G.; Christensen, Carol A.

    1992-01-01

    The nature of neural coding of visual (Vis) and vestibular (Vst) information on translational motion in the region of the vestibular nuclei was investigated using extracellular single-unit recordings in alert adult cats. Responses were recorded and averaged over 60 cycles of stimulation in the vertical and horizontal planes, which included the Vst (movement of the animal in the dark), Vis (movement within lighted visual surround), and combined Vis and Vst (movement of the animal within the lighted stationary visual surround). Data are reported on responses to stimulations along the axis showing maximal sensitivity. A small number of units were identified that showed an antagonistic relationship between their Vis and Vst responses (since they were maximally excited by Vis and by Vst stimulations in the same direction). Results suggest that antagonistic units may belong to an infrequently encountered, but functionally distinct, class of neurons.

  8. Histamine-2 receptor antagonists as immunomodulators: new therapeutic views?

    DEFF Research Database (Denmark)

    Nielsen, Hans Jørgen

    1996-01-01

    from such studies are currently accumulating and suggest that the histamine-2 receptor antagonists have potential beneficial effects in the treatment of certain malignant, autoimmune and skin diseases, either alone or in combination with other drugs. The beneficial effect of histamine-2 receptor......Considerable evidence has emerged to suggest that histamine participates in the regulation of the inflammatory response, immune reaction, coagulation cascade, and cardiovascular function. Furthermore, histamine may play a major role in the growth of normal and malignant tissue as a regulator of...... proliferation and angiogenesis. Specific histamine receptors have been identified on the surface of bone marrow cells, immune competent cells, endothelial cells, fibroblasts, and also on malignant cells. This has prompted research in regulation by specific histamine receptor agonists and antagonists. Results...

  9. Potential Clinical Implications of the Urotensin II Receptor Antagonists

    Directory of Open Access Journals (Sweden)

    Emilie Kane

    2011-07-01

    Full Text Available Urotensin-II (UII, which binds to its receptor UT, plays an important role in the heart, kidneys, pancreas, adrenal gland and CNS. In the vasculature, it acts as a potent endothelium-independent vasoconstrictor and endothelium-dependent vasodilator. In disease states, this constriction-dilation equilibrium is disrupted. There is an upregulation of the UII system in heart disease, metabolic syndrome and kidney failure. The increase in UII release and UT expression suggest that UII system may be implicated in the pathology and pathogenesis of these diseases by causing an increase in ACAT-1 activity leading to SMC proliferation and foam cell infiltration, insulin resistance (DMII, as well as inflammation, high blood pressure and plaque formation. Recently, UT antagonists such as SB-611812, palosuran, and most recently a piperazino-isoindolinone based antagonist have been developed in the hope of better understanding the UII system and treating its associated diseases.

  10. Endothelin receptor antagonists as disease modifiers in systemic sclerosis.

    Science.gov (United States)

    Shetty, Nagalakshmi; Derk, Chris T

    2011-02-01

    Systemic sclerosis (SSc) is a multisystem connective tissue disease of unknown etiology that is characterized by inflammation, vascular dysfunction and fibrosis of the skin and visceral organs. SSc is clinically diverse both in terms of the burden of skin and organ involvement and the rate of progression of the disease. Recent studies indicate that the endothelin system, especially ET-1 and the ETA and ETB receptors may play a key role in the pathogenesis of SSc. A new class of drugs, endothelin receptor antagonists has been introduced for treatment of patients with pulmonary arterial hypertension (PAH). Bosentan, a dual endothelin receptor antagonist as well as Sitaxsentan and Ambrisentan, selective blockers of the ETA receptor have proven effective in SSc-PAH. This effect may be mediated through both a vasodilatory and antifibrotic effect, thus making these agents attractive as potential disease modifying agents for SSc. PMID:21184655

  11. Montelukast: More than a Cysteinyl Leukotriene Receptor Antagonist?

    OpenAIRE

    Tintinger, Gregory R.; Charles Feldman; Theron, Annette J.; Ronald Anderson

    2010-01-01

    The prototype cysteinyl leukotriene receptor antagonist, montelukast, is generally considered to have a niche application in the therapy of exercise- and aspirin-induced asthma. It is also used as add-on therapy in patients whose asthma is poorly controlled with inhaled corticosteroid monotherapy, or with the combination of a long-acting β(2)-agonist and an inhaled corticosteroid. Recently, however, montelukast has been reported to possess secondary anti-inflammatory properties, apparently un...

  12. Surfen, a small molecule antagonist of heparan sulfate

    OpenAIRE

    Schuksz, Manuela; Fuster, Mark M.; Brown, Jillian R.; Crawford, Brett E.; Ditto, David P.; Lawrence, Roger; Glass, Charles A; Wang, Lianchun; Tor, Yitzhak; Esko, Jeffrey D

    2008-01-01

    In a search for small molecule antagonists of heparan sulfate, we examined the activity of bis-2-methyl-4-amino-quinolyl-6-carbamide, also known as surfen. Fluorescence-based titrations indicated that surfen bound to glycosaminoglycans, and the extent of binding increased according to charge density in the order heparin > dermatan sulfate > heparan sulfate > chondroitin sulfate. All charged groups in heparin (N-sulfates, O-sulfates, and carboxyl groups) contributed to binding, consistent with...

  13. Construction, purification, and characterization of a chimeric TH1 antagonist

    Directory of Open Access Journals (Sweden)

    Javier-González Luís

    2006-05-01

    Full Text Available Abstract Background TH1 immune response antagonism is a desirable approach to mitigate some autoimmune and inflammatory reactions during the course of several diseases where IL-2 and IFN-γ are two central players. Therefore, the neutralization of both cytokines could provide beneficial effects in patients suffering from autoimmune or inflammatory illnesses. Results A chimeric antagonist that can antagonize the action of TH1 immunity mediators, IFN-γ and IL-2, was designed, engineered, expressed in E. coli, purified and evaluated for its in vitro biological activities. The TH1 antagonist molecule consists of the extracellular region for the human IFNγ receptor chain 1 fused by a four-aminoacid linker peptide to human 60 N-terminal aminoacid residues of IL-2. The corresponding gene fragments were isolated by RT-PCR and cloned in the pTPV-1 vector. E. coli (W3110 strain was transformed with this vector. The chimeric protein was expressed at high level as inclusion bodies. The protein was partially purified by pelleting and washing. It was then solubilized with strong denaturant and finally refolded by gel filtration. In vitro biological activity of chimera was demonstrated by inhibition of IFN-γ-dependent HLA-DR expression in Colo 205 cells, inhibition of IFN-γ antiproliferative effect on HEp-2 cells, and by a bidirectional effect in assays for IL-2 T-cell dependent proliferation: agonism in the absence versus inhibition in the presence of IL-2. Conclusion TH1 antagonist is a chimeric protein that inhibits the in vitro biological activities of human IFN-γ, and is a partial agonist/antagonist of human IL-2. With these attributes, the chimera has the potential to offer a new opportunity for the treatment of autoimmune and inflammatory diseases.

  14. Alternation of Agonists and Antagonists During Turtle Hindlimb Motor Rhythms

    OpenAIRE

    Stein, Paul S.G.

    2010-01-01

    In a variety of vertebrates, including turtle, many classical and contemporary studies of spinal cord neuronal networks generating rhythmic motor behaviors emphasize a Reciprocal Model with alternation of agonists and antagonists, alternation of excitatory and inhibitory postsynaptic potentials, and reciprocal inhibition. Some studies of spinal cord neuronal networks, including those in turtle during scratch motor rhythms, describe a Balanced Model with concurrent excitatory and inhibitory po...

  15. NMDA antagonist properties of the putative antiaddictive drug, ibogaine.

    Science.gov (United States)

    Popik, P; Layer, R T; Fossom, L H; Benveniste, M; Geter-Douglass, B; Witkin, J M; Skolnick, P

    1995-11-01

    Both anecdotal reports in humans and preclinical studies indicate that ibogaine interrupts addiction to a variety of abused substances including alcohol, opiates, nicotine and stimulants. Based on the similarity of these therapeutic claims to recent preclinical studies demonstrating that N-methyl-D-aspartate (NMDA) antagonists attenuate addiction-related phenomena, we examined the NMDA antagonist properties of ibogaine. Pharmacologically relevant concentrations of ibogaine produce a voltage-dependent block of NMDA receptors in hippocampal cultures (Ki, 2.3 microM at -60 mV). Consistent with this observation, ibogaine competitively inhibits [3H]1-[1-(2-thienyl)-cyclohexyl]piperidine binding to rat forebrain homogenates (Ki, 1.5 microM) and blocks glutamate-induced cell death in neuronal cultures (IC50, 4.5 microM). Moreover, at doses previously reported to interfere with drug-seeking behaviors, ibogaine substitutes as a discriminative stimulus (ED50, 64.9 mg/kg) in mice trained to discriminate the prototypic voltage-dependent NMDA antagonist, dizocilpine (0.17 mg/kg), from saline. Consistent with previous reports, ibogaine reduced naloxone-precipitated jumping in morphine-dependent mice (ED50, 72 mg/kg). Although pretreatment with glycine did not affect naloxone-precipitated jumping in morphine-dependent mice, it abolished the ability of ibogaine to block naloxone-precipitated jumping. Taken together, these findings link the NMDA antagonist actions of ibogaine to a putative "antiaddictive" property of this alkaloid, its ability to reduce the expression of morphine dependence. PMID:7473163

  16. Optimization of amide-based EP3 receptor antagonists.

    Science.gov (United States)

    Lee, Esther C Y; Futatsugi, Kentaro; Arcari, Joel T; Bahnck, Kevin; Coffey, Steven B; Derksen, David R; Kalgutkar, Amit S; Loria, Paula M; Sharma, Raman

    2016-06-01

    Prostaglandin E receptor subtype 3 (EP3) antagonism may treat a variety of symptoms from inflammation to cardiovascular and metabolic diseases. Previously, most EP3 antagonists were large acidic ligands that mimic the substrate, prostaglandin E2 (PGE2). This manuscript describes the optimization of a neutral small molecule amide series with improved lipophilic efficiency (LipE) also known as lipophilic ligand efficiency (LLE) ((a) Nat. Rev. Drug Disc.2007, 6, 881; (b) Annu. Rep. Med. Chem.2010, 45, 380). PMID:27107947

  17. Ondansetron, a 5-HT3 antagonist, improves cerebellar tremor.

    OpenAIRE

    Rice, G P; Lesaux, J; Vandervoort, P.; Macewan, L; Ebers, G C

    1997-01-01

    It has been previously shown that ondansetron, a 5-HT3 antagonist, can ameliorate vertigo in patients with acute brainstem disorders. A coincidental benefit was the improvement of cerebellar tremor in some patients with both vertigo and tremor. To further evaluate this effect, a placebo controlled, double blind, crossover study was conducted of a single dose of intravenous ondansetron in 20 patients with cerebellar tremor caused by multiple sclerosis, cerebellar degeneration, or drug toxicity...

  18. attracting antagonists: does floral nectar increase leaf herbivory?

    OpenAIRE

    Adler, L.S.; Bronstein, J. L.

    2004-01-01

    Traits that are attractive to mutualists may also attract antagonists, resulting in conflicting selection pressures. Here we develop the idea that increased floral nectar production can, in some cases, increase herbivory. In these situations, selection for increased nectar production to attract pollinators may be constrained by a linked cost of herbivore attraction. In support of this hypothesis, we report that experimentally supplementing nectar rewards in Datura stramonium led to increased ...

  19. Biological control of Fusarium graminearum on wheat by antagonistic bacteria

    OpenAIRE

    Javad Nourozian; Hassan Reza Etebarian; Gholam Khodakaramian

    2006-01-01

    Bacillus subtilis strains 53 and 71, Pseudomonas fluorescens biov1 strain 32 and Streptomyces sp. Strain 3 were evaluated as potential biological agents for control of fusarium head blight (FHB) caused by Fusarium graminearum. Mycelial growth of the pathogen was reduced by cell free and volatile metabolites of bacterial antagonists by 37%-97%. Streptomyces sp. Strain 3 reduced disease severity of FHB 21 d after inoculation. The yield of wheat from plants treated with Streptomyces sp. strain 3...

  20. ANTIHYPERTENSIVE TREATMENT IN ELDERLY PATIENTS WITH DIHYDROPYRIDINE CALCIUM ANTAGONISTS

    OpenAIRE

    Y. A. Karpov; V. V. Buza

    2016-01-01

    The proofs of necessity of active arterial hypertension (AH) treatment in elderly patients are given. Peculiarities of pathogenesis of AH in elderly patients, connected predominantly with loss of big arteries elasticity and reasoning widely spread of isolated systolic AH in these patients, are discussed. Advantages of dihydropyridine calcium antagonists (DPCA) for AH treatment in elderly patients are proved, safety of treatment with DPCA is discussed. Data of clinical studies is analyzed. Ana...

  1. μ Opioid receptor: novel antagonists and structural modeling

    Science.gov (United States)

    Kaserer, Teresa; Lantero, Aquilino; Schmidhammer, Helmut; Spetea, Mariana; Schuster, Daniela

    2016-02-01

    The μ opioid receptor (MOR) is a prominent member of the G protein-coupled receptor family and the molecular target of morphine and other opioid drugs. Despite the long tradition of MOR-targeting drugs, still little is known about the ligand-receptor interactions and structure-function relationships underlying the distinct biological effects upon receptor activation or inhibition. With the resolved crystal structure of the β-funaltrexamine-MOR complex, we aimed at the discovery of novel agonists and antagonists using virtual screening tools, i.e. docking, pharmacophore- and shape-based modeling. We suggest important molecular interactions, which active molecules share and distinguish agonists and antagonists. These results allowed for the generation of theoretically validated in silico workflows that were employed for prospective virtual screening. Out of 18 virtual hits evaluated in in vitro pharmacological assays, three displayed antagonist activity and the most active compound significantly inhibited morphine-induced antinociception. The new identified chemotypes hold promise for further development into neurochemical tools for studying the MOR or as potential therapeutic lead candidates.

  2. Affinity and selectivity of beta-adrenoceptor antagonists in vitro

    International Nuclear Information System (INIS)

    The potency order of the catecholamines (-)-isoprenaline (Iso), (-)-noradrenaline (NA), and (-)-adrenaline (Adr) in competition for radiolabelled sites is used for their pharmacological classification. It is shown that the radioligand 3H-CGP 12177 exclusively labels beta 1-adrenoceptors in rat salivary gland membranes (Iso greater than NA greater than Adr), and beta 2-adrenoceptors in rat reticulocytes (Iso greater than Adr greater than or equal to NA). These models are then used to derive the subtype-selectivity of the classical beta-adrenoceptor antagonists (+/-)-propranolol (prop; twofold beta 2-selective) and (+/-)-atenolol (aten; 35-fold beta 1-selective), as well as of the newer antagonists (+/-)-betaxolol and (+/-)-bisoprolol (betax and biso; 35-fold and 75-fold beta 1-selective, respectively). The ligand with the highest selectivity is ICI 118,551 (ICI), with a 300-fold beta 2-subtype selectivity. For comparison with antagonistic effects in humans at given plasma concentrations, the equilibrium dissociation constants of the ligands are measured in the presence of native human plasma and yield values for the relative selectively labelled subtype in the mean (Ki-values in nmol/l): prop: 20, aten: 250, biso: 24, betax: 23, and ICI: 2.5

  3. Comparative effects of beta-adrenergic agonist supplementation on the yield and quality attributes of selected subprimals from calf-fed Holstein steers.

    Science.gov (United States)

    Martin, J N; Garmyn, A J; Miller, M F; Hodgen, J M; Pfeiffer, K D; Thomas, C L; Rathmann, R J; Yates, D A; Hutcheson, J P; Brooks, J C

    2014-09-01

    Mechanical portioning tests were performed on beef rib, strip loin, tenderloin, and top sirloin subprimals obtained from calf-fed Holstein steers to characterize the influence of zilpaterol hydrochloride (ZH), ractopamine hydrochloride (RH), or no β-adrenergic agonist (βAA; CON) on subprimal and steak yield. In addition, βAA effects on tenderness, composition, and raw and cooked color of steaks from the aforementioned strip loin subprimals were characterized. At 14 to 15 d (ribs, tenderloins, and top sirloin) or 16 d (strip loin) postmortem, subprimals were portioned into steaks using a mechanical portioning machine. The appropriate variables were measured before and after portioning to determine βAA influence on trimmed and untrimmed subprimal weight, subprimal length (rib only), steak weight and yield, and steak thickness (rib only). Steaks obtained from the strip loin subprimals were subjected to analysis of raw instrument color (L*, a*, b*), proximate composition, and pH. In addition, strip steaks were aged (16 or 23 d) before analysis of cooked internal color, Warner-Bratzler shear force (WBSF), and slice shear force (SSF). Briefly, ZH supplementation increased (P 0.05). There was no interaction between βAA treatment and postmortem aging length for WBSF or SSF (P > 0.10). However, CON steaks (3.25 kg) had lower WBSF values (P < 0.05) than ZH or RH steaks (3.68 and 3.67 kg, respectively). Regardless, aging for 23 d vs. 16 d resulted in decreased WBSF and SSF (P < 0.01) for all βAA treatments. Although differences were numerically small, evaluations indicated the internal cooked surfaces of ZH and RH steaks were less red (P < 0.05) than CON steaks. Overall, these data reemphasize increased subprimal weights due to βAA supplementation, particularly ZH. However, the data are not indicative of increased steak yield due to βAA supplementation. Furthermore, the data demonstrate βAA supplementation increases the shear force of calf-fed Holstein strip steaks regardless of postmortem aging period. However, no differences in shear force between the βAA treatments (ZH or RH) were noted. PMID:25006060

  4. Sympathetic reflex control of skeletal muscle blood flow in patients with congestive heart failure: evidence for beta-adrenergic circulatory control

    Energy Technology Data Exchange (ETDEWEB)

    Kassis, E.; Jacobsen, T.N.; Mogensen, F.; Amtorp, O.

    1986-11-01

    Mechanisms controlling forearm muscle vascular resistance (FMVR) during postural changes were investigated in seven patients with severe congestive heart failure (CHF) and in seven control subjects with unimpaired left ventricular function. Relative brachioradial muscle blood flow was determined by the local /sup 133/Xe-washout technique. Unloading of baroreceptors with use of 45 degree upright tilt was comparably obtained in the patients with CHF and control subjects. Control subjects had substantially increased FMVR and heart rate to maintain arterial pressure whereas patients with CHF had decreased FMVR by 51 +/- 11% and had no increase in heart rate despite a fall in arterial pressure during upright tilt. The autoregulatory and local vasoconstrictor reflex responsiveness during postural changes in forearm vascular pressures were intact in both groups. In the patients with CHF, the left axillary nerve plexus was blocked by local anesthesia. No alterations in forearm vascular pressures were observed. This blockade preserved the local regulation of FMVR but reversed the vasodilator response to upright tilt as FMVR increased by 30 +/- 7% (p less than .02). Blockade of central neural impulses to this limb combined with brachial arterial infusions of phentolamine completely abolished the humoral vasoconstriction in the tilted position. Infusions of propranolol to the contralateral brachial artery that did not affect baseline values of heart rate, arterial pressure, or the local reflex regulation of FMVR reversed the abnormal vasodilator response to upright tilt as FMVR increased by 42 +/- 12% (p less than .02). Despite augmented baseline values, forearm venous but not arterial plasma levels of epinephrine increased in the tilted position, as did arteri rather than venous plasma concentrations of norepinephrine in these patients.

  5. Sympathetic reflex control of skeletal muscle blood flow in patients with congestive heart failure: evidence for beta-adrenergic circulatory control

    International Nuclear Information System (INIS)

    Mechanisms controlling forearm muscle vascular resistance (FMVR) during postural changes were investigated in seven patients with severe congestive heart failure (CHF) and in seven control subjects with unimpaired left ventricular function. Relative brachioradial muscle blood flow was determined by the local 133Xe-washout technique. Unloading of baroreceptors with use of 45 degree upright tilt was comparably obtained in the patients with CHF and control subjects. Control subjects had substantially increased FMVR and heart rate to maintain arterial pressure whereas patients with CHF had decreased FMVR by 51 +/- 11% and had no increase in heart rate despite a fall in arterial pressure during upright tilt. The autoregulatory and local vasoconstrictor reflex responsiveness during postural changes in forearm vascular pressures were intact in both groups. In the patients with CHF, the left axillary nerve plexus was blocked by local anesthesia. No alterations in forearm vascular pressures were observed. This blockade preserved the local regulation of FMVR but reversed the vasodilator response to upright tilt as FMVR increased by 30 +/- 7% (p less than .02). Blockade of central neural impulses to this limb combined with brachial arterial infusions of phentolamine completely abolished the humoral vasoconstriction in the tilted position. Infusions of propranolol to the contralateral brachial artery that did not affect baseline values of heart rate, arterial pressure, or the local reflex regulation of FMVR reversed the abnormal vasodilator response to upright tilt as FMVR increased by 42 +/- 12% (p less than .02). Despite augmented baseline values, forearm venous but not arterial plasma levels of epinephrine increased in the tilted position, as did arteri rather than venous plasma concentrations of norepinephrine in these patients

  6. The Relationship between Birthweight and Longitudinal Changes of Blood Pressure Is Modulated by Beta-Adrenergic Receptor Genes: The Bogalusa Heart Study

    Directory of Open Access Journals (Sweden)

    Wei Chen

    2010-01-01

    Full Text Available This study examines the genetic influence of β-adrenergic receptor gene polymorphisms (β2-AR Arg16Gly and β3-AR Trp64Arg on the relationship of birthweight to longitudinal changes of blood pressure (BP from childhood to adulthood in 224 black and 515 white adults, aged 21–47 years, enrolled in the Bogalusa Heart Study. Blacks showed significantly lower birthweight and frequencies of β2-AR Gly16 and β3-AR Trp64 alleles and higher BP levels and age-related trends than whites. In multivariable regression analyses using race-adjusted BP and birthweight, low birthweight was associated with greater increase in age-related trend of systolic BP (standardized regression coefficient β=−0.09, P=.002 and diastolic BP (β=−0.07, P=.037 in the combined sample of blacks and whites, adjusting for the first BP measurement in childhood, sex, age, and gestational age. Adjustment for the current body mass index strengthened the birthweight-BP association. Importantly, the strength of the association, measured as regression coefficients, was modulated by the combination of β2-AR and β3-AR genotypes for systolic (P=.042 for interaction and diastolic BP age-related trend (P=.039 for interaction, with blacks and whites showing a similar trend in the interaction. These findings indicate that the intrauterine programming of BP regulation later in life depends on β-AR genotypes.

  7. No effect of beta-adrenergic blockade on hypoglycaemic effect of glucagon-like peptide-1 (GLP-1) in normal subjects

    DEFF Research Database (Denmark)

    Toft-Nielsen, M; Hvidberg, A; Hilsted, Jannik;

    1996-01-01

    GLP-1 administration decreases blood glucose levels in normal subjects and non-insulin-dependent diabetes mellitus patients and is therefore proposed as a treatment for diabetic hyperglycaemia. The glucose lowering effect of GLP-1 is glucose dependent and therefore self-limiting, but it is not...... min-1). In a control experiment, saline and propranolol were infused. Hepatic glucose production was measured and blood was analysed for plasma glucose, insulin, glucagon, catecholamines, and radioactivity. Plasma GLP-1 levels were similar on the two GLP-1 infusion days and resulted in: (1) a...... significant decrease in plasma glucose from 5.2 +/- 0.2 to 4.1 +/- 0.1 mmol l-1 with GLP-1/propranolol infusion, and from 5.2 +/- 0.1 to 4.0 +/- 0.1 mmol l-1 with GLP-1/saline infusion (NS); (2) a corresponding significant increase in plasma insulin from 58.0 +/- 6.3 to 144.5 +/- 22.3 pmol l-1 and from 61...

  8. Oleoylethanolamide enhances beta-adrenergic-mediated thermogenesis and white-to-brown adipocyte phenotype in epididymal white adipose tissue in rat

    OpenAIRE

    Suarez, J.; P. Rivera; Arrabal, S.; Crespillo, A; A. Serrano; Baixeras, E. (Elena); Pavon, F. J.; Cifuentes, M; Nogueiras, R.; Ballesteros, J.; Dieguez, C.; Rodriguez De Fonseca, F.

    2014-01-01

    β-adrenergic receptor activation promotes brown adipose tissue (BAT) β-oxidation and thermogenesis by burning fatty acids during uncoupling respiration. Oleoylethanolamide (OEA) can inhibit feeding and stimulate lipolysis by activating peroxisome proliferator-activating receptor-α (PPARα) in white adipose tissue (WAT). Here we explore whether PPARα activation potentiates the effect of β3-adrenergic stimulation on energy balance mediated by the respective agonists OEA and CL316243. The effect ...

  9. Effect of Serum from Chickens Treated with Clenbuterol on Myosin Accumulation, Beta-Adrenergic Receptor Population, and Cyclic AM Synthesis in Embryonic Chicken Skeletal Muscle Cell Cultures

    Science.gov (United States)

    Young, R. B.; Bridge, K. Y.; Wuethrich, A. J.; Hancock, D. L.; Whitaker, Ann F. (Technical Monitor)

    2001-01-01

    Broiler chickens at 35 days of age were fed 1 ppm clenbuterol for 14 days. This level of dietary clenbuterol led to 5-7% increases in weights of leg and breast muscle tissue. At the end of the 14-day period, serum was prepared from both control and clenbuterol-treated chickens and was then employed as a component of cell culture media at a final concentration of 20% (v/v). Muscle cell cultures were prepared from both the leg and breast muscle groups of twelve-day chick embryos. Treatment groups included control chicken serum to which 10 nM, 50 nM, and 1 micron clenbuterol had been added, as well as cells grown in media containing 10% horse serum. Cultures were subjected to each treatment for 3 days beginning on the seventh day in culture. Neither the percent fusion nor the number of nuclei in myotubes were significantly affected by any of the treatments. The quantity of MHC was not increased by serum from clenbuterol-treated chickens in either breast and leg muscle cultures; however, MHC quantity was 50- 100% higher in cultures grown in control chicken serum to which 10 nM and 50 nM clenbuterol had also been added. The Beta-AR population was 4,000-7,000 Beta-AR per cell in cultures grown in chicken serum, with leg muscle cultures having approximately 25-30% more receptors than breast muscle cultures. Receptor population was not significantly affected by the presence of clenbuterol or by the presence of serum from clenbuterol-treated chickens. In contrast, the Beta-AR population in leg and breast muscle cultures grown in the presence of 10% horse serum was 18,000-20,000 Beta-AR per cell. Basal concentration of cAMP was not significantly affected by any of the treatments. When cultures grown in chicken serum were stimulated for 10 min with 1 micron isoproterenol, limited increases of 12-20% in cAMP concentration above basal levels were observed. However, when cultures grown in the presence of horse serum were stimulated with 1 micron isoproterenol, increases of 600-800 % in cAMP concentration above basal levels were observed. Thus, not only did cells grown in horse serum have a higher Beta-AR population, each receptor had a higher capacity for cAMP synthesis following isoproterenol stimulation. Finally, the hypothesis was tested that clenbuterol exerts its action on muscle protein content by changes in cAMP concentration. No correlation was apparent between basal cAMP concentration and MHC content.

  10. Effect of Serum from Chickens Treated with Clenbuterol on Myosin Accumulation, Beta-Adrenergic Receptor Population, and Cyclic AMP Synthesis in Embryonic Chicken Skeletal Muscle Cell Cultures

    Science.gov (United States)

    Young, Ronald B.; Bridge, Kristin Y.; Wuethrich, Andrew J.; Hancock, Deana L.

    2002-01-01

    Broiler chickens at 35 d of age were fed 1 ppm clenbuterol for 14 d. This level of dietary clenbuterol led to 5-7% increases in the weights of leg and breast muscle tissue. At the end of the 14-d period, serum was prepared from both control and clenbuterol-treated chickens, and was then employed as a component of cell culture media at a final concentration of 20% (v/v). Muscle cell cultures were prepared from both the leg and the breast muscle groups of 12-d chick embryos. Treatment groups included control chicken serum to which 10 nM, 50 nM, and 1 uM clenbuterol had been added, as well as cells grown in media containing 10% horse serum. Cultures were subjected to each treatment for 3 d, beginning on the seventh d in culture. Neither the percent fusion nor the number of nuclei in myotubes was significantly affected by any of the treatments. The quantity of myosin heavy chains (MHCs) was not increased by serum from clenbuterol-treated chickens in either breast or leg muscle cultures; however, the MHC quantity was 50-150% higher in cultures grown in control chicken serum to which 10 and 50 nM clenbuterol had also been added. The B-adrenergic receptor (betaAR) population was 4000-7000 betaARs per cell in cultures grown in chicken serum with leg muscle cultures having approximately 25-30% more receptors than breast muscle Culture. Receptor population was not significantly affected by the presence of clenbuterol or by the presence of serum from clenbuterol-treated chickens. In contrast, the betaAR Population in leg and breast muscle cultures grown in the presence of 10% horse serum was 16,000-18,000 betaARs per cell. Basal concentration of cyclic adenosine 3':5'monophosphate (cAMP) was not significantly affected by the treatments. When cultures grown in chicken serum were stimulated for 10 min with 1 uM isoproterenol, limited increases of 12-20% in cAMP Concentration above the. basal levels were observed. However, when cultures grown in the presence of horse serum were stimulated with 1 uM isoproterenol, cAMP concentration was stimulated 5- to 9-fold above the basal levels. Thus, not only did cells, grown in horse serum have a higher PAR population, but also each receptor had a higher capacity for cAMP synthesis following isoproterenol stimulation. Finally, the hypothesis that clenbuterol exerts its action on muscle protein content by changes in cAMP concentration was tested. No correlation was apparent between basal cAMP concentration and MHC content.

  11. sup 86 Rb(K) influx and ( sup 3 H)ouabain binding by human platelets: Evidence for beta-adrenergic stimulation of Na-K ATPase activity

    Energy Technology Data Exchange (ETDEWEB)

    Turaihi, K.; Khokher, M.A.; Barradas, M.A.; Mikhailidis, D.P.; Dandona, P. (Royal Free Hospital and School of Medicine, London (England))

    1989-08-01

    Although active transport of potassium into human platelets has been demonstrated previously, there is hitherto no evidence that human platelets have an ouabain-inhibitable Na-K ATPase in their membrane. The present study demonstrates active rubidium (used as an index of potassium influx), {sup 86}Rb(K), influx into platelets, inhibitable by ouabain, and also demonstrates the presence of specific ({sup 3}H)ouabain binding by the human platelet. This {sup 86}Rb(K) influx was stimulated by adrenaline, isoprenaline, and salbutamol, but noradrenaline caused a mild inhibition. Active {sup 86}Rb(K) influx by platelets was inhibited markedly by timolol, mildly by atenolol, but not by phentolamine. Therefore, active {sup 86}Rb(K) influx in human platelets is enhanced by stimulation of beta adrenoceptors of the beta 2 subtype. The platelet may therefore replace the leukocyte in future studies of Na-K ATPase activity. This would be a considerable advantage in view of the ease and rapidity of preparation of platelets.

  12. Hormonal regulation of hepatic glycogenolysis in the carp, Cyprinus carpio

    Energy Technology Data Exchange (ETDEWEB)

    Janssens, P.A.; Lowrey, P.

    1987-04-01

    Carp (Cyprinus carpio) liver maintained normal glycogen content and enzyme complement for several days in organ culture. Epinephrine-stimulated glycogenolysis, phosphorylase activation, and cyclic AMP (cAMP) accumulation in a concentration-dependent manner with EC/sub 50/s of 100, 100, and 500 nM, respectively. These actions were blocked by the ..beta..-adrenergic antagonist, propranolol, but not by the ..cap alpha..-adrenergic antagonist phentolamine. Glycogenolysis and tissue cAMP were uninfluenced by 10/sup -6/ M arginine vasotocin, arginine vasopressin, lysine vasotocin, lysine vasopressin, mesotocin, or oxytocin, but were slightly increased by 10/sup -5/ M isotocin and slightly decreased by 10/sup -6/ M angiotensin II. (/sup 125/I)-iodocyanopindolol (ICP), a ..beta..-adrenergic ligand, bound to isolated carp liver membranes with a K/sub D/ of 83 pM. Maximum binding of 45 fmol/mg protein was at 600 pM. Propranolol, isoprenaline, epinephrine, phenylephrine, norepinephrine, and phenoxybenzamine displaced ICP with K/sub D/s of 100 nM, 2, 20, 20, 60, and 200 ..mu..M, respectively. The ..cap alpha..-adrenergic antagonists, yohimbine and prazosin, showed no specific binding. These data provide evidence that catecholamines act via ..beta..-adrenergic receptors in carp liver and that ..cap alpha..-adrenergic receptors are not present. Vasoactive peptides play no significant role in regulation of carp liver glycogenolysis.

  13. Effects of VLA-4 antagonists in rat whole embryo culture.

    Science.gov (United States)

    Spence S; Vetter C; Hagmann WK; Van Riper G; Williams H; Mumford RA; Lanza TJ; Lin LS; Schmidt JA

    2002-01-01

    BACKGROUND: Pharmacological antagonism of VLA-4 (Very Late Antigen 4, alpha(4)beta(1) integrin) has become an attractive target for the treatment of predominantly eosinophil mediated disease states such as asthma, allergic rhinitis, multiple sclerosis, rheumatoid arthritis, diabetes, and inflammatory bowel disease. Gene knockouts of the alpha(4)-integrin subunit of VLA-4 or its cell surface ligand, VCAM-1, however, have been shown to result in embryo-lethality in homozygous null mice due to defects in chorio-allantoic or epi-myocardial fusion. Although gene knockout phenotypes are not always manifested by pharmacological antagonism, those studies suggested that VLA-4 antagonists might cause embryo-lethality or drug-induced malformations.METHODS: To test these concepts, early neurulating rat embryos were cultured by the methods of New ('78) after intra-coelomic microinjection of a VLA-4 blocking antibody or in the presence of small molecule VLA-4 antagonists.RESULTS: Defects in chorio-allantoic fusion were induced after microinjection of VLA4 blocking antibody and after continuous exposure to small molecule antagonists. In a minority of affected embryos chorio-allantoic fusion was completely blocked whereas the majority of affected embryos had only superficial chorio-allantoic fusion and the allantois was enlarged and edematous. Although the allantoic mesoderm covered the trophoblasts of the chorionic plate and contained blood vessels there was only minimal invasion of the trophoblasts by the allantoic mesoderm. The lowest observed effect level generally correlated with the IC(approximately 95), as determined in 90% plasma.DISCUSSION: Based on these data, VLA-4 antagonism might represent a significant risk to the developing embryo/fetus. In vitro exposure, however, is "constant" and does not take into account the elimination phase of these xenobiotics in vivo. Given the high concentrations required to elicit an effect, therapeutic blood levels in vivo may be several

  14. Sexually antagonistic "zygotic drive" of the sex chromosomes.

    Directory of Open Access Journals (Sweden)

    William R Rice

    2008-12-01

    Full Text Available Genomic conflict is perplexing because it causes the fitness of a species to decline rather than improve. Many diverse forms of genomic conflict have been identified, but this extant tally may be incomplete. Here, we show that the unusual characteristics of the sex chromosomes can, in principle, lead to a previously unappreciated form of sexual genomic conflict. The phenomenon occurs because there is selection in the heterogametic sex for sex-linked mutations that harm the sex of offspring that does not carry them, whenever there is competition among siblings. This harmful phenotype can be expressed as an antagonistic green-beard effect that is mediated by epigenetic parental effects, parental investment, and/or interactions among siblings. We call this form of genomic conflict sexually antagonistic "zygotic drive", because it is functionally equivalent to meiotic drive, except that it operates during the zygotic and postzygotic stages of the life cycle rather than the meiotic and gametic stages. A combination of mathematical modeling and a survey of empirical studies is used to show that sexually antagonistic zygotic drive is feasible, likely to be widespread in nature, and that it can promote a genetic "arms race" between the homo- and heteromorphic sex chromosomes. This new category of genomic conflict has the potential to strongly influence other fundamental evolutionary processes, such as speciation and the degeneration of the Y and W sex chromosomes. It also fosters a new genetic hypothesis for the evolution of enigmatic fitness-reducing traits like the high frequency of spontaneous abortion, sterility, and homosexuality observed in humans.

  15. Central actions of a novel and selective dopamine antagonist

    International Nuclear Information System (INIS)

    Receptors for the neurotransmitter dopamine traditionally have been divided into two subgroups: the D1 class, which is linked to the stimulation of adenylate cyclase-activity, and the D2 class which is not. There is much evidence suggesting that it is the D2 class which is not. There is much evidence suggesting that it is the D2 dopamine receptor that mediates the physiological and behavioral actions of dopamine in the intact animal. However, the benzazepine SCH23390 is a dopamine antagonist which has potent behavioral actions while displaying apparent neurochemical selectivity for the D1 class of dopamine receptors. The purpose of this dissertation was to (1) confirm and characterize this selectivity, and (2) test certain hypothesis related to possible modes of action of SCH233390. The inhibition of adenylate cyclase by SCH23390 occurred via an action at the dopamine receptor only. A radiolabeled analog of SCH23390 displayed the receptor binding properties of a specific high-affinity ligand, and regional receptor densities were highly correlated with dopamine levels. The subcellular distribution of [3H]-SCH23390 binding did not correspond completely with that of dopamine-stimulated adenylate cyclase. The neurochemical potency of SCH23390 as a D1 receptor antagonist was preserved following parental administration. A variety of dopamine agonists and antagonists displayed a high correlation between their abilities to compete for [3H]-SCH23390 binding in vitro and to act at an adenylate cyclase-linked receptor. Finally, the relative affinities of dopamine and SCH23390 for both D1 receptors and [3H]-SCH23390 binding sites were comparable. It is concluded that the behavioral effects of SCH23390 are mediated by actions at D1 dopamine receptors only, and that the physiological importance of this class of receptors should be reevaluated

  16. The role of oxytocin antagonists in repeated implantation failure

    OpenAIRE

    Decleer, W.; Osmanagaoglu, K.; Devroey, P.

    2012-01-01

    A prospective cohort study has been performed to find out if the administration of an oxytocin antagonist (Atosiban) at the occasion of embryo transfer has an effect on the pregnancy rate in patients with repeated failure of implantation. A total of 52 women with repeated failure of implantation after IVF/ICSI were included in this study. The ongoing pregnancy rate (OPR) in the total group of patients was 12 out of 52 (23.1%). Based on embryo quality all cases were categorized in two groups. ...

  17. The opiate antagonist, naltrexone, in the treatment of trichotillomania

    DEFF Research Database (Denmark)

    Grant, Jon E; Odlaug, Brian Lawrence; Schreiber, Liana R N;

    2014-01-01

    Trichotillomania (TTM) is characterized by repetitive hair pulling resulting in hair loss. Data on the pharmacological treatment of TTM are limited. This study examined the opioid antagonist, naltrexone, in adults with TTM who had urges to pull their hair. Fifty-one individuals with TTM were...... randomized to naltrexone or placebo in an 8-week, double-blind trial. Subjects were assessed with measures of TTM severity and selected cognitive tasks. Naltrexone failed to demonstrate significantly greater reductions in hair pulling compared to placebo. Cognitive flexibility, however, significantly...

  18. Synthesis of carbon-11 labelled calcium channel antagonists

    International Nuclear Information System (INIS)

    A useful synthetic approach to carbon-11 labelled 1,4-dihydropyridines is described. Carbon-11 labelled calcium channel antagonists 11C-Nifedipine, 11C-Nisoldipine, 11C-nitrendipine and 11C-CF3-Nifedipine were synthesized by a modified Hantzsch method using protected carboxy functions. Deprotection of the carboxylic acids by alkaline hydrolysis followed by conversion into the corresponding potassium salts and subsequent methylation with 11CH3I produced the labelled compounds in very good chemical and radiochemical yields (94%). (author)

  19. Interaction of palmitoyl carnitine with calcium antagonists in myocytes.

    OpenAIRE

    Patmore, L; Duncan, G. P.; Spedding, M.

    1989-01-01

    1. Beating of aggregates of embryonic chick myocytes, in primary culture, was quantified by use of a motion-detector and video-recorder technique. Interactions of palmitoyl carnitine, a putative endogenous ligand at Ca2+ channels, with calcium antagonists were investigated. 2. Bay K 8644 (1-100 nM) and palmitoyl carnitine (0.2-30 microM) increased edge movement of the aggregates; beats fused so that there was an increase in baseline 'tone'. The concentrations required to produce a 50% increas...

  20. Komplikationer til langtidsbehandling med vitamin K-antagonister

    DEFF Research Database (Denmark)

    May, O; Garne, E; Mickley, H

    1990-01-01

    Long-term treatment with vitamin K antagonists (vKA) frequently involves complications. The commonest complication is haemorrhage and cases of serious haemorrhage are stated in the literature to occur with a frequency per 1,000 treatment years of 12-108, of which 2-17 are fatal. The majority of...... deaths associated with haemorrhage are due to intracranial haemorrhage. Notifications of complications of vKA treatment in Denmark are considerably fewer than might be anticipated from the literature. The stability of anticoagulation treatment decreases with the number of drugs administered...

  1. ANTIHYPERTENSIVE TREATMENT IN ELDERLY PATIENTS WITH DIHYDROPYRIDINE CALCIUM ANTAGONISTS

    Directory of Open Access Journals (Sweden)

    Y. A. Karpov

    2016-01-01

    Full Text Available The proofs of necessity of active arterial hypertension (AH treatment in elderly patients are given. Peculiarities of pathogenesis of AH in elderly patients, connected predominantly with loss of big arteries elasticity and reasoning widely spread of isolated systolic AH in these patients, are discussed. Advantages of dihydropyridine calcium antagonists (DPCA for AH treatment in elderly patients are proved, safety of treatment with DPCA is discussed. Data of clinical studies is analyzed. Analysis of target levels of blood pressure for antihypertensive treatment in elderly hypertensive patients is made. As a conclusion DPCA are the medicines of choice for AH treatment in elderly patients.

  2. The Rotavirus Interferon Antagonist NSP1: Many Targets, Many Questions.

    Science.gov (United States)

    Arnold, Michelle M

    2016-06-01

    Rotavirus is a leading cause of death due to diarrhea among young children across the globe. Despite the limited coding capacity that is characteristic of RNA viruses, rotavirus dedicates substantial resources to avoiding the host innate immune response. Among these strategies is use of the interferon antagonist protein NSP1, which targets cellular proteins required for interferon production to be degraded by the proteasome. Although numerous cellular targets have been described, there remain many questions about the mechanism of NSP1 activity and its role in promoting replication in specific host species. PMID:27009959

  3. Expression of Interleukin 1 Receptor Antagonist in Human Cornea

    OpenAIRE

    Heur, Martin; Shyam S. Chaurasia; Wilson, Steven E.

    2008-01-01

    The purpose of this study was to confirm the expression of interleukin-1 receptor antagonist (IL-1 Ra) in the human cornea. Four samples of human ex vivo corneal epithelium were obtained from patients undergoing photorefractive keratectomy. RT-PCR was performed using mRNA isolated from the corneal epithelium and oligo-dT primers. PCR was performed on the cDNA products using primers specific for human IL-1Ra. The PCR products were subcloned and sequenced. Human cornea sections were prepared fr...

  4. Antagonist of prostaglandin E2 receptor 4 induces metabolic alterations in liver of mice.

    Science.gov (United States)

    Li, Ning; Zhang, Limin; An, Yanpeng; Zhang, Lulu; Song, Yipeng; Wang, Yulan; Tang, Huiru

    2015-03-01

    Prostaglandin E2 receptor 4 (EP4) is one of the receptors for prostaglandin E2 and plays important roles in various biological functions. EP4 antagonists have been used as anti-inflammatory drugs. To investigate the effects of an EP4 antagonist (L-161982) on the endogenous metabolism in a holistic manner, we employed a mouse model, and obtained metabolic and transcriptomic profiles of multiple biological matrixes, including serum, liver, and urine of mice with and without EP4 antagonist (L-161982) exposure. We found that this EP4 antagonist caused significant changes in fatty acid metabolism, choline metabolism, and nucleotide metabolism. EP4 antagonist exposure also induced oxidative stress to mice. Our research is the first of its kind to report information on the alteration of metabolism associated with an EP4 antagonist. This information could further our understanding of current and new biological functions of EP4. PMID:25669961

  5. Contributions of different modes of TRPV1 activation to TRPV1 antagonist-induced hyperthermia

    OpenAIRE

    Garami, Andras; Shimansky, Yury P.; Pakai, Eszter; Oliveira, Daniela L.; Gavva, Narender R.; Romanovsky, Andrej A

    2010-01-01

    Transient receptor potential vanilloid-1 (TRPV1) antagonists are widely viewed as next-generation pain therapeutics. However, these compounds cause hyperthermia, a serious side effect. TRPV1 antagonists differentially block three modes of TRPV1 activation: by heat, protons, and chemical ligands (e.g., capsaicin). We asked what combination of potencies in these three modes of TRPV1 activation corresponds to the lowest potency of a TRPV1 antagonist to cause hyperthermia. We studied hyperthermic...

  6. The kappa opioid receptor antagonist JDTic attenuates alcohol seeking and withdrawal anxiety

    OpenAIRE

    Schank, Jesse R.; Goldstein, Andrea L.; Rowe, Kelly E.; King, Courtney E.; Marusich, Julie A.; Wiley, Jenny L; Carroll, F. Ivy; Thorsell, Annika; Heilig, Markus

    2012-01-01

    The role of kappa-opioid receptors (KOR) in regulation of alcohol-related behaviors is not completely understood. For example, alcohol consumption has been reported to increase following treatment with KOR antagonists in rats, but was decreased in mice with genetic deletion of KOR. Recent studies have further suggested that KOR antagonists may selectively decrease alcohol self-administration in rats following a history of dependence. We assessed the effects of the KOR antagonist JDTic on alco...

  7. A Selective TSH Receptor Antagonist Inhibits Stimulation of Thyroid Function in Female Mice

    OpenAIRE

    Neumann, Susanne; Nir, Eshel A; Eliseeva, Elena; Huang, Wenwei; Marugan, Juan; Xiao, Jingbo; Dulcey, Andrés E.; Gershengorn, Marvin C.

    2013-01-01

    Because the TSH receptor (TSHR) plays an important role in the pathogenesis of thyroid disease, a TSHR antagonist could be a novel treatment. We attempted to develop a small molecule, drug-like antagonist of TSHR signaling that is selective and active in vivo. We synthesized NCGC00242364 (ANTAG3) by chemical modification of a previously reported TSHR antagonist. We tested its potency, efficacy, and selectivity in a model cell system in vitro by measuring its activity to inhibit stimulation of...

  8. The neuromedin B receptor antagonist, BIM-23127, is a potent antagonist at human and rat urotensin-II receptors

    OpenAIRE

    Herold, Christopher L; Behm, David J.; Buckley, Peter T.; Foley, James J; William E Wixted; Sarau, Henry M; Douglas, Stephen A

    2003-01-01

    The functional activity of the peptidic neuromedin B receptor antagonist BIM-23127 was investigated at recombinant and native urotensin-II receptors (UT receptors). Human urotensin-II (hU-II) promoted intracellular calcium mobilization in HEK293 cells expressing the human UT (hUT) or rat UT (rUT) receptors with pEC50 values of 9.80±0.34 (n=6) and 9.06±0.32 (n=4), respectively. While BIM-23127 alone had no effect on calcium responses in either cell line, it was a potent and competitive antagon...

  9. Human homosexuality: a paradigmatic arena for sexually antagonistic selection?

    Science.gov (United States)

    Camperio Ciani, Andrea; Battaglia, Umberto; Zanzotto, Giovanni

    2015-04-01

    Sexual conflict likely plays a crucial role in the origin and maintenance of homosexuality in our species. Although environmental factors are known to affect human homosexual (HS) preference, sibling concordances and population patterns related to HS indicate that genetic components are also influencing this trait in humans. We argue that multilocus, partially X-linked genetic factors undergoing sexually antagonistic selection that promote maternal female fecundity at the cost of occasional male offspring homosexuality are the best candidates capable of explaining the frequency, familial clustering, and pedigree asymmetries observed in HS male proband families. This establishes male HS as a paradigmatic example of sexual conflict in human biology. HS in females, on the other hand, is currently a more elusive phenomenon from both the empirical and theoretical standpoints because of its fluidity and marked environmental influence. Genetic and epigenetic mechanisms, the latter involving sexually antagonistic components, have been hypothesized for the propagation and maintenance of female HS in the population. However, further data are needed to truly clarify the evolutionary dynamics of this trait. PMID:25635045

  10. Discovery of tetrahydroisoquinoline-based CXCR4 antagonists.

    Science.gov (United States)

    Truax, Valarie M; Zhao, Huanyu; Katzman, Brooke M; Prosser, Anthony R; Alcaraz, Ana A; Saindane, Manohar T; Howard, Randy B; Culver, Deborah; Arrendale, Richard F; Gruddanti, Prahbakar R; Evers, Taylor J; Natchus, Michael G; Snyder, James P; Liotta, Dennis C; Wilson, Lawrence J

    2013-11-14

    A de novo hit-to-lead effort involving the redesign of benzimidazole-containing antagonists of the CXCR4 receptor resulted in the discovery of a novel series of 1,2,3,4-tetrahydroisoquinoline (TIQ) analogues. In general, this series of compounds show good potencies (3-650 nM) in assays involving CXCR4 function, including both inhibition of attachment of X4 HIV-1IIIB virus in MAGI-CCR5/CXCR4 cells and inhibition of calcium release in Chem-1 cells. Series profiling permitted the identification of TIQ-(R)-stereoisomer 15 as a potent and selective CXCR4 antagonist lead candidate with a promising in vitro profile. The drug-like properties of 15 were determined in ADME in vitro studies, revealing low metabolic liability potential. Further in vivo evaluations included pharmacokinetic experiments in rats and mice, where 15 was shown to have oral bioavailability (F = 63%) and resulted in the mobilization of white blood cells (WBCs) in a dose-dependent manner. PMID:24936240

  11. Evodiamine as a novel antagonist of aryl hydrocarbon receptor

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Hui [State Key Laboratory of Trauma, Burns, and Combined Injury, Department 1, Research Institute of Surgery, Daping Hospital, The Third Military Medical University, Chongqing 400042 (China); Department of Laboratory Medicine, The Affiliated Tenth People' s Hospital, Tongji University, Shanghai 200072 (China); Tu, Yongjiu; Zhang, Chun; Fan, Xia; Wang, Xi [State Key Laboratory of Trauma, Burns, and Combined Injury, Department 1, Research Institute of Surgery, Daping Hospital, The Third Military Medical University, Chongqing 400042 (China); Wang, Zhanli [College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014 (China); Liang, Huaping, E-mail: huaping_liang@yahoo.com.cn [State Key Laboratory of Trauma, Burns, and Combined Injury, Department 1, Research Institute of Surgery, Daping Hospital, The Third Military Medical University, Chongqing 400042 (China)

    2010-11-05

    Research highlights: {yields} Evodiamine interacted with the AhR. {yields} Evodiamine inhibited the specific binding of [{sup 3}H]-TCDD to the AhR. {yields} Evodiamine acts as an antagonist of the AhR. -- Abstract: Evodiamine, the major bioactive alkaloid isolated from Wu-Chu-Yu, has been shown to interact with a wide variety of proteins and modify their expression and activities. In this study, we investigated the interaction between evodiamine and the aryl hydrocarbon receptor (AhR). Molecular modeling results revealed that evodiamine directly interacted with the AhR. Cytosolic receptor binding assay also provided the evidence that evodiamine could interact with the AhR with the K{sub i} value of 28.4 {+-} 4.9 nM. In addition, we observed that evodiamine suppressed the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induced nuclear translocation of the AhR and the expression of CYP1A1 dose-dependently. These results suggested that evodiamine was able to bind to the AhR as ligand and exhibit antagonistic effects.

  12. Novel potent selective phenylglycine antagonists of metabotropic glutamate receptors.

    Science.gov (United States)

    Bedingfield, J S; Jane, D E; Kemp, M C; Toms, N J; Roberts, P J

    1996-08-01

    The metabotropic glutamate (mGlu) receptor antagonist properties of novel phenylglycine analogues were investigated in adult rat cortical slices (mGlu receptors negatively coupled to adenylyl cyclase), neonatal rat cortical slices and in cultured rat cerebellar granule cells (mGlu receptors coupled to phosphoinositide hydrolysis). (RS)-alpha-methyl-4-phosphonophenylglycine (MPPG), (RS)-alpha-methyl-4-sulphonophenylglycine (MSPG), (RS)-alpha-methyl-4-tetrazolylphenylglycine (MTPG), (RS)-alpha-methyl-3-carboxymethyl-4-hydroxyphenylglycine (M3CM4HPG) and (RS)-alpha-methyl-4-hydroxy-3-phosphonomethylphenylglycine (M4H3PMPG) were demonstrated to have potent and selective effects against 10 microM L-2-amino-4-phosphonobutyrate (L-AP4)- and 0.3 microM (2S,1'S,2'S)-2-(2-carboxycyclopropyl)glycine (L-CCG-1)-mediated inhibition of forskolin-stimulated cAMP accumulation in the adult rat cortex. In contrast, these compounds demonstrated either weak or no antagonism at mGlu receptors coupled to phosphoinositide hydrolysis in either neonatal rat cortex or in cultured cerebellar granule cells. These compounds thus appear to be useful discriminatory pharmacological tools for mGlu receptors and form the basis for the further development of novel antagonists. PMID:8864696

  13. Scaffold Optimisation of Tetravalent Antagonists of the Mannose Binding Lectin.

    Science.gov (United States)

    Goti, Giulio; Palmioli, Alessandro; Stravalaci, Matteo; Sattin, Sara; De Simoni, Maria-Grazia; Gobbi, Marco; Bernardi, Anna

    2016-03-01

    Antagonists of mannose binding lectin (MBL) have shown a protective role against brain reperfusion damage after acute ischemic stroke. Here we describe the design and streamlined synthesis of glycomimetic MBL antagonists based on a new tetravalent dendron scaffold. The dendron was developed by optimisation of a known polyester structure previously demonstrated to be very efficient for ligand presentation to MBL. Replacement of a labile succinyl ester bond with a more robust amide functionality, use of a longer and more hydrophilic linker, fast modular synthesis and orthogonal functionalisation at the focal point are the main features of the new scaffold. The glycoconjugate constructs become stable to silica gel chromatography and to water solutions at physiological pH, while preserving water solubility and activity in an SPR assay against the murine MBL-C isoform. Higher-order constructs were easily assembled, as demonstrated by the synthesis of a 16-valent dendrimer, which leads to two orders of magnitude increase in activity over the tetravalent version against MBL-C. PMID:26696414

  14. Rogue sperm indicate sexually antagonistic coevolution in nematodes.

    Directory of Open Access Journals (Sweden)

    Ronald E Ellis

    2014-07-01

    Full Text Available Intense reproductive competition often continues long after animals finish mating. In many species, sperm from one male compete with those from others to find and fertilize oocytes. Since this competition occurs inside the female reproductive tract, she often influences the outcome through physical or chemical factors, leading to cryptic female choice. Finally, traits that help males compete with each other are sometimes harmful to females, and female countermeasures may thwart the interests of males, which can lead to an arms race between the sexes known as sexually antagonistic coevolution. New studies from Caenorhabditis nematodes suggest that males compete with each other by producing sperm that migrate aggressively and that these sperm may be more likely to win access to oocytes. However, one byproduct of this competition appears to be an increased probability that these sperm will go astray, invading the ovary, prematurely activating oocytes, and sometimes crossing basement membranes and leaving the gonad altogether. These harmful effects are sometimes observed in crosses between animals of the same species but are most easily detected in interspecies crosses, leading to dramatically lowered fitness, presumably because the competitiveness of the sperm and the associated female countermeasures are not precisely matched. This mismatch is most obvious in crosses involving individuals from androdioecious species (which have both hermaphrodites and males, as predicted by the lower levels of sperm competition these species experience. These results suggest a striking example of sexually antagonistic coevolution and dramatically expand the value of nematodes as a laboratory system for studying postcopulatory interactions.

  15. Implications of hedgehog signaling antagonists for cancer therapy

    Institute of Scientific and Technical Information of China (English)

    Jingwu Xie

    2008-01-01

    The hedgehog(Hh)pathway,initially discovered inDrosophila by two Nobel laureates,Dr.Eric Wieschaus and Dr.Christiane Nusslein-Volhard,is a major regulator for cell differentiation,tissue polarity and cell proliferation.Studies from many laboratories,including ours,reveal activation of this pathway in most basal cell carcinomas and in approximately 30% of extracutaneous human cancers,including medulloblastomas,gastrointestinal,lung,breast and prostate cancers.Thus,it is believed that targeted inhibition of Hh signaling may be effective in treating and preventing many types of human cancers.Even more exciting is the discovery and synthesis of specific signaling antagonists for the Hh pathway,which have significant clinical implications in novel cancer therapeutics.This review discusses the major advances in the current understanding of Hh signaling activation in different types of human cancers,the molecular basis of Hh signaling activation,the major antagonists for Hh signaling inhibition and their potential clinical application in human cancer therapy.

  16. Evidence for a possible calcium flux dependent cardiomyopathy in hyperthyroidism

    International Nuclear Information System (INIS)

    This study was designed to test the hypothesis that the impaired functional cardiac reserve to exercise in hyperthyroidism is related to alterations in the regulation of calcium transport. In 2l hyperthyroid patients, the left ventricular ejection fraction (LVEF) was measured using equilibrium gated radionuclide angiocardiography at rest and during supine dynamic exercise. After a recovery period, the patients performed a second exercise study after random administration of Verapamil, a calcium entry blocker (11 pts), or propanolol, a beta adrenergic antagonist (10 pts) for comparison. The results showed i) normal resting LVEF with no significant change during exercise before any medication, ii) resting LVEF significantly decreased after Propanolol, and no significantly changed after Verapamil, iii) during exercise, significant increase of LVEF after Verapamil, and no significant change after Propanolol. These results are consistent with previous studies showing that abnormal change in LVEF during exercise in hyperthyroidism seems independent of beta adrenergic activation, and suggest a reversible functional cardiomyopathy dependent of calcium transporting systems

  17. The effect of timolol maleate on the disruption of the blood-aqueous barrier in the rabbit eye

    Energy Technology Data Exchange (ETDEWEB)

    Holmdahl, G.; Bengtsson, E.

    1981-06-01

    A disruption of the blood-aqueous barrier in rabbit eyes was elicited by use of topical prostaglandin E2(PGE2), infrared irradiation of the iris, or by subcutaneous alpha-melanocyte-stimulating hormone (alpha-MSH). The aqueous flare provoked was measured quantitatively with a photoelectric instrument. The effect of the (topical) beta-adrenergic antagonist timolol maleate on the breakdown of the blood-aqueous barrier was tested. Timolol applied topically in very large doses had no effect on exogenously administered PGE2. However, even in a very small concentration applied topically, timolol reduced the flare response to both infrared irradiation and alpha-MSH. These results support the theory that the effect of alpha-MSH and infrared irradiation on the blood-aqueous barrier is dependent on intact beta-adrenergic receptor sites.

  18. The Cultivation of Antagonistic Bacteria in Irradiated Sludge for Biological Control of Soft Rot Erwinias : Screening of Antagonistic Bacteria for biological Control of Soft Rot Erwinias

    International Nuclear Information System (INIS)

    Pure cultures of 57 bacterial isolates for antagonistic activity screening were isolated from three areas of soft rot infested vegetable soil and 58 isolates were obtained from commercial seed compost and seed compost product of Division of Soil and Water Conservation, Department of Land Development. A total of 115 bacterial isolates were evaluated for antagonizing activity against Erwinia carotovora subsp. atroceptica in vitro. Out of them, 18 isolates were antagonists by showing zone of inhibition ranging from 1 to 17 mm by diameter. Most of antagonistic bacteria were identified as Bacillus spp. whereas only one isolate was Pseudomonas vesicularis

  19. Functionalized Congeners of P2Y1 Receptor Antagonists:

    Energy Technology Data Exchange (ETDEWEB)

    de Castro, Sonia [National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; Maruoka, Hiroshi [National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; Hong, Kunlun [ORNL; Kilbey, II, S Michael [ORNL; Costanzi, Stefano [National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; Hechler, Béatrice [University of Strasbourg; Gachet, Christian [EFS-Alsace, Strasbourg, France; Harden, T. Kendall [University of North Carolina School of Medicine; Jacobson, Kenneth A. [National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health

    2010-01-01

    The P2Y{sub 1} receptor is a prothrombotic G protein-coupled receptor (GPCR) activated by ADP. Preference for the North (N) ring conformation of the ribose moiety of adenine nucleotide 3',5'-bisphosphate antagonists of the P2Y{sub 1} receptor was established by using a ring-constrained methanocarba (a bicyclo[3.1.0]hexane) ring as a ribose substitute. A series of covalently linkable N{sup 6}-methyl-(N)-methanocarba-2'-deoxyadenosine-3',5'-bisphosphates containing extended 2-alkynyl chains was designed, and binding affinity at the human (h) P2Y{sub 1} receptor determined. The chain of these functionalized congeners contained hydrophilic moieties, a reactive substituent, or biotin, linked via an amide. Variation of the chain length and position of an intermediate amide group revealed high affinity of carboxylic congener 8 (K{sub i} 23 nM) and extended amine congener 15 (K{sub i} 132 nM), both having a 2-(1-pentynoyl) group. A biotin conjugate 18 containing an extended {epsilon}-aminocaproyl spacer chain exhibited higher affinity than a shorter biotinylated analogue. Alternatively, click coupling of terminal alkynes of homologous 2-dialkynyl nucleotide derivatives to alkyl azido groups produced triazole derivatives that bound to the P2Y{sub 1} receptor following deprotection of the bisphosphate groups. The preservation of receptor affinity of the functionalized congeners was consistent with new P2Y{sub 1} receptor modeling and ligand docking. Attempted P2Y{sub 1} antagonist conjugation to PAMAM dendrimer carriers by amide formation or palladium-catalyzed reaction between an alkyne on the dendrimer and a 2-iodopurine-derivatized nucleotide was unsuccessful. A dialkynyl intermediate containing the chain length favored in receptor binding was conjugated to an azide-derivatized dendrimer, and the conjugate inhibited ADP-promoted human platelet aggregation. This is the first example of attaching a strategically functionalized P2Y receptor

  20. Bronchoprotection with a leukotriene receptor antagonist in asthmatic preschool children

    DEFF Research Database (Denmark)

    Bisgaard, H; Nielsen, K G

    2000-01-01

    We hypothesized that a leukotriene receptor antagonist (LTRA) could provide bronchoprotection against the cold, dry air-induced response in asthmatic preschool children. In a randomized, double-blind, placebo-controlled crossover study, we examined the effect of the specific LTRA montelukast at 5...... repeatability of the bronchoprotection was examined by repeating the placebo-controlled study in six of the 13 children. sRaw increased by an average of 46% (95% confidence interval [CI]: 30 to 63%) after placebo treatment and 17% (95% CI: 3 to 31%) after montelukast (p < 0.01). Eight of the children were...... receiving regular treatment with budesonide delivered by an inhaler with a spacer in a mean daily dose of 350 microg, but the bronchoprotection provided by montelukast was independent of concurrent steroid treatment. There was no convincing evidence of failure to respond, and the protective effect of...

  1. Identification of Bexarotene as a PPARγ Antagonist with HDX

    Directory of Open Access Journals (Sweden)

    David P. Marciano

    2015-01-01

    Full Text Available The retinoid x receptors (RXRs are the pharmacological target of Bexarotene, an antineoplastic agent indicated for the treatment of cutaneous T cell lymphoma (CTCL. The RXRs form heterodimers with several nuclear receptors (NRs, including peroxisome proliferator-activated receptor gamma (PPARγ, to regulate target gene expression through cooperative recruitment of transcriptional machinery. Here we have applied hydrogen/deuterium exchange (HDX mass spectrometry to characterize the effects of Bexarotene on the conformational plasticity of the intact RXRα:PPARγ heterodimer. Interestingly, addition of Bexarotene to PPARγ in the absence of RXRα induced protection from solvent exchange, suggesting direct receptor binding. This observation was confirmed using a competitive binding assay. Furthermore, Bexarotene functioned as a PPARγ antagonist able to alter rosiglitazone induced transactivation in a cell based promoter:reporter transactivation assay. Together these results highlight the complex polypharmacology of lipophilic NR targeted small molecules and the utility of HDX for identifying and characterizing these interactions.

  2. Physico-chemical pathways in radioprotective action of calmodulin antagonists

    International Nuclear Information System (INIS)

    Ghost membranes prepared from erythrocytes of Swiss albino mice were irradiated with gamma rays at a dose rate of 0.9 Gy/s. The fluidity of membrane decreased with radiation dose and in the presence of calmodulin antagonists (CA) like chlorpromazine (CPZ), promethazine (PMZ), and trimeprazone (TMZ) it increased. Radiation induced release of Ca2+ from membranes. This release was inhibited by CA mainly by CPZ and PMZ. Being Ca2+ dependent, the changes in the activity of acetylcholine estrase (AchE) following irradiation was also studied. Radiation decreased the activity of AchE in dose dependent manner. Presence of CPZ and PMZ diminished the radiation induced inhibition of AchE but not in the presence of TMZ at the lower concentration tested. It is suggested that apart from scavenging of free radicals, CA perhaps exert their euxoic radioprotective effect through Ca2+ dependent processes. (author)

  3. Biological control of soybean damping-off by antagonistic rhizobacteria.

    Science.gov (United States)

    Sharifi Tehrani, A; Zebarjad, A; Hedjaroud, Gh A; Mohammadi, M

    2002-01-01

    Experiments were carried out with 133 bacterial isolates that were collected from soybean rhizosphere. These strains were used to investigate their biocontrol traits in vitro and their ability to suppress the soybean damping-off in vivo (soil and seed treatments). Three highly effective isolates were selected from these antagonists for subsequent studies. According to the biochemical, physiological and morphological tests, these isolates (B-2, B-12 and B-80) were identified as Bacillus spp. In soil treatment, the isolate B-3 with 70.8%, B-12 with 66.7%, B-80 with 54.2% had the highest effect on reducing the soybean damping-off. In seed treatment, the isolates B-43 with 62.5%, B-12 with 58.4 and B-80 with 45.8%, had the greatest effect on reducing the disease. These isolates produced volatile metabolites that inhibited mycelial growth of Phytophthora sojae. PMID:12701446

  4. Calcium-antagonists and islet function. Pt. 5

    International Nuclear Information System (INIS)

    R33711, a new drug with presumed potent calcium-antagonistic property, was found to suppress the insulinotropic action of glucose und gliclazide but not that of theophylline. A 0.2 μM concentration of R33711 was sufficient to abolish glucose-induced insulin release. At this concentration, R33711 inhibited the net uptake of 45Ca2+ by isolated islets, whether in the absence or presence of either glucose or sulfonylurea. In the isolated islets, R33711 failed to affect the glucose-stimulated production of lactate, the rate of 45Ca2+ efflux, the inhibitory action of glucose upon such an efflux and its increase in response to theophylline. These data are compatible with the view that R33711 inhibits entry of Ca2+ into the B-cell and that integrity of such an inward cationic movement usually plays a permissive role in the maintenance of the Ca2+-dependent insulin secretory process. (orig.)

  5. Effect of diseases on response to vitamin K antagonists.

    Science.gov (United States)

    Self, Timothy H; Owens, Ryan E; Sakaan, Sami A; Wallace, Jessica L; Sands, Christopher W; Howard-Thompson, Amanda

    2016-04-01

    Introduction The purpose of this review article is to summarize the literature on diseases that are documented to have an effect on response to warfarin and other VKAs. Methods We searched the English literature from 1946 to September 2015 via PubMed, EMBASE, and Scopus for the effect of diseases on response vitamin K antagonists including warfarin, acenocoumarol, phenprocoumon, and fluindione. Discussion Among many factors modifying response to VKAs, several disease states are clinically relevant. Liver disease, hyperthyroidism, and CKD are well documented to increase response to VKAs. Decompensated heart failure, fever, and diarrhea may also elevate response to VKAs, but more study is needed. Hypothyroidism is associated with decreased effect of VKAs, and obese patients will likely require higher initial doses of VKAs. Conclusion In order to minimize risks with VKAs while ensuring efficacy, clinicians must be aware of the effect of disease states when prescribing these oral anticoagulants. PMID:26695107

  6. Research progress of antagonistic interactions among root canal irrigations disease

    Directory of Open Access Journals (Sweden)

    Chen QU

    2013-07-01

    Full Text Available Root canal therapy is the most effective way to treat various pulposis and periapical disease. Simple mechanical apparatus can not clean root canal thoroughly, but may affect tight filling instead. It can achieve a satisfactory cleansing effect only when it is combined with a chemical solution. Irrigation fluid for root canal should possess the properties of tissue dissolution, antimicrobial, lubrication, and removal of smear layer. So far, no solution is able to fulfill all these functions. Therefore, a combined use of multiple irrigation solutions is suggested. It can not only achieve good effect in cleaning and disinfection, also it can lower the concentration of different solutions, thus reducing the side effects. Nevertheless, some experiments proved that antagonism existed among the chemicals used for irrigations. The purpose of present article is to review the antagonistic effect among the chemicals used for irrigation when they are used together for root canal treatment.

  7. Effects of TNF antagonists on immune and neuroendocrine system

    Directory of Open Access Journals (Sweden)

    M. Cutolo

    2011-09-01

    Full Text Available In the article, the literature on the effects of TNFa-antagonists (etanercept, infliximab and adalimumab on the immune system is reviewed. These biologic agents are employed in chronic inflammatory diseases such as rheumatoid arthritis, seronegative spondyloarthritides, as well as psoriasis and Crohn’s disease. The differences of these drugs, testified by the different effects on the immune response, are discussed. These molecules exert their effect through cytokine inhibition, but they present striking differences since they can modulate macrophage activity, T cells apoptosis, leukocyte migration, and angiogenesis to a different degree. Some studies showed that these agents also affect the hypothalamo- pituitary-adrenal axis. The potential immunogenicity of these biologic agents is also discussed.

  8. GABAA receptor modulating steroid antagonists (GAMSA) are functional in vivo.

    Science.gov (United States)

    Johansson, Maja; Strömberg, Jessica; Ragagnin, Gianna; Doverskog, Magnus; Bäckström, Torbjörn

    2016-06-01

    GABAA receptor modulating steroid antagonists (GAMSA) selectively inhibit neurosteroid-mediated enhancement of GABA-evoked currents at the GABAA receptor. 3α-hydroxy-neurosteroids, notably allopregnanolone and tetrahydrodeoxycorticosterone (THDOC), potentiate GABAA receptor-mediated currents. On the contrary, various 3β-hydroxy-steroids antagonize this positive neurosteroid-mediated modulation. Importantly, GAMSAs are specific antagonists of the positive neurosteroid-modulation of the receptor and do not inhibit GABA-evoked currents. Allopregnanolone and THDOC have both negative and positive actions. Allopregnanolone can impair encoding/consolidation and retrieval of memories. Chronic administration of a physiological allopregnanolone concentration reduces cognition in mice models of Alzheimer's disease. In humans an allopregnanolone challenge impairs episodic memory and in hepatic encephalopathy cognitive deficits are accompanied by increased brain ammonia and allopregnanolone. Hippocampal slices react in vitro to ammonia by allopregnanolone synthesis in CA1 neurons, which blocks long-term potentiation (LTP). Thus, allopregnanolone may impair learning and memory by interfering with hippocampal LTP. Contrary, pharmacological treatment with allopregnanolone can promote neurogenesis and positively influence learning and memory of trace eye-blink conditioning in mice. In rat the GAMSA UC1011 inhibits an allopregnanolone-induced learning impairment and the GAMSA GR3027 restores learning and motor coordination in rats with hepatic encephalopathy. In addition, the GAMSA isoallopregnanolone antagonizes allopregnanolone-induced anesthesia in rats, and in humans it antagonizes allopregnanolone-induced sedation and reductions in saccadic eye velocity. 17PA is also an effective GAMSA in vivo, as it antagonizes allopregnanolone-induced anesthesia and spinal analgesia in rats. In vitro the allopregnanolone/THDOC-increased GABA-mediated GABAA receptor activity is antagonized

  9. Alpha antagonists and intraoperative floppy iris syndrome: A spectrum

    Directory of Open Access Journals (Sweden)

    Sharif A Issa

    2008-07-01

    Full Text Available Sharif A Issa, Omar H Hadid, Oliver Baylis, Margaret DayanDepartment of Ophthalmology, Royal Victoria Infirmary, Newcastle upon Tyne, UKBackground: To determine occurrence of features of intraoperative floppy iris syndrome (IFIS during cataract surgery in patients taking systemic alpha-antagonists (AA.Methods: We prospectively studied patients on AA and who underwent phacoemulsification. The following were recorded: pupil diameter preoperatively, iris flaccidity, iris prolapse and peroperative miosis.Results: We studied 40 eyes of 31 subjects. Mean age was 78 years. Overall, 14 eyes (13 patients showed signs of IFIS: 9/13 (69% eyes of patients on tamsulosin, 1/18 (6% eyes in the doxazosin group, 2/2 prazosin patients, 1/4 eyes in the indoramin group, and 1/2 eyes in two patients on a combination of doxazosin and tamsulosin. Most cases (92% had only one or two signs of IFIS. Bilateral cataract surgery was undertaken in 9 patients but only one patient (on tamsulosin had features of IFIS in both eyes, while 4 patients (2 on tamsulosin and 2 on other AA showed signs of IFIS in one eye only, and 4 patients did not show IFIS in either eye.Conclusion: Most AA were associated with IFIS, but it tends to present as a spectrum of signs rather than full triad originally described. Tamsulosin was most likely to be associated with IFIS; however, its intake does not necessarily mean that IFIS will occur. For patients on AA, the behavior of the iris intraoperatively in one eye is a poor predictor of the other eye. Surgeons should anticipate the occurrence of IFIS in any patient on AA.Keywords: alpha blocker, alpha antagonist, cataract surgery, intraoperative floppy iris syndrome, tamsulosin.

  10. Hotspots of damage by antagonists shape the spatial structure of plant-pollinator interactions.

    Science.gov (United States)

    Rodríguez-Rodríguez, María C; Jordano, Pedro; Valido, Alfredo

    2015-08-01

    The balance between mutualistic and antagonistic plant-animal interactions and their spatial variation results in a highly dynamic mosaic of reproductive success within plant populations. Yet, the ecological drivers of this small-scale heterogeneity of interaction patterns and their outcomes remain virtually unexplored. We analyzed spatial structure in the frequency and intensity of interactions that vertebrate pollinators (birds and lizards) and invertebrate antagonists (florivores, nectar larcenists, and seed predators) had when interacting with the insular plant Isoplexis canariensis, and their effect on plant fitness. Spatially autocorrelated variation in plant reproductive success (fruit and viable seed set) emerged from the combined action of mutualists and antagonists, rather than reflecting the spatial pattern of any specific animal group. However, the influence of antagonists on plant fitness was stronger primarily due to the florivores' action on earlier reproductive stages, consuming and damaging floral structures before the arrival of pollinators. Our results indicate that the early action of antagonists creates hotspots of increased plant damage, where the effects of later acting mutualists are not translated into increased reproductive benefits. We foresee the potential for antagonists to shape the intra-population mosaics of plant fitness in situations where antagonists outnumber mutualists, when their interactions occur before those of mutualists, and when mutualists can detect and avoid damaged plants while foraging. Severely damaged plants in antagonistic hotspots might be excluded from the mating network and render a limited production of viable seeds, reducing both the growth rate of the plant population and the effective population size. PMID:26405743

  11. Screening of antagonistic activity of microorganisms against Colletotrichum acutatum and Colletotrichum gloeosporioides

    OpenAIRE

    Živković Svetlana; Stojanović S.; Ivanović Ž.; Gavrilović V.; Popović Tatjana; Balaž Jelica

    2010-01-01

    The antagonistic activities of five biocontrol agents: Trichoderma harzianum, Gliocladium roseum, Bacillus subtilis, Streptomyces noursei and Streptomyces natalensis, were tested in vitro against Colletotrichum acutatum and Colletotrichum gloeosporioides, the causal agents of anthracnose disease in fruit crops. The microbial antagonists inhibited mycelial growth in the dual culture assay and conidial germination of Colletotrichum isolates. The two Streptomyces species exhibited the strongest ...

  12. Folic acid sensitive birth defects in association with intrauterine exposure to folic acid antagonists

    NARCIS (Netherlands)

    Meijer, W.M.; Walle, H.E.K.de; Kerstjens-Frederikse, W.S; de Jong-van den Berg, Lolkje Theodora Wilhelmina

    2005-01-01

    Since the protective effect of folic acid (FA) on birth defects is well known, it is reasonable to assume intrauterine exposure to FA antagonists increases the risk on these defects. We have therefore performed case-control analyses to investigate the risk of intrauterine exposure to FA antagonists,

  13. Anti-inflammatory properties of a novel peptide interleukin 1 receptor antagonist

    DEFF Research Database (Denmark)

    Klementiev, Boris; Li, Shizhong; Korshunova, Irina; Dmytriyeva, Oksana; Pankratova, Stanislava; Walmod, Peter S; Kjær, Laura K; Dahllöf, Mattias S; Lundh, Morten; Christensen, Dan P; Mandrup-Poulsen, Thomas; Bock, Elisabeth; Berezin, Vladimir

    2014-01-01

    Interleukin 1 (IL-1) is implicated in neuroinflammation, an essential component of neurodegeneration. We evaluated the potential anti-inflammatory effect of a novel peptide antagonist of IL-1 signaling, Ilantide.......Interleukin 1 (IL-1) is implicated in neuroinflammation, an essential component of neurodegeneration. We evaluated the potential anti-inflammatory effect of a novel peptide antagonist of IL-1 signaling, Ilantide....

  14. Impact of Trichoderma spp. on Soybean Seed Germination and Potential Antagonistic Effect on Sclerotinia sclerotiorum

    OpenAIRE

    Sonja Tančić; Jelica Skrobonja; Mirjana Lalošević; Radivoje Jevtić; Miloš Vidić

    2013-01-01

    Trichoderma species have been registered as species with important plant growth promoting potential and antagonistic effect against various phytopathogens. Trichoderma isolates originating from different soil types from the Vojvodina region (Serbia) were screened using dual culture test for their antagonistic effect against the pathogen Sclerotinia sclerotiorum. All tested isolates had high radial growth inhibition (RGI) factors of the pathogen and high col...

  15. Control of blue mold of apple by combining controlled atmosphere, antagonist mixtures and sodium bicarbonate

    Science.gov (United States)

    'Golden Delicious' apples were wound-inoculated with Penicillium expansum, treated with various combinations of sodium bicarbonate and two antagonists, and stored in air or controlled atmosphere (1.4% O2, 3% CO2). The fruit were stored for 2 or 4 months at 1°C. The antagonists survived and their p...

  16. Discovery and mapping of an intracellular antagonist binding site at the chemokine receptor CCR2

    DEFF Research Database (Denmark)

    Zweemer, Annelien J M; Bunnik, Julia; Veenhuizen, Margo; Miraglia, Fabiana; Lenselink, Eelke B; Vilums, Maris; de Vries, Henk; Gibert, Arthur; Thiele, Stefanie; Rosenkilde, Mette M; IJzerman, Adriaan P; Heitman, Laura H

    2014-01-01

    The chemokine receptor CCR2 is a G protein-coupled receptor that is involved in many diseases characterized by chronic inflammation, and therefore a large variety of CCR2 small molecule antagonists has been developed. On the basis of their chemical structures these antagonists can roughly be divi...

  17. Beta-adrenoceptor antagonists enhance white blood cell aggregation in patients with ischaemic heart disease.

    OpenAIRE

    Bridges, A B; Pringle, T. H.; McNeill, G P; Tavendale, R; Belch, J J

    1992-01-01

    The effects of beta-adrenoceptor antagonists, calcium channel blockers and long acting nitrates on white blood cell (WBC) aggregation were studied in patients with ischaemic heart disease. WBC aggregation was significantly increased by beta-adrenoceptor antagonists (P = 0.011) but was unaffected by either calcium channel blockers or long acting nitrates. Enhanced WBC aggregation promotes microvascular occlusion and damage.

  18. Design and synthesis of substituted 2-naphthyloxyethylamines as potential 5-HT 1A antagonists

    Directory of Open Access Journals (Sweden)

    Joshi Urmila

    2007-01-01

    Full Text Available Although 5-HT 1A antagonists are known to be useful in the treatment of depression, no specific 5-HT 1A antagonist is available clinically. Propranolol is one of the important ligands acting at the presynaptic 5-HT 1A receptor. This article deals with the design of 5-HT 1A antagonists based on propranolol using the pharmacophoric requirements of the receptor and the other SAR data, synthesis of these compounds and their preliminary evaluation for the 5-HT 1A antagonistic activity against a specific partial agonist. This was done by measuring the reversal of agonist-induced hypothermia in mice. The synthesized compounds showed a promising 5-HT 1A antagonistic activity.

  19. Antagonistic activity of autosimbionts А. viridans, B. subtilis and their probiotic association to conditionally microflora

    Directory of Open Access Journals (Sweden)

    Stepansky D.A.

    2015-03-01

    Full Text Available In this research the data on examination of antagonist qualities of bioassotiantes A. viridans and strain B. subtilis 3 towards pathogenic and opportunistic pathogenic microflora isolated from oropharynx and nasopharynx of children who were in contact with patients with pulmonary tuberculosis (MBT + are submitted. The expressed antagonist activity of autosimbionts A. viridans towards pathogenic and opportunistic pathogenic microflora was shown. Common antagonist activity of A. viridans (k N 1 and B. subtilis 3 towards diverse strains of test-cultures is 1,5-2 times higher, than separate antagonist activity of A. viridans (k №1 and B. subtilis 3. Received research data showed the possibility of continuing work on development of probiotic associations, that contain representatives of normal microflora - bioassociants A. viridans and probiotic strains B. subtilis 3 with broadspectrum of antagonistic activity in relation to the various groups of bacterium.

  20. The Role of α1-Adrenoceptor Antagonists in the Treatment of Prostate and Other Cancers.

    Science.gov (United States)

    Batty, Mallory; Pugh, Rachel; Rathinam, Ilampirai; Simmonds, Joshua; Walker, Edwin; Forbes, Amanda; Anoopkumar-Dukie, Shailendra; McDermott, Catherine M; Spencer, Briohny; Christie, David; Chess-Williams, Russ

    2016-01-01

    This review evaluates the role of α-adrenoceptor antagonists as a potential treatment of prostate cancer (PCa). Cochrane, Google Scholar and Pubmed were accessed to retrieve sixty-two articles for analysis. In vitro studies demonstrate that doxazosin, prazosin and terazosin (quinazoline α-antagonists) induce apoptosis, decrease cell growth, and proliferation in PC-3, LNCaP and DU-145 cell lines. Similarly, the piperazine based naftopidil induced cell cycle arrest and death in LNCaP-E9 cell lines. In contrast, sulphonamide based tamsulosin did not exhibit these effects. In vivo data was consistent with in vitro findings as the quinazoline based α-antagonists prevented angiogenesis and decreased tumour mass in mice models of PCa. Mechanistically the cytotoxic and antitumor effects of the α-antagonists appear largely independent of α 1-blockade. The proposed targets include: VEGF, EGFR, HER2/Neu, caspase 8/3, topoisomerase 1 and other mitochondrial apoptotic inducing factors. These cytotoxic effects could not be evaluated in human studies as prospective trial data is lacking. However, retrospective studies show a decreased incidence of PCa in males exposed to α-antagonists. As human data evaluating the use of α-antagonists as treatments are lacking; well designed, prospective clinical trials are needed to conclusively demonstrate the anticancer properties of quinazoline based α-antagonists in PCa and other cancers. PMID:27537875

  1. The Role of α1-Adrenoceptor Antagonists in the Treatment of Prostate and Other Cancers

    Directory of Open Access Journals (Sweden)

    Mallory Batty

    2016-08-01

    Full Text Available This review evaluates the role of α-adrenoceptor antagonists as a potential treatment of prostate cancer (PCa. Cochrane, Google Scholar and Pubmed were accessed to retrieve sixty-two articles for analysis. In vitro studies demonstrate that doxazosin, prazosin and terazosin (quinazoline α-antagonists induce apoptosis, decrease cell growth, and proliferation in PC-3, LNCaP and DU-145 cell lines. Similarly, the piperazine based naftopidil induced cell cycle arrest and death in LNCaP-E9 cell lines. In contrast, sulphonamide based tamsulosin did not exhibit these effects. In vivo data was consistent with in vitro findings as the quinazoline based α-antagonists prevented angiogenesis and decreased tumour mass in mice models of PCa. Mechanistically the cytotoxic and antitumor effects of the α-antagonists appear largely independent of α 1-blockade. The proposed targets include: VEGF, EGFR, HER2/Neu, caspase 8/3, topoisomerase 1 and other mitochondrial apoptotic inducing factors. These cytotoxic effects could not be evaluated in human studies as prospective trial data is lacking. However, retrospective studies show a decreased incidence of PCa in males exposed to α-antagonists. As human data evaluating the use of α-antagonists as treatments are lacking; well designed, prospective clinical trials are needed to conclusively demonstrate the anticancer properties of quinazoline based α-antagonists in PCa and other cancers.

  2. Impact of plant species and site on rhizosphere-associated fungi antagonistic to Verticillium dahliae kleb.

    Science.gov (United States)

    Berg, Gabriele; Zachow, Christin; Lottmann, Jana; Götz, Monika; Costa, Rodrigo; Smalla, Kornelia

    2005-08-01

    Fungi with antagonistic activity toward plant pathogens play an essential role in plant growth and health. To analyze the effects of the plant species and the site on the abundance and composition of fungi with antagonistic activity toward Verticillium dahliae, fungi were isolated from oilseed rape and strawberry rhizosphere and bulk soil from three different locations in Germany over two growing seasons. A total of 4,320 microfungi screened for in vitro antagonism toward Verticillium resulted in 911 active isolates. This high proportion of fungi antagonistic toward the pathogen V. dahliae was found for bulk and rhizosphere soil at all sites. A plant- and site-dependent specificity of the composition of antagonistic morphotypes and their genotypic diversity was found. The strawberry rhizosphere was characterized by preferential occurrence of Penicillium and Paecilomyces isolates and low numbers of morphotypes (n = 31) and species (n = 13), while Monographella isolates were most frequently obtained from the rhizosphere of oilseed rape, for which higher numbers of morphotypes (n = 41) and species (n = 17) were found. Trichoderma strains displayed high diversity in all soils, but a high degree of plant specificity was shown by BOX-PCR fingerprints. The diversity of rhizosphere-associated antagonists was lower than that of antagonists in bulk soil, suggesting that some fungi were specifically enriched in each rhizosphere. A broad spectrum of new Verticillium antagonists was identified, and the implications of the data for biocontrol applications are discussed. PMID:16085804

  3. [Distribution and characteristics of soil antagonistic actinomycetes on northern slope of Taibai Mountain, Qinling].

    Science.gov (United States)

    Zhu, Wen-Jie; Xue, Quan-Hong; Cao, Yan-Ru; Xue, Lei; Shen, Guang-Hui; Lai, Hang-Xian

    2011-11-01

    Twelve representative soil samples were collected from different altitudes on the northern slope of Taibai Mountain to study the distribution and characteristics of soil antagonistic actinomyces by using agar block method. There existed a great deal of soil antagonistic actinomyces in the study area. Among the 141 actinomycete strains isolated, 116 strains (82.3%) showed antagonism toward 12 target bacteria or fungi. The antagonistic strains at altitudes 800-1845, 3488, 3655, and 3670 m occupied 73.7% -86.8%, 81.3%, 78.9% and 82.3% of the total, respectively. 42.1% of the strains at altitudes 1200-2300 m and > 3400 m showed strong and broad spectrum antagonistic activity, suggesting that there was a great potential for the isolation of actinomycete strains with strong anti-biotic capability at these altitudes. 24.1% of the antagonistic actinomycetes showed antagonism against Staphyloccocus aureu, and 2.4%, 6.9% and 11.2% of them showed activity toward Verticillium dahliae in cotton, Phytophthora sp. in strawberry and Neonectria radiciccla in ginseng, respectively. This study showed that the soil actinomycete antagonistic potentiality (SAAP) could be used as a quantitative indicator to evaluate the potential of antagonistic actinomycete resources in soil. PMID:22303680

  4. Effect of calmodulin antagonists on the growth and graviresponsiveness of primary roots of maize

    Science.gov (United States)

    Stinemetz, C. L.; Hasenstein, K. H.; Young, L. M.; Evans, M. L.

    1992-01-01

    We examined the effect of calmodulin (CaM) antagonists applied at the root tip on root growth, gravity-induced root curvature, and the movement of calcium across the root tip and auxin (IAA) across the elongation zone of gravistimulated roots. All of the CaM antagonists used in these studies delayed gravity-induced curvature at a concentration (1 micromole) that did not affect root growth. Calmodulin antagonists (> or = 1 micromole) inhibited downward transport of label from 45Ca2+ across the caps of gravistimulated roots relative to the downward transport of 45Ca2+ in gravistimulated roots which were not treated with CaM antagonists. Application of CaM antagonists at the root tip (> or = 1 micromole) also decreased the relative downward movement of label from 3H-IAA applied to the upper side of the elongation zone of gravistimulated roots. In general, tip application of antagonists inhibited neither the upward transport of 45Ca2+ in the root tip nor the upward movement of label from 3H-IAA in the elongation zone of gravistimulated roots. Thus, roots treated with CaM antagonists > or = 1 micromole become less graviresponsive and exhibit reduced or even a reversal of downward polarity of calcium transport across the root tip and IAA transport across the elongation zone. The results indicate that calmodulin-regulated events play a role in root gravitropism.

  5. A general population genetic framework for antagonistic selection that accounts for demography and recurrent mutation.

    Science.gov (United States)

    Connallon, Tim; Clark, Andrew G

    2012-04-01

    Antagonistic selection--where alleles at a locus have opposing effects on male and female fitness ("sexual antagonism") or between components of fitness ("antagonistic pleiotropy")--might play an important role in maintaining population genetic variation and in driving phylogenetic and genomic patterns of sexual dimorphism and life-history evolution. While prior theory has thoroughly characterized the conditions necessary for antagonistic balancing selection to operate, we currently know little about the evolutionary interactions between antagonistic selection, recurrent mutation, and genetic drift, which should collectively shape empirical patterns of genetic variation. To fill this void, we developed and analyzed a series of population genetic models that simultaneously incorporate these processes. Our models identify two general properties of antagonistically selected loci. First, antagonistic selection inflates heterozygosity and fitness variance across a broad parameter range--a result that applies to alleles maintained by balancing selection and by recurrent mutation. Second, effective population size and genetic drift profoundly affect the statistical frequency distributions of antagonistically selected alleles. The "efficacy" of antagonistic selection (i.e., its tendency to dominate over genetic drift) is extremely weak relative to classical models, such as directional selection and overdominance. Alleles meeting traditional criteria for strong selection (N(e)s > 1, where N(e) is the effective population size, and s is a selection coefficient for a given sex or fitness component) may nevertheless evolve as if neutral. The effects of mutation and demography may generate population differences in overall levels of antagonistic fitness variation, as well as molecular population genetic signatures of balancing selection. PMID:22298707

  6. Drug: D01182 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D01182 Drug Alprenolol hydrochloride (JP16/USAN); Regletin (TN) C15H23NO2. HCl 285....1496 285.8096 D01182.gif Anti-adrenergic [beta-receptor] Therapeutic category: 2123 ATC code: C07AA01 beta1-adr...energic receptor antagonist [HSA:153] [KO:K04141]; beta2-adrenergic receptor antagonist [HSA:154] [KO:K04142]; beta3-adr...+155) Calcium signaling pathway hsa04080(153+154+155) Neuroactive ligand-receptor interaction hsa04261(153+154) Adr...] map07037 Antiarrhythmic drugs map07214 beta-Adrenergic receptor agonists/antago

  7. Orexin receptor antagonists as therapeutic agents for insomnia

    Directory of Open Access Journals (Sweden)

    Ana Clementina Equihua

    2013-12-01

    Full Text Available Insomnia is a common clinical condition characterized by difficulty initiating or maintaining sleep, or non-restorative sleep with impairment of daytime functioning.Currently, treatment for insomnia involves a combination of cognitive behavioral therapy and pharmacological therapy. Among pharmacological interventions, the most evidence exists for benzodiazepine receptor agonist drugs (GABAA receptor, although concerns persist regarding their safety and their limited efficacy. The use of these hypnotic medications must be carefully monitored for adverse effects.Orexin (hypocretin neuropeptides have been shown to regulate transitions between wakefulness and sleep by promoting cholinergic/monoaminergic neural pathways. This has led to the development of a new class of pharmacological agents that antagonize the physiological effects of orexin. The development of these agents may lead to novel therapies for insomnia without the side effect profile of hypnotics (e.g. impaired cognition, disturbed arousal, and motor balance difficulties. However, antagonizing a system that regulates the sleep-wake cycle may create an entirely different side effect profile. In this review, we discuss the role of orexin and its receptors on the sleep-wake cycle and that of orexin antagonists in the treatment of insomnia.

  8. Chromatographic resolution of angiotensin II receptor antagonists (sartans).

    Science.gov (United States)

    Tahir, Muhammad Saqlain; Adnan, Ahmad; Syed, Quratulain

    2016-08-01

    First time a simple, sensitive and unified quantification method has been developed to analyze the complete class of angiotensin II receptor antagonists which are used in the treatment of hypertension either alone or in combination with some other drugs. The most important advantage of developed method was that the eight separate drugs can be determined on a single chromatographic system without modifications in detection wavelength and mobile phase. The drugs were separated on a Purospher Star 4.6mm×25cm, 5μm, C18 column maintained at 40°C with 1mLmin(-1) flow rate using ultra violet detection at 254nm. Good separation (Rs>2.0) was achieved in a short analysis allowing simultaneous determination of all eight sartans. The effect of variation in flow rate, detection wavelength and column oven temperature was also studied. The proposed method was statistically validated in terms of precision, accuracy, linearity, specificity and robustness. The newly developed method proved to be specific, robust and accurate for the quantification of eight sartans in commercial pharmaceutical formulations. PMID:27258943

  9. Blockade of smoking satisfaction using the peripheral nicotinic antagonist trimethaphan.

    Science.gov (United States)

    Rose, J E; Westman, E C; Behm, F M; Johnson, M P; Goldberg, J S

    1999-01-01

    The present study was conducted to investigate the role of peripheral nicotinic receptors in mediating the rewarding effects of cigarette smoking. Twelve cigarette smokers rated cigarettes after intravenous infusion of the short-acting peripheral nicotinic receptor antagonist trimethaphan and after placebo (saline) infusions. Subjects were blinded to the infusion and cigarette conditions. Cigarette conditions included subjects' usual brand of cigarette, denicotinized tobacco cigarettes, and nicotine-injected cigarettes that had a tar delivery equal to that of the denicotinized cigarettes but with an enhanced nicotine delivery equal to that of subjects' usual brands. The latter cigarettes were rated as extremely harsh due to the high nicotine/tar ratio. Trimethaphan significantly attenuated the airway sensations associated with nicotine, and eliminated the difference in smoking satisfaction between the usual brand of cigarette and the other two cigarettes. These findings suggest that nicotinic receptors on peripheral nerve endings in the respiratory tract modulate smoking satisfaction and may be important in the maintenance of cigarette addiction. PMID:9972860

  10. Competitive binding of antagonistic peptides fine-tunes stomatal patterning.

    Science.gov (United States)

    Lee, Jin Suk; Hnilova, Marketa; Maes, Michal; Lin, Ya-Chen Lisa; Putarjunan, Aarthi; Han, Soon-Ki; Avila, Julian; Torii, Keiko U

    2015-06-25

    During development, cells interpret complex and often conflicting signals to make optimal decisions. Plant stomata, the cellular interface between a plant and the atmosphere, develop according to positional cues, which include a family of secreted peptides called epidermal patterning factors (EPFs). How these signalling peptides orchestrate pattern formation at a molecular level remains unclear. Here we report in Arabidopsis that Stomagen (also called EPF-LIKE9) peptide, which promotes stomatal development, requires ERECTA (ER)-family receptor kinases and interferes with the inhibition of stomatal development by the EPIDERMAL PATTERNING FACTOR 2 (EPF2)-ER module. Both EPF2 and Stomagen directly bind to ER and its co-receptor TOO MANY MOUTHS. Stomagen peptide competitively replaced EPF2 binding to ER. Furthermore, application of EPF2, but not Stomagen, elicited rapid phosphorylation of downstream signalling components in vivo. Our findings demonstrate how a plant receptor agonist and antagonist define inhibitory and inductive cues to fine-tune tissue patterning on the plant epidermis. PMID:26083750

  11. The role of oxytocin antagonists in repeated implantation -failure.

    Science.gov (United States)

    Decleer, W; Osmanagaoglu, K; Devroey, P

    2012-01-01

    A prospective cohort study has been performed to find out if the administration of an oxytocin antagonist (Atosiban) at the occasion of embryo transfer has an effect on the pregnancy rate in patients with repeated failure of implantation. A total of 52 women with repeated failure of implantation after IVF/ICSI were included in this study. The ongoing pregnancy rate (OPR) in the total group of patients was 12 out of 52 (23.1%). Based on embryo quality all cases were categorized in two groups. One with good embryo quality (Group A) and one with poor quality embryos (Group B). Of all patients who became pregnant, 11 belonged to the group of 26 patients with good quality embryos (OPR 42.3 %) and only one to the group of 26 patients with poor quality embryos (OPR 3.8 %). Our results indicate that when good quality embryos can be obtained, the use of Atosiban at the occasion of embryo transfer might offer a significant better implantation rate in women with repeated implantation failure after IVF/ICSI. PMID:24753913

  12. Discovery and Characterization of an Endogenous CXCR4 Antagonist

    Directory of Open Access Journals (Sweden)

    Onofrio Zirafi

    2015-05-01

    Full Text Available CXCL12-CXCR4 signaling controls multiple physiological processes and its dysregulation is associated with cancers and inflammatory diseases. To discover as-yet-unknown endogenous ligands of CXCR4, we screened a blood-derived peptide library for inhibitors of CXCR4-tropic HIV-1 strains. This approach identified a 16 amino acid fragment of serum albumin as an effective and highly specific CXCR4 antagonist. The endogenous peptide, termed EPI-X4, is evolutionarily conserved and generated from the highly abundant albumin precursor by pH-regulated proteases. EPI-X4 forms an unusual lasso-like structure and antagonizes CXCL12-induced tumor cell migration, mobilizes stem cells, and suppresses inflammatory responses in mice. Furthermore, the peptide is abundant in the urine of patients with inflammatory kidney diseases and may serve as a biomarker. Our results identify EPI-X4 as a key regulator of CXCR4 signaling and introduce proteolysis of an abundant precursor protein as an alternative concept for chemokine receptor regulation.

  13. Iontophoretic studies on rat hippocampus with some novel GABA antagonists.

    Science.gov (United States)

    Dalkara, T; Saederup, E; Squires, R F; Krnjevic, K

    1986-08-01

    Twelve substances which appear to be GABA antagonists, judging by their ability to reverse the inhibitory effect of GABA on 35S-TBPS binding to rat brain membranes, were tested iontophoretically on population spikes in the rat hippocampus. Eight of them, including seven which completely reversed the inhibitory action of GABA on 35S-TBPS binding, caused a marked enhancement of population spikes, with slow onset and long duration and they antagonized the inhibition of population spikes by GABA. These effects were similar to those produced by bicuculline. Electrophysiologically, the most potent of the "complete reversers" were bathophenanthroline disulfonate and brucine. In vitro, amoxapine and brucine most effectively reversed the inhibitory action of GABA on 35S-TBPS binding. Of the five substances which only partly reversed the inhibitory effect of GABA on 35S-TBPS binding, four depressed the population spikes and potentiated the inhibitory action of GABA. The fifth "partial reverser", pipazethate, potently increased the population spikes, like the "complete reversers". Although other interpretations are possible the results are consistent with the existence of several GABA-A receptor types in brain, only some of which are blocked by certain partial reversers. PMID:2874465

  14. Sexually antagonistic epigenetic marks that canalize sexually dimorphic development.

    Science.gov (United States)

    Rice, William R; Friberg, Urban; Gavrilets, Sergey

    2016-04-01

    The sexes share the same autosomal genomes, yet sexual dimorphism is common due to sex-specific gene expression. When present, XX and XY karyotypes trigger alternate regulatory cascades that determine sex-specific gene expression profiles. In mammals, secretion of testosterone (T) by the testes during foetal development is the master switch influencing the gene expression pathways (male vs. female) that will be followed, but many genes have sex-specific expression prior to T secretion. Environmental factors, like endocrine disruptors and mimics, can interfere with sexual development. However, sex-specific ontogeny can be canalized by the production of epigenetic marks (epimarks) generated during early ontogeny that increase sensitivity of XY embryos to T and decrease sensitivity of XX embryos. Here, we integrate and synthesize the evidence indicating that canalizing epimarks are produced during early ontogeny. We will also describe the evidence that such epimarks sometimes carry over across generations and produce mosaicism in which some traits are discordant with the gonad. Such carryover epimarks are sexually antagonistic because they benefit the individual in which they were formed (via canalization) but harm opposite-sex offspring when they fail to erase across generations and produce gonad-trait discordances. SA-epimarks have the potential to: i) magnify phenotypic variation for many sexually selected traits, ii) generate overlap along many dimensions of the masculinity/femininity spectrum, and iii) influence medically important gonad-trait discordances like cryptorchidism, hypospadias and idiopathic hirsutism. PMID:26600375

  15. Can paternal leakage maintain sexually antagonistic polymorphism in the cytoplasm?

    Science.gov (United States)

    Kuijper, B; Lane, N; Pomiankowski, A

    2015-02-01

    A growing number of studies in multicellular organisms highlight low or moderate frequencies of paternal transmission of cytoplasmic organelles, including both mitochondria and chloroplasts. It is well established that strict maternal inheritance is selectively blind to cytoplasmic elements that are deleterious to males - 'mother's curse'. But it is not known how sensitive this conclusion is to slight levels of paternal cytoplasmic leakage. We assess the scope for polymorphism when individuals bear multiple cytoplasmic alleles in the presence of paternal leakage, bottlenecks and recurrent mutation. When fitness interactions among cytoplasmic elements within an individual are additive, we find that sexually antagonistic polymorphism is restricted to cases of strong selection on males. However, when fitness interactions among cytoplasmic elements are nonlinear, much more extensive polymorphism can be supported in the cytoplasm. In particular, mitochondrial mutants that have strong beneficial fitness effects in males and weak deleterious fitness effects in females when rare (i.e. 'reverse dominance') are strongly favoured under paternal leakage. We discuss how such epistasis could arise through preferential segregation of mitochondria in sex-specific somatic tissues. Our analysis shows how paternal leakage can dampen the evolution of deleterious male effects associated with predominant maternal inheritance of cytoplasm, potentially explaining why 'mother's curse' is less pervasive than predicted by earlier work. PMID:25653025

  16. Streptomycetes and micromycetes as perspective antagonists of fungal phytopathogens.

    Science.gov (United States)

    Postolaky, O; Syrbu, T; Poiras, N; Baltsat, K; Maslobrod, S; Boortseva, S

    2012-01-01

    Among natural factors that permanently influence on the plants, the soil microorganisms play a special role for the growing of plants as habitants of their rhizosphere. Mainly they are the representatives of actinomycetes genus Streptomyces and fungal genus Penicillium and their metabolic products stimulate plant growth and inhibit the growth of pathogenic fungi and bacteria. The aim of our study was to determine the antagonism of actinomycetes and micromycetes isolated from soils of R. Moldova against the fungal pathogens of agricultural plants. The strains were isolated from 5 types of chernozem (black soil) from central zone of R. Moldova, with different concentration of humus. Most of micromycetes and streptomycetes were isolated from soil sample 1 (monoculture of maize) and soil sample 2 (Poltava road border) with similar humus content (2.4-2.6%). The antifungal activity of micromycetes strains was occurring mostly against Fusarium solani and Thelaviopsis basicola, at streptomycetes against Alternaria alternata and Botrytis cinerea. It was revealed the strains completely inhibit the growth of Alt. alternata (streptomycetes strains 23, 33, 37), B. cinerea (Streptomyces sp. 17), and F. solani (Penicillium sp. 104). Our results allow to consider the actinomycetes Streptomyces sp.9, Streptomyces sp. 12, Streptomyces sp. 17, Streptomyces sp. 37 Streptomyces sp. 66 and micromycetes Penicillium sp. 5, Penicillium sp. 65, Penicillium sp. 104 isolated from soils of R. Moldova, as prospective strains-antagonists against the phytopathogenic fungus, the causative agents of agricultural plants deseasis. PMID:23878981

  17. Cetirizine a histamine H1 receptor antagonist improves viral myocarditis

    Directory of Open Access Journals (Sweden)

    Yamamoto Kanjo

    2010-08-01

    Full Text Available Abstract Background We showed that mast cells played a critical role in the progression of heart failure induced by pressure overload and viral myocarditis in mice. In this study, we investigated the effect of cetirizine, a selective H1 receptor antagonist, on experimental viral myocarditis induced by encephalomyocarditis (EMC virus. Methods Four-week-old inbred male DBA/2 mice were inoculated intraperitoneally with 10 plaque-forming units (pfu of the EMC virus. Cetirizine was administered orally at a dose of 1 or 10 mg/kg per day for the survival study, and 1 mg/kg for the histologic and gene expression studies, beginning on the day of viral inoculation. Results Cetirizine improved survival dose dependently. Heart weight to body weight ratio was significantly decreased in mice treated with cetirizine. The area of myocardial necrosis was significantly smaller in the hearts of mice treated with cetirizine compared with controls. Gene expressions of tumor necrosis factor, interleukin 6, and metalloproteinase 2 were significantly suppressed in the hearts of mice treated with cetirizine. Conclusion These results suggest that cetirizine exerts its beneficial effects on viral myocarditis by suppressing expression of pro-inflammatory cytokines, genes related to cardiac remodeling in the hearts of mice.

  18. Bovine pancreatic polypeptide as an antagonist of muscarinic cholinergic receptors

    International Nuclear Information System (INIS)

    In dispersed acini from rat pancreas, it was found that bovine pancreatic polypeptide (BPP) and its C-fragment hexapeptide amide (PP-6), at concentrations of 0.1 and 30 μM, respectively, could significantly inhibit amylase secretion stimulated by carbachol, and this inhibition by BPP was dose dependent. 45Ca outflux induced by carbachol was also inhibited by BPP or PP-6, but they had no effect on cholecystokinin octapeptide- (CCK-8) or A23187-stimulated 45Ca outflux. BPP was also capable of displacing the specific binding of [3H]-quinuclidinyl benzilate to its receptors, and it possessed a higher affinity (K/sub i/35nM) than carbachol (K/sub i/ 1.8 μM) in binding with M-receptors. It is concluded from this study that BPP acts as an antagonist of muscarinic cholinergic receptors in rat pancreatic acini. In addition, BPP inhibited the potentiation of amylase secretion caused by the combination of carbachol plus secretin or vasoactive intestinal peptide. This may be a possible explanation of the inhibitory effect of BPP on secretin-induced pancreatic enzyme secretion shown in vivo, since pancreatic enzyme secretion stimulated by secretin under experimental conditions may be the result of potentiation of enzyme release produced by the peptide in combination with a cholinergic stimulant

  19. Antagonist effects of calcium on borosilicate glass alteration

    Energy Technology Data Exchange (ETDEWEB)

    Mercado-Depierre, S. [CEA Marcoule, DTCD SPDE LCLT, 30207 Bagnols sur Cèze (France); Angeli, F., E-mail: frederic.angeli@cea.fr [CEA Marcoule, DTCD SPDE LCLT, 30207 Bagnols sur Cèze (France); Frizon, F. [CEA Marcoule, DTCD SECM LP2C, 30207 Bagnols sur Cèze (France); Gin, S. [CEA Marcoule, DTCD SPDE LCLT, 30207 Bagnols sur Cèze (France)

    2013-10-15

    Graphical abstract: Display Omitted -- Highlights: •Kinetic study of glass alteration is investigated in calcium-enriched solutions. •New insights into silicon–calcium interactions in glass/cement systems are proposed. •Glass alteration is controlled by pH, Ca concentration and reaction progress. •Evidence of antagonist effects according to the importance of these parameters. -- Abstract: Numerous studies have been conducted on glass and cement durability in contact with water, but very little work to date has focused directly on interactions between the two materials. These interactions are mostly controlled by silicon–calcium reactivity. However, the physical and chemical processes involved remain insufficiently understood to predict the evolution of coupled glass–cement systems used in several industrial applications. Results are reported from borosilicate glass alteration in calcium-rich solutions. Our data show that four distinct behaviors can be expected according to the relative importance of three key parameters: the pH, the reaction progress (short- or long-term alteration) and the calcium concentration. Glass alteration is thus controlled by specific mechanisms depending on the solution chemistry: calcium complexation at the glass surface, precipitation of calcium silicate hydrates (C–S–H) or calcium incorporation in the altered layer. These findings highlight the impact of silicon–calcium interactions on glass durability and open the way for a better understanding of glass–cement mixing in civil engineering applications as well as in nuclear waste storage.

  20. Inhibition of radiation-induced polyuria by histamine receptor antagonists

    International Nuclear Information System (INIS)

    In previous studies the authors have demonstrated that gamma radiation results in polyuria, which is preceded by polydypsia. This suggests that the increased thirst elicited by radiation causes increased urinary volume (UV). Histamine, which is released following radiation exposure, also elicits drinking by nonirradiated rats when administered exogenously. In this study the authors have investigated both the role of water deprivation and the effect of histamine receptor antagonists (HRA) on radiation-induced polyuria. Sprague-Dawley rats were housed individually in metabolic cages. Water was allowed ad libitum except in deprivation experiments where water was removed for 24 hr immediately following radiation. Cimetidine (CIM), an H2 HRA, and dexbromopheniramine (DXB), an H1 HRA, were administered i.p. (16 and 1 mg/kg, respectively) 30 min prior to irradiation (950 rads from a cobalt source). UV was determined at 24-hr intervals for 3 days preceding irradiation and 24 hr postirradiation. UV in DXB treated rats was significantly reduced 24 hr postirradiation (CON = 427 +/- 54%; DXB = 247 +/- 39% of preirradiated CON) compared to postirradiation control values. CIM did not affect postirradiation UV. These data suggest that radiation-induced polyuria is caused by polydypsia which is, in part, mediated by histamine induced by an H1 receptor

  1. Angiotensin antagonists in the dog with chronic pericardial tamponade

    International Nuclear Information System (INIS)

    Assessing the role played by angiotensin in the pathogenesis and maintenance of the renal function and perfusion abnormalities dogs with chronic pericardial tamponade were used in the experiment as a stable model of chronic low output heart failure. The heptapeptide and octapeptide antagonist were used. The results of the experiments suggest that there is a role for angiotensin in the pathologenesis of congestive heart failure. The renin-angiotensin system was activated in the model. Plasma renin activity was elevated and increased further in response to angiotensin blockade. Under the experiment condition there was no evidence for a role for angiotensin in the maintenance of arterial blood pressure. But there was angiotensin-mediated renal vasoconstriction and a reduction in renal blood flow. Both analogues of angiotensin were able to antagonize this effect in similar fashion. Failure to achieve a natriuresis in response to angiotensin blockade may reflect the redistribution of blood flow that occured and suggests that additional factors are operative in this model. (APR)

  2. [Management of vitamin K antagonists in the elderly].

    Science.gov (United States)

    Belleville, Tiphaine; Pautas, Éric; Gaussem, Pascale; Siguret, Virginie

    2014-01-01

    Elderly patients of 80 years and above are commonly frail, due to substantial comorbid conditions and numerous medications. Managing elderly patients receiving vitamin K antagonists (VKA) is challenging because those patients are at high risk of both thrombosis and bleeding. Special considerations on the choice of the VKA drug, dosing and monitoring have to be taken into account in the elderly in order to avoid over-anticoagulation and to minimize the haemorrhagic risk which consequences may be dramatic or fatal in this age group. In these patients, INR monitoring is crucial, especially at the start of treatment. The use of dosing algorithms specifically developed for elderly patients allows to decrease over-anticoagulation during the initiation period. INR has to be monitored more frequently in case of acute illness or in case of modification of the associated drugs. Patient information and education are of great importance, even in geriatric patients and has been shown to improve the quality of anticoagulation. Even though the use of direct oral anticoagulants is currently expanding, prescribing VKA in elderly patients in whom the prevalence of severe renal insufficiency remains up to date. PMID:24736138

  3. Antagonistic bioenergies: Technological divergence of the ethanol industry in Brazil

    International Nuclear Information System (INIS)

    We present evidence for the coexistence of two antagonistic sugarcane ethanol production technologies in Brazil, with the Southeast region of the country having relatively mechanized production processes, and the Northeast area using labor-intensive ones. We highlight the main differences between the hand-production and fully automated mechanical manufacturing in the Brazilian ethanol industry and examine the historical, political, and economic factors that induced this regional technology gap that is currently observed. We then construct an environmental model based on a 375-industry interregional input-output system for the Brazilian regions, in order to determine the extent to which the primitive ethanol production of Northern Brazil differs from the automated manufacture technologies of the South in terms of greenhouse gas emissions. We show that ethanol produced with modern technologies generates lower carbon dioxide (CO2) emissions than ethanol produced with traditional production processes. We also demonstrate that ethanol, regardless of the technology with which it was produced, is more carbon-efficient than petrochemical products. - Research Highlights: →The ethanol industry in Brazil exhibits major regional technological differences. →Traditional ethanol production processes are more polluting than mechanized ones. →The lowest carbon-intensity for an ethanol sector is found in the southeast region. →Ethanol explains less than 1% of the land-transport sector's carbon-intensity. →Ethanol is less polluting than natural gas, oil by-products and electricity.

  4. [Antagonistic properties of Lactobacillus plantarum strains, isolated from traditional fermented products of Ukraine].

    Science.gov (United States)

    Vasyliuk, O M; Kovalenko, N K; Harmasheva, I L

    2014-01-01

    The antagonistic activity of 109 lactobacillus strains, isolated from traditional fermented products of Ukraine, has been investigated and it has been shown that the significant part of strains show different levels of inhibition of opportunistic and phytopathogenic microorganisms. It has been shown that the antagonistic effect of Lactobacillus plantarum strains on the opportunistic and phytopathogenic microorganisms was dependent on the sources of Lactobacillus strains isolation. L. plantarum strains show a higher level of inhibition against phytopathogenic microorganisms than opportunistic test-strains. Eleven strains of L. plantarum demonstrated antagonistic activity for all used test-strains. PMID:25007440

  5. Growth Hormone Receptor Antagonist Treatment Reduces Exercise Performance in Young Males

    DEFF Research Database (Denmark)

    Goto, K.; Doessing, S.; Nielsen, R.H.; Flyvbjerg, A.; Kjaer, M.

    2009-01-01

    Context: The effects of GH on exercise performance remain unclear. Objective: The aim of the study was to examine the effects of GH receptor (GHR) antagonist treatment on exercise performance. Design: Subjects were treated with the GHR antagonist pegvisomant or placebo for 16 d. After the treatment...... period, they exercised to determine exercise performance and hormonal and metabolic responses. Participants: Twenty healthy males participated in the study. Intervention: Subjects were treated with the GHR antagonist (n = 10; 10 mg/d) or placebo (n = 10). After the treatment period, they performed a...

  6. The risk of tuberculosis related to tumour necrosis factor antagonist therapies: a TBNET consensus statement

    DEFF Research Database (Denmark)

    Solovic, I; Sester, M; Gomez-Reino, J J;

    2010-01-01

    risk of reactivating latent infections, especially tuberculosis (TB). Following TNF antagonist therapy, the relative risk for TB is increased up to 25 times, depending on the clinical setting and the TNF antagonist used. Interferon-¿ release assays or, as an alternative in individuals without a history...... of bacille Calmette-Guérin vaccination, tuberculin skin testing is recommended to screen all adult candidates for TNF antagonist treatment for the presence of latent infection with Mycobacterium tuberculosis. Moreover, paediatric practice suggests concomitant use of both the tuberculin skin test and...

  7. Antagonist muscle moment is increased in ACL deficient subjects during maximal dynamic knee extension

    DEFF Research Database (Denmark)

    Alkjær, Tine; Simonsen, Erik B; Magnusson, S Peter; Dyhre-Poulsen, Poul; Aagaard, Per

    2012-01-01

    INTRODUCTION: Coactivation of the hamstring muscles during dynamic knee extension may compensate for increased knee joint laxity in anterior cruciate ligament (ACL) deficient subjects. This study examined if antagonist muscle coactivation during maximal dynamic knee extension was elevated in...... subjects with anterior cruciate ligament (ACL) deficiency compared to age-matched healthy controls. METHODS: Electromyography (EMG) and net knee joint moments were recorded during maximal concentric quadriceps and eccentric hamstring contractions, performed in an isokinetic dynamometer (ROM: 90......-10°, angular speed: 30°/s). Hamstring antagonist EMG recorded during concentric quadriceps contraction was converted into antagonist moment based on the EMG-moment relationship observed during eccentric agonist contractions. RESULTS: The magnitude of antagonist hamstring EMG was 65.5% higher in ACL deficient...

  8. Kynurenic acid amides as novel NR2B selective NMDA receptor antagonists.

    Science.gov (United States)

    Borza, István; Kolok, Sándor; Galgóczy, Kornél; Gere, Anikó; Horváth, Csilla; Farkas, Sándor; Greiner, István; Domány, György

    2007-01-15

    A novel series of kynurenic acid amides, ring-enlarged derivatives of indole-2-carboxamides, was prepared and identified as in vivo active NR2B subtype selective NMDA receptor antagonists. The synthesis and SAR studies are discussed. PMID:17074483

  9. A novel antagonistic role of natural compound icariin on neurotoxicity of amyloid β peptide

    Directory of Open Access Journals (Sweden)

    Jianhui Liu

    2015-01-01

    Interpretation & conclusions: The results indicated a novel antagonistic role of icariin in the neurotoxicity of Aβ1-42 via inhibiting its aggregation, suggesting that icariin might have potential therapeutic benefits to delay or modify the progression of AD.

  10. Could antagonists of excitatory amino acid receptors be used as antiepileptics in pediatric epileptology?

    Czech Academy of Sciences Publication Activity Database

    Mareš, Pavel

    2006. s. 76-76. [Eilat conference on new antiepileptic drugs /8./. 10.09.2006-14.09.2006, Sitges] Institutional research plan: CEZ:AV0Z50110509 Keywords : anticonvulsive effect * antagonists * glutamate receptors Subject RIV: ED - Physiology

  11. Update on leukotriene receptor antagonists in preschool children wheezing disorders

    Directory of Open Access Journals (Sweden)

    Montella Silvia

    2012-06-01

    Full Text Available Abstract Asthma is the most common chronic disease in young children. About 40% of all preschool children regularly wheeze during common cold infections. The heterogeneity of wheezing phenotypes early in life and various anatomical and emotional factors unique to young children present significant challenges in the clinical management of this problem. Anti-inflammatory therapy, mainly consisting of inhaled corticosteroids (ICS, is the cornerstone of asthma management. Since Leukotrienes (LTs are chemical mediators of airway inflammation in asthma, the leukotriene receptor antagonists (LTRAs are traditionally used as potent anti-inflammatory drugs in the long-term treatment of asthma in adults, adolescents, and school-age children. In particular, montelukast decreases airway inflammation, and has also a bronchoprotective effect. The main guidelines on asthma management have confirmed the clinical utility of LTRAs in children older than five years. In the present review we describe the most recent advances on the use of LTRAs in the treatment of preschool wheezing disorders. LTRAs are effective in young children with virus-induced wheeze and with multiple-trigger disease. Conflicting data do not allow to reach definitive conclusions on LTRAs efficacy in bronchiolitis or post-bronchiolitis wheeze, and in acute asthma. The excellent safety profile of montelukast and the possibility of oral administration, that entails better compliance from young children, represent the main strengths of its use in preschool children. Montelukast is a valid alternative to ICS especially in poorly compliant preschool children, or in subjects who show adverse effects related to long-term steroid therapy.

  12. Hepcidin antagonists for potential treatments of disorders with hepcidin excess

    Directory of Open Access Journals (Sweden)

    Poli eMaura

    2014-04-01

    Full Text Available The discovery of hepcidin clarified the basic mechanism of the control of systemic iron homeostasis. Hepcidin is mainly produced by the liver as a propeptide and processed by furin into the mature active peptide. Hepcidin binds ferroportin, the only cellular iron exporter, causing the internalization and degradation of both. Thus hepcidin blocks iron export from the key cells for dietary iron absorption (enterocytes, recycling of haemoglobin iron (the macrophages and the release of storage iron from hepatocytes, resulting in the reduction of systemic iron availability. The BMP/HJV/SMAD pathway is the major regulator of hepcidin expression that responds to iron status. Also inflammation stimulates hepcidin via the IL6/STAT3 pathway with a support of an active BMP/HJV/SMAD pathway. In some pathological conditions hepcidin level is inadequately elevated and reduces iron availability in the body, resulting in anemia. These conditions occur in the genetic Iron Refractory Iron Deficiency Anemia (IRIDA and the common Anemia of Chronic Disease (ACD or Anemia of Inflammation. Currently, there is no definite treatment for ACD. Erythropoiesis stimulating agents and intravenous iron have been proposed in some cases but they are scarcely effective and may have adverse effects. Alternative approaches aimed to a pharmacological control of hepcidin expression have been attempted, targeting different regulatory steps. They include hepcidin sequestering agents (antibodies, anticalins and aptamers, inhibitors of BMP/SMAD or of IL6/STAT3 pathway or of hepcidin transduction (siRNA/shRNA or ferroportin stabilizers. In this review we summarized the biochemical interactions of the proteins involved in the BMP/HJV/SMAD pathway and its natural inhibitors, the murine and rat models with high hepcidin levels currently available and finally the progresses in the development of hepcidin antagonists, with particular attention to the role of heparins and heparin sulphate

  13. Endothelin receptor antagonist and airway dysfunction in pulmonary arterial hypertension

    Directory of Open Access Journals (Sweden)

    Borst Mathias M

    2009-12-01

    Full Text Available Abstract Background In idiopathic pulmonary arterial hypertension (IPAH, peripheral airway obstruction is frequent. This is partially attributed to the mediator dysbalance, particularly an excess of endothelin-1 (ET-1, to increased pulmonary vascular and airway tonus and to local inflammation. Bosentan (ET-1 receptor antagonist improves pulmonary hemodynamics, exercise limitation, and disease severity in IPAH. We hypothesized that bosentan might affect airway obstruction. Methods In 32 IPAH-patients (19 female, WHO functional class II (n = 10, III (n = 22; (data presented as mean ± standard deviation pulmonary vascular resistance (11 ± 5 Wood units, lung function, 6 minute walk test (6-MWT; 364 ± 363.7 (range 179.0-627.0 m, systolic pulmonary artery pressure, sPAP, 79 ± 19 mmHg, and NT-proBNP serum levels (1427 ± 2162.7 (range 59.3-10342.0 ng/L were measured at baseline, after 3 and 12 months of oral bosentan (125 mg twice per day. Results and Discussion At baseline, maximal expiratory flow at 50 and 25% vital capacity were reduced to 65 ± 25 and 45 ± 24% predicted. Total lung capacity was 95.6 ± 12.5% predicted and residual volume was 109 ± 21.4% predicted. During 3 and 12 months of treatment, 6-MWT increased by 32 ± 19 and 53 ± 69 m, respectively; p Conclusion This study gives first evidence in IPAH, that during long-term bosentan, improvement of hemodynamics, functional parameters or serum biomarker occur independently from persisting peripheral airway obstruction.

  14. ANTAGONISTIC ACTIVITY OF SERRATIA MARCESCENS AGAINST PYRICULARIA ORYZAE

    Directory of Open Access Journals (Sweden)

    V. JAIGANESH

    2007-08-01

    Full Text Available Rice is an important crop, widely affected by quite a number of diseases that results in higher yield losses. Among the fungal diseases, blast incited by Pyricularia oryzae is a major disease. The biological method of plant disease management seems to be an alternative to chemical fungicides in managing the blast disease. A new bio control agent viz., Serratia marcescens appears to be an ideal agent for the control of P. oryzae, because it produces chitinolytic enzymes which causes degradation of the fungal cell walls, induction of plant defence reaction and certain antifungal low molecular weight molecules. A study was undertaken to investigate the effect of a new bio control agent like S. marcescens against P. oryzae. The talc based formulation of S. marcescens (@ 1.0, 1.5, 2.0 and 2.5 kg/ha was sprayed on old IR 50 rice plants in fields. Out of the six-bio protectants tested, S. marcescens was found very effective against P. oryzae under in vitro conditions. S. marcescens could be isolated from shoots as well as roots emerging from the treated seeds and the plant parts from treated seeds inhibited P. oryzae. The antagonist S. marcescens survived in the phyllosphere even 80 days after spray. The results revealed that rice blast control was achieved by spraying S. marcescens @ 1.0 kg/ha. The increasing dose of talc-based inoculum when applied on foliage increased the phyllosphere population of S. marcescens and controlled rice blast. The maximum disease control was achieved when inoculum was applied at 2.5 kg/ha.

  15. Calcium antagonist properties of the bisbenzylisoquinoline alkaloid cycleanine.

    Science.gov (United States)

    Martínez, J A; Bello, A; Rubio, L L; Rodríguez, C; Galán, L; Caudales, E; Alvarez, J L

    1998-01-01

    The alkaloid cycleanine ([12aR-(12aR,24aR)]-2,3,12a,13,14,15,24,24a-octa hydro-5,6,17,18- tetramethoxy-1,13-dimethyl-8, 11:20,23-dietheno-1H,12H [1,10]dioxacyclooctadecino[2,3,4-ij:11,12,13-i'j']diisoquinolin e) was extracted from the bulbs of Stephania glabra (Roxb) Miers and its effects on cardiac and smooth muscle preparations were studied and compared to those of nifedipine (1,4-dihydro-2, 6-dimethyl-4-(2-nitrophenyl)-3,5-pyridine dicarboxylic acid dimethylesther). Cycleanine inhibited the KCl-induced contraction of rabbit aortic rings with higher potency than nifedipine. IC50s for cycleanine and nifedipine were 0.8 and 7.10(-9) M respectively. Cycleanine had minor effects on the norepinephrine-induced contraction of rabbit aortic rings. Cycleanine and nifedipine also depressed the contraction of rat ventricular preparations but with lower potency (IC50 = 3 and 0.03.10(-6) M respectively). Action potential duration of rat right ventricular strips was decreased by both compounds. L-type Ca-current (ICaL) of single rat ventricular cardiomyocytes was inhibited by cycleanine in a voltage- and frequency-dependent manner. With a higher potency nifedipine inhibited ICaL in a tonic and almost frequency-independent manner. The results suggest that cycleanine can act as a potent vascular selective Ca-antagonist. PMID:9565772

  16. Effects of combining opioids and clinically available NMDA receptor antagonists in the treatment of pain

    OpenAIRE

    Snijdelaar, D.G.

    2005-01-01

    This thesis concerns the effects of combining opioids with clinically available NMDA receptor antagonists in the treatment of acute and chronic pain. There are a number of problems with the use of opioids, such as, the development of tolerance/hyperalgesia, the reduced effectiveness in (central) neuropathic pain, and troublesome adverse effects. These problems might be resolved by the combined use of opioids and clinically available drugs with N-methyl-D-aspartate (NMDA) receptor antagonist p...

  17. Adenosine A1 Receptor Antagonist Versus Montelukast on Airway Reactivity and Inflammation

    OpenAIRE

    Nadeem, Ahmed; Obiefuna, Peter C.M.; Wilson, Constance N.; Mustafa, S. Jamal

    2006-01-01

    Adenosine produces bronchoconstriction in allergic rabbits, primates, and humans by activating adenosine A1 receptors. Previously, it is reported that a high dose of L-97-1, a water-soluble, small molecule adenosine A1 receptor antagonist, blocks early and late allergic responses, and bronchial hyper-responsiveness to histamine in a hyper-responsive rabbit model of allergic asthma. Effects of a lower dose of L-97-1 are compared to montelukast, a cysteinyl leukotriene-1 receptor antagonist on ...

  18. Agonist versus antagonist protocol in induction of ovulation and its outcome

    OpenAIRE

    Prasad Lele; Raju Agarwal; Chuni Selden

    2016-01-01

    Background: Gonadotropin-releasing hormone (GnRH) antagonist produces immediate suppression of gonadotrophins secretion without the initial stimulatory effect of premature luteinizing hormone (LH) .The aim of the study was to compare the agonist and the antagonist protocol in the induction of ovulation. Methods: The study is a comparative study conducted from 01 November 2011 to 31 August 2013. All patients of primary or secondary infertility underwent a baseline transvaginal sonography on...

  19. Competitive dopamine receptor antagonists increase the equiactive cocaine concentration during self-administration

    OpenAIRE

    Norman, Andrew B.; Norman, Mantana K.; Tabet, Michael R.; Tsibulsky, Vladimir L.; Pesce, Amadeo J

    2010-01-01

    Competitive dopamine receptor antagonists increase the rate of cocaine self-administration. As the rate of self-administration at a particular unit dose is determined by the satiety threshold and the elimination half-life (t1/2) of cocaine, we investigated whether dopamine receptor antagonists altered these parameters. The plasma cocaine concentration at the time of each self-administration was constant during a session demonstrating that this satiety threshold concentration represents an equ...

  20. Biological Control of Apple Anthracnose by Paenibacillus polymyxa APEC128, an Antagonistic Rhizobacterium

    OpenAIRE

    Kim, Young Soo; Balaraju, Kotnala; Jeon, Yongho

    2016-01-01

    The present study investigated the suppression of the disease development of anthracnose caused by Colletotrichum gloeosporioides and C. acutatum in harvested apples using an antagonistic rhizobacterium Paenibacillus polymyxa APEC128 (APEC128). Out of 30 bacterial isolates from apple rhizosphere screened for antagonistic activity, the most effective strain was APEC128 as inferred from the size of the inhibition zone. This strain showed a greater growth in brain-heart infusion (BHI) broth comp...

  1. The classification of peripheral 5-HT2-like receptors using tryptamine agonist and antagonist analogues.

    OpenAIRE

    Leff, P.; Martin, G. R.; Morse, J. M.

    1986-01-01

    In a previous study, we attempted to verify the classification of 5-hydroxytryptamine2 (5-HT2) receptors in three vascular tissues, by use of the conventional antagonists, ketanserin, spiperone, methysergide and trazodone. However, it was not possible to conclude homogeneity of the receptor type in the three tissues due to the inconsistent behaviour of these antagonists, in particular, their apparently variable affinities between the tissues. These results led to the reliability of the conven...

  2. The molecular marker of antagonistic genes of biological bacteria against rice sheath blight by RAPD

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    @@Forrty-one isolates of Bacillus amyloliquefaciens were differentiated from 184 G + bacterial strains having genetic similarities over 75%based on BOX-PCR fingerprint. Antagonism against to Rhizotonia solani in vitro was tested.Four isolates of B. arayloliquefaciens (2 isolates with antagonistic ability, G 396 + and G229 +, and 2 isolates without antagonistic ability, G433-and G434-) were selected to screen effective primers for RAPD analysis. Of 124 random primers (AA, AB, AC, AD, AE, AM, and AL) tested.

  3. Inhibition of Flavobacterium psychrophilum biofilm formation using a biofilm of the antagonist Pseudomonas fluorescens FF48

    OpenAIRE

    De la Fuente, Mery; Vidal, José M; Miranda, Claudio D; González, Gerardo; Urrutia, Homero

    2013-01-01

    The most important bacterial pathology currently occurring in Chilean freshwater salmon farming is the cold-water disease produced by the psychrotrophic bacteria Flavobacterium psychrophilum. The main aim of this study was to characterize the inhibitory activity of an antagonist strain on the formation of biofilms of a F. psychrophilum strain. The antagonistic strain Pseudomonas fluorescens FF48 was isolated from the sediment beneath the salmon cages of a freshwater Chilean salmon farm and wa...

  4. Antimüllerian hormone in gonadotropin releasing-hormone antagonist cycles

    DEFF Research Database (Denmark)

    Arce, Joan-Carles; La Marca, Antonio; Mirner Klein, Bjarke;

    2013-01-01

    To assess the relationships between serum antimüllerian hormone (AMH) and ovarian response and treatment outcomes in good-prognosis patients undergoing controlled ovarian stimulation using a gonadotropin-releasing hormone (GnRH) antagonist protocol.......To assess the relationships between serum antimüllerian hormone (AMH) and ovarian response and treatment outcomes in good-prognosis patients undergoing controlled ovarian stimulation using a gonadotropin-releasing hormone (GnRH) antagonist protocol....

  5. The Effect of Sympathetic Antagonists on the Antidepressant Action of Alprazolam

    Directory of Open Access Journals (Sweden)

    Gorash ZM

    2008-01-01

    Full Text Available Alprazolam is an anti-anxiety drug shown to be effective in the treatment of depression. In this study, the effect of sympathetic receptor antagonists on alprazolam–induced antidepressant action was studied using a mouse model of forced swimming behavioral despair. The interaction of three sympathetic receptor antagonists with benzodiazepines, which may impact the clinical use of alprazolam, was also studied. Behavioral despair was examined in six groups of albino mice. Drugs were administered intraperitoneally. The control group received only a single dose of 1% Tween 80. The second group received a single dose of alprazolam, and the third group received an antagonist followed by alprazolam. The fourth group was treated with imipramine, and the fifth group received an antagonist followed by imipramine. The sixth group was treated with a single dose of an antagonist alone (atenolol, a β1-selective adrenoceptor antagonist; propranolol, a non selective β-adrenoceptor antagonist; and prazocin, an α1-adrenoceptor antagonist. Results confirmed the antidepressant action of alprazolam and imipramine. Prazocin treatment alone produced depression, but it significantly potentiated the antidepressant actions of imipramine and alprazolam. Atenolol alone produced an antidepressant effect and potentiated the antidepressant action of alprazolam. Propranolol treatment alone produced depression, and antagonized the effects of alprazolam and imipramine, even producing depression in combined treatments. In conclusion, our results reveal that alprazolam may produce antidepressant effects through the release of noradrenaline, which stimulates β2 receptors to produce an antidepressant action. Imipramine may act by activating β2 receptors by blocking or down-regulating β1 receptors.

  6. Rigidified 2-aminopyrimidines as histamine H4 receptor antagonists: effects of substitution about the rigidifying ring.

    Science.gov (United States)

    Koenig, John R; Liu, Huaqing; Drizin, Irene; Witte, David G; Carr, Tracy L; Manelli, Arlene M; Milicic, Ivan; Strakhova, Marina I; Miller, Thomas R; Esbenshade, Timothy A; Brioni, Jorge D; Cowart, Marlon

    2010-03-15

    Three novel series of histamine H(4) receptor (H(4)R) antagonists containing the 2-aminopyrimidine motif are reported. The best of these compounds display good in vitro potency in both functional and binding assays. In addition, representative compounds are able to completely block itch responses when dosed ip in a mouse model of H(4)-agonist induced scratching, thus demonstrating their activities as H(4)R antagonists. PMID:20171098

  7. Impact of Plant Species and Site on Rhizosphere-Associated Fungi Antagonistic to Verticillium dahliae Kleb.

    OpenAIRE

    Berg, Gabriele; Zachow, Christin; Lottmann, Jana; Götz, Monika; Costa, Rodrigo; Smalla, Kornelia

    2005-01-01

    Fungi with antagonistic activity toward plant pathogens play an essential role in plant growth and health. To analyze the effects of the plant species and the site on the abundance and composition of fungi with antagonistic activity toward Verticillium dahliae, fungi were isolated from oilseed rape and strawberry rhizosphere and bulk soil from three different locations in Germany over two growing seasons. A total of 4,320 microfungi screened for in vitro antagonism toward Verticillium resulte...

  8. Plant-Dependent Genotypic and Phenotypic Diversity of Antagonistic Rhizobacteria Isolated from Different Verticillium Host Plants

    OpenAIRE

    Berg, Gabriele; Roskot, Nicolle; Steidle, Anette; Eberl, Leo; Zock, Angela; Smalla, Kornelia

    2002-01-01

    To study the effect of plant species on the abundance and diversity of bacterial antagonists, the abundance, the phenotypic diversity, and the genotypic diversity of rhizobacteria isolated from potato, oilseed rape, and strawberry and from bulk soil which showed antagonistic activity towards the soilborne pathogen Verticillium dahliae Kleb. were analyzed. Rhizosphere and soil samples were taken five times over two growing seasons in 1998 and 1999 from a randomized field trial. Bacterial isola...

  9. Biological control of chestnut canker, caused by Cryphonectria parasitica, by antagonistic organisms and hypovirulent isolates

    OpenAIRE

    AKILLI, Seçil; KATIRCIOĞLU, Yakup Zekai; MADEN, Salih

    2011-01-01

    Biological control of chestnut blight was investigated by using 3 hypovirulent isolates of Cryphonectria parasitica, 5 Trichoderma sp., 4 Penicillium sp., and 4 Bacillus sp. isolates. Hypovirulent isolates and antagonistic organisms were obtained from samples collected from the Black Sea region of Turkey, in 2008 and 2009. Effectiveness of the hypovirulent isolates and antagonistic microorganisms was tested on 3-year-old chestnut saplings. In the tests, bark disks of 6 mm were removed from th...

  10. Therapeutic potential for cytokine antagonists: Thalidomide and pentoxifylline in Hansen’s disease

    OpenAIRE

    1995-01-01

    Cytokine antagonists are a group of drugs defined by their actions on specific cytokines. Cytokine antagonists can inhibit action of cytokines by acting directly on receptors, by affecting production of cytokines or by binding to cytokines and preventing their subsequent action. Recent evidence suggests that Hansen’s disease, which is characterized by reactional states, is associated with elevated serum levels of tumour necrosis factor-α (tnf-α) and interleukin-1β during these reactional stat...

  11. Nitric oxide (NO) and an NMDA receptor antagonist in pentylenetetrazole-induced convulsions

    OpenAIRE

    Jelenković Ankica V.; Jovanović Marina D.; Ninković Milica; Maksimović Milan; Bošković Bogdan

    2003-01-01

    Controversy about proconvulsant and anticonvulsant nitric oxide (NO) effects and the place of oxidative stress in convulsions, are still a matter of research. We investigated the interaction between 2-amino-5-phosphonovaleric acid (APV), a competitive N-methyl-D-aspartate (NMDA) receptor antagonist and Nw-nitro-L-arginine methyl ester (L-NAME), a nonselective nitric oxide synthase (NOS) antagonist, in pentylenetetrazole (PTZ)-induced convulsions. Pentylenetetrazole was applied to adult Wistar...

  12. Oleoylethanolamide: A Novel Potential Pharmacological Alternative to Cannabinoid Antagonists for the Control of Appetite

    OpenAIRE

    Adele Romano; Roberto Coccurello; Giacomo Giacovazzo; Gaurav Bedse; Anna Moles; Silvana Gaetani

    2014-01-01

    The initial pharmaceutical interest for the endocannabinoid system as a target for antiobesity therapies has been restricted by the severe adverse effects of the CB1 antagonist rimonabant. This study points at oleoylethanolamide (OEA), a monounsaturated analogue, and functional antagonist of anandamide, as a potential and safer antiobesity alternative to CB1 antagonism. Mice treated with equal doses (5 or 10 mg/kg, i.p.) of OEA or rimonabant were analyzed for the progressive expression of spo...

  13. Growth of cultured human glioma tumour cells can be regulated with histamine and histamine antagonists.

    OpenAIRE

    Van der Ven, L. T.; Prinsen, I. M.; Jansen, G H; Roholl, P.J.; Defferrari, R.; Slater, R.; DEN OTTER;, W.

    1993-01-01

    The 50% survival time for low grade astrocytomas is 50 months and for high grade astrocytomas it is 13 months, underlining the need for new therapies. Several reports show that in vivo histamine antagonists cause retardation of tumour growth in some animal models and prolonged survival in cancer patients. Therefore we have tested the growth modulating effects of histamine and histamine antagonists on human glioma cultures. Twelve freshly excised human gliomas were cultured and tested for thei...

  14. Histamine H3 receptor antagonist decreases cue-induced alcohol reinstatement in mice.

    Science.gov (United States)

    Nuutinen, Saara; Mäki, Tiia; Rozov, Stanislav; Bäckström, Pia; Hyytiä, Petri; Piepponen, Petteri; Panula, Pertti

    2016-07-01

    We have earlier found that the histamine H3 receptor (H3R) antagonism diminishes motivational aspects of alcohol reinforcement in mice. Here we studied the role of H3Rs in cue-induced reinstatement of alcohol seeking in C57BL/6J mice using two different H3R antagonists. Systemic administration of H3R antagonists attenuated cue-induced alcohol seeking suggesting that H3R antagonists may reduce alcohol craving. To understand how alcohol affects dopamine and histamine release, a microdialysis study was performed on C57BL/6J mice and the levels of histamine, dopamine and dopamine metabolites were measured in the nucleus accumbens. Alcohol administration was combined with an H3R antagonist pretreatment to reveal whether modulation of H3R affects the effects of alcohol on neurotransmitter release. Alcohol significantly increased the release of dopamine in the nucleus accumbens but did not affect histamine release. Pretreatment with H3R antagonist ciproxifan did not modify the effect of alcohol on dopamine release. However, histamine release was markedly increased with ciproxifan. In conclusion, our findings demonstrate that H3R antagonism attenuates cue-induced reinstatement of alcohol seeking in mice. Alcohol alone does not affect histamine release in the nucleus accumbens but H3R antagonist instead increases histamine release significantly suggesting that the mechanism by which H3R antagonist inhibits alcohol seeking found in the present study and the decreased alcohol reinforcement, reward and consumption found earlier might include alterations in the histaminergic neurotransmission in the nucleus accumbens. These findings imply that selective antagonists of H3Rs could be a therapeutic strategy to prevent relapse and possibly diminish craving to alcohol use. This article is part of the Special Issue entitled 'Histamine Receptors'. PMID:26107118

  15. Molecular Gymnastics: Mechanisms of HIV-1 Resistance to CCR5 Antagonists and Impact on Virus Phenotypes.

    Science.gov (United States)

    Roche, Michael; Borm, Katharina; Flynn, Jacqueline K; Lewin, Sharon R; Churchill, Melissa J; Gorry, Paul R

    2016-01-01

    Human immunodeficiency virus type 1 (HIV-1) enters host cells through the binding of its envelope glycoproteins (Env) to the host cell receptor CD4 and then subsequent binding to a chemokine coreceptor, either CCR5 or CXCR4. CCR5 antagonists are a relatively recent class addition to the armamentarium of anti-HIV-1 drugs. These compounds act by binding to a hydrophobic pocket formed by the transmembrane helices of CCR5 and altering the conformation of the extracellular domains, such that they are no longer recognized by Env. Maraviroc is the first drug within this class to be licenced for use in HIV-1 therapy regimens. HIV resistance to CCR5 antagonists occurs either through outgrowth of pre-existing CXCR4-using viruses, or through acquisition of the ability of CCR5-using HIV-1 to use the antagonist bound form of CCR5. In the latter scenario, the mechanism underlying resistance is through complex alterations in the way that resistant Envs engage CCR5. These significant changes are unlikely to occur without consequence to the viral entry phenotype and may also open up new avenues to target CCR5 antagonist resistant viruses. This review discusses the mechanism of action of CCR5 antagonists, how HIV resistance to CCR5 antagonists occurs, and the subsequent effects on Env function. PMID:26324043

  16. Management of Fusarium Head Blight of Wheat and Deoxynivalenol Accumulation Using Antagonistic Microorganisms

    Directory of Open Access Journals (Sweden)

    G.M. Riungu

    2008-01-01

    Full Text Available Laboratory and green house studies were conducted at the Faculty of Agriculture, University of Nairobi, to evaluate the efficacy of Epicoccum sp., Alternaria sp., Trichoderma sp. and Bacillus sp. in control of Fusarium head blight of wheat caused by F. graminearum. Fungicides folicur® and copper oxychloride were used as standard checks. Laboratory assay was carried out by paired cultures and antagonism was measured as reduction in pathogen colony diameter. Green house experiments involved dual inoculation of pathogen and antagonist onto wheat ears and head blight severity and grain yield determined. Doxynivalenol content in the resulting grain was determined by competitive direct ELISA. The antagonists and fungicides significantly reduced the growth of Fusarium graminearum colonies in culture. Folicur® and copper oxychloride completely inhibited the growth of the pathogen while Trichoderma sp. showed 64% colony growth reduction. However, the antagonists showed limited reduction in head blight severity in green house trials. Trichoderma sp. reduced head blight severity by 18% while folicur® reduced the disease by 28%. All the antagonists had little or no significant effect on grain yield. Only folicur®, copper oxychloride and Alternaria sp. reduced DON in grain by 76 to 93%. Obtained results indicate that microbial antagonists may offer potential benefit in FHB management and screening of more antagonists both under controlled and field conditions is necessary.

  17. Effects of certain muscarinic antagonists on the actions of anticholinesterases on cat skeletal muscle.

    Science.gov (United States)

    Brimblecombe, R W; French, M C; Webb, S N

    1979-04-01

    1. The effects of some muscarinic antagonists, namely, N-ethyl-2-pyrrolidylmethyl-cyclopentylphenyl glycollate (PMCG), N-methyl-4-piperidyl-phenylcyclohexyl glycollate (PPCG, racemate and R and S enantiomers) and 4'-N-methyl-piperidyl-1-phenyl-cyclopentane carboxylate (G3063) on organophosphate (sarin, soman)- and carbamate (neostigmine)-induced twitch augmentation have been studied in cat soleus muscle. 2. The results of a preliminary study comparing the potency of sarin and soman in inhibiting the acetylcholinesterase activity of muscle in relation to the effect on the maximal twitch response indicated that there is not a simple relationship between degree of enzyme inhibition by these drugs and alteration of muscle function. 3. The muscarinic antagonists studied were capable of preventing or reversing sarin-, soman- or neostigmine-induced twitch augmentation. Doses sufficient to give complete protection from the effects of the anticholinesterase agents had little or no effect on the twitch response of normal muscle. 4. The protective action of these muscarinic antagonists is dose-dependent but independent of known antagonist actions at muscarinic receptors. 5. The effects of some local anaesthetics (lignocaine, prilocaine, cinchocaine, procaine) and other membrane stabilizers (quinine, ketamine, chlorpromazine, triflupromazine) were compared with those of the muscarinic antagonists in an attempt to elucidate the mode of action of these acetylcholine antagonists. The evidence is insufficient to exclude the involvement of a membrane stabilizing action. PMID:435681

  18. The effect of H 1 and H 2 receptor antagonists on melanogenesis

    Directory of Open Access Journals (Sweden)

    Tag S Anbar

    2012-01-01

    Full Text Available Background: Histamine was found to stimulate melanogenesis in cultured human melanocytes specifically mediated by histamine H 2 receptors via protein kinase A activation. Based on this finding, the effect of topically applied H 2 antagonist on UVB-irradiated Guinea pigs′ skin was examined and found to be suppressive on the post-irradiation melanogenesis. Aims: In this study, we tried to explore the role of topically applied H 1 and H 2 receptor antagonists, in inhibition of UVB-induced melanization. Methods: The effect of topically applied H 1 and H 2 receptor antagonists in inhibition of melanization was done clinically and histochemically using Fontana Masson and DOPA reactions compared with placebo. Results: The post-irradiation pigmentation was found to be brownish/black instead of the original light brown color. This color change occurred below the shaved orange-red fur suggesting a switch of melanogenesis from pheomelanin to eumelanin. The induced pigmentation was suppressed by topically applied H 2 antagonist while both H 1 antagonist and vehicle had no effect. The microscopic examination showed that the keratinocytes in the H 2 antagonist-treated areas contained few melanosomes while the nearby dendrites are full of them. Conclusion: H 2 antagonists′ inhibition of UVB-induced pigmentation is not only due to suppression of melanization but also due to a specific action on melanosomes′ transfer.

  19. Analyzing the antagonistic potential of the lichen microbiome against pathogens by bridging metagenomic with culture studies

    Directory of Open Access Journals (Sweden)

    Tomislav eCernava

    2015-06-01

    Full Text Available Naturally occurring antagonists towards pathogens play an important role to avoid pathogen outbreaks in ecosystems, and they can be applied as biocontrol agents for crops. Lichens present long-living symbiotic systems continuously exposed to pathogens. To analyze the antagonistic potential in lichens, we studied the bacterial community active against model bacteria and fungi by an integrative approach combining isolate screening, omics techniques and high resolution mass spectrometry. The highly diverse microbiome of the lung lichen (Lobaria pulmonaria (L. Hoffm. included an abundant antagonistic community dominated by Stenotrophomonas, Pseudomonas and Burkholderia. While antagonists represent 24.5% of the isolates, they were identified with only 7% in the metagenome; which means that they were overrepresented in the culturable fraction. Isolates of the dominant antagonistic genus Stenotrophomonas produced spermidine as main bioactive component. Moreover, spermidine-related genes, especially for the transport, were identified in the metagenome. The majority of hits identified belonged to Alphaproteobacteria, while Stenotrophomonas-specific spermidine synthases were not present in the dataset. Evidence for plant growth promoting effects was found for lichen-associated strains of Stenotrophomonas. Linking of metagenomic and culture data was possible but showed partly contradictory results, which required a comparative assessment. However, we have shown that lichens are important reservoirs for antagonistic bacteria, which open broad possibilities for biotechnological applications.

  20. Analyzing the antagonistic potential of the lichen microbiome against pathogens by bridging metagenomic with culture studies.

    Science.gov (United States)

    Cernava, Tomislav; Müller, Henry; Aschenbrenner, Ines A; Grube, Martin; Berg, Gabriele

    2015-01-01

    Naturally occurring antagonists toward pathogens play an important role to avoid pathogen outbreaks in ecosystems, and they can be applied as biocontrol agents for crops. Lichens present long-living symbiotic systems continuously exposed to pathogens. To analyze the antagonistic potential in lichens, we studied the bacterial community active against model bacteria and fungi by an integrative approach combining isolate screening, omics techniques, and high resolution mass spectrometry. The highly diverse microbiome of the lung lichen [Lobaria pulmonaria (L.) Hoffm.] included an abundant antagonistic community dominated by Stenotrophomonas, Pseudomonas, and Burkholderia. While antagonists represent 24.5% of the isolates, they were identified with only 7% in the metagenome; which means that they were overrepresented in the culturable fraction. Isolates of the dominant antagonistic genus Stenotrophomonas produced spermidine as main bioactive component. Moreover, spermidine-related genes, especially for the transport, were identified in the metagenome. The majority of hits identified belonged to Alphaproteobacteria, while Stenotrophomonas-specific spermidine synthases were not present in the dataset. Evidence for plant growth promoting effects was found for lichen-associated strains of Stenotrophomonas. Linking of metagenomic and culture data was possible but showed partly contradictory results, which required a comparative assessment. However, we have shown that lichens are important reservoirs for antagonistic bacteria, which open broad possibilities for biotechnological applications. PMID:26157431

  1. Isolation and Characterisation of Antagonistic Actinobacteria from Mangrove Soil

    Directory of Open Access Journals (Sweden)

    Venkata Raghava Rao

    2012-04-01

    Full Text Available 1024x768 The aim of the present study was to isolate and screen actinobacteria having antagonistic activities against pathogenic microorganisms. A total of twenty actinobacteria strains were isolated from the mangrove sediment. Of these four active isolates were identified as Streptomyces species by means of morphological, physiological, biochemical and cultural characteristics. These isolates were subjected to shake flask fermentation and the secondary metabolites were extracted with ethyl acetate and screened for their antimicrobial activities against selected bacterial and fungal pathogens. The results showed that among the active isolates, four isolates (BC 01, BC 02, BC 03 and BC 04 showed promising activities against the selected test pathogens. These four extracted isolates were analyzed for UV Spectrophotometric and HPLC. Spectral data of the extracted compound revealed its antimicrobial nature. The UV spectrum of the methanol extracts for the active isolates showed absorbance peaks ranging between 207-223 nm. Two to three bioactive regions were detected on the HPLC. The results indicate that Streptomyces strains isolated from mangrove sediment produce potential antibacterial, antifungal and broad spectrum antibiotic compounds. Normal 0 false false false EN-US X-NONE X-NONE /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-qformat:yes; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Calibri","sans-serif"; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"Times New Roman"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi;}

  2. Penicillium expansum versus antagonist yeasts and patulin degradation in vitro

    Directory of Open Access Journals (Sweden)

    Alexandre Rodrigo Coelho

    2007-07-01

    Full Text Available Taking into account the preliminary antagonistic/biodegradation property showed by Pichia membranifaciens and Sporobolomyces roseus, which decreased the initial patulin concentration of 588.4 to 290.0 µg/mL, ability of P. ohmeri 158 in biocontrol against Penicillium expansum and patulin decrease in vitro was performed. The culture supernatant of P. ohmeri 158 was effective against 66.17% micelial growth, indicating antibiosis related with the killer phenomenon. The initial patulin concentration of 223 µg in the presence of P. ohmeri 158 cells was decreased over 83% of the original concentration, when incubated at 25ºC/2 days and > 99% after 5 days incubation time, with undetectable patulin level after 15 days. The initial pH 4.0 decreased to pH 3.3 along 15 days experiment, suggesting that patulin decrease was an active process and a consequence of yeast metabolism. The results suggested that P. ohmeri 158 could be a promising alternative for the inhibition of P. expansum growth and patulin degradation.Considerando o antagonismo e degradação de patulina detectados em Pichia membranifaciens e Sporobolomyces roseus no estudo preliminar, este trabalho avaliou o efeito antagônico de Pichia ohmeri 158 no desenvolvimento de Penicillium expansum e a degradação de patulina "in vitro". O sobrenadante do cultivo de P. ohmeri 158 inibiu 66,17% do desenvolvimento micelial, indicando antibiose relacionada ao fator killer. A concentração inicial de patulina (223 µg na presença de células íntegras de P. ohmeri foi reduzida em mais de 83% após dois dias de incubação a 25ºC e superior a 99% após 5 dias, com níveis indetectáveis no 15º dia. O decréscimo do pH 4,0 inicial para pH 3,3 sugeriu que a eliminação de patulina é um processo ativo e uma conseqüência do metabolismo da levedura. Os resultados obtidos concluem que P. ohmeri 158 é uma alternativa promissora na inibição do desenvolvimento de P. expansum e na degradação de

  3. Cloning and analysis of the antagonistic related genes of Enterobacter cloacae B8

    Institute of Scientific and Technical Information of China (English)

    YU Xuping; ZHU Junli; YAO Xunping; HE Shicheng; HUANG Haining; CHEN Weiliang; LI Debao

    2004-01-01

    To understand the antagonistic mechanism of the broad spectrum antagonistic Enterobacter cloacae B8,Tn5 transposon-mediated mutagenesis is performed using suicide plasmid pZJ25. Two mutant strains that lost antagonistic character are isolated. Tagging with kanr gene on Tn5,an antagonistic related DNA fragment, the F fragment, right of the Tn5 insertion site is cloned in a plasmid named pTLF,from one of the mutant strains B8F. The 735 bp F fragment is then sequenced after subcloning. Genomic DNA of the original B8 strain is isolated, digested with Pst I and ligated to Pst I cassette. DNA fragments left and right of the F fragment are amplified from the Pst I cassette library using cassette primer and specific primers designed according to known sequence. 1106 bp sequence left of the F fragment and 664bp sequence right of the F fragment are finally obtained. Bioinformatics analysis shows that the contig assembled from the sequences of the cloned antagonistic related DNA fragments of B8 encodes three ORFs and is homogeneous to admM,admN and admO genes of Pantoea agglomerans andrimid biosynthetic gene cluster (AY192157). The ORF, named anrF gene which encodes a polyketide synthase, knocked out by Tn5 insertion, is a homology of admM and the insertion site of Tn5 is at 214 bp upstream of the stop codon. It is concluded that the anrF gene is a gene related to the antagonistic activity of E. cloacae B8, and speculated that the antagonistic substance produced by B8 is an andrimid.

  4. Plant-dependent genotypic and phenotypic diversity of antagonistic rhizobacteria isolated from different Verticillium host plants.

    Science.gov (United States)

    Berg, Gabriele; Roskot, Nicolle; Steidle, Anette; Eberl, Leo; Zock, Angela; Smalla, Kornelia

    2002-07-01

    To study the effect of plant species on the abundance and diversity of bacterial antagonists, the abundance, the phenotypic diversity, and the genotypic diversity of rhizobacteria isolated from potato, oilseed rape, and strawberry and from bulk soil which showed antagonistic activity towards the soilborne pathogen Verticillium dahliae Kleb. were analyzed. Rhizosphere and soil samples were taken five times over two growing seasons in 1998 and 1999 from a randomized field trial. Bacterial isolates were obtained after plating on R2A (Difco, Detroit, Mich.) or enrichment in microtiter plates containing high-molecular-weight substrates followed by plating on R2A. A total of 5,854 bacteria isolated from the rhizosphere of strawberry, potato, or oilseed rape or bulk soil from fallow were screened by dual testing for in vitro antagonism towards VERTICILLIUM: The proportion of isolates with antagonistic activity was highest for strawberry rhizosphere (9.5%), followed by oilseed rape (6.3%), potato (3.7%), and soil (3.3%). The 331 Verticillium antagonists were identified by their fatty acid methyl ester profiles. They were characterized by testing their in vitro antagonism against other pathogenic fungi; their glucanolytic, chitinolytic, and proteolytic activities; and their BOX-PCR fingerprints. The abundance and composition of Verticillium antagonists was plant species dependent. A rather high proportion of antagonists from the strawberry rhizosphere was identified as Pseudomonas putida B (69%), while antagonists belonging to the Enterobacteriaceae (Serratia spp., Pantoea agglomerans) were mainly isolated from the rhizosphere of oilseed rape. For P. putida A and B plant-specific genotypes were observed, suggesting that these bacteria were specifically enriched in each rhizosphere. PMID:12089011

  5. The intricate relationship between sexually antagonistic selection and the evolution of sex chromosome fusions.

    Science.gov (United States)

    Matsumoto, Tomotaka; Kitano, Jun

    2016-09-01

    Sex chromosomes are among the most evolutionarily labile features in some groups of animals. One of the mechanisms causing structural changes of sex chromosomes is fusion with an autosome. A recent study showed that the establishment rates of Y chromosome-autosome fusions are much higher than those of other fusions (i.e., X-autosome, W-autosome, and Z-autosome fusions) in fishes and reptiles. Although sexually antagonistic selection may be one of the most important driving forces of sex chromosome-autosome fusions, a previous theoretical analysis showed that sexually antagonistic selection alone cannot explain the excess of Y-autosome fusions in these taxa. This previous analysis, however, is based on the assumption that sexually antagonistic selection is symmetric, sexually antagonistic alleles are maintained only by selection-drift balance (i.e., no supply of mutation), and only one type of fusion arises within a population. Here, we removed these assumptions and made an individual-based model to simulate the establishment of sex chromosome-autosome fusions. Our simulations showed that the highest establishment rate of Y-autosome fusion can be achieved when the fusion captures a rare male-beneficial allele, if the recurrent mutation rates are high enough to maintain the polymorphism of alleles with asymmetric, sexually antagonistic effects. Our results demonstrate that sexually antagonistic selection can influence the dynamics of sex chromosome structural changes, but the type of fusion that becomes the most common depends on fusion rates, recurrent mutation rates, and selection regimes. Because the evolutionary fate of sex chromosome-autosome fusions is highly parameter-sensitive, further attempts to empirically measure these parameters in natural populations are essential for a better understanding of the roles of sexually antagonistic selection in sex chromosome evolution. PMID:27259387

  6. Inhibition of rabbit platelet activation in vitro by antagonists of platelet-activating factor (PAF)

    International Nuclear Information System (INIS)

    The authors used washed, [3H]serotonin-labeled rabbit platelets to study the in vitro aggregation and secretion responses induced by graded doses of PAF in the presence or absence of specific antagonists of PAF. These antagonists included CV-3988, L-652,731, triazolam and alprazolam. Platelets were pretreated with either an antagonist or the appropriate diluent for 60 sec prior to the addition of PAF (2 x 10-10 to 2 x 10-7 M). Aggregation was monitored continuously and recorded as the height of the aggregation tracing at 60 sec post-PAF. Secretion of [3H]-serotonin was measured in a sample of the platelets removed at 60 sec post-PAF. When 2 x 10-10 M PAF was used as the stimulus, the concentration of antagonist needed for 50% inhibition (IC50) of secretion was obtained at 0.05 μM, 0.15 μM, 0.6 μM and 2.5 μM, respectively, for L-652,731, CV-3988, triazolam and alprazolam. The corresponding IC50 for aggregation was obtained at 0.2 μM, 0.1 μM, 1.5 μM and 6.5 μM, respectively. The inhibitory effects of these antagonists could be overcome by increasing the dose of PAF used. Although all of the antagonists were capable of completely inhibiting platelet aggregation and secretion, L-652,731 was the most potent PAF antagonist on a molar basis

  7. Orexin 1 receptor antagonists in compulsive behaviour and anxiety: possible therapeutic use.

    Directory of Open Access Journals (Sweden)

    Emilio eMerlo-Pich

    2014-02-01

    Full Text Available Fifteen years after the discovery of hypocretin/orexin a large body of evidence has been collected supporting its critical role in the modulation of several regulatory physiological functions. While reduced levels of hypocretin/orexin were early on associated with narcolepsy, increased levels have been linked in recent years to pathological states of hypervigilance and, in particular, to insomnia. The filing to FDA of the dual-activity orexin receptor antagonist (DORA suvorexant for the indication of insomnia further corroborates the robustness of such evidences. However, as excessive vigilance is also typical of anxiety and panic episodes, as well as of abstinence and craving in substance misuse disorders, in this review we briefly discuss the evidence supporting the development of hypocretin/orexin receptor 1 (OX1 antagonists for these indications. Experiments using the OX1 antagonist SB-334867 and mutant mice have involved the OX1 receptor in mediating the compulsive reinstatement of drug seeking for ethanol, nicotine, cocaine, cannabinoids and morphine. More recently, data have been generated with the novel selective OX1 antagonists GSK1059865 and ACT-335827 on behavioural and cardiovascular response to stressors and panic-inducing agents in animals. Concluding, while waiting for pharmacologic data to become available in humans, risks and benefits for the development of an OX1 receptor antagonist for Binge Eating and Anxiety Disorders are discussed.

  8. 5-HT2B Receptor Antagonists Inhibit Fibrosis and Protect from RV Heart Failure

    Directory of Open Access Journals (Sweden)

    Wiebke Janssen

    2015-01-01

    Full Text Available Objective. The serotonin (5-HT pathway was shown to play a role in pulmonary hypertension (PH, but its functions in right ventricular failure (RVF remain poorly understood. The aim of the current study was to investigate the effects of Terguride (5-HT2A and 2B receptor antagonist or SB204741 (5-HT2B receptor antagonist on right heart function and structure upon pulmonary artery banding (PAB in mice. Methods. Seven days after PAB, mice were treated for 14 days with Terguride (0.2 mg/kg bid or SB204741 (5 mg/kg day. Right heart function and remodeling were assessed by right heart catheterization, magnetic resonance imaging (MRI, and histomorphometric methods. Total secreted collagen content was determined in mouse cardiac fibroblasts isolated from RV tissues. Results. Chronic treatment with Terguride or SB204741 reduced right ventricular fibrosis and showed improved heart function in mice after PAB. Moreover, 5-HT2B receptor antagonists diminished TGF-beta1 induced collagen synthesis of RV cardiac fibroblasts in vitro. Conclusion. 5-HT2B receptor antagonists reduce collagen deposition, thereby inhibiting right ventricular fibrosis. Chronic treatment prevented the development and progression of pressure overload-induced RVF in mice. Thus, 5-HT2B receptor antagonists represent a valuable novel therapeutic approach for RVF.

  9. Design and Synthesis of Benzimidazoles As Novel Corticotropin-Releasing Factor 1 Receptor Antagonists.

    Science.gov (United States)

    Mochizuki, Michiyo; Kori, Masakuni; Kobayashi, Katsumi; Yano, Takahiko; Sako, Yuu; Tanaka, Maiko; Kanzaki, Naoyuki; Gyorkos, Albert C; Corrette, Christopher P; Cho, Suk Young; Pratt, Scott A; Aso, Kazuyoshi

    2016-03-24

    Benzazole derivatives with a flexible aryl group bonded through a one-atom linker as a new scaffold for a corticotropin-releasing factor 1 (CRF1) receptor antagonist were designed, synthesized, and evaluated. We expected that structural diversity could be expanded beyond that of reported CRF1 receptor antagonists. In a structure-activity relationship study, 4-chloro-N(2)-(4-chloro-2-methoxy-6-methylphenyl)-1-methyl-N(7),N(7)-dipropyl-1H-benzimidazole-2,7-diamine 29g had the most potent binding activity against a human CRF1 receptor and the antagonistic activity (IC50 = 9.5 and 88 nM, respectively) without concerns regarding cytotoxicity at 30 μM. Potent CRF1 receptor-binding activity in brain in an ex vivo test and suppression of stress-induced activation of the hypothalamus-pituitary-adrenocortical (HPA) axis were also observed at 138 μmol/kg of compound 29g after oral administration in mice. Thus, the newly designed benzimidazole 29g showed in vivo CRF1 receptor antagonistic activity and good brain penetration, indicating that it is a promising lead for CRF1 receptor antagonist drug discovery research. PMID:26901666

  10. Pathophysiology of the cysteinyl leukotrienes and effects of leukotriene receptor antagonists in asthma.

    Science.gov (United States)

    Bisgaard, H

    2001-01-01

    Cysteinyl leukotrienes, synthesized de novo from cell membrane phospholipids, are proinflammatory mediators that play an important role in the pathophysiology of asthma. These mediators are among the most potent of bronchoconstrictors and cause vasodilation, increased microvascular permeability, exudation of macromolecules and edema. The cysteinyl leukotrienes also have potent chemoattractant properties for eosinophils, causing an influx of eosinophils into the airway mucosa, which further fuels the inflammatory process. In addition, the cysteinyl leukotrienes are potent secretagogues and reduce ciliary motility, which may hinder mucociliary clearance. Asthmatic patients demonstrate increased production of cysteinyl leukotrienes during naturally occurring asthma and acute asthma attacks as well as after allergen and exercise challenge. The leukotriene receptor antagonists montelukast, zafirlukast and pranlukast inhibit bronchoconstriction in asthmatic patients undergoing allergen, exercise, cold air or aspirin challenge. They attenuate the hallmarks of asthmatic inflammation, including eosinophilia in the airway mucosa and peripheral blood. Moreover, exhaled nitric oxide concentrations, another correlate of airway inflammation, are decreased during montelukast treatment in children. Cysteinyl leukotriene synthesis is not blocked by corticosteroid therapy. This important observation suggests that the leukotriene receptor antagonists represent a novel therapeutic approach, one that may provide benefits that are additive with corticosteroid therapy. This supposition is supported by clinical observations that treatment with leukotriene receptor antagonists significantly improve asthma control when added to inhaled corticosteroid therapy. Moreover, the bronchodilator properties of the leukotriene receptor antagonists are additive with those of beta agonists. These data provide strong support for the use of leukotriene receptor antagonists for treating asthma. PMID

  11. [Fermentation of Bacillus subtilis ge25 strain and preliminary study on its antagonistic substances].

    Science.gov (United States)

    Hu, Chen-Yun; Li, Yong; Liu, Min; Ding, Wan-Long; Qin, Min-Jian

    2014-07-01

    Panax ginseng is one of the most important traditional Chinese herbal medicine, soil borne diseases influenced the yield and quality severely. In our previous work, endophytic Bacillus subtilis ge25 strain was isolated from ginseng root, and which showed significant antagonistic activity against several most destructive ginseng phytopathogens. In the present work, crude protein and lipopeptid extracts were prepared from LB and Landy supernate by salting out, acid precipitation methods respectively. The antagonistic activity of crude extracts and stability to temperature and protease digestion were examined by ginseng phytopathogen Alternaria panax. Results showed that, the antagonistic activity of crude protein extracts from LB culture was complete and partially lost when treated by high temperature and proteinase K. However, crude lipopeptid from Landy culture showed significant stabile antagonistic activity to them. Acid-hydrolyzation and TLC-bioautography analysis showed, that the crude lipopeptide contained at least one cyclic lipopeptide. In consideration of the stability and perfect antagonistic activity of ge25, further researches will promote the biocontrol of ginseng diseases in the field. PMID:25272485

  12. Investigation of pregnancy outcome and ovarian hyper stimulation syndrome prevention in agonist and antagonist gonadotropin-releasing hormone protocol

    OpenAIRE

    Behnaz Khani Rabati; Setare Nasiri Zeidi

    2012-01-01

    Background: Given the controversies regarding the effectiveness of gonadotropin-releasing hormone (GnRH) antagonists in prevention of ovarian hyper stimulation syndrome stimulation, this study was designed to compare GnRH agonist protocol with GnRH antagonist protocol in patients who were candidate for assisted reproductive techniques (ARTs). Materials and Methods: This investigation was performed on 136 patients who were randomly allocated to two groups of GnRH agonist and GnRH antagonist. I...

  13. Bradykinin as a pain mediator: receptors are localized to sensory neurons, and antagonists have analgesic actions

    International Nuclear Information System (INIS)

    Autoradiographic studies localize [3H]bradykinin receptor binding sites to the substantia gelatinosa, dorsal root, and a subset of small cells in both the dorsal root and trigeminal ganglia of the guinea pig. [3H]Bradykinin labeling is also observed over myocardinal/coronary visceral afferent fibers. The localization of [3H]bradykinin receptors to nociceptive pathways supports a role for bradykinin in pain mediation. Several bradkykinin antagonists block bradykinin-induced acute vascular pain in the rat. The bradykinin antagonists also relieve bradykinin- and urate-induced hyperalgesia in the rat paw. These results indicate that bradykinin is a physiologic mediator of pain and that bradykinin antagonists have analgesic activity in both acute and chronic pain models

  14. Structure-based design of eugenol analogs as potential estrogen receptor antagonists.

    Science.gov (United States)

    Anita, Yulia; Radifar, Muhammad; Kardono, Leonardus Bs; Hanafi, Muhammad; Istyastono, Enade P

    2012-01-01

    Eugenol is an essential oil mainly found in the buds and leaves of clove (Syzygium aromaticum (L.) Merrill and Perry), which has been reported to have activity on inhibition of cell proliferation and apoptosis induction in human MCF-7 breast cancer cells. This biological activity is correlated to its activity as an estrogen receptor antagonist. In this article, we present the construction and validation of structure-based virtual screening (SBVS) protocols to identify the potent estrogen receptor α (ER) antagonists. The selected protocol, which gave acceptable enrichment factors as a virtual screening protocol, subsequently used to virtually screen eugenol, its analogs and their dimers. Based on the virtual screening results, dimer eugenol of 4-[4-hydroxy-3-(prop-2-en-1- yl)phenyl]-2-(prop-2-en-1-yl)phenol is recommended to be developed further in order to discover novel and potent ER antagonists. PMID:23144548

  15. Synthesis and Biological Evaluation of Substituted Desloratadines as Potent Arginine Vasopressin V2 Receptor Antagonists

    Directory of Open Access Journals (Sweden)

    Shuai Mu

    2014-02-01

    Full Text Available Twenty-one non-peptide substituted desloratadine class compounds were synthesized as novel arginine vasopressin receptor antagonists from desloratadine via successive acylation, reduction and acylation reactions. Their structures were characterized by 1H-NMR and HRMS, their biological activity was evaluated by in vitro and in vivo studies. The in vitro binding assay and cAMP accumulation assay indicated that these compounds are potent selective V2 receptor antagonists. Among them compounds 1n, 1t and 1v exhibited both high affinity and promising selectivity for V2 receptors. The in vivo diuretic assay demonstrated that 1t presented remarkable diuretic activity. In conclusion, 1t is a potent novel AVP V2 receptor antagonist candidate.

  16. Fluorescent Pseudomonads in the Phyllosphere of Wheat: Potential Antagonists Against Fungal Phytopathogens.

    Science.gov (United States)

    Müller, Thomas; Behrendt, Undine; Ruppel, Silke; von der Waydbrink, Grit; Müller, Marina E H

    2016-04-01

    Fluorescent pseudomonads isolated from wheat leaves were characterized regarding their antagonistic potential and taxonomy in relation to protect crop plants from infestation by Fusarium and Alternaria fungi causing diseases in wheat. Using a dual culture assay, inhibition of fungal growth was found for 40 isolates of 175 fluorescent pseudomonads. Twenty-two of the antagonists were able to suppress strains of Fusarium as well as Alternaria. By means of real-time qPCR, the phlD gene encoding the antibiotic 2,4-diacetylphloroglucinol was detected in 20 isolates. On the basis of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry spectral patterns, the isolates with antagonistic activity were assigned to the phylogenetic subgroup Pseudomonas fluorescens and the closely related Pseudomonas gessardii subgroup. The results of the study suggest that pseudomonads in the phyllosphere of crop plants may possibly contribute to natural plant protection. PMID:26687461

  17. Study on Ca2+ antagonistic effect and mechanism of Chinese herbal drugs using 45Ca

    International Nuclear Information System (INIS)

    The Ca2+ antagonistic effect and mechanism of Chinese herbal drugs are studied by using 45Ca. The results indicate that potential-dependent Ca2+ channel (PDC) and receptor-operated Ca2+ channel (ROC) in cell membranes of smooth muscle can be blocked by several Chinese herbal drugs, including as Crocus sativus L., Carthamus L., Di-ao-xin-xue-kang (DAXXG) and Ginkgo biloba L. leaves. Among them Crocus sativus L. has the strongest antagonistic effect on Ca2+ channel, while Ginkgo biloba L. leaves has no obvious effect. The whole prescription and the other functional drugs have significant effect on ROC and PDC. The compositions extracted by hexane have the strongest antagonistic. The wrinkled giant hyssop have five active compositions and Pei-lan have two active compositions

  18. Antagonistic interactions and phylogenetic diversity of antimicrobial agents producing marine bacteria in Suez Bay

    Directory of Open Access Journals (Sweden)

    Sahar Wefky Mostafa Hassan

    2015-01-01

    Full Text Available Estimation of the total viable bacterial counts and some physicochemical parameters in different sites selected along the Suez Bay was carried out. The highest bacterial density is positively correlated with pollution strength and is localized at the end of the Suez Bay on the one hand of Suez Gulf. It is also function of pollution strength at different examined sites. Antagonistic interactions among the most dominating twenty-two bacterial isolates were assayed. The marine isolate AB12 isolated from sea water of NIOF station displayed the highest antagonistic activity (42.8%. Antagonistic isolates were assigned to phylogenetically 4 different phena which were identified as Staphylococcus, Micrococcus, Enterococcus and Enterobacter species in addition to 5 single clusters which were identified as Acinetobacter sp. and Pseudomonas sp. The promising strain was identified at the molecular level as Pseudoalteromonas piscicida.

  19. Orexin Receptor Antagonists: New Therapeutic Agents for the Treatment of Insomnia.

    Science.gov (United States)

    Roecker, Anthony J; Cox, Christopher D; Coleman, Paul J

    2016-01-28

    Since its discovery in 1998, the orexin system, composed of two G-protein coupled receptors, orexins 1 and 2, and two neuropeptide agonists, orexins A and B, has captured the attention of the scientific community as a potential therapeutic target for the treatment of obesity, anxiety, and sleep/wake disorders. Genetic evidence in rodents, dogs, and humans was revealed between 1999 and 2000, demonstrating a causal link between dysfunction or deletion of the orexin system and narcolepsy, a disorder characterized by hypersomnolence during normal wakefulness. These findings encouraged efforts to discover agonists to treat narcolepsy and, alternatively, antagonists to treat insomnia. This perspective will focus on the discovery and development of structurally diverse orexin antagonists suitable for preclinical pharmacology studies and human clinical trials. The work described herein culminated in the 2014 FDA approval of suvorexant as a first-in-class dual orexin receptor antagonist for the treatment of insomnia. PMID:26317591

  20. Discovery of novel indazole derivatives as dual angiotensin II antagonists and partial PPARγ agonists.

    Science.gov (United States)

    Lamotte, Yann; Faucher, Nicolas; Sançon, Julien; Pineau, Olivier; Sautet, Stéphane; Fouchet, Marie-Hélène; Beneton, Véronique; Tousaint, Jean-Jacques; Saintillan, Yannick; Ancellin, Nicolas; Nicodeme, Edwige; Grillot, Didier; Martres, Paul

    2014-02-15

    Identification of indazole derivatives acting as dual angiotensin II type 1 (AT1) receptor antagonists and partial peroxisome proliferator-activated receptor-γ (PPARγ) agonists is described. Starting from Telmisartan, we previously described that indole derivatives were very potent partial PPARγ agonists with loss of AT1 receptor antagonist activity. Design, synthesis and evaluation of new central scaffolds led us to the discovery of pyrrazolopyridine then indazole derivatives provided novel series possessing the desired dual activity. Among the new compounds, 38 was identified as a potent AT1 receptor antagonist (IC50=0.006 μM) and partial PPARγ agonist (EC50=0.25 μM, 40% max) with good oral bioavailability in rat. The dual pharmacology of compound 38 was demonstrated in two preclinical models of hypertension (SHR) and insulin resistance (Zucker fa/fa rat). PMID:24462665

  1. 7-Chloroarctinone-b as a new selective PPARγ antagonist potently blocks adipocyte differentiation

    Institute of Scientific and Technical Information of China (English)

    Yong-tao LI; Li LI; Jing CHEN; Tian-cen HU; Jin HUANG; Yue-wei GUO; Hua-liang JIANG; Xu SHEN

    2009-01-01

    Aim: Peroxisome proliferator-activated receptor gamma (PPARy) is a therapeutic target for obesity, cancer and diabetes mellitus. In order to develop potent lead compounds for obesity treatment, we screened a natural product library for novel PPARy antagonists with inhibitory effects on adipocyte differentiation. Methods: Surface plasmon resonance (SPR) technology and cell-based transactivation assay were used to screen for PPARy antago-nists. To investigate the antagonistic mechanism of the active compound, we measured its effect on PPARy/RXRα heterodimerization and PPARy co-activator recruitment using yeast two-hybrid assay, Gal4/UAS cell-based assay and SPR based assay. The 3T3-L1 cell differentiation assay was used to evaluate the effect of the active compound on adipocyte differentiation. Results: A new thiophene-acetylene type of natural product, 7-chloroarctinone-b (CAB), isolated from the roots of Rhaponticum uniflo-rum, was discovered as a novel PPARγ antagonist capable of inhibiting rosiglitazone-induced PPARγ transcriptional activity. SPR analy-sis suggested that CAB bound tightly to PPARγ and considerably antagonized the potent PPARy agonist rosigtitazone-stimulated PPARγ-LBD/RXRα-LBD binding. Gal4/UAS and yeast two-hybrid assays were used to evaluate the antagonistic activity of CAB on rosiglitazone-induced recruitment of the coactivator for PPARy. CAB could efficiently antagonize both hormone and rosiglitazone-induced adipocyte differentiation in cell culture. Conclusion: CAB shows antagonistic activity to PPARγ and can block the adipocyte differentiation, indicating it may be of potential use as a lead therapeutic compound for obesity.

  2. Radiolabelled GLP-1 receptor antagonist binds to GLP-1 receptor-expressing human tissues

    Energy Technology Data Exchange (ETDEWEB)

    Waser, Beatrice; Reubi, Jean Claude [University of Berne, Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, PO Box 62, Berne (Switzerland)

    2014-06-15

    Radiolabelled glucagon-like peptide 1 (GLP-1) receptor agonists have recently been shown to successfully image benign insulinomas in patients. For the somatostatin receptor targeting of tumours, however, it was recently reported that antagonist tracers were superior to agonist tracers. The present study therefore evaluated various forms of the {sup 125}iodinated-Bolton-Hunter (BH)-exendin(9-39) antagonist tracer for the in vitro visualization of GLP-1 receptor-expressing tissues in rats and humans and compared it with the agonist tracer {sup 125}I-GLP-1(7-36)amide. Receptor autoradiography studies with {sup 125}I-GLP-1(7-36)amide agonist or {sup 125}I-BH-exendin(9-39) antagonist radioligands were performed in human and rat tissues. The antagonist {sup 125}I-BH-exendin(9-39) labelled at lysine 19 identifies all human and rat GLP-1 target tissues and GLP-1 receptor-expressing tumours. Binding is of high affinity and is comparable in all tested tissues in its binding properties with the agonist tracer {sup 125}I-GLP-1(7-36)amide. For comparison, {sup 125}I-BH-exendin(9-39) with the BH labelled at lysine 4 did identify the GLP-1 receptor in rat tissues but not in human tissues. The GLP-1 receptor antagonist exendin(9-39) labelled with {sup 125}I-BH at lysine 19 is an excellent GLP-1 radioligand that identifies human and rat GLP-1 receptors in normal and tumoural tissues. It may therefore be the molecular basis to develop suitable GLP-1 receptor antagonist radioligands for in vivo imaging of GLP-1 receptor-expressing tissues in patients. (orig.)

  3. 5-HT6 Receptor Antagonists: Potential Efficacy for the Treatment of Cognitive Impairment in Schizophrenia.

    Science.gov (United States)

    de Bruin, Natasja M W J; Kruse, Chris G

    2015-01-01

    5-hydroxytryptamine6 receptor (5-HT6R) antagonists have shown efficacy in animal models for cognitive impairment in multiple cognitive domains relevant for schizophrenia. Improvements were found with 5-HT6R antagonists in preclinical tests for episodic memory, social cognition, executive function, working memory and several other tests for both learning and memory. In contrast, there is little evidence for efficacy on attention. It will be interesting to further investigate 5-HT6R antagonists in neurodevelopmental animal models which are based on prenatal exposure to specific environmental insults, and are characterized by a high level of face, construct and predictive validity for cognitive impairments associated with schizophrenia. It is also important to do more add-on preclinical studies of 5-HT6 antagonists with antipsychotics. Possible mechanisms of action to improve cognition have been described. 5-HT6R antagonists decrease GABA release and GABAergic interneuron excitability, which subsequently disinhibits glutamate and/or acetylcholine release and results in enhancement of synaptic plasticity. Furthermore, cognition could be improved by 5-HT6R antagonists, because these compounds increase the number of NCAM PSA-immunoreactive neurons in the dendate gyrus, inhibit mTOR and Fyn-tyrosine kinase and interact with DARPP-32. Interestingly, there is increasing preclinical evidence that could support additional benefits of 5-HT6R ligandson comorbid conditions in schizophrenia such as drug abuse, depression, anxiety, obesity andantipsychotic-induced EPS. Finally, we briefly give an overview of the 5-HT6R compounds that are currently in clinical development for the treatment of cognitive impairment in both schizophrenia and Alzheimer's disease. PMID:26044973

  4. Identification of short-acting κ-opioid receptor antagonists with anxiolytic-like activity.

    Science.gov (United States)

    Peters, Matthew F; Zacco, Anna; Gordon, John; Maciag, Carla M; Litwin, Linda C; Thompson, Carolann; Schroeder, Patricia; Sygowski, Linda A; Piser, Timothy M; Brugel, Todd A

    2011-07-01

    The κ-opioid receptor plays a central role in mediating the response to stressful life events. Inhibiting κ-opioid receptor signaling is proposed as a mechanism for treating stress-related conditions such as depression and anxiety. Preclinical testing consistently confirms that disruption of κ-opioid signaling is efficacious in animal models of mood disorders. However, concerns about the feasibility of developing antagonists into drugs stem from an unusual pharmacodynamic property of prototypic κ-opioid receptor-selective antagonists; they inhibit receptor signaling for weeks to months after a single dose. Several fundamental questions include - is it possible to identify short-acting antagonists; is long-lasting inhibition necessary for efficacy; and is it safe to develop long-acting antagonists in the clinic. Here, we test representative compounds (AZ-ECPC, AZ-MTAB, and LY-DMPF) from three new chemical series of κ-opioid receptor ligands for long-lasting inhibition. Each compound dose-dependently reversed κ-opioid agonist-induced diuresis. However, unlike the prototypic antagonist, nBNI, which fully inhibited evoked diuresis for at least four weeks, the new compounds showed no inhibition after one week. The two compounds with greater potency and selectivity were tested in prenatally-stressed rats on the elevated plus maze, an exploration-based model of anxiety. Spontaneous exploration of open arms in the elevated plus maze was suppressed by prenatal stress and restored with both compounds. These findings indicate that persistent inhibition is not an inherent property of κ-opioid-selective antagonists and that post-stress dosing with transient inhibitors can be effective in a mood disorder model. This further supports κ-opioid receptor as a promising target for developing novel psychiatric medications. PMID:21539838

  5. Synthesis and evaluation of radioiodinated NPC 22009, a putative CRF receptor antagonist

    International Nuclear Information System (INIS)

    Several studies have suggested that corticotropin-releasing factor (CRF) plays a role in stress-related disorders such as anxiety, depression, anorexia nervosa and stress-induced immune suppression. Hence CRF antagonists have potential therapeutic utility. Recently the authors discovered that pyrazolones such as NPC 22009 and the corresponding disulfide behave as CRF antagonists in vitro with micromolar potency. To probe the nature of this CRF antagonism they developed a convenient synthesis of radioiodinated NPC 22009. Details of the synthesis and preliminary pharmacological studies are presented

  6. Molecular determinants of non-competitive antagonist binding to the mouse GPRC6A receptor

    DEFF Research Database (Denmark)

    Faure, Helene; Gorojankina, Tatiana; Rice, Nadejda;

    2009-01-01

    Calindol antagonist activity but was without effect on NPS2143 inhibitory response. In summary, these data suggest that Calindol is primarily anchored through an H-bond to E816(7.39) in TM7 and highlight important local differences at the level of the CaSR and GPRC6A allosteric binding pockets. We have...... identified the first antagonists of GPRC6A that could represent new tools to analyze GPRC6A functions and serve as chemical leads for the development of more specific modulators....

  7. Effects of MCH and a MCH1-receptor antagonist on (palatable) food and water intake

    OpenAIRE

    Morens, C.; Norregaard, P; Receveur, JM; van Dijk, G.; SCHEURINK, AJW; Nørregaard, Pia; Receveur, Jean-Marie

    2005-01-01

    Melanin concentrating hormone (MCH) is a regulator of ingestive behavior, but several issues regarding its effects on specific components of ingestive behavior remain to be elucidated. Therefore, we injected, in the 3rd ventricle of male Wistar rats, saline, MCH (5 mu g), MCH (5 mu g) together with a MCH1-R antagonist (A, 10 mu g) and the antagonist alone (A, 10 mu g). Our results show that (1) central administration of MCH stimulates food intake (lab chow and medium high fat diet) and this c...

  8. Discovery of N-(3-fluoro-4-methylsulfonamidomethylphenyl)urea as a potent TRPV1 antagonistic template.

    Science.gov (United States)

    Ann, Jihyae; Sun, Wei; Zhou, Xing; Jung, Aeran; Baek, Jisoo; Lee, Sunho; Kim, Changhoon; Yoon, Suyoung; Hong, Sunhye; Choi, Sun; Turcios, Noe A; Herold, Brienna K A; Esch, Timothy E; Lewin, Nancy E; Abramovitz, Adelle; Pearce, Larry V; Blumberg, Peter M; Lee, Jeewoo

    2016-08-01

    A series of homologous analogues of prototype antagonist 1 and its urea surrogate were investigated as hTRPV1 ligands. Through one-carbon elongation in the respective pharmacophoric regions, N-(3-fluoro-4-methylsulfonamidomethylphenyl)urea was identified as a novel and potent TRPV1 antagonistic template. Its representative compound 27 showed a potency comparable to that of lead compound 1. Docking analysis of compound 27 in our hTRPV1 homology model indicated that its binding mode was similar with that of 1S. PMID:27317643

  9. Critical evaluation of P2X7 receptor antagonists in selected seizure models

    OpenAIRE

    Fischer, Wolfgang; Franke, Heike; Krügel, Ute; Müller, Heiko; Dinkel, Klaus; Lord, Brian; Letavic, Michael A; Henshall, David C.; Engel, Tobias

    2016-01-01

    The ATP-gated P2X7 receptor (P2X7R) is a non-selective cation channel which senses high extracellular ATP concentrations and has been suggested as a target for the treatment of neuroinflammation and neurodegenerative diseases. The use of P2X7R antagonists may therefore be a viable approach for treating CNS pathologies, including epileptic disorders. Recent studies showed anticonvulsant potential of P2X7R antagonists in certain animal models. To extend this work, we tested three CNS-permeable ...

  10. In vitro histamine H2-antagonist activity of the novel compound HUK 978

    International Nuclear Information System (INIS)

    Histamine stimulated adenylate cyclase from guinea-pig fundic mucosa and 3H-tiotidine binding in guinea-pig cerebral cortex were used to assess the in-vitro histamine H2-activity of the novel H2-antagonist HUK 978. The results showed that HUK 978 was a more potent H2-antagonist than either cimetidine or ranitidine. HUK 978 was also shown to be devoid of activity at the histamine H-1-receptor, the muscarinic receptor and the α and β-adrenergic receptors

  11. Comparison of the antagonistic effects of different angiotensin II receptor blockers in human coronary arteries

    DEFF Research Database (Denmark)

    Pantev, Emil; Stenman, Emelie; Wackenfors, Angelica;

    2002-01-01

    undertaken to evaluate the inhibitory effects of ARBs on vasoconstriction in humans. METHODS: Vasomotor tone was analyzed in endothelium denuded, human coronary artery (HCA) segments. Ang II type 1 (AT(1)) and type 2 (AT(2)) receptor mRNA expression was examined by reverse transcriptase-polymerase chain...... presence of 100 nM losartan elicited a depression of the Ang II response to 32%. Its active metabolite, EXP 3174 (1 nM),abolished the Ang II contraction. The AT(1) receptor antagonists had the following order of blocking effect; EXP 3174 > candesartan = valsartan > losartan. The AT(2) receptor antagonist...

  12. Isolation and characterization of antagonistic Bacillus strains capable to degrade ethylenethiourea.

    Science.gov (United States)

    Vágvölgyi, Csaba; Sajben-Nagy, Enikő; Bóka, Bettina; Vörös, Mónika; Berki, Adrienn; Palágyi, Andrea; Krisch, Judit; Skrbić, Biljana; Durišić-Mladenović, N; Manczinger, László

    2013-03-01

    In this study, more than 150 bacteria showing antagonistic properties against bacterial and fungal pathogens of the tomato plant were isolated and characterized. The most efficient agents against these phytopathogenic microorganisms belong to the genus Bacillus: the best biocontrol isolates were representatives of Bacillus subtilis, B. mojavensis and B. amyloliquefaciens species. They intensively produced fengycin or/and surfactin depsipeptide antibiotics and also proved to be excellent protease secretors. It was proved, that the selected strains were able to use ethylenethiourea (ETU) as sole nitrogen source. These antagonistic and ETU-degrading Bacillus strains can be applied as biocontrol and also as bioremediation agents. PMID:23143288

  13. Pathophysiology of the cysteinyl leukotrienes and effects of leukotriene receptor antagonists in asthma

    DEFF Research Database (Denmark)

    Bisgaard, H

    2001-01-01

    ciliary motility, which may hinder mucociliary clearance. Asthmatic patients demonstrate increased production of cysteinyl leukotrienes during naturally occurring asthma and acute asthma attacks as well as after allergen and exercise challenge. The leukotriene receptor antagonists montelukast, zafirlukast...... provide benefits that are additive with corticosteroid therapy. This supposition is supported by clinical observations that treatment with leukotriene receptor antagonists significantly improve asthma control when added to inhaled corticosteroid therapy. Moreover, the bronchodilator properties of the......Cysteinyl leukotrienes, synthesized de novo from cell membrane phospholipids, are proinflammatory mediators that play an important role in the pathophysiology of asthma. These mediators are among the most potent of bronchoconstrictors and cause vasodilation, increased microvascular permeability...

  14. Antagonistic Activities of Purple Non-sulfur Bacterial Extracts Against Antibiotic Resistant Vibrio sp.

    Directory of Open Access Journals (Sweden)

    Chandrasekaran, R.

    2011-01-01

    Full Text Available Solvent extracts of native purple non-sulfur bacterial (PNSB isolates from the effluents of brackish shrimp culture ponds, near Nagapattinam coast (South India were evaluated for antibacterial activity by the disc diffusion method. Best results were shown by the chloroform extracts against oxytetracycline resistant Vibrio harveyi and Vibrio fischerii. Among the purple non-sulfur bacterial isolates, Rhodobacter sphaeroides, showed maximum antagonistic activity. The findings suggest that the antagonistic extracts from Rba. sphaeroides could be used as an effective antibiotic in controlling Vibrio spp., in aquaculture systems.

  15. A RNA antagonist of hypoxia-inducible factor-1alpha, EZN-2968, inhibits tumor cell growth

    DEFF Research Database (Denmark)

    Greenberger, Lee M; Horak, Ivan D; Filpula, David; Sapra, Puja; Westergaard, Majken; Frydenlund, Henrik F; Albaek, Charlotte; Schrøder, Henrik; Ørum, Henrik

    2008-01-01

    pathways, is associated with poor prognosis in many types of cancer. Therefore, down-regulation of HIF-1alpha protein by RNA antagonists may control cancer growth. EZN-2968 is a RNA antagonist composed of third-generation oligonucleotide, locked nucleic acid, technology that specifically binds and inhibits......-regulation of endogenous HIF-1alpha and vascular endothelial growth factor in the liver. The effect can last for days after administration of single dose of EZN-2968 and is associated with long residence time of locked nucleic acid in certain tissues. In efficacy studies, tumor reduction was found in nude mice...

  16. Zyklophin, a short-acting kappa opioid antagonist, induces scratching in mice

    OpenAIRE

    DiMattio, K.M.; T.V. Yakovleva; Aldrich, J V; Cowan, A; Liu-Chen, L.Y.

    2014-01-01

    It has been shown previously that norbinaltorphimine (norBNI) and 5΄-guanidinonaltrindole (5΄-GNTI), long-acting kappa opioid receptor (KOPR) antagonists, cause frenzied scratching in mice [1;2]. In the current study, we examined if zyklophin, a short-acting cyclic peptide KOPR antagonist, also elicited scratching behavior. When injected s.c. in the nape of the neck of male Swiss-Webster mice, zyklophin at doses of 0.1, 0.3 and 1 mg/kg induced dose-related hindleg scratching of the neck betwe...

  17. Chemogenomic discovery of allosteric antagonists at the GPRC6A receptor

    DEFF Research Database (Denmark)

    Gloriam, David E.; Wellendorph, Petrine; Johansen, Lars Dan; Thomsen, Alex Rojas Bie; Phonekeo, Karina; Pedersen, Daniel Sejer; Bräuner-Osborne, Hans

    2011-01-01

    pharmacological character: (1) chemogenomic lead identification through the first, to our knowledge, ligand inference between two different GPCR families, Families A and C; and (2) the discovery of the most selective GPRC6A allosteric antagonists discovered to date. The unprecedented inference of...... pharmacological activity across GPCR families provides proof-of-concept for in silico approaches against Family C targets based on Family A templates, greatly expanding the prospects of successful drug design and discovery. The antagonists were tested against a panel of seven Family A and C G protein-coupled receptors...

  18. Metabolism of the broad-spectrum neuropeptide growth factor antagonist: [D-Arg1, D-Phe5, D-Trp7,9, Leu11]-substance P.

    OpenAIRE

    Jones, D. A.; Cummings, J.; Langdon, S. P.; Maclellan, A. J.; Higgins, T; Rozengurt, E; Smyth, J. F.

    1996-01-01

    Broad-spectrum neuropeptide growth factor antagonists, such as [D-Arg1, D-Phe5, D-Trp7,9, Leu11]substance P (antagonist D) and [Arg6, D-Trp7,9, NmePhe8]substance P(6-11) (antagonist G), are currently being investigated as possible anti-tumour agents. These compounds are hoped to be effective against neuropeptide-driven cancers such as small-cell lung cancer. Antagonist D possesses a broader antagonistic spectrum than antagonist G and hence may be of greater therapeutic use. The in vitro metab...

  19. AMPA and GABA receptor antagonists and their interaction in rats with a genetic form of absence epilepsy

    NARCIS (Netherlands)

    Kaminski, R.M.; Rijn, C.M. van; Turski, W.A.; Czuczwar, S.J.; Luijtelaar, E.L.J.M. van

    2001-01-01

    The effects of combined and single administration of the -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, 7,8-methylenedioxy-1-(4-aminophenyl)-4-methyl-3-acetyl-4,5-dihydro-2,3 -benzodiazepine (LY 300164), and of the GABAB receptor antagonist -aminopropyl-n-butyl-phosp

  20. A novel series of piperazinyl-pyridine ureas as antagonists of the purinergic P2Y12 receptor.

    Science.gov (United States)

    Bach, Peter; Boström, Jonas; Brickmann, Kay; van Giezen, J J J; Hovland, Ragnar; Petersson, Annika U; Ray, Asim; Zetterberg, Fredrik

    2011-05-15

    A novel series of P2Y(12) antagonists for development of drugs within the antiplatelet area is presented. The synthesis of the piperazinyl-pyridine urea derivatives and their structure-activity relationships (SAR) are described. Several compounds showed P2Y(12) antagonistic activities in the sub-micromolar range. PMID:21507636

  1. Examining SLV-323, a novel NK1 receptor antagonist, in a chronic psychosocial stress model for depression

    NARCIS (Netherlands)

    Czeh, B; Pudovkina, O; van der Hart, MGC; Simon, M; Heilbronner, U; Michaelis, T; Watanabe, T; Frahm, J; Fuchs, E

    2005-01-01

    Rationale: Substance P antagonists have been proposed as candidates for a new class of antidepressant compounds. Objectives: We examined the effects of SLV-323, a novel neurokinin 1 receptor (NK1R) antagonist, in the chronic psychosocial stress paradigm of adult male tree shrews. Methods: Animals we

  2. Drug: D00644 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D00644 Drug Esmolol hydrochloride (JAN/USAN); Brevibloc (TN) C16H25NO4. HCl 331.155... 331.8349 D00644.gif Anti-adrenergic [beta-receptor] Therapeutic category: 2123 ATC code: C07AB09 beta1-adre...active ligand-receptor interaction hsa04261(153) Adrenergic signaling in cardiomy...ocytes hsa04970(153) Salivary secretion map07214 beta-Adrenergic receptor agonists/antagonists Therapeutic category of dr...iarrhythmic agents 2123 Beta blockers D00644 Esmolol hydrochloride (JAN/USAN) Ana

  3. Effect of esmolol on myocardial protection in pediatrics congenital heart defects

    OpenAIRE

    Fazelifar, Saeed; Bigdelian, Hamid

    2015-01-01

    Background: Although it is accepted that inducing cardioplegia is the gold standard in myocardial protection, there is still no consensus on the exact type of the cardioplegia. There are fewer studies on the type of the cardioplegia in hearts of the children than adults and they are contradictory. The effects of esmolol have been reviewed (a type of ultrashort-acting beta-adrenergic antagonist, i.e., ß-blockers) in conjunction with the cardioplegia due to the effect of the β-blockers in reduc...

  4. Therapeutic potential of vanilloid receptor TRPV1 agonists and antagonists as analgesics: Recent advances and setbacks.

    Science.gov (United States)

    Wong, Gilbert Y; Gavva, Narender R

    2009-04-01

    The vanilloid receptor TRPV1 is a homotetrameric, non-selective cation channel abundantly expressed in the nociceptors (c-fibers). TRPV1 is considered as a highly validated pain target because, i) its agonists such as capsaicin cause desensitization of TRPV1 channels that relieves pain behaviors in preclinical species, and ii) its antagonists relieve pain behaviors in rodent models of inflammation, osteoarthritis, and cancer. Hence, both agonists and antagonists of TRPV1 are being evaluated as potential analgesics in clinical trials. Clinical trial results of TRPV1 agonists such as resiniferatoxin in interstitial cystitis, NGX 4010 in post-herpetic neuralgia, and 4975 (Adlea) in osteoarthritis, bunionectomy, and Morton's neuroma have been reported. Similarly, clinical trial results of TRPV1 antagonists such as SB-705498 and AMG 517 have also been published recently. Overall, some molecules (e.g., capsaicin) demonstrated potential analgesia in certain conditions (postsurgical pain, postherpetic neuralgia, pain in diabetic neuropathy, osteoarthritis, bunionectomy, and Morton's neuroma), whereas others fell out of the clinic due to on-target liabilities or failed to demonstrate efficacy. This review summarizes recent advances and setbacks of TRPV1 agonists and antagonists in the clinic and predicts future directions. PMID:19150372

  5. Expression of secreted Wnt antagonists in gastrointestinal tissues: potential role in stem cell homeostasis

    OpenAIRE

    Byun, T; Karimi, M.; Marsh, J L; Milovanovic, T; Lin, F; Holcombe, R F

    2005-01-01

    Background: Wnt signalling dysregulation has been implicated in cancer, including colon and gastric cancer. Initiation of Wnt signalling is modulated by soluble Wnt antagonists (sWAs), including soluble frizzled related proteins, dickkopf (Dkk) proteins, and Wnt inhibitory factor-1 (Wif1).

  6. Effect of calmodulin antagonists on contraction and45Ca movements in rat aorta

    NARCIS (Netherlands)

    Wermelskirchen, D.; Koch, P.; Wilhelm, D.; Nebel, U.; Leidig, A.; Wilffert, B.; Peters, Thies

    1989-01-01

    To study the selectivity of calmodulin antagonists it was assumed that they should inhibit noradrenaline (NA)- and K+-induced contractions similarly without an accompanying inhibition of45Ca uptake. Therefore, in isolated rat aorta the effects of W-7, calmidazolium and trifluoperazine on contraction

  7. In vitro wear of four ceramic materials and human enamel on enamel antagonist.

    Science.gov (United States)

    Nakashima, Jun; Taira, Yohsuke; Sawase, Takashi

    2016-06-01

    The purpose of the present study was to evaluate the wear of four different ceramics and human enamel. The ceramics used were lithium disilicate glass (e.max Press), leucite-reinforced glass (GN-Ceram), yttria-stabilized zirconia (Aadva Zr), and feldspathic porcelain (Porcelain AAA). Hemispherical styli were fabricated with these ceramics and with tooth enamel. Flattened enamel was used for antagonistic specimens. After 100,000 wear cycles of a two-body wear test, the height and volume losses of the styli and enamel antagonists were determined. The mean and standard deviation for eight specimens were calculated and statistically analyzed using a non-parametric (Steel-Dwass) test (α = 0.05). GN-Ceram exhibited greater stylus height and volume losses than did Porcelain AAA. E.max Press, Porcelain AAA, and enamel styli showed no significant differences, and Aadva Zr exhibited the smallest stylus height and volume losses. The wear of the enamel antagonist was not significantly different among GN-Ceram, e.max Press, Porcelain AAA, and enamel styli. Aadva Zr resulted in significantly lower wear values of the enamel antagonist than did GN-Ceram, Porcelain AAA, and enamel styli. In conclusion, leucite-reinforced glass, lithium disilicate glass, and feldspathic porcelain showed wear values closer to those for human enamel than did yttria-stabilized zirconia. PMID:27059093

  8. New benzoyl urea derivatives as novel NR2B selective NMDA receptor antagonists.

    Science.gov (United States)

    Borza, I; Greiner, I; Kolok, S; Galgóczy, K; Ignácz-Szendrei, Gy; Horváth, Cs; Farkas, S; Gáti, T; Háda, V; Domány, Gy

    2006-09-01

    A novel series of benzoyl urea derivatives was prepared and identified as NR2B selective NMDA receptor antagonists. The influence of the substitution of the piperidine ring on the biological activity of the compounds was studied. Compound 9 was active in the formalin test in mice. PMID:17020160

  9. I. Effects of a Dopamine Receptor Antagonist on Fathead Minnow, Pimephales promelas ,Reproduction

    Science.gov (United States)

    This study used a 21 d fathead minnow (Pimephales promelas) reproduction assay to test the hypothesis that exposure to the dopamine 2 receptor (D2R) antagonist, haloperidol, would impair fish reproduction. Additionally, a 96 h experiment with fathead minnows and zebrafish (Danio ...

  10. Screening of Antagonistic Bacteria from Phyllosphere towards Tobacco Brown Spot Fungus Alternaria alternata

    Institute of Scientific and Technical Information of China (English)

    ZHANG Chengsheng; KONG Fanyu; LI Duochuan; WANG Jing; WANG Fenglong

    2006-01-01

    The possibility of employing antagonistic bacteria for the control of tobacco brown spot was studied. Approximately 136 strains of bacteria were isolated from phyllospheres of tobacco and 9 of these possessed high levels of antagonistic properties. They significantly reduced brown spot in detached tobacco leaves when artificially inoculated with Alternaria alternata. Culture filtrate of the most effective bacterial isolate which designated as Tpb88 was shown to be very efficient in inhibiting mycelial growth of A alternata in dual cultures. Culture filtrate of Tpb88 inhibited germination and germ tube elongation of A alternata. The results showed that the culture filtrate directly inhibited spore germination of A. alternata, especially during the first hours of the paired cultivation. The rate of antagonistic activity of culture filtrate of Tpb88 depended on its concentration in the mixture. The greatest inhibition of spore germination was ob served at the highest concentration of filtrate (filtrate to fungal spores inocula mixed in proportion 1: 50). These suggest that the hypothetic mechanism of Tpb88 against tobacco brown spot is to produce antagonistic substances.

  11. 5-Hydroxytryptamine antagonists and the 5-methoxy-N,N-dimethyltryptamine-induced changes of postdecapitation convulsions.

    Science.gov (United States)

    Archer, T

    1987-01-01

    The ability of various compounds to antagonise the 5-MeODMT induced prolongations of latency and duration of postdecapitation convulsions (PDCs) were compared. The 5-hydroxytryptamine (5-HT) receptor antagonists, mianserin, methergoline, cinanserin and methysergide antagonised the 5-MeODMT (0.5 to 4.0 mg/kg) induced prolongations of latency to onset of convulsions substantially and to a lesser extent the prolongation of duration. The efficacy of the 5-HT antagonists for blocking 5-MeODMT changes of PDCs was roughly of the order mianserin greater than cinanserin greater than methysergide greater than methergoline. Pirenperone, the 5-HT2 antagonist, and pimozide, the dopamine receptor antagonist did not antagonise the 5-MeODMT induced changes. Mianserin, methergoline, cinanserin and methysergide, by themselves, prolonged the duration of PDCs but did not affect latency. Pirenperone (0.25 mg/kg) prolonged both the latency and duration of the PDCs while pimozide (0.5-2.0 mg/kg) had no effect upon PDCs. This evidence suggests that 5-MeODMT induced changes of PDCs are mediated via 5-HT1 receptors and thus a reliable model to combine with other measures of spinal function is suggested. PMID:3562388

  12. Antimicrobial activity of extracellular metabolites from antagonistic bacteria isolated from potato (Solanum phureja) crops

    OpenAIRE

    Sinar David Granada García; Antoni Rueda Lorza; Carlos Alberto Peláez

    2014-01-01

    Microorganisms for biological control are capable of producing active compounds that inhibit the development of phytopathogens, constituting a promising tool toob tain active principles that could replace synthetic pesticides. This study evaluatedtheability of severalpotentialbiocontrol microorganismsto produce active extracellular metabolites. In vitro antagonistic capability of 50 bacterial isolates from rhizospheric soils of "criolla" potato (Solanum phureja) was tested through dual cultur...

  13. Synthesis and pharmacological evaluation of DHβE analogs as neuronal nicotinic acetylcholine receptor antagonists

    DEFF Research Database (Denmark)

    Jepsen, Tue H.; Jensen, Anders A.; Lund, Mads Henrik; Glibstrup, Emil; Kristensen, Jesper Langgaard

    2014-01-01

    Dihydro-β-erythroidine (DHβE) is a member of the Erythrina family of alkaloids and a potent competitive antagonist of the α4β2-subtype of the nicotinic acetylcholine receptors (nAChRs). Guided by an X-ray structure of DHβE in complex with an ACh binding protein, we detail the design, synthesis, and...

  14. Tying up Nicotine: New Selective Competitive Antagonist of the Neuronal Nicotinic Acetylcholine Receptors

    DEFF Research Database (Denmark)

    Petersen, Ida Nymann; Crestey, François; Jensen, Anders A; Indurthi, Dinesh C; Pedersen, Henrik; Andreasen, Jesper T; Balle, Thomas; Kristensen, Jesper L

    2015-01-01

    Conformational restriction of the pyrrolidine nitrogen in nicotine by the introduction of an ethylene bridge provided a potent and selective antagonist of the α4β2-subtype of the nicotinic acetylcholine receptors. Resolution by chiral SFC, pharmacological characterization of the two enantiomers...

  15. GnRH-agonist versus GnRH-antagonist IVF cycles

    DEFF Research Database (Denmark)

    Papanikolaou, E G; Pados, G; Grimbizis, G;

    2012-01-01

    In view of the current debate concerning possible differences in efficacy between the two GnRH analogues used in IVF stimulated cycles, the current study aimed to explore whether progesterone control in the late follicular phase differs when GnRH antagonist is used as compared with GnRH agonist...

  16. Attenuation of antagonist-induced impairment of dopamine receptors by L-prolyl-L-leucyl-glycinamide

    International Nuclear Information System (INIS)

    The present study was undertaken in order to determine whether chronic,long-term postnatal challenge of rat pups per se, with specific dopamine D1 and D2 receptor antagonists, would modify the ontogeny of the respective receptor types. Since the neuropeptide L-prolyl-L-leucyl-glycinamide (PLG) attenuates the effect of haloperidol on dopamine D2 receptors in adult rats it was of interest to determine whether PLG would modulate antagonists-induced alterations in the ontogeny of striatal dopamine D1 and D2 receptors. Half of the rats were treated daily for 32 days from birth with SCH-23390, a selective dopamine D1 antagonist; or spiroperidol, a selective dopamine D2 antagonists; or both SCH-23390 and spiroperidol; or saline. The other half of the litters were treated with PLG, in combination with the other treatments. Animals were decapitated at 5, 8, and 12 weeks from birth for neurochemical analysis of the striatum. Chronic SCH-23390 treatment produced a 70-80% decrease in the binding of [3H] SCH-23390 to striatal homogenates. The alteration at 5 weeks was associated with a 78% decrease in the Bmax for [3H] SCH-23390 binding, and no change in the KD. Similarly, at 5, 8, and 12 weeks, chronic spiroperidol treatment reduced the binding of [3H] spiroperidol to striatal homogenates by 70-80%

  17. GABA-B antagonist potentiates cortical epileptic afterdischarges in immature rats

    Czech Academy of Sciences Publication Activity Database

    Mareš, Pavel

    2005-01-01

    Roč. 46, č. S6 (2005), s. 358-358. ISSN 0013-9580. [International Epilepsy Congress /26./. 28.08.2005-01.09.2005, Paris] Institutional research plan: CEZ:AV0Z50110509 Keywords : GAGA-B antagonist * cortical afterdischarges * immature rat Subject RIV: ED - Physiology

  18. Antagonistic and Inhibitory Effect of Bacillus subtilis Against Certain Plant Pathogenic Fungi, I

    Directory of Open Access Journals (Sweden)

    S. M. Matar

    2009-01-01

    Full Text Available The antagonistic and inhibitory activity of fourteen Bacillus subtilis isolates (B1 to B14 obtained from different Egyptian sites, were tested against six fungal isolates belonging to four different genera, Rhizoctonia solani, Helminthosporium spp., Alternaria spp. and Fusarium oxysporum. Cultural, morphological and physiological characteristics of these isolates were found to be identical to Bacillus subtilis. When the fourteen B. subtilis isolates were tested as biological control agents for their antagonistic effect on the in vitro growth of the fungal isolates, four B. subtilis isolates B1, B4, B7, B8 had more antagonistic effect on all fungal isolates. Supernatant of B. subtilis isolate B7 had antagonistic effect on 6 fungal isolates but it was more effective on Helminthosporium spp., Alternaria spp. and F. oxysporum. B. subtilis as well as, isolate B7 showed effectiveness in reducing disease incidence and severity levels of tomato plants when added to the F. oxysporum and R. solani-infested soil. Also, it stimulated the growth of tomato plants compared to the other. HPLC analysis of the HCl precipitate of B. subtilis isolate B7 culture supernatant revealed that an identical pattern of five peaks to that of a purified preparation of iturin A was obtained.

  19. Development of co-cultivated mixtures of antagonists active against Fusarium head blight of wheat

    Science.gov (United States)

    Multistrain mixtures of biocontrol agents can foster greater and more consistent reductions of plant disease. Several different mixtures of Agricultural Research Service/Ohio State University-discovered antagonists reduced Fusarium head blight (FHB) in field studies. Microbial mixtures commonly ar...

  20. Plant patch structure influences plant fitness via antagonistic and mutualistic interactions but in different directions.

    Science.gov (United States)

    Andersson, Petter; Ehrlén, Johan; Hambäck, Peter A

    2016-04-01

    Plant patch structure and environmental context can influence the outcome of antagonistic and mutualistic plant-insect interactions, leading to spatially variable fitness effects for plants. We investigated the effects of herbivory and pollen limitation on plant reproductive performance in 28 patches of the self-compatible perennial herb Scrophularia nodosa and assessed how such effects varied with plant patch size, plant density and tree cover. Both antagonistic and mutualistic interactions had strong effects on plant reproductive performance. Leaf feeding from herbivores reduced both fruit production and seed germination, and leaf herbivory increased with plant patch size. Experimentally hand-pollinated flowers produced more seeds than open-pollinated flowers, and pollen limitation was more severe in patches with fewer plants. Our study on S. nodosa is one of few which documents that plant patch structure influences the outcome of both antagonistic and mutualistic plant-insect interactions. The results thus provide an example of how variation in plant patch structure and environmental factors can lead to spatially variable fitness effects from mutualistic and antagonistic interactions. PMID:26714828

  1. Non-vitamin K antagonist oral anticoagulation usage according to age among patients with atrial fibrillation

    DEFF Research Database (Denmark)

    Staerk, Laila; Fosbøl, Emil Loldrup; Gadsbøll, Kasper;

    2016-01-01

    Among atrial fibrillation (AF) patients, Danish nationwide registries (2011-2015) were used to examine temporal trends of initiation patterns of oral anticoagulation (OAC) treatment according to age. Overall, 43,299 AF patients initiating vitamin K antagonists (VKA) (42%), dabigatran (29%), rivar...

  2. Mouse bioassay for in vivo screening of oestrogen and progesterone antagonists

    Czech Academy of Sciences Publication Activity Database

    Škarda, Josef; Köhlerová, Eva

    2006-01-01

    Roč. 53, 3 (2006), s. 145-153. ISSN 0931-184X R&D Projects: GA ČR GA524/02/0406; GA AV ČR IBS5045302 Institutional research plan: CEZ:AV0Z50450515 Keywords : antagonists Subject RIV: FB - Endocrinology, Diabetology, Metabolism, Nutrition Impact factor: 0.627, year: 2006

  3. The Oxytocin-Oxytocin Receptor System and Its Antagonists as Tocolytic Agents

    Directory of Open Access Journals (Sweden)

    Nikolaos Vrachnis

    2011-01-01

    Full Text Available Oxytocin, a hormone involved in numerous physiologic processes, plays a central role in the mechanisms of parturition and lactation. It acts through its receptor, which belongs to the G-protein-coupled receptor superfamily, while Gq/phospholipase C (PLC/inositol 1,4,5-triphosphate (InsP3 is the main pathway via which it exerts its action in the myometrium. Changes in receptor levels, receptor desensitization, and locally produced oxytocin are factors that influence the effect of oxytocin on uterine contractility in labor. Activation of oxytocin receptor causes myometrial contractions by increasing intracellular Ca+2 and production of prostaglandins. Since oxytocin induces contractions, the inhibition of its action has been a target in the management of preterm labor. Atosiban is today the only oxytocin receptor antagonist that is available as a tocolytic. However, the quest for oxytocin receptor antagonists with a better pharmacological profile has led to the synthesis of peptide and nonpeptide molecules such as barusiban, retosiban, L-368,899, and SSR-126768A. Many of these oxytocin receptor antagonists are used only as pharmacological tools, while others have tocolytic action. In this paper, we summarize the action of oxytocin and its receptor and we present an overview of the clinical and experimental data of oxytocin antagonists and their tocolytic action.

  4. Bicyclams, selective antagonists of the human chemokine receptor CXCR4, potently inhibit feline immunodeficiency virus replication

    NARCIS (Netherlands)

    Horzinek, M.C.; Egberink, H.F.; Clercq, E. de; Vliet, A.L.W. van; Balzarini, J.; Bridger, G.J.; Henson, G.; Schols, D.

    1999-01-01

    Bicyclams are low-molecular-weight anti-human immunodeficiency virus (HIV) agents that have been shown to act as potent and selective CXC chemokine receptor 4 (CXCR4) antagonists. Here, we demonstrate that bicyclams are potent inhibitors of feline immunodeficiency virus (FIV) replication when evalua

  5. Possible lack of full cross-resistance of 5HT3 antagonists; a pilot study

    NARCIS (Netherlands)

    M.F. de Boer (Maarten); R. de Wit (Ronald); G. Stoter (Gerrit); J. Verweij (Jaap)

    1995-01-01

    textabstractWe investigated the potential of cross-over to the serotonin receptor (5HT3) antagonist ondansetron after protection failure with tropisetron. Several cases of complete protection were observed. These limited data suggest that there is an indication for retreatment with a different 5HT3

  6. Treatment of hyperemesis gravidarum with the 5-HT3 antagonist ondansetron (Zofran).

    OpenAIRE

    Tincello, D. G.; Johnstone, M. J.

    1996-01-01

    Ondansetron is a 5-hydroxytryptamine receptor antagonist which is known to be a highly effective anti-emetic drug for chemotherapy-associated nausea and vomiting and for postoperative nausea. We report here a case where ondansetron was used in severe hyperemesis gravidarum to avoid parenteral nutrition. The drug was used intermittently in every trimester with no apparent adverse effects on mother or infant.

  7. Antagonistic rhizobacteria and jasmonic acid induce resistance against tomato bacterial spot

    Directory of Open Access Journals (Sweden)

    Hélvio Gledson Maciel Ferraz

    2015-12-01

    Full Text Available AbstractTomato bacterial spot on tomato may be caused by four species of Xanthomonas and among them X. gardneri(Xg is the most destructive one, especially in areas irrigated using a center pivot system in Minas Gerais state and the midwest region of Brazil. Due to the ineffectiveness of chemical control and the lack of cultivars with high levels of genetic resistance, this study investigated the potential of three antagonists (Streptomyces setonii (UFV618, Bacillus cereus (UFV592 and Serratia marcescens (UFV252, and the hormone jasmonic acid (JA as a positive control, to reduce bacterial spot symptoms and to potentiate defense enzymes in the leaves of tomato plants infected by Xg. Tomato seeds were microbiolized with each antagonist, and the soil was drenched with these bacteria. The plants were sprayed with JA 48 h before Xginoculation. The final average severity on the tomato plants was reduced by 29.44, 59.26 and 61.33% in the UFV592, UFV618 and JA treatments, respectively. The UFV618 antagonist was as effective as JA in reducing bacterial spot symptoms on tomatoes, which can be explained by the greater activities of defense enzymes that are commonly involved in host resistance against bacterial diseases. These results suggest that JA and the UFV618 antagonist can be used in the integrated management of bacterial spot on tomatoes.

  8. Impact of peptide ghrelin antagonists on metabolic syndrome in female obese mice

    Czech Academy of Sciences Publication Activity Database

    Maletínská, Lenka; Železná, Blanka; Matyšková, Resha; Maixnerová, Jana; Pýchová, Miroslava; Špolcová, Andrea; Blechová, Miroslava; Jurcovicová, J.; Haluzník, M.

    2010-01-01

    Roč. 16, S1 (2010), s. 116-117. ISSN 1075-2617. [European Peptide Symposium /31./. 05.09.2010-09.09.2010, Copenhagen] R&D Projects: GA ČR GA303/09/0744 Institutional research plan: CEZ:AV0Z40550506 Keywords : DIO * OVX * mice * ghrelin antagonist Subject RIV: CC - Organic Chemistry

  9. Draft Genome Sequence of Streptomyces silvensis ATCC 53525, a Producer of Novel Hormone Antagonists.

    Science.gov (United States)

    Johnston, Chad W; Li, Yongchang; Magarvey, Nathan A

    2016-01-01

    Streptomyces silvensis produces nonribosomal peptides that act as antagonists of the human oxytocin and vasopressin receptors. Here, we present the genome sequence of S. silvensis ATCC 53525 and demonstrate that this organism possesses a number of additional biosynthetic gene clusters and might be a promising source for genome-guided drug discovery efforts. PMID:26893408

  10. Inhibition of Acetylcholinesterase Modulates NMDA Receptor Antagonist Mediated Alterations in the Developing Brain

    Directory of Open Access Journals (Sweden)

    Ivo Bendix

    2014-03-01

    Full Text Available Exposure to N-methyl-d-aspartate (NMDA receptor antagonists has been demonstrated to induce neurodegeneration in newborn rats. However, in clinical practice the use of NMDA receptor antagonists as anesthetics and sedatives cannot always be avoided. The present study investigated the effect of the indirect cholinergic agonist physostigmine on neurotrophin expression and the extracellular matrix during NMDA receptor antagonist induced injury to the immature rat brain. The aim was to investigate matrix metalloproteinase (MMP-2 activity, as well as expression of tissue inhibitor of metalloproteinase (TIMP-2 and brain-derived neurotrophic factor (BDNF after co-administration of the non-competitive NMDA receptor antagonist MK801 (dizocilpine and the acetylcholinesterase (AChE inhibitor physostigmine. The AChE inhibitor physostigmine ameliorated the MK801-induced reduction of BDNF mRNA and protein levels, reduced MK801-triggered MMP-2 activity and prevented decreased TIMP-2 mRNA expression. Our results indicate that AChE inhibition may prevent newborn rats from MK801-mediated brain damage by enhancing neurotrophin-associated signaling pathways and by modulating the extracellular matrix.

  11. Dual-function CXCR4 Antagonist Polyplexes to Deliver Gene Therapy and Inhibit Cancer Cell Invasion**

    OpenAIRE

    Li, Jing; Zhu, Yu; Hazeldine, Stuart T.; Li, Chunying; Oupický, David

    2012-01-01

    A bicyclam-based biodegradable polycation with CXCR4 antagonistic activity was developed with potential for combined drug/gene cancer therapies. The dual-function polycation prevents cancer cell invasion by inhibiting CXCL12 stimulated CXCR4 activation, while at the same time efficiently and safely delivers plasmid DNA into cancer cells.

  12. Friendly and Antagonistic Contact between Former Spouses after Divorce: Patterns and Determinants

    Science.gov (United States)

    Fischer, Tamar F. C.; de Graaf, Paul M.; Kalmijn, Matthijs

    2005-01-01

    This study presents descriptive and explanatory analyses of contact between former spouses, using data on 1,791 previously married men and women in the Netherlands. The authors employ a typology of relationships between former spouses, differentiating between friendly contact, antagonistic contact, and no contact. Ten years after divorce, still…

  13. The Tunisian oasis ecosystem is a source of antagonistic Bacillus spp. producing diverse antifungal lipopeptides.

    Science.gov (United States)

    El Arbi, Amel; Rochex, Alice; Chataigné, Gabrielle; Béchet, Max; Lecouturier, Didier; Arnauld, Ségolène; Gharsallah, Néji; Jacques, Philippe

    2016-01-01

    The use of microbial products has become a promising alternative approach to controlling plant diseases caused by phytopathogenic fungi. Bacteria isolated from the date palm tree rhizosphere of the Tunisian oasis ecosystem could provide new biocontrol microorganisms adapted to extreme conditions, such as drought, salinity and high temperature. The aim of this study was to screen bacteria isolated from the rhizosphere of the date palm tree for their ability to inhibit phytopathogenic fungi, and to identify molecules responsible for their antifungal activity. Screening for antifungal activity was performed on twenty-eight isolates. Five antagonistic isolates were selected and identified as different species of Bacillus using phenotypical methods and a molecular approach. The five antagonistic Bacillus isolated showed tolerance to abiotic stresses (high temperature, salinity, drought). Their ability to produce lipopeptides was investigated using a combination of two techniques: PCR amplification and MALDI-ToF mass spectrometry. Analyses revealed that the antagonistic isolates produced a high diversity of lipopeptides that belonged to surfactin, fengycin, iturin and kurstakin families. Their antagonistic activity, related to their capacity for producing diverse antifungal lipopeptides and their tolerance to abiotic stresses, highlighted Bacillus strains isolated from the rhizosphere of the date palm tree as potential biocontrol agents for combatting plant diseases in extreme environments. PMID:26428248

  14. Opioid analgesics as noncompetitive N-methyl-D-aspartate (NMDA) antagonists

    DEFF Research Database (Denmark)

    Ebert, B; Thorkildsen, C; Andersen, S; Christrup, Lona Louring; Hjeds, H

    1998-01-01

    Much evidence points to the involvement of N-methyl-D-aspartate (NMDA) receptors in the development and maintainance of neuropathic pain. In neuropathic pain, there is generally involved a presumed opioid-insensitive component, which apparently can be blocked by NMDA receptor antagonists. However...

  15. 4-Acylamino-and 4-ureidobenzamides as melanin-concentrating hormone (MCH) receptor 1 antagonists

    DEFF Research Database (Denmark)

    Receveur, Jean-Marie; Bjurling, Emelie; Ulven, Trond;

    2004-01-01

    Synthesis, in vitro biological evaluation and structure-activity relationships of 4-acylamino-and 4-ureidobenzamides as novel hMCH1R-antagonists are disclosed. The nature of the amine side chains could be varied considerably in contrast to the central benzamide scaffold and aromatic substituents....

  16. Aldosterone antagonists in monotherapy are protective against streptozotocin-induced diabetic nephropathy in rats.

    Science.gov (United States)

    Banki, Nora F; Ver, Agota; Wagner, Laszlo J; Vannay, Adam; Degrell, Peter; Prokai, Agnes; Gellai, Renata; Lenart, Lilla; Szakal, Dorottya-Nagy; Kenesei, Eva; Rosta, Klara; Reusz, Gyorgy; Szabo, Attila J; Tulassay, Tivadar; Baylis, Chris; Fekete, Andrea

    2012-01-01

    Angiotensin converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB) are the standard clinical therapy of diabetic nephropathy (DN), while aldosterone antagonists are only used as adjuncts. Previously in experimental DN we showed that Na/K ATPase (NKA) is mislocated and angiotensin II leads to superimposed renal progression. Here we investigated the monotherapeutic effect of aldosterone blockers on the progression of DN and renal NKA alteration in comparison to ACEi and ARBs. Streptozotocin-diabetic rats developing DN were treated with aldosterone antagonists; ACEi and ARB. Renal function, morphology, protein level and tubular localization of NKA were analyzed. To evaluate the effect of high glucose per se; HK-2 proximal tubular cells were cultured in normal or high concentration of glucose and treated with the same agents. Aldosterone antagonists were the most effective in ameliorating functional and structural kidney damage and they normalized diabetes induced bradycardia and weight loss. Aldosterone blockers also prevented hyperglycemia and diabetes induced increase in NKA protein level and enzyme mislocation. A monotherapy with aldosterone antagonists might be as, or more effective than ACEi or ARBs in the prevention of STZ-induced DN. Furthermore the alteration of the NKA could represent a novel pathophysiological feature of DN and might serve as an additional target of aldosterone blockers. PMID:22761931

  17. Aldosterone antagonists in monotherapy are protective against streptozotocin-induced diabetic nephropathy in rats.

    Directory of Open Access Journals (Sweden)

    Nora F Banki

    Full Text Available Angiotensin converting enzyme inhibitors (ACEi and angiotensin II receptor blockers (ARB are the standard clinical therapy of diabetic nephropathy (DN, while aldosterone antagonists are only used as adjuncts. Previously in experimental DN we showed that Na/K ATPase (NKA is mislocated and angiotensin II leads to superimposed renal progression. Here we investigated the monotherapeutic effect of aldosterone blockers on the progression of DN and renal NKA alteration in comparison to ACEi and ARBs. Streptozotocin-diabetic rats developing DN were treated with aldosterone antagonists; ACEi and ARB. Renal function, morphology, protein level and tubular localization of NKA were analyzed. To evaluate the effect of high glucose per se; HK-2 proximal tubular cells were cultured in normal or high concentration of glucose and treated with the same agents. Aldosterone antagonists were the most effective in ameliorating functional and structural kidney damage and they normalized diabetes induced bradycardia and weight loss. Aldosterone blockers also prevented hyperglycemia and diabetes induced increase in NKA protein level and enzyme mislocation. A monotherapy with aldosterone antagonists might be as, or more effective than ACEi or ARBs in the prevention of STZ-induced DN. Furthermore the alteration of the NKA could represent a novel pathophysiological feature of DN and might serve as an additional target of aldosterone blockers.

  18. Agonist versus antagonist protocol in induction of ovulation and its outcome

    Directory of Open Access Journals (Sweden)

    Prasad Lele

    2016-06-01

    Conclusions: The GnRH antagonist therefore seems to be a more patient friendly protocol for the first choice in ART cycle with lower incidence of side effects and similar pregnancy rate. It is also time saving and simple protocol with good clinical outcome. [Int J Reprod Contracept Obstet Gynecol 2016; 5(6.000: 1748-1753

  19. The effects of the CXCR2 antagonist, MK-7123, on bone marrow functions in healthy subjects

    DEFF Research Database (Denmark)

    Hastrup, Nina; Khalilieh, Sauzanne; Dale, David C.;

    2015-01-01

    cells; or bone marrow fat to cell balance as assessed by MRI. MK-7123 was generally well tolerated with neutropenia being the most common adverse event; however, there were no clinical symptoms associated with decreased ANCs. These findings indicate that the CXCR2 antagonist MK-7123 causes rapidly...

  20. The risk of tuberculosis related to tumour necrosis factor antagonist therapies: a TBNET consensus statement

    DEFF Research Database (Denmark)

    Solovic, I.; Sester, M.; Gomez-Reino, J.J.;

    2010-01-01

    history of bacille Calmette-Guerin vaccination, tuberculin skin testing is recommended to screen all adult candidates for TNF antagonist treatment for the presence of latent infection with Mycobacterium tuberculosis. Moreover, paediatric practice suggests concomitant use of both the tuberculin skin test...

  1. A cross-laboratory preclinical study on the effectiveness of interleukin-1 receptor antagonist in stroke.

    Science.gov (United States)

    Maysami, Samaneh; Wong, Raymond; Pradillo, Jesus M; Denes, Adam; Dhungana, Hiramani; Malm, Tarja; Koistinaho, Jari; Orset, Cyrille; Rahman, Mahbubur; Rubio, Marina; Schwaninger, Markus; Vivien, Denis; Bath, Philip M; Rothwell, Nancy J; Allan, Stuart M

    2016-03-01

    Stroke represents a global challenge and is a leading cause of permanent disability worldwide. Despite much effort, translation of research findings to clinical benefit has not yet been successful. Failure of neuroprotection trials is considered, in part, due to the low quality of preclinical studies, low level of reproducibility across different laboratories and that stroke co-morbidities have not been fully considered in experimental models. More rigorous testing of new drug candidates in different experimental models of stroke and initiation of preclinical cross-laboratory studies have been suggested as ways to improve translation. However, to our knowledge, no drugs currently in clinical stroke trials have been investigated in preclinical cross-laboratory studies. The cytokine interleukin 1 is a key mediator of neuronal injury, and the naturally occurring interleukin 1 receptor antagonist has been reported as beneficial in experimental studies of stroke. In the present paper, we report on a preclinical cross-laboratory stroke trial designed to investigate the efficacy of interleukin 1 receptor antagonist in different research laboratories across Europe. Our results strongly support the therapeutic potential of interleukin 1 receptor antagonist in experimental stroke and provide further evidence that interleukin 1 receptor antagonist should be evaluated in more extensive clinical stroke trials. PMID:26661169

  2. Gonadotropin-releasing hormone agonist versus HCG for oocyte triggering in antagonist assisted reproductive technology cycles

    NARCIS (Netherlands)

    M.A.F.M. Youssef; F. van der Veen; H.G. Al-Inany; G. Griesinger; M.H. Mochtar; M. van Wely

    2010-01-01

    Background Gonadotropin-releasing hormone (GnRH) antagonist protocols for pituitary down regulation in in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI) allow the use of GnRH agonists for triggering final oocyte maturation. Currently, human chorionic gonadotropin (HCG) is stil

  3. No effect of angiotensin II AT(2)-receptor antagonist PD 123319 on cerebral blood flow autoregulation

    DEFF Research Database (Denmark)

    Estrup, T M; Paulson, O B; Strandgaard, S

    2001-01-01

    Blockade of the renin-angiotensin system with angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin AT1-receptor antagonists shift the limits of autoregulation of cerebral blood flow (CBF) towards lower blood pressure (BP). The role of AT2-receptors in the regulation of the cerebral cir...

  4. Novel selective thiazoleacetic acids as CRTH2 antagonists developed from in silico derived hits. Part 1

    DEFF Research Database (Denmark)

    Rist, Oystein; Grimstrup, Marie; Receveur, Jean-Marie; Frimurer, Thomas M; Ulven, Trond; Kostenis, Evi; Högberg, Thomas

    2009-01-01

    . Several compounds with double digit nanomolar binding affinity and full antagonistic efficacy for human CRTH2 receptor were obtained in all subclasses. The most potent compound was [2-(4-chloro-benzyl)-4-(4-phenoxy-phenyl)-thiazol-5-yl]acetic acid having an binding affinity of 3.7nM and functional...

  5. Design, synthesis and biological evaluation of Erythrina alkaloid analogues as neuronal nicotinic acetylcholine receptor antagonists

    DEFF Research Database (Denmark)

    Crestey, François; Jensen, Anders A.; Borch, Morten;

    2013-01-01

    -selective antagonists for the nAChRs and thereby probe the potential of using these natural products as scaffolds for further ligand optimization. The most selective and potent nAChR ligand to come from the series, 6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline (3c) (also a natural product by the name of O...

  6. Novel N-acyl-carbazole derivatives as 5-HT7R antagonists.

    Science.gov (United States)

    Kim, Youngjae; Yeom, Miyoung; Tae, Jinsung; Rhim, Hyewhon; Choo, Hyunah

    2016-03-01

    To discover a novel 5-HT7R antagonist for treatment of depression, we designed N-acyl-carbazole derivatives which were synthesized and biologically evaluated against 5-HT7R. Among total 30 compounds synthesized, four compounds 27-30 showed good binding affinities with Ki values of <100 nM. The compound 28, 1-(9H-carbazol-9-yl)-6-(4-(2-methoxyphenyl)piperazin-1-yl)hexan-1-one, showed good selectivity over other serotonin receptor subtypes and turned out to be a novel selective 5-HT7R antagonist following functional assays. The compound 28 showed moderate activity on hERG channel and good stability in microsomal stability test. The compound 28 exhibited a good pharmacokinetic profile with 67.8% oral bioavailability and good penetration to the brain. The compound 28 was also tested in in vivo depression animal model and showed antidepressant effect in the forced swimming test. Therefore, the selective 5-HT7R antagonist 28 can be considered as a good lead for discovery of novel 5-HT7R antagonists as antidepressants. PMID:26852005

  7. Temporal trends in the prescription of vitamin K antagonists in patients with atrial fibrillation

    DEFF Research Database (Denmark)

    Friberg, J; Gislason, G H; Gadsbøll, N;

    2006-01-01

    OBJECTIVES: Anticoagulation therapy is recommended in patients with atrial fibrillation (AF) and risk factors for stroke. We studied the temporal trends in the prescription of vitamin K antagonists (VKA) in patients with a first hospital diagnosis of AF in Denmark, 1995-2002. DESIGN: The Danish...

  8. Mineralocorticoid receptor antagonists for heart failure with reduced ejection fraction : integrating evidence into clinical practice

    NARCIS (Netherlands)

    Zannad, Faiez; Stough, Wendy Gattis; Rossignol, Patrick; Bauersachs, Johann; McMurray, John J. V.; Swedberg, Karl; Struthers, Allan D.; Voors, Adriaan A.; Ruilope, Luis M.; Bakris, George L.; O'Connor, Christopher M.; Gheorghiade, Mihai; Mentz, Robert J.; Cohen-Solal, Alain; Maggioni, Aldo P.; Beygui, Farzin; Filippatos, Gerasimos S.; Massy, Ziad A.; Pathak, Atul; Pina, Ileana L.; Sabbah, Hani N.; Sica, Domenic A.; Tavazzi, Luigi; Pitt, Bertram

    2012-01-01

    Mineralocorticoid receptor antagonists (MRAs) improve survival and reduce morbidity in patients with heart failure, reduced ejection fraction (HFREF), and mild-to-severe symptoms, and in patients with left ventricular systolic dysfunction and heart failure after acute myocardial infarction. These cl

  9. Discovery of non-peptide small molecular CXCR4 antagonists as anti-HIV agents: Recent advances and future opportunities.

    Science.gov (United States)

    Zhang, Heng; Kang, Dongwei; Huang, Boshi; Liu, Na; Zhao, Fabao; Zhan, Peng; Liu, Xinyong

    2016-05-23

    CXCR4 plays vital roles in HIV-1 life cycle for it's essential in mediating the interaction of host and virus and completing the entry process in the lifecycle of HIV-1 infection. Compared with some traditional targets, CXCR4 provides a novel and less mutated drug target in the battle against AIDS. Its antagonists have no cross resistance with other antagonists. Great achievements have been made recent years and a number of small molecular CXCR4 antagonists with diversity scaffolds have been discovered. In this review, recent advances in the discovery of CXCR4 antagonists with special attentions on their evolution and structure-activity relationships of representative CXCR4 antagonists are described. Moreover, some classical medicinal chemistry strategies and novel methodologies are also introduced. PMID:26974376

  10. Endothelin receptor B antagonists decrease glioma cell viability independently of their cognate receptor

    International Nuclear Information System (INIS)

    Endothelin receptor antagonists inhibit the progression of many cancers, but research into their influence on glioma has been limited. We treated glioma cell lines, LN-229 and SW1088, and melanoma cell lines, A375 and WM35, with two endothelin receptor type B (ETRB)-specific antagonists, A-192621 and BQ788, and quantified viable cells by the capacity of their intracellular esterases to convert non-fluorescent calcein AM into green-fluorescent calcein. We assessed cell proliferation by labeling cells with carboxyfluorescein diacetate succinimidyl ester and quantifying the fluorescence by FACS analysis. We also examined the cell cycle status using BrdU/propidium iodide double staining and FACS analysis. We evaluated changes in gene expression by microarray analysis following treatment with A-192621 in glioma cells. We examined the role of ETRB by reducing its expression level using small interfering RNA (siRNA). We report that two ETRB-specific antagonists, A-192621 and BQ788, reduce the number of viable cells in two glioma cell lines in a dose- and time-dependent manner. We describe similar results for two melanoma cell lines. The more potent of the two antagonists, A-192621, decreases the mean number of cell divisions at least in part by inducing a G2/M arrest and apoptosis. Microarray analysis of the effects of A-192621 treatment reveals up-regulation of several DNA damage-inducible genes. These results were confirmed by real-time RT-PCR. Importantly, reducing expression of ETRB with siRNAs does not abrogate the effects of either A-192621 or BQ788 in glioma or melanoma cells. Furthermore, BQ123, an endothelin receptor type A (ETRA)-specific antagonist, has no effect on cell viability in any of these cell lines, indicating that the ETRB-independent effects on cell viability exhibited by A-192621 and BQ788 are not a result of ETRA inhibition. While ETRB antagonists reduce the viability of glioma cells in vitro, it appears unlikely that this effect is mediated by

  11. The kappa opioid receptor antagonist JDTic attenuates alcohol seeking and withdrawal anxiety.

    Science.gov (United States)

    Schank, Jesse R; Goldstein, Andrea L; Rowe, Kelly E; King, Courtney E; Marusich, Julie A; Wiley, Jenny L; Carroll, F Ivy; Thorsell, Annika; Heilig, Markus

    2012-05-01

    The role of kappa-opioid receptors (KOR) in the regulation of alcohol-related behaviors is not completely understood. For example, alcohol consumption has been reported to increase following treatment with KOR antagonists in rats, but was decreased in mice with genetic deletion of KOR. Recent studies have further suggested that KOR antagonists may selectively decrease alcohol self-administration in rats following a history of dependence. We assessed the effects of the KOR antagonist JDTic on alcohol self-administration, reinstatement of alcohol seeking induced by alcohol-associated cues or stress, and acute alcohol withdrawal-induced anxiety ('hangover anxiety'). JDTic dose-dependently reversed hangover anxiety when given 48 hours prior to testing, a time interval corresponding to the previously demonstrated anxiolytic efficacy of this drug. In contrast, JDTic decreased alcohol self-administration and cue-induced reinstatement of alcohol seeking when administered 2 hours prior to testing, but not at longer pre-treatment times. For comparison, we determined that the prototypical KOR antagonist nor-binaltorphimine can suppress self-administration of alcohol at 2 hours pre-treatment time, mimicking our observations with JDTic. The effects of JDTic were behaviorally specific, as it had no effect on stress-induced reinstatement of alcohol seeking, self-administration of sucrose, or locomotor activity. Further, we demonstrate that at a 2 hours pre-treatment time JDTic antagonized the antinociceptive effects of the KOR agonist U50,488H but had no effect on morphine-induced behaviors. Our results provide additional evidence for the involvement of KOR in regulation of alcohol-related behaviors and provide support for KOR antagonists, including JDTic, to be evaluated as medications for alcoholism. PMID:22515275

  12. Switch from antagonist to agonist after addition of a DOTA chelator to a somatostatin analog

    Energy Technology Data Exchange (ETDEWEB)

    Reubi, Jean Claude; Cescato, Renzo; Waser, Beatrice [University of Berne, Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, PO Box 62, Berne (Switzerland); Erchegyi, Judit; Rivier, Jean E. [The Salk Institute for Biological Studies, The Clayton Foundation Laboratories for Peptide Biology, La Jolla, CA (United States)

    2010-08-15

    Peptide receptor targeting has become an increasingly attractive method to target tumors diagnostically and radiotherapeutically. Peptides linked to a variety of chelators have been developed for this purpose. They have, however, rarely been tested for their agonistic or antagonistic properties. We report here on a somatostatin antagonist that switched to an agonist upon coupling to a DOTA chelator. Two novel somatostatin analogs, 406-040-15 and its DOTA-coupled counterpart 406-051-20, with and without cold Indium labeling, were tested for their somatostatin receptor subtypes 1-5 (sst{sub 1}-sst{sub 5}) binding affinity using receptor autoradiography. Moreover, they were tested functionally for their ability to affect sst{sub 2} and sst{sub 3} internalization in vitro in HEK293 cells stably expressing the human sst{sub 2} or sst{sub 3} receptor, using an immunofluorescence microscopy-based internalization assay. All three compounds were characterized as pan-somatostatin analogs having a high affinity for all five sst. In the sst{sub 2} internalization assay, all three compounds showed an identical behavior, namely, a weak agonistic effect complemented by a weak antagonistic effect, compatible with the behavior of a partial agonist. Conversely, in the sst{sub 3} internalization assay, 406-040-15 was a full antagonist whereas its DOTA-coupled counterpart, 406-051-20, with and without Indium labeling, switched to a full agonist. Adding the DOTA chelator to the somatostatin analog 406-040-15 triggers a switch at sst{sub 3} receptor from an antagonist to an agonist. This indicates that potential radioligands for tumor targeting should always be tested functionally before further development, in particular if a chelator is added. (orig.)

  13. A high-throughput screening assay to identify bacterial antagonists against Fusarium verticillioides.

    Science.gov (United States)

    Figueroa-López, Alejandro Miguel; Cordero-Ramírez, Jesús Damián; Quiroz-Figueroa, Francisco Roberto; Maldonado-Mendoza, Ignacio Eduardo

    2014-07-01

    A high-throughput antagonistic assay was developed to screen for bacterial isolates capable of controlling the maize fungal phytopathogen Fusarium verticillioides. This assay combines a straightforward methodology, in which the fungus is challenged with bacterial isolates in liquid medium, with a novel approach that uses the plant lectin wheat germ agglutinin (WGA) coupled to a fluorophore (Alexa-Fluor® 488) under the commercial name of WGA, Alexa Fluor® 488 conjugate. The assay is performed in a 96-well plate format, which reduces the required laboratory space and streamlines quantitation and automation of the process, making it fast and accurate. The basis of our assay is that fungal biomass can be assessed by WGA, Alexa Fluor® 488 conjugate staining, which recognizes the chitin in the fungal cell wall and thus permits the identification of potential antagonistic bacteria that inhibit fungal growth. This principle was validated by chitin-competition binding assays against WGA, Alexa Fluor® 488 conjugate; confocal laser microscopy confirmed that the fluorescent WGA, Alexa Fluor® 488 conjugate binds to the chitin of the fungal cell wall. The majority of bacterial isolates did not bind to the WGA, Alexa Fluor® 488 conjugate. Furthermore, including washing steps significantly reduced any bacterial staining to background levels, even in the rare cases where bacterial isolates were capable of binding to WGA. Confirmatory conventional agar plate antagonistic assays were also conducted to validate our technique. We are now successfully employing this large-scale antagonistic assay as a pre-screening step for potential fungal antagonists in extensive bacteria collections (on the order of thousands of isolates). PMID:23787812

  14. A selective TSH receptor antagonist inhibits stimulation of thyroid function in female mice.

    Science.gov (United States)

    Neumann, Susanne; Nir, Eshel A; Eliseeva, Elena; Huang, Wenwei; Marugan, Juan; Xiao, Jingbo; Dulcey, Andrés E; Gershengorn, Marvin C

    2014-01-01

    Because the TSH receptor (TSHR) plays an important role in the pathogenesis of thyroid disease, a TSHR antagonist could be a novel treatment. We attempted to develop a small molecule, drug-like antagonist of TSHR signaling that is selective and active in vivo. We synthesized NCGC00242364 (ANTAG3) by chemical modification of a previously reported TSHR antagonist. We tested its potency, efficacy, and selectivity in a model cell system in vitro by measuring its activity to inhibit stimulation of cAMP production stimulated by TSH, LH, or FSH. We tested the in vivo activity of ANTAG3 by measuring its effects to lower serum free T4 and thyroid gene expression in female BALB/c mice continuously treated with ANTAG3 for 3 days and given low doses of TRH continuously or stimulated by a single administration of a monoclonal thyroid-stimulating antibody M22. ANTAG3 was selective for TSHR inhibition; half-maximal inhibitory doses were 2.1 μM for TSHR and greater than 30 μM for LH and FSH receptors. In mice treated with TRH, ANTAG3 lowered serum free T4 by 44% and lowered mRNAs for sodium-iodide cotransporter and thyroperoxidase by 75% and 83%, respectively. In mice given M22, ANTAG3 lowered serum free T4 by 38% and lowered mRNAs for sodium-iodide cotransporter and thyroperoxidase by 73% and 40%, respectively. In conclusion, we developed a selective TSHR antagonist that is effective in vivo in mice. This is the first report of a small-molecule TSHR antagonist active in vivo and may lead to a drug to treat Graves' disease. PMID:24169564

  15. Left-shifted Nav channels in injured bilayer: primary targets for neuroprotective Nav antagonists?

    Directory of Open Access Journals (Sweden)

    BelaJoos

    2012-02-01

    Full Text Available In sodium channel (Nav-rich axon initial segments and nodes of Ranvier, mechanical, ischemic and inflammatory injuries render these voltage-gated channels dangerously leaky. Extrapolating from recombinant Nav1.6 behavior (Wang et al 2009 Am J Physiol 297:C823, we postulate that the structural degradation of axolemmal bilayer, a common feature of neuoropathologic conditions, fosters ENa dissipation by favoring left-shifted Nav channel operation. This “sick excitable cell Nav-leak” would encompass left-shifted Itransient and Ipersistent components (fast-mode Iwindow, slow-mode Ipersistent. Ideally, bilayer damage-induced malfunction of Nav channels could be studied in Nav-rich myelinated axon nodes, exploiting the INa(v,t hysteresis of sawtooth ramp voltage clamp. We hypothesize that protective lipophilic Nav antagonists (e.g., ranolazine, riluzole partition more avidly into disorderly bilayers of traumatically (ischemically, etc damaged axons than into well-packed undamaged bilayers. Whereas inhibitors using aqueous routes would access all Navs equally, differential partitioning into “sick bilayer” would co-localize lipophilic antagonists with “sick Nav channels”, allowing for more specific targeting of impaired cells. Molecular fine-tuning effective antagonists for maximal partitioning into damaged-membrane milieus (thereby avoiding healthy cells could help reduce Nav antagonist side-effects. In potentially salvageable neurons of traumatic and/or ischemic penumbra, in inflammatory neuropathies, in muscular dystrophy, in myocytes of cardiac infarct borders, Nav-leak driven excitotoxicity too easily overwhelms cellular repair mechanisms. Precision-tuned Nav antagonist variants that preferred mildly, as opposed to severely, damaged Nav-rich axolemma or sarcolemma might be suitable for the prolonged continuous administration needed to allow for excitable cell remodeling and hence for improved functional recovery.

  16. Switch from antagonist to agonist after addition of a DOTA chelator to a somatostatin analog

    International Nuclear Information System (INIS)

    Peptide receptor targeting has become an increasingly attractive method to target tumors diagnostically and radiotherapeutically. Peptides linked to a variety of chelators have been developed for this purpose. They have, however, rarely been tested for their agonistic or antagonistic properties. We report here on a somatostatin antagonist that switched to an agonist upon coupling to a DOTA chelator. Two novel somatostatin analogs, 406-040-15 and its DOTA-coupled counterpart 406-051-20, with and without cold Indium labeling, were tested for their somatostatin receptor subtypes 1-5 (sst1-sst5) binding affinity using receptor autoradiography. Moreover, they were tested functionally for their ability to affect sst2 and sst3 internalization in vitro in HEK293 cells stably expressing the human sst2 or sst3 receptor, using an immunofluorescence microscopy-based internalization assay. All three compounds were characterized as pan-somatostatin analogs having a high affinity for all five sst. In the sst2 internalization assay, all three compounds showed an identical behavior, namely, a weak agonistic effect complemented by a weak antagonistic effect, compatible with the behavior of a partial agonist. Conversely, in the sst3 internalization assay, 406-040-15 was a full antagonist whereas its DOTA-coupled counterpart, 406-051-20, with and without Indium labeling, switched to a full agonist. Adding the DOTA chelator to the somatostatin analog 406-040-15 triggers a switch at sst3 receptor from an antagonist to an agonist. This indicates that potential radioligands for tumor targeting should always be tested functionally before further development, in particular if a chelator is added. (orig.)

  17. Expression of histamine H4 receptor in human epidermal tissues and attenuation of experimental pruritus using H4 receptor antagonist.

    Science.gov (United States)

    Yamaura, Katsunori; Oda, Manabu; Suwa, Eriko; Suzuki, Masahiko; Sato, Hiromi; Ueno, Koichi

    2009-10-01

    Many medicines exist which can cause pruritus (itching) as "serious adverse events." Many severe pruritic conditions respond poorly to histamine H1 receptor antagonists; there is no generally accepted antipruritic treatment. Recently described histamine H4 receptors are expressed in haematopoietic cells and have been linked to the pathology of allergy and asthma. We previously reported their expression in human dermal fibroblasts; in this study we have investigated H4 receptor expression in human epidermal tissue and found it to be greater in keratinocytes in the epidermal upper layer than in the lower layer. We have also investigated the effect of histamine H4 receptor antagonists on histamine H1 receptor antagonist-resistant pruritus using a mouse model. Scratching behavior was induced by histamine (300 nmol) or substance P (100 nmol) injected intradermally into the rostral part of the back of each mouse. Fexofenadine, a histamine H1 receptor antagonist, reduced scratching induced by histamine but not by substance P, whereas JNJ7777120, a histamine H4 receptor antagonist, significantly reduced both histamine- and substance P-induced scratching. These results suggest that H4 receptor antagonists may be useful for treatment of H1 receptor antagonist-resistant pruritus. PMID:19652466

  18. Opposing actions of dibutyryl cyclic AMP and GMP on temperature in conscious guinea-pigs

    Science.gov (United States)

    Kandasamy, S. B.; Williaes, B. A.

    1983-01-01

    It is shown that the intracerebroventricular administration of dibutyryl cyclic AMP (Db-cAMP) induced hyperthermia in guinea pigs which was not mediated through prostaglandins or norepinephrine since a prostaglandin synthesis inhibitor and an alpha-adrenergic receptor blocking agent did not antagonize the hyperthermia. However, the hyperthermic response to Db-cAMP was attenuated by the central administration of a beta-adrenergic receptor antagonist, which indicates that cAMP may be involved, through beta-adrenergic receptors, in the central regulation of heat production and conservation. The central administration of Db-cGMP produced hypothermia which was not mediated via histamine H1 or H2 receptors and serotonin. The antagonism of hypothermia induced by Db-cGMP and acetylcholine + physostigmine by central administration of a cholinergic muscarine receptor antagonist and not by a cholinergic nicotinic receptor antagonist suggests that cholinoceptive neurons and endogenous cGMP may regulate heat loss through cholinergic muscarine receptors. It is concluded that these results indicate a regulatory role in thermoregulation provided by a balance between opposing actions of cAMP and cGMP in guinea pigs.

  19. The Peptide Oxytocin Antagonist F-792, When Given Systemically, Does Not Act Centrally in Lactating Rats.

    Science.gov (United States)

    Leng, G; Russell, J A

    2016-04-01

    Oxytocin secreted by nerve terminals in the posterior pituitary has important actions for ensuring a successful outcome of pregnancy: it stimulates uterine contractions that lead to birth and it is essential in the milk-ejection reflex, enabling milk to be expelled from the mammary glands into the mouths of suckling young. Oxytocin also has important actions in the brain: released from dendrites of neurones that innervate the posterior pituitary, oxytocin auto-excites the neurones to fire action potentials in co-ordinated bursts, causing secretion of pulses of oxytocin. Central oxytocin actions are blocked by an oxytocin antagonist given into the brain and, consequently, milk transfer stops. Systemic peptide oxytocin antagonist (atosiban) treatment is used clinically in management of pre-term labour, a major obstetric problem. Hence, it is important to know whether an oxytocin antagonist given peripherally can enter the brain and interfere with central oxytocin actions. In the present study, we tested F792, a peptide oxytocin antagonist. In urethane-anaesthetised suckled rats, we show that the mammary gland responsiveness to oxytocin is blocked by i.v. injections of 7 μg/kg of F792, and the milk-ejection reflex is blocked when F792 is given directly into the brain at a dose of 0.2 μg. To critically test whether F792 given systemically can enter the brain, we recorded the suckling- and oxytocin-induced burst-firing of individual antidromically identified oxytocin neurones in the paraventricular nucleus. Given systemically at 100 μg/kg i.v., F792 acted only peripherally, blocking the milk-ejecting actions of oxytocin, but not the burst-firing of oxytocin neurones during suckling (n = 5 neurones in five rats). Hence, this peptide oxytocin antagonist does not enter the brain from the circulation to interfere with an essential oxytocin function in the brain. Furthermore, the functions of oxytocin in the brain evidently cannot be explored with a systemic peptide

  20. Spinal GABA-B receptor modulates neutrophil recruitment to the knee joint in zymosan-induced arthritis.

    Science.gov (United States)

    Bassi, Gabriel S; do C Malvar, David; Cunha, Thiago M; Cunha, Fernando Q; Kanashiro, Alexandre

    2016-08-01

    Recent studies have demonstrated that the central nervous system controls inflammatory responses by activating complex efferent neuroimmune pathways. The present study was designed to evaluate the role that central gamma-aminobutyric acid type B (GABA-B) receptor plays in neutrophil migration in a murine model of zymosan-induced arthritis by using different pharmacological tools. We observed that intrathecal administration of baclofen, a selective GABA-B agonist, exacerbated the inflammatory response in the knee after zymosan administration characterized by an increase in the neutrophil recruitment and knee joint edema, whereas saclofen, a GABA-B antagonist, exerted the opposite effect. Intrathecal pretreatment of the animals with SB203580 (an inhibitor of p38 mitogen-activated protein kinase) blocked the pro-inflammatory effect of baclofen. On the other hand, systemic administration of guanethidine, a sympatholytic drug that inhibits catecholamine release, and nadolol, a beta-adrenergic receptor antagonist, reversed the effect of saclofen. Moreover, saclofen suppressed the release of the pro-inflammatory cytokines into the knee joint (ELISA) and pain-related behaviors (open field test). Since the anti-inflammatory effect of saclofen depends on the sympathetic nervous system integrity, we observed that isoproterenol, a beta-adrenergic receptor agonist, mimics the central GABA-B blockade decreasing knee joint neutrophil recruitment. Together, these results demonstrate that the pharmacological manipulation of spinal GABAergic transmission aids control of neutrophil migration to the inflamed joint by modulating the activation of the knee joint-innervating sympathetic terminal fibers through a mechanism dependent on peripheral beta-adrenergic receptors and central components, such as p38 MAPK. PMID:27106212

  1. Cessation of gonadotropin-releasing hormone antagonist on triggering day in flexible multiple-dose protocol: A randomized controlled study

    OpenAIRE

    Chang, Hye Jin; Lee, Jung Ryeol; Jee, Byung Chul; Suh, Chang Suk; Lee, Won Don; Kim, Seok Hyun

    2013-01-01

    Objective To investigate outcomes of stimulated IVF cycles in which GnRH antagonist was omitted on the ovulation triggering day. Methods A total of 86 women who underwent controlled ovarian hyperstimulation with recombinant FSH and GnRH antagonist flexible multiple-dose protocols were recruited and prospectively randomized into the conventional group (group A) or cessation group (group B). The GnRH antagonist, 0.25 mg/day of cetrorelix, was started when the leading follicle reached 14 mm in d...

  2. IDENTIFICATION OF ANTAGONISTS OF Xanthomonas campestris ISOLATED FROM RHIZOSPHERE ZONE OF BROCCOLI FARM AT KEMBANG MERTA VILLAGE, TABANAN, BALI

    Directory of Open Access Journals (Sweden)

    Nadya Treesna Wulansari

    2015-03-01

    Full Text Available The main objectives of this research were to isolate and identify antagonists of Xanthomonas campestris from rhizosphere zone of broccoli plants. Soil samples were collected from broccoli farm located at Kembang Merta village, Tabanan, Bali. Isolation and identification of the antagonists were conducted at the Laboratory of Microbiology, Udayana University. Two fungal (Trichoderma harzianum and Trichoderma viride and two bacterial (Bacillus sp. and Pseudomonas sp. antagonists potentially to be developed as biocontrol agents of Xanthomonas campestris were successfully identified in this research

  3. Effect of the calcitonin gene-related peptide (CGRP) receptor antagonist telcagepant in human cranial arteries

    DEFF Research Database (Denmark)

    Edvinsson, Lars; Chan, Kayi Y; Eftekhari, Sajedeh;

    2010-01-01

    INTRODUCTION: Calcitonin gene-related peptide (CGRP) is a neuronal messenger in intracranial sensory nerves and is considered to play a significant role in migraine pathophysiology. MATERIALS AND METHODS: We investigated the effect of the CGRP receptor antagonist, telcagepant, on CGRP-induced cra......INTRODUCTION: Calcitonin gene-related peptide (CGRP) is a neuronal messenger in intracranial sensory nerves and is considered to play a significant role in migraine pathophysiology. MATERIALS AND METHODS: We investigated the effect of the CGRP receptor antagonist, telcagepant, on CGRP......-induced cranial vasodilatation in human isolated cerebral and middle meningeal arteries. We also studied the expression of the CGRP receptor components in cranial arteries with immunocytochemistry. Concentration response curves to αCGRP were performed in human isolated cerebral and middle meningeal arteries in...

  4. PROTECTIVE EFFECTS OF CALCIUM ANTAGONIST ON VASCULAR SYSTEM AGAINST TOXICITY INDUCED BY MERCURIC CHLORIDE

    Institute of Scientific and Technical Information of China (English)

    马欣; 厉英倩; 白宇飞; 刘明

    2004-01-01

    Objective To explore the toxic effects of mercuric chloride (HgCl2) on vascular smooth muscle as well as its relationship to calcium antagonist. Methods By using isolated vascular tension methods, we studied the effect of HgCl2 on isolated rabbit aortic rings. Results HgCl2 (1-100μmol*L-1) caused a concentration-dependent contraction of rabbit aortic rings, which did not change with phentolamin or without endothelium. In KH solution with Ca2+ , the maximum contraction amplitude reduced by(61.2±3.3)%. Nifedipine produced a concentration-dependent decrease of the maximum contraction amplitude. Conclusion Calcium antagonist has protective effects on vascular smooth muscle against damage induced by HgCl2.

  5. The safety of interleukin-1 receptor antagonist (anakinra in the treatment of rheumatoid arthritis

    Directory of Open Access Journals (Sweden)

    L. Riente

    2011-09-01

    Full Text Available The safety profile of interleukin-1 receptor antagonist (anakinra has been studied with randomised, placebo-controlled trials involving 2932 patients affected by rheumatoid arthritis. The most frequently reported adverse events were represented by injection site reactions (71% and headache (13.6%. No statistically significant difference in the incidence of infections was observed among the patients treated with the interleukin-1 receptor antagonist and the patients receiving placebo. In particular, the incidence of serious infections was 1,8% in rheumatoid arthritis patients on anakinra therapy and 0,7% in patients on placebo. The reported serious infections consisted of pneumonia, cellulitis, bone and joint infections, bursitis. No case of opportunistic infections or tubercolosis was observed. The results of clinical studies suggest that anakinra is a new well-tolerated drug for the treatment of patients affected by rheumatoid arthritis.

  6. Biocontrol Efficacy of Two Antagonistic Yeasts Against Postharvest Diseases in Peach Fruits During Storage Periods

    Institute of Scientific and Technical Information of China (English)

    LIN Li; TIAN Shi-ping; QIN Guo-zheng; XU Yong

    2003-01-01

    Two antagonistic yeasts, Thichosporon pullulans and Cryptococcus laurentii, were investigated for their biocontrol potential to blue mold rot and rhizopus rot on harvested peach fruits (Prunus persica L. Batsch, cv. Okubao), alone or in combination with a Iow dose of iprodione (50 μg mi-1 ). The results indicated that T. pullulans and C. laurentii were effective at reducing disease incidence and severity of blue mold rot and rhizopus rot in peach fruits. Biocontrol efficacy of C. laurentii and T. pullulans were significantly enhanced by combination with a Iow dose of iprodione (50 μg mi-1) against blue mold and rhizopus rot in peach fruits. T. pullulans and C. laurentii combined with a low dose of iprodione (50 μg mi-1 ) resulted in better disease control than either iprodione or the yeasts used alone. Dipping fruits in suspensions of antagonist cells showed the similar control effect as the treatment with iprodione (500 μg ml-1 ).

  7. Dual Alleviation of Acute and Neuropathic Pain by Fused Opioid Agonist-Neurokinin 1 Antagonist Peptidomimetics.

    Science.gov (United States)

    Betti, Cecilia; Starnowska, Joanna; Mika, Joanna; Dyniewicz, Jolanta; Frankiewicz, Lukasz; Novoa, Alexandre; Bochynska, Marta; Keresztes, Attila; Kosson, Piotr; Makuch, Wioletta; Van Duppen, Joost; Chung, Nga N; Vanden Broeck, Jozef; Lipkowski, Andrzej W; Schiller, Peter W; Janssens, Frans; Ceusters, Marc; Sommen, François; Meert, Theo; Przewlocka, Barbara; Tourwé, Dirk; Ballet, Steven

    2015-12-10

    Herein, the synthesis and biological evaluation of dual opioid agonists-neurokinin 1 receptor (NK1R) antagonists is described. In these multitarget ligands, the two pharmacophores do not overlap, and this allowed maintaining high NK1R affinity and antagonist potency in compounds 12 and 13. Although the fusion of the two ligands resulted in slightly diminished opioid agonism at the μ- and δ-opioid receptors (MOR and DOR, respectively), as compared to the opioid parent peptide, balanced MOR/DOR activities were obtained. Compared to morphine, compounds 12 and 13 produced more potent antinociceptive effects in both acute (tail-flick) and neuropathic pain models (von Frey and cold plate). Similarly to morphine, analgesic tolerance developed after repetitive administration of these compounds. To our delight, compound 12 did not produce cross-tolerance with morphine and high antihyperalgesic and antiallodynic effects could be reinstated after chronic administration of each of the two compounds. PMID:26713106

  8. Compensatory mutations cause excess of antagonistic epistasis in RNA secondary structure folding

    CERN Document Server

    Wilke, C O; Adami, C; Wilke, Claus O; Lenski, Richard E; Adami, Christoph

    2003-01-01

    Background: The rate at which fitness declines as an organism's genome accumulates random mutations is an important variable in several evolutionary theories. At an intuitive level, it might seem natural that random mutations should tend to interact synergistically, such that the rate of mean fitness decline accelerates as the number of random mutations is increased. However, in a number of recent studies, a prevalence of antagonistic epistasis (the tendency of multiple mutations to have a mitigating rather than reinforcing effect) has been observed. Results: We studied in silico the net amount and form of epistatic interactions in RNA secondary structure folding by measuring the fraction of neutral mutants as a function of mutational distance d. We found a clear prevalence of antagonistic epistasis in RNA secondary structure folding. By relating the fraction of neutral mutants at distance d to the average neutrality at distance d, we showed that this prevalence derives from the existence of many compensatory...

  9. 3D printing antagonistic systems of artificial muscle using projection stereolithography.

    Science.gov (United States)

    Peele, Bryan N; Wallin, Thomas J; Zhao, Huichan; Shepherd, Robert F

    2015-10-01

    The detailed mechanical design of a digital mask projection stereolithgraphy system is described for the 3D printing of soft actuators. A commercially available, photopolymerizable elastomeric material is identified and characterized in its liquid and solid form using rheological and tensile testing. Its capabilities for use in directly printing high degree of freedom (DOF), soft actuators is assessed. An outcome is the ∼40% strain to failure of the printed elastomer structures. Using the resulting material properties, numerical simulations of pleated actuator architectures are analyzed to reduce stress concentration and increase actuation amplitudes. Antagonistic pairs of pleated actuators are then fabricated and tested for four-DOF, tentacle-like motion. These antagonistic pairs are shown to sweep through their full range of motion (∼180°) with a period of less than 70 ms. PMID:26353071

  10. ANALYSIS OF INTERLEUKIN-1 RECEPTOR ANTAGONIST GENE POLYMORPHISM IN CHINESE PATIENTS WITH ALZHEIMER'S DISEASE

    Institute of Scientific and Technical Information of China (English)

    Sheng Bi; De-sheng Wang; Guo-lin Li; Shang-ha Pan

    2004-01-01

    Objective To identify an interaction between the interleukin-1 receptor antagonist gene polymorphism and risk of Alzheimer's disease.Methods The study included 117 healthy controls, 85 patients with Alzheimer's disease in a Northeastern Chinese population of Han nationality. Genotypes were determined by a polymerase chain reaction amplification of the intron 2 fragment,harbouring a variable number of short tandem nucleotide sequences. Amplification products were separated on a 2% agarose gel.Results The allele 2 frequency was 27% in healthy controls, and 21% in patients with Alzheimer's disease. Thus for allele 2 as well as for all other alleles, genotypes, or carriage rates, no significant differences compared with controls.Conclusions No association ofinterleukin-1 receptor antagonist gene polymorphism with Alzheimer's disease was identified in this population. It is also possible that the increased risk and disease modifying effects are caused by linkage disequilibrium with other genomic variants in other nearby genes.

  11. Screening of antagonistic activity of microorganisms against Colletotrichum acutatum and Colletotrichum gloeosporioides

    Directory of Open Access Journals (Sweden)

    Živković Svetlana

    2010-01-01

    Full Text Available The antagonistic activities of five biocontrol agents: Trichoderma harzianum, Gliocladium roseum, Bacillus subtilis, Streptomyces noursei and Streptomyces natalensis, were tested in vitro against Colletotrichum acutatum and Colletotrichum gloeosporioides, the causal agents of anthracnose disease in fruit crops. The microbial antagonists inhibited mycelial growth in the dual culture assay and conidial germination of Colletotrichum isolates. The two Streptomyces species exhibited the strongest antagonism against isolates of C. acutatum and C. gloeosporioides. Microscopic examination showed that the most common mode of action was antibiosis. The results of this study identify T. harzianum, G. roseum, B. subtilis, S. natalensis and S. noursei as promising biological control agents for further testing against anthracnose disease in fruits. .

  12. Antagonistic-synergistic muscle action at the knee during competitive weightlifting.

    Science.gov (United States)

    Collins, J J

    1994-03-01

    A sagittal-plane model of the knee, which takes account of the movements of the flexion axis relative to the femur and tibia and considers the possibility of antagonistic and synergistic muscle action, is used to determine the values of the forces transmitted by the muscles, cruciate ligaments and intra-articular surfaces during the clean phase of the clean-and-jerk weightlift. The theoretical analyses demonstrate that it is geometrically and mechanically possible for the knee musculature to unload and thereby protect the cruciate ligaments throughout a substantial portion of the lift. The price to be paid for this protection, in the case of the co-contraction of antagonistic muscles, is larger muscle and tibio-fermoral contact forces. The application of synergistic muscle action, however, results in smaller individual muscle and intra-articular contact forces. PMID:8022213

  13. Couple Control Model Implementation on Antagonistic Mono- and Bi-Articular Actuators

    CERN Document Server

    Prattico, Flavio; Yamamoto, Shin-ichiroh

    2014-01-01

    Recently, robot assisted therapy devices are increasingly used for spinal cord injury (SCI) rehabilitation in assisting handicapped patients to regain their impaired movements. Assistive robotic systems may not be able to cure or fully compensate impairments, but it should be able to assist certain impaired functions and ease movements. In this study, a couple control model for lower-limb orthosis of a body weight support gait training system is proposed. The developed leg orthosis implements the use of pneumatic artificial muscle as an actuation system. The pneumatic muscle was arranged antagonistically to form two pair of mono-articular muscles (i.e., hip and knee joints), and a pair of bi-articular actuators (i.e., rectus femoris and hamstring). The results of the proposed couple control model showed that, it was able to simultaneously control the antagonistic mono- and bi-articular actuators and sufficiently performed walking motion of the leg orthosis.

  14. Exploring Western Ghats microbial diversity for antagonistic microorganisms against fungal phytopathogens of pepper and chickpea

    Directory of Open Access Journals (Sweden)

    B.N. RAMKUMAR

    2015-08-01

    Full Text Available Newly isolated microbial cultures from Western Ghat soil samples of Kerala region in India were screened for antagonistic activity by well diffusion and dual culture plating against Phytophthora capsici and Rhizoctonia solani, infecting pepper and chickpea, respectively. Bioactive samples were made by varying solvent extraction of the culture broths of the potent isolates belongs to Actinomycetes, Pseudomonas, Bacillus and Trichoderma. The efficacy of the isolates to produce other potent antifungal metabolites such as cell wall degrading enzymes, HCN and volatile compounds were also checked. Treatment with antagonistic isolates in vivo under greenhouse conditions revealed significant reduction of the disease intensity of foot rot disease of black pepper and collar rot of chick pea.

  15. AMD3465, a monomacrocyclic CXCR4 antagonist and potent HIV entry inhibitor

    DEFF Research Database (Denmark)

    Hatse, Sigrid; Princen, Katrien; De Clercq, Erik;

    2005-01-01

    3100, AMD3465 was even 10-fold more effective as a CXCR4 antagonist, while showing no interaction whatsoever with CCR5. As expected, AMD3465 proved highly potent against X4 HIV strains (IC50: 1-10 nM), but completely failed to inhibit the replication of CCR5-using (R5) viruses. In conclusion, AMD3465......The chemokine receptors CCR5 and CXCR4 function as coreceptors for human immunodeficiency virus (HIV) and are attractive targets for the development of anti-HIV drugs. The most potent CXCR4 antagonists described until today are the bicyclams. The prototype compound, AMD3100, exhibits potent and...... selective anti-HIV activity against CXCR4-using (X4) viruses and showed antiviral efficacy in X4 HIV-1-infected persons in a phase II clinical trial. However, AMD3100 lacks oral bioavailability due to its high overall positive charge. Initial structure-activity relationship studies with bicyclam analogues...

  16. Radiolabeling with fluorine-18 of a protein, interleukin-1 receptor antagonist

    International Nuclear Information System (INIS)

    IL-1RA is a naturally occurring antagonist of the pro-inflammatory cytokine interleukin-1 (IL-1) with high therapeutic promise, but its pharmacokinetic remains poorly documented. In this report, we describe the radiolabeling of recombinant human interleukin-1 receptor antagonist (rhIL-1RA) with fluorine-18 to allow pharmacokinetic studies by positron emission tomography (PET). rhIL-1RA was labeled randomly by reductive alkylation of free amino groups (the ε-amino group of lysine residues or amino-terminal residues) using [18F]fluoroacetaldehyde under mild reaction conditions. Radiosyntheses used a remotely controlled experimental rig within 100 min and the radiochemical yield was in the range 7.1-24.2% (decay corrected, based on seventeen syntheses). We showed that the produced [18F]fluoroethyl-rhIL-1ra retained binding specificity by conducting an assay on rat brain sections, allowing its pharmakokinetic study using PET.

  17. The architecture of antagonistic networks: Node degree distribution, compartmentalization and nestedness

    Directory of Open Access Journals (Sweden)

    Savannah Nuwagaba

    2015-12-01

    Full Text Available Describing complex ecosystems as networks of interacting components has proved fruitful - revealing many distinctive patterns and dynamics of ecological systems. Of these patterns, three have often been brought up in literature, including species degree distribution, compartmentalization and nestedness, due largely to their implications for the functionality and stability of communities. Here, using 61 empirical antagonistic networks, we aim to settle the inconsistency in literature by (i fitting their node degree distributions to five different parametric models and identifying the one fits the best, (ii measuring the levels of nestedness and compartmentalization of these 61 networks and testing their significance using different null models, and (iii exploring how network connectance affects these three network architecture metrics. This research showed that most antagonistic networks do not display power law degree distributions and that resource species are generally uniformly distributed. We also clearly showed that the conclusion of whether a network is significantly compartmentalized or nested depends largely on the null model used.

  18. Differential binding of urokinase and peptide antagonists to the urokinase receptor

    DEFF Research Database (Denmark)

    Engelholm, L H; Behrendt, N

    2001-01-01

    though these sequences contain very few substitutions relative to the human uPAR, the receptor protein products differ markedly in terms of ligand selectivity. Thus, a well described competitive peptide antagonist directed against the human uPAR reacts with only one of the monkey receptors (chimpanzee u......PAR), in spite of the fact that uPAR from all of the four species cross-reacts with human uPA. Notably, uPAR from African green monkey, which is completely devoid of reactivity with the peptide, contains only three substitutions relative to chimpanzee uPAR in the molecular regions critical for binding....... These findings aid the elucidation of the structure/function relationship of uPAR and, unexpectedly, identify a structural distinction governing the binding of uPA and a very similar peptide antagonist....

  19. Androgen receptor antagonists compromise T cell response against prostate cancer leading to early tumor relapse.

    Science.gov (United States)

    Pu, Yang; Xu, Meng; Liang, Yong; Yang, Kaiting; Guo, Yajun; Yang, Xuanming; Fu, Yang-Xin

    2016-04-01

    Surgical and medical androgen deprivation therapy (ADT) is a cornerstone for prostate cancer treatment, but relapse usually occurs. We herein show that orchiectomy synergizes with immunotherapy, whereas the more widely used treatment of medical ADT involving androgen receptor (AR) antagonists suppresses immunotherapy. Furthermore, we observed that the use of medical ADT could unexpectedly impair the adaptive immune responses through interference with initial T cell priming rather than in the reactivation or expansion phases. Mechanistically, we have revealed that inadvertent immunosuppression might be potentially mediated by a receptor shared with γ-aminobutyric acid. Our data demonstrate that the timing and dosing of antiandrogens are critical to maximizing the antitumor effects of combination therapy. This study highlights an underappreciated mechanism of AR antagonist-mediated immunosuppression and provides a new strategy to enhance immune response and prevent the relapse of advanced prostate cancer. PMID:27053771

  20. Postcountershock myocardial damage after pretreatment with adrenergic and calcium channel antagonists in halothane-anesthetized dogs

    International Nuclear Information System (INIS)

    Transthoracic electric countershock can cause necrotic myocardial lesions in humans as well as experimental animals. The authors investigated the effect on postcountershock myocardial damage of pretreatment with prazosin, an alpha-1 antagonist; L-metoprolol, a beta-1 antagonist, and verapamil, a calcium channel-blocking agent. Twenty dogs were anesthetized with halothane and given two transthoracic countershocks of 295 delivered joules each after drug or vehicle treatment. Myocardial injury was quantitated 24 h following countershock by measuring the uptake of technetium-99m pyrophosphate in the myocardium. Elevated technetium-99m pyrophosphate uptake occurred in visible lesions in most dogs regardless of drug treatment. For each of four parameters of myocardial damage there was no statistically significant difference between control animals and those treated with prazosin, metoprolol, or verapamil. These data suggest that adrenergic or calcium channel-mediated mechanisms are not involved in the pathogenesis of postcountershock myocardial damage

  1. Postcountershock myocardial damage after pretreatment with adrenergic and calcium channel antagonists in halothane-anesthetized dogs

    Energy Technology Data Exchange (ETDEWEB)

    Gaba, D.M.; Metz, S.; Maze, M.

    1985-05-01

    Transthoracic electric countershock can cause necrotic myocardial lesions in humans as well as experimental animals. The authors investigated the effect on postcountershock myocardial damage of pretreatment with prazosin, an alpha-1 antagonist; L-metoprolol, a beta-1 antagonist, and verapamil, a calcium channel-blocking agent. Twenty dogs were anesthetized with halothane and given two transthoracic countershocks of 295 delivered joules each after drug or vehicle treatment. Myocardial injury was quantitated 24 h following countershock by measuring the uptake of technetium-99m pyrophosphate in the myocardium. Elevated technetium-99m pyrophosphate uptake occurred in visible lesions in most dogs regardless of drug treatment. For each of four parameters of myocardial damage there was no statistically significant difference between control animals and those treated with prazosin, metoprolol, or verapamil. These data suggest that adrenergic or calcium channel-mediated mechanisms are not involved in the pathogenesis of postcountershock myocardial damage.

  2. Platelet deposition in rat heart allografts and the effect of a thromboxane receptor antagonist

    Energy Technology Data Exchange (ETDEWEB)

    Foegh, M.L.; Khirabadi, B.S.; Ramwell, P.W.

    1986-07-01

    The effect of a thromboxane antagonist, L640,035 on platelet deposition in heart allografts was studied. Twenty Lewis rats received heterotopic allografts from Lewis x Brown-Norway F1 hybrid. All recipients received azathioprine (5 mg/kg/day). The rats were divided into three groups. Groups II and III were also treated daily with either the vehicle for L640,035 or L640,035 respectively. Syngeneic indium-111-labeled platelet deposition was determined in the allograft and the native heart at 6, 9, and 13 days after transplantation; group III was studied on the sixth and ninth day only. A rapidly increasing platelet deposition was seen in allografts from rats given azathioprine; whereas the thromboxane antagonist prevented the increase in platelet deposition on the ninth day.

  3. Platelet deposition in rat heart allografts and the effect of a thromboxane receptor antagonist

    International Nuclear Information System (INIS)

    The effect of a thromboxane antagonist, L640,035 on platelet deposition in heart allografts was studied. Twenty Lewis rats received heterotopic allografts from Lewis x Brown-Norway F1 hybrid. All recipients received azathioprine (5 mg/kg/day). The rats were divided into three groups. Groups II and III were also treated daily with either the vehicle for L640,035 or L640,035 respectively. Syngeneic indium-111-labeled platelet deposition was determined in the allograft and the native heart at 6, 9, and 13 days after transplantation; group III was studied on the sixth and ninth day only. A rapidly increasing platelet deposition was seen in allografts from rats given azathioprine; whereas the thromboxane antagonist prevented the increase in platelet deposition on the ninth day

  4. Functional antagonistic properties of clozapine at the 5-HT3 receptor.

    Science.gov (United States)

    Hermann, B; Wetzel, C H; Pestel, E; Zieglgänsberger, W; Holsboer, F; Rupprecht, R

    1996-08-23

    The atypical neuroleptic clozapine is thought to exert its psychopharmacological actions through a variety of neurotransmitter receptors. It binds preferentially to D4 and 5-HT2 receptors; however, little is known on it's interaction with the 5-HT3 receptor. Using a cell line stably expressing the 5-HT3 receptor, whole-cell voltage-clamp analysis revealed functional antagonistic properties of clozapine at low nanomolar concentrations in view of a binding affinity in the upper nanomolar range. Because the concentration of clozapine required for an interaction with the 5-HT3 receptor can be achieved with therapeutical doses, functional antagonistic properties at this ligand-gated ion channel may contribute to its unique psychopharmacological profile. PMID:8780717

  5. Treatment of canine pyometra with the gonadotropin-releasing hormone antagonist acyline: a case series.

    Science.gov (United States)

    Batista, Pablo R; Blanco, Paula G; Gobello, Cristina

    2015-03-01

    To describe the effect of the third-generation gonadotropin-releasing hormone antagonist acyline in the treatment of 4 diestrous bitches with the cystic endometrial hyperplasia-pyometra complex. The 4 bitches were treated with 330 μg/kg of subcutaneous acyline on day 0 and antibiotics, and followed up for 2 weeks. One closed-cervix case showed cervical dilatation 36 hours after treatment, and all the 4 animals showed resolution of clinical signs starting on day 3 posttreatment. Ultrasonographic uterine diameters and luminal contents decreased in the bitches having high progesterone serum concentrations before treatment but not in those with low levels. Serum progesterone importantly decreased from high to basal concentrations in the 3 "ultrasonographically cured" animals. No local or systemic side effects related to the treatment were observed. The gonadotropin-releasing hormone antagonist acyline may have a promising place for the medical treatment of cystic endometrial hyperplasia-pyometra complex in dogs. PMID:26041594

  6. In vitro competitive adhesion and production of antagonistic compounds by lactic acid bacteria against fish pathogens.

    Science.gov (United States)

    Balcázar, José Luis; Vendrell, Daniel; de Blas, Ignacio; Ruiz-Zarzuela, Imanol; Gironés, Olivia; Múzquiz, José Luis

    2007-06-21

    The present study describes the screening of five lactic acid bacteria (LAB) for use as probiotics based on their competitive adhesion and production of antagonistic substances against some fish pathogens. A reduction of adhesion of all pathogenic strains tested was obtained with three of the LAB strains (Lactococcus lactis subsp. lactis CLFP100, Lactococcus lactis subsp. cremoris CLFP102 and Lactobacillus curvatus CLFP150). With the exception of fish pathogens Flavobacterium psychrophilum and Renibacterium salmoninarum that were not inhibited by LAB strains, production of antagonistic compounds by all tested LAB was observed against at least one of the indicator strains. Based on mucus adhesion, competitive exclusion, and suppression of fish pathogen growth, the selected LAB strains can be considered for future challenge experiments in fish as a very promising alternative to the use of chemotherapeutic agents. PMID:17336468

  7. Phosphorylation of influenza A virus NS1 protein at threonine 49 suppresses its interferon antagonistic activity.

    Science.gov (United States)

    Kathum, Omer Abid; Schräder, Tobias; Anhlan, Darisuren; Nordhoff, Carolin; Liedmann, Swantje; Pande, Amit; Mellmann, Alexander; Ehrhardt, Christina; Wixler, Viktor; Ludwig, Stephan

    2016-06-01

    Phosphorylation and dephosphorylation acts as a fundamental molecular switch that alters protein function and thereby regulates many cellular processes. The non-structural protein 1 (NS1) of influenza A virus is an important factor regulating virulence by counteracting cellular immune responses against viral infection. NS1 was shown to be phosphorylated at several sites; however, so far, no function has been conclusively assigned to these post-translational events yet. Here, we show that the newly identified phospho-site threonine 49 of NS1 is differentially phosphorylated in the viral replication cycle. Phosphorylation impairs binding of NS1 to double-stranded RNA and TRIM25 as well as complex formation with RIG-I, thereby switching off its interferon antagonistic activity. Because phosphorylation was shown to occur at later stages of infection, we hypothesize that at this stage other functions of the multifunctional NS1 beyond its interferon-antagonistic activity are needed. PMID:26687707

  8. Drug Insight: endothelin-receptor antagonists for pulmonary arterial hypertension in systemic rheumatic diseases.

    Science.gov (United States)

    Humbert, Marc; Simonneau, Gérald

    2005-12-01

    Rapid advances in the understanding of endothelin as a naturally occurring peptide with developmental and regulatory roles in normal physiology, along with a number of deleterious effects under pathologic conditions (including vasoconstriction, fibrosis, vascular hypertrophy, and inflammation) have led to the development of endothelin-receptor antagonists (ERAs). Bosentan, an antagonist with dual specificity for the endothelin-receptor subtypes A and B, has been shown to be efficacious and well tolerated in placebo-controlled clinical trials and is now approved in many countries, including the US, Canada, and Europe, for treatment of pulmonary arterial hypertension (PAH), including PAH associated with rheumatic diseases. ERAs with specificity for the endothelin-receptor subtype A, including sitaxsentan and ambrisentan, are currently undergoing investigation. This article reviews PAH associated with systemic rheumatic diseases and describes the role of ERAs in this setting. PMID:16932638

  9. Small-molecule endothelin receptor antagonists: a review of patenting activity across therapeutic areas.

    Science.gov (United States)

    Mucke, Hermann A M

    2009-06-01

    In the field of nonpeptide NCEs with endothelin receptor antagonist activity, a burst in corporate IP filings occurred in the 1990s once the human endothelin system had been characterized, but patent activity has declined in the past decade. Universities have not been active in this area of research to a degree that would have led to many patent applications. While three endothelin receptor antagonists (bosentan, sitaxentan and ambrisentan) are already available for the treatment of pulmonary arterial hypertension, the use of such compounds for the larger therapy areas of heart failure, cancer and nephropathy is still being evaluated in late-stage clinical trials. Marketed and advanced-stage endothelin receptor blockers have remarkably little chemical diversity; thus, the substantially larger chemical space defined by patenting remains to be explored. PMID:19517317

  10. Cysteinyl leukotriene receptor antagonist regulates allergic airway inflammation in an organ- and cytokine-specific manner

    OpenAIRE

    Kawano, Tetsuya; Matsuse, Hiroto; Tsuchida, Tomoko; Fukahori, Susumu; Fukushima, Chizu; Nishino, Tomoya; Kohno, Shigeru

    2014-01-01

    Background Cysteinyl leukotrienes (cys-LTs) are very important factors in the pathophysiology of bronchial asthma. Cys-LT receptor antagonists (LTRAs) decrease allergic airway inflammation. The aim of the present study was to determine the differential effects of LTRAs and corticosteroids on allergic airway inflammation and allergen-specific cytokine production from lymphoid tissues using a murine model of asthma. Material/Methods Four groups of female BALB/c mice [control (Cont); Dermatophag...

  11. Differential sleep-promoting effects of dual orexin receptor antagonists and GABAA receptor modulators

    OpenAIRE

    Gotter, Anthony L.; Garson, Susan L.; Stevens, Joanne; Munden, Regina L; Fox, Steven V.; Tannenbaum, Pamela L.; Yao, Lihang; Kuduk, Scott D.; McDonald, Terrence; Uslaner, Jason M.; Tye, Spencer J.; Coleman, Paul J.; Winrow, Christopher J; Renger, John J.

    2014-01-01

    Background The current standard of care for insomnia includes gamma-aminobutyric acid receptor A (GABAA) activators, which promote sleep as well as general central nervous system depression. Dual orexin receptor antagonists (DORAs) represent an alternative mechanism for insomnia treatment that induces somnolence by blocking the wake-promoting effects of orexin neuropeptides. The current study compares the role and interdependence of these two mechanisms on their ability to influence sleep arc...

  12. Intra-locus sexual conflict and sexually antagonistic genetic variation in hermaphroditic animals

    OpenAIRE

    Abbott, Jessica K.

    2010-01-01

    Intra-locus sexual conflict results when sex-specific selection pressures for a given trait act against the intra-sexual genetic correlation for that trait. It has been found in a wide variety of taxa in both laboratory and natural populations, but the importance of intra-locus sexual conflict and sexually antagonistic genetic variation in hermaphroditic organisms has rarely been considered. This is not so surprising given the conceptual and theoretical association of intra-locus sexual confl...

  13. Discriminative stimulus properties of the dopamine D3 antagonist PNU-99194A.

    Science.gov (United States)

    Franklin, S R; Baker, L E; Svensson, K A

    1998-07-01

    It was recently documented that the relatively selective dopamine D3 receptor antagonist, PNU-99194A, is capable of establishing discriminative stimulus control in rats and that the discriminative cue associated with this compound is not similar to that produced by psychostimulants. The present experiment further characterized the discriminative stimulus properties of PNU-99194A by examining several other dopaminergic agents for stimulus generalization in 23 male Sprague-Dawley rats trained to discriminate 10 mg/kg PNU-99194A (SC, 15 min) from vehicle in a two-choice discrimination procedure under an FR10 schedule of food reinforcement. Rats achieved a criterion of ten consecutive sessions with correct lever choice after a median of 35.5 sessions (range 23-78). In substitution tests, the non-selective D2 receptor antagonist, haloperidol (0.01- 0.1 mg/kg), and the mixed D2/D3 antagonists, amisulpiride (3.2-32 mg/kg) and sulpiride (32-200 mg/kg), failed to produce stimulus generalization, while the D3-preferring antagonists, (-)-DS121 (1-10 mg/kg) and (+)-AJ76 (3.2-32 mg/kg), produced complete stimulus generalization. Direct and indirect DA agonists, including apomorphine (0.01-0.32 mg/kg) and d-amphetamine (0.1-1 mg/kg), the D1 agonist SKF38393 (10-100 mg/kg), the D2 selective agonist PNU-95666E (0.32-3.2 mg/kg) and the D3-preferring agonist pramipexole (0.032-1 mg/kg), all produced non-significant amounts of drug-appropriate responding and significantly reduced response rate. It is concluded that PNU-99194A produces a distinctive subjective cue which is probably based on D3 receptor antagonism. PMID:9694525

  14. Cysteinyl Leukotriene Receptor Antagonists Inhibit Tumor Metastasis by Inhibiting Capillary Permeability

    OpenAIRE

    Nozaki, Masako; Yoshikawa, Masanobu; Ishitani, Kunihiko; Kobayashi, Hiroyuki; HOUKIN, KIYOHIRO; Imai, Kohzoh; Ito, Yoichiro; Muraki, Takamura

    2010-01-01

    We explored the possibility of the cysteinyl leukotriene receptor antagonists, pranlukast and montelukast, preventing tumor cell migration through both cerebral and peripheral capillaries. To study tumor cell migration through brain capillaries, male Fisher rats were cannulated via the cisterna magna under pentobarbital anesthesia. RCN9 cells labeled with a fluorescent marker PKH67 were intravenously administered following arachidonic acid administration into the subarachnoid space, and speci...

  15. Effect of Leukotriene Receptor Antagonist Montelukast Along with Curcumin against Gastric Ulceration

    OpenAIRE

    UM Viradia; Shenoy AM; Rajan MS; AR Shabaraya; Kothadia AD; Patel NH

    2011-01-01

    Curcumin, a yellow pigment in the spice turmeric, has been used for centuries as a treatment for inflammatory diseases. This yellow pigment has anti-secretary property in different experimental ulcer models. Montelukast, a leukotriene receptor antagonist has been used for the treatment of inflammatory disease. This substance has antioxidant property in different experimental models. This data supports to evaluate the synergistic effect of Montelukast along with Curcumin against gastric ulcera...

  16. Complex Actions of Thyroid Hormone Receptor Antagonist NH-3 on Gene Promoters in Different Cell Lines

    OpenAIRE

    Shah, Vanya; Nguyen, Van Phuong; Nguyen, Ngoc-Ha; Togashi, Marie; Scanlan, Thomas S.; Baxter, John D.; Webb, Paul

    2008-01-01

    It is desirable to obtain new antagonists for thyroid hormone (TRs) and other nuclear receptors (NRs). We previously used X-ray structural models of TR ligand binding domains (LBDs) to design compounds, such as NH-3, that impair coactivator binding to activation function 2 (AF-2) and block thyroid hormone (triiodothyronine, T3) actions. However, TRs bind DNA and are transcriptionally active without ligand. Thus, NH-3 could modulate TR activity via effects on other coregulator interaction surf...

  17. Effect of glutamate antagonists on nitric oxide production in rat brain following intrahippocampal injection

    OpenAIRE

    Radenović Lidija; Selaković Vesna; Janać Branka; Todorović Dajana

    2007-01-01

    Stimulation of glutamate receptors induces neuronal nitric oxide (NO) release, which in turn modulates glutamate transmission. The involvement of ionotropic glutamate NMDA and AMPA/kainate receptors in induction of NO production in the rat brain was examined after injection of kainate, a non-NMDA receptor agonist; kainate plus 6-cyano- 7-nitroquinoxaline-2,3-dione (CNQX), a selective AMPA/kainate receptor antagonist; or kainate plus 2-amino-5-phosphonopentanoic acid (APV), a selective NMDA re...

  18. Effect of gonadal hormones on hypophagic property of opioid antagonist Naloxone

    OpenAIRE

    Gargate Ashwini R, Kulkarni Dushant V

    2014-01-01

    Background: Studies have shown that hormonal fluctuations that occur over the estrous cycle in rats affect food intake. It is possible that estrogen affects food intake via Opioid system and other brain areas which are involved in regulation of food intake. Therefore it may affect the sensitivity of female rats to hypophagic effect of Opioid antagonist Naloxone. Testosterone in male rats also changes food intake. However, little is known about hoe these Gonadal hormones interact with Opioid ...

  19. Benzimidazole-2-carboxamides as novel NR2B selective NMDA receptor antagonists.

    Science.gov (United States)

    Borza, István; Kolok, Sándor; Gere, Anikó; Nagy, József; Fodor, László; Galgóczy, Kornél; Fetter, József; Bertha, Ferenc; Agai, Béla; Horváth, Csilla; Farkas, Sándor; Domány, György

    2006-09-01

    A novel series of benzimidazole-2-carboxamide derivatives was prepared and identified as NR2B selective NMDA receptor antagonists. The influence of some structural elements, like H-bond donor groups placed on the benzimidazole skeleton and the substitution pattern of the piperidine ring, on the biological activity was studied. Compound 6a showed excellent analgetic activity in the mouse formalin test following po administration. PMID:16782335

  20. Learned Avoidance in the Male Syrian Hamster: Investigating the Outcome of a Glucocorticoid Antagonist on Reconsolidation

    OpenAIRE

    Erik Haugsnes; Alicia Askew

    2015-01-01

    In this experiment, we used our Conflict Alleyway Apparatus and a glucocorticoid antagonist, mifepristone, to investigate the role of glucocorticoids in the reconsolidation of learned avoidance in defeated male Syrian hamsters. Subjects were tested for memory deficits 48 hours and 96 hours after the drug/vehicle was administered. It were hypothesized that mifepristone administration would produce memory deficits when the defeat memory had been reactivated, and that this deficit would be prese...

  1. Development of Time Resolved Fluorescence Resonance Energy Transfer-based Assay for FXR Antagonist Discovery

    OpenAIRE

    Yu, Donna D.; Lin, Wenwei; Chen, Taosheng; Forman, Barry M.

    2013-01-01

    FXR (farnesoid X receptor, NRIH4), a nuclear receptor, plays a major role in the control of cholesterol metabolism. FXR ligands have been investigated in preclinical studies for targeted therapy against metabolic diseases, but have shown limitations. Therefore, there is a need for new agonist or antagonist ligands of FXR, both for potential clinical applications, as well as to further elucidate its biological functions. Here we describe the use of the X-ray crystal structure of FXR complexed ...

  2. Supply chains : ago-antagonistic systems through co-opetition game theory lens

    OpenAIRE

    Zouaghi, I.; Spalanzani, A.

    2009-01-01

    cahier de recherche n°2009-13 E5 Supply chain configurations, as hybrid governance structures, allow companies to be sufficiently integrated while keeping a certain level of flexibility. This enables them, on one hand, to converge towards common interests through the development of cooperation; and on the other hand, to diverge on their own interests by remaining in competition. This dynamics generates an ago-antagonistic system where both of these two concepts, namely cooperation and comp...

  3. An Efficient Synthesis of Selective Human NR2A Antagonist NVP-AAM077

    Institute of Scientific and Technical Information of China (English)

    LI, Gang-Qin; SU, Wei-Ke; YAO, Zhu-Jun

    2006-01-01

    A short and efficient synthesis of the selective human N-methyl-D-aspartate (NMDA) receptor 2A (NR2A) antagonist NVP-AAM077 is described. The target was achieved in 8 steps and in 54% overall yield from the commercially available chemical 3-methylbenzene-1,2-diamine. A NaIO4/DMF-based oxidation of the bromide to corresponding aldehyde and an addition of phosphinic acid ester to the aldimine successfully served as the key steps.

  4. Radiolabeled somatostatin receptor antagonists are preferable to agonists for in vivo peptide receptor targeting of tumors

    OpenAIRE

    Ginj, Mihaela; Zhang, Hanwen; Waser, Beatrice; Cescato, Renzo; Wild, Damian; Wang, Xuejuan; Erchegyi, Judit; Rivier, Jean; Mäcke, Helmut R.; Reubi, Jean Claude

    2006-01-01

    Targeting neuroendocrine tumors expressing somatostatin receptor subtypes (sst) with radiolabeled somatostatin agonists is an established diagnostic and therapeutic approach in oncology. While agonists readily internalize into tumor cells, permitting accumulation of radioactivity, radiolabeled antagonists do not, and they have not been considered for tumor targeting. The macrocyclic chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) was coupled to two potent somatostatin...

  5. Pathophysiology of a severe case of Puumala hantavirus infection successfully treated with bradykinin receptor antagonist icatibant.

    Science.gov (United States)

    Vaheri, Antti; Strandin, Tomas; Jääskeläinen, Anne J; Vapalahti, Olli; Jarva, Hanna; Lokki, Marja-Liisa; Antonen, Jaakko; Leppänen, Ilona; Mäkelä, Satu; Meri, Seppo; Mustonen, Jukka

    2014-11-01

    We recently described a patient with very severe Puumala hantavirus infection manifested by capillary leakage syndrome and shock. He was successfully treated with the bradykinin receptor antagonist, icatibant (Antonen et al., 2013). Here we report analysis of the pathophysiology which indicated pronounced complement activation, prolonged leukocytosis, extensive fibrinolysis, circulating histones, and defects in liver function. The patient had an uncommon HLA-phenotype, which may have contributed to the severe course of the disease. PMID:25194993

  6. A Review on Biological Control of Fungal Plant Pathogens Using Microbial Antagonists

    OpenAIRE

    Mohammad Pessarakli; Asghar Heydari

    2010-01-01

    The objective of this study was to review the published research works on biological control of fungal plant diseases during past 50 years. Fungal plant pathogens are among the most important factors that cause serious losses to agricultural products every year. Biological control of plant diseases including fungal pathogens has been considered a viable alternative method to chemical control. In plant pathology, the term biocontrol applies to the use of microbial antagonists to suppress disea...

  7. Plant growth-promoting rhizobacteria (PGPR): Their potential as antagonists and biocontrol agents

    OpenAIRE

    Anelise Beneduzi; Adriana Ambrosini; Luciana M.P. Passaglia

    2012-01-01

    Bacteria that colonize plant roots and promote plant growth are referred to as plant growth-promoting rhizobacteria (PGPR). PGPR are highly diverse and in this review we focus on rhizobacteria as biocontrol agents. Their effects can occur via local antagonism to soil-borne pathogens or by induction of systemic resistance against pathogens throughout the entire plant. Several substances produced by antagonistic rhizobacteria have been related to pathogen control and indirect promotion of growt...

  8. The necessity and effectiveness of mineralocorticoid receptor antagonist in the treatment of diabetic nephropathy.

    Science.gov (United States)

    Sato, Atsuhisa

    2015-06-01

    Diabetes mellitus is a major cause of chronic kidney disease (CKD), and diabetic nephropathy is the most common primary disease necessitating dialysis treatment in the world including Japan. Major guidelines for treatment of hypertension in Japan, the United States and Europe recommend the use of angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers, which suppress the renin-angiotensin system (RAS), as the antihypertensive drugs of first choice in patients with coexisting diabetes. However, even with the administration of RAS inhibitors, failure to achieve adequate anti-albuminuric, renoprotective effects and a reduction in cardiovascular events has also been reported. Inadequate blockade of aldosterone may be one of the reasons why long-term administration of RAS inhibitors may not be sufficiently effective in patients with diabetic nephropathy. This review focuses on treatment in diabetic nephropathy and discusses the significance of aldosterone blockade. In pre-nephropathy without overt nephropathy, a mineralocorticoid receptor antagonist can be used to enhance the blood pressure-lowering effects of RAS inhibitors, improve insulin resistance and prevent clinical progression of nephropathy. In CKD categories A2 and A3, the addition of a mineralocorticoid receptor antagonist to an RAS inhibitor can help to maintain 'long-term' antiproteinuric and anti-albuminuric effects. However, in category G3a and higher, sufficient attention must be paid to hyperkalemia. Mineralocorticoid receptor antagonists are not currently recommended as standard treatment in diabetic nephropathy. However, many studies have shown promise of better renoprotective effects if mineralocorticoid receptor antagonists are appropriately used. PMID:25762415

  9. Rivaroxaban versus enoxaparin/vitamin K antagonist therapy in patients with venous thromboembolism and renal impairment

    OpenAIRE

    Bauersachs, Rupert M.; Lensing, Anthonie WA; Prins, Martin H.; Kubitza, Dagmar; Pap, Ákos F; Decousus, Hervé; Beyer-Westendorf, Jan; Prandoni, Paolo

    2014-01-01

    Background Patients with renal impairment receiving classical anticoagulation for venous thromboembolism (VTE) are at increased risk of bleeding and possibly pulmonary embolism. We examined the efficacy and safety of oral rivaroxaban in patients with VTE with and without renal impairment. Methods Prespecified subgroup analysis of the EINSTEIN DVT and EINSTEIN PE studies comparing fixed-dose rivaroxaban with enoxaparin/a vitamin K antagonist (VKA), performed in 8246 patients enrolled from 2007...

  10. APPLICATION OF CALCIUM ANTAGONISTS IN PREVENTION OF CARDIOVASCULAR COMPLICATIONS DURING CARDIAC SURGERY

    OpenAIRE

    S. V. Nedogoda

    2016-01-01

    Results of randomized clinical trials on the usage of calcium antagonists (CA) in order to prevent perioperative complications during aortocoronary bypass procedure and operations on heart valves are analyzed. CA reduced the risk of perioperative myocardial infarctions and episodes of reversible myocardial ischemia. After angioplasty of coronary arteries CA (particularly amlodipine) show positive effects on restenosis incidence and reduce about 3 times a number of repeated angioplasty and aor...

  11. Orexin / hypocretin 1 receptor antagonist reduces heroin self-administration and cue-induced heroin seeking

    OpenAIRE

    Smith, Rachel J; Aston-Jones, Gary

    2012-01-01

    The orexin / hypocretin system is involved in several addiction-related behaviors. The present experiments examined the involvement of orexin in heroin reinforcement and relapse by administering the orexin 1 receptor antagonist SB-334867 prior to heroin self-administration or prior to cue- or heroin-induced reinstatement of extinguished heroin seeking in male Sprague Dawley rats. SB-334867 (30 mg/kg, i.p.) reduced heroin intake during self-administration under fixed ratio-1 (FR-1) and progres...

  12. Discovery and characterization of a potent and selective EP4 receptor antagonist.

    Science.gov (United States)

    Schiffler, Matthew A; Chandrasekhar, Srinivasan; Fisher, Matthew J; Harvey, Anita; Kuklish, Steven L; Wang, Xu-Shan; Warshawsky, Alan M; York, Jeremy S; Yu, Xiao-Peng

    2015-08-15

    EP4 is a prostaglandin E2 receptor that is a target for potential anti-nociceptive therapy. Described herein is a class of amphoteric EP4 antagonists which reverses PGE2-induced suppression of TNFα production in human whole blood. From this class, a potent and highly bioavailable compound (6) has been selected for potential clinical studies. EP4 binding and functional data, selectivity, and pharmacokinetic properties of this compound are included. PMID:26091726

  13. Effects of autacoid inhibitors and of an antagonist on malaria infection in mice

    Directory of Open Access Journals (Sweden)

    Iwalewa E.O.

    2004-01-01

    Full Text Available The effects of p-chlorophenylalanine, an inhibitor of serotonin synthesis, indomethacin, an inhibitor of prostaglandin synthesis, cyproheptadine, a serotonin, bradykinin and histamine antagonist, were assessed separately and in combination with chloroquine (CQ in Vom strains of Swiss albino mice (18-22 g of either sex infected intraperitoneally with 1 x 10(7 Plasmodium yoelii nigeriensis-induced malaria. As prophylactic, these agents reduced from 31.9 ± 4.5 to 16.1 ± 8.1% the level of parasitemia relative to control but had no appreciable activity as curative agents when administered subcutaneously once daily for 4 days after 72 h of parasites innoculum in vivo. However, CQ alone and the combination of these agents with CQ in curative and prophylactic treatments significantly reduced (from 50.3 ± 5.8 to 4.9 ± 0.75% the level of parasitemia (P < 0.05, which was taken only once 72 h after the parasites innoculum. The prophylactic result was shown to produce better results than the curative treatment. The data indicate that inhibitors and an antagonist can reduce the parasitemia load (the extent of damage and the severity of infection as well as enhance the effects of CQ when combined with it for malaria therapy. The study reveals that the production of autacoids in established infection renders autacoid inhibitors and an antagonist ineffective for radical cure in malarial mice; however, selective inhibition of local hormones implicated in the pathological manifestations of malaria infection by autacoid inhibitors and an antagonist may be a possible pathway to reduce the severity of infection and the associated tissue damage and to enhance the efficacy of available anti-malarials.

  14. Antagonistic action of Streptococcus salivarius and Streptococcus faecalis to Mycobacterium tuberculosis.

    Science.gov (United States)

    Darling, C L; Hart, G D

    1976-01-01

    Streptococcus salivarius and Streptococcus faecalis were found to inhibit the growth of Mycobacterium tuberculosis on Löwenstein-Jensen and Middlebrook 7H11 agars, but not on the latter medium when antibacterial drugs were added. S. faecalis was found to be more inhibitory than S. salivarius to 15 strains of M. tuberculosis. S. salivarius produced little or no inhibition of growth of Runyon group III organisms but was very antagonistic to Runyon group I mycobacteria. Images PMID:824304

  15. Effect of vibration frequency on agonist and antagonist arm muscle activity

    OpenAIRE

    Rodríguez Jiménez, Sergio; Benítez Herrera, Adolfo; García González, Miguel Ángel; Moras-Feliu, Gerard; Maffiuletti, Nicola A

    2015-01-01

    Purpose This study aimed to assess the effect of vibration frequency (fout) on the electromyographic (EMG) activity of the biceps brachii (BB) and triceps brachii (TB) muscles when acting as agonist and antagonist during static exercises with different loads. Methods Fourteen healthy men were asked to hold a vibratory bar as steadily as possible for 10 s during lying row (pulling) and bench press (pushing) exercise at fout of 0 (non-vibration condition), 18, 31 and 42 Hz with loads of 20, ...

  16. Behavioral sensitization to apomorphine in pigeons (Columba livia) : blockade by the D₁ dopamine antagonist SCH-23390

    OpenAIRE

    Acerbo, Martin J.; Delius, Juan

    2004-01-01

    Repeated administration of apomorphine leads to a context-dependent pecking response sensitization. Previously sensitized pigeons (Columba livia) challenged with saline in the same context show a conditioned response (CR). The authors studied the effects of intrastriatal injections of the dopamine (D₁) antagonist SCH-23390 on both the sensitized response and the CR. When coadministered with apomorphine, SCH-23390 inhibited the initial response to apomorphine, prevented the development of sens...

  17. Adenosine receptor antagonists alter the stability of human epileptic GABAA receptors

    Science.gov (United States)

    Roseti, Cristina; Martinello, Katiuscia; Fucile, Sergio; Piccari, Vanessa; Mascia, Addolorata; Di Gennaro, Giancarlo; Quarato, Pier Paolo; Manfredi, Mario; Esposito, Vincenzo; Cantore, Gianpaolo; Arcella, Antonella; Simonato, Michele; Fredholm, Bertil B.; Limatola, Cristina; Miledi, Ricardo; Eusebi, Fabrizio

    2008-01-01

    We examined how the endogenous anticonvulsant adenosine might influence γ-aminobutyric acid type A (GABAA) receptor stability and which adenosine receptors (ARs) were involved. Upon repetitive activation (GABA 500 μM), GABAA receptors, microtransplanted into Xenopus oocytes from neurosurgically resected epileptic human nervous tissues, exhibited an obvious GABAA-current (IGABA) run-down, which was consistently and significantly reduced by treatment with the nonselective adenosine receptor antagonist CGS15943 (100 nM) or with adenosine deaminase (ADA) (1 units/ml), that inactivates adenosine. It was also found that selective antagonists of A2B (MRS1706, 10 nM) or A3 (MRS1334, 30 nM) receptors reduced IGABA run-down, whereas treatment with the specific A1 receptor antagonist DPCPX (10 nM) was ineffective. The selective A2A receptor antagonist SCH58261 (10 nM) reduced or potentiated IGABA run-down in ≈40% and ≈20% of tested oocytes, respectively. The ADA-resistant, AR agonist 2-chloroadenosine (2-CA) (10 μM) potentiated IGABA run-down but only in ≈20% of tested oocytes. CGS15943 administration again decreased IGABA run-down in patch-clamped neurons from either human or rat neocortex slices. IGABA run-down in pyramidal neurons was equivalent in A1 receptor-deficient and wt neurons but much larger in neurons from A2A receptor-deficient mice, indicating that, in mouse cortex, GABAA-receptor stability is tonically influenced by A2A but not by A1 receptors. IGABA run-down from wt mice was not affected by 2-CA, suggesting maximal ARs activity by endogenous adenosine. Our findings strongly suggest that cortical A2–A3 receptors alter the stability of GABAA receptors, which could offer therapeutic opportunities. PMID:18809912

  18. MINIATURIZED FERMENTATION IN EPPENDORF TUBES FOR THE DETECTION OF ANTAGONISTIC ACTINOMYCETES

    OpenAIRE

    2012-01-01

    Actinomycetes are recognized as a prolific source for bioactive metabolites. Screening adequate number of strains by appropriate high quality screening protocol determines success of drug discovery programs. To accomplish screening for antagonistic actinomycetes at higher rate, the fermentation stage of the initial screening needs to be miniaturized. The present study is attempted for miniaturized production of bioactive compounds from 40 actinomycetes isolated from less explored ecosystems. ...

  19. THE ANTAGONISTIC ACTIVITY OF ACTINOMYCETES OF STREPTOMYCES GENUS IN RELATION TO TRICHODERMA KONINGII

    OpenAIRE

    Barbara Breza-Boruta; Zbigniew Paluszak

    2016-01-01

    The aim of the study was to estimate the effect of actinomycetes of genus Streptomyces on the growth of the antagonistic fungus Trichoderma koningii. 150 strains of Streptomyces spp. isolated from two potato cropping systems were used to the tests. Analyses were conducted experimentally in vitro on PDA medium with pH 6 and 7. The results obtained clearly indicate the inhibitory effect of actinomycetes on the fungus T. koningii. Of the tested population of actinomycetes only two strains did no...

  20. Conjugation of ß-Adrenergic Antagonist Alprenolol to Implantable Polymer-Aescin Matrices for Local Delivery

    OpenAIRE

    Ewa Oledzka; Dagmara Pachowska; Marcin Sobczak; Agnieszka Lis-Cieplak; Grzegorz Nalecz-Jawecki; Anna Zgadzaj; Waclaw Kolodziejski

    2015-01-01

    The sustained release of alprenolol, a ß-adrenergic antagonist, could be beneficial for the treatment of various heart diseases while reducing the side effects resulting from its continuous use. The novel and branched copolymers uniquely composed of biodegradable components (lactide and glycolide) have been synthesized using natural and therapeutically-efficient ß-aescin-initiator, and consequently characterized to determine their structures and physicochemical properties. The obtained matric...