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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. Hypersomnolence with beta-adrenergic blockers.

    Science.gov (United States)

    Thachil, J; Zeller, J R; Kochar, M S

    1987-11-01

    An elderly, mildly demented, hypertensive male patient developed hypersomnolence on administration of propranolol for treatment of hypertension; no other cause for hypersomnolence was detected. Upon replacement of propranolol with atenolol, he felt better but continued to be quite somnolent. When atenolol was discontinued, he reported to have lack of sleep. On readministration of subtherapeutic doses of the same beta-adrenergic blocking agents, he once again experienced excessive sleepiness. By discontinuing beta-blocking agents and introducing captopril, he felt much better, became pleasant and talkative, and blood pressure was well controlled. Beta antagonists are important drugs in the management of many cardiovascular problems. Propranolol, a lipophilic beta-blocking agent, and atenolol, a hydrophilic beta-blocking agent, are two of the major agents currently used clinically in the United States. Numerous neuropsychiatric side-effects of the beta-adrenergic blocking drugs have been reported, but hypersomnolence is not readily recognized as one of them. PMID:3665616

  3. 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

  4. 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 pati......-selective beta-adrenergic receptor antagonist attenuates cerebral non-oxidative metabolism Udgivelsesdato: 2009/11......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...

  5. Changes of lymphocyte beta-adrenergic receptors after surgical stress.

    Science.gov (United States)

    Eandi, M; Buraglio, M; Arduino, C; Viano, I; Sansalvadore, G; Arbinolo, M A

    1984-01-01

    In this study the authors' purpose was to observe the effects of surgical stress on the number of lymphocyte beta-adrenergic receptors in hypertensive and normotensive subjects. It was noticed that after surgery a significant reduction occurred in the number of binding sites of lymphocytes of both hypertensive and normotensive subjects. The time course of recovery to the pre-operative values of binding sites varied between the two groups, being slower in normotensive than in hypertensive patients. This might suggest a different pattern of regulation of the beta-adrenergic receptor between hypertensive and normotensive subjects.

  6. 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.

  7. 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

  8. 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.

  9. 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

  10. 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...

  11. 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.

  12. 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.

  13. 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...

  14. 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.

  15. 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...

  16. 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

  17. Beta-adrenergically stimulated fat oxidation is diminished in middle-aged compared to young subjects.

    NARCIS (Netherlands)

    Blaak, E.E.; van Baak, M.A.; Saris, W.H.M.

    1999-01-01

    The effect of aging on beta-adrenergically mediated substrate utilization was investigated in nine young (25.2 +/- 1.7 yr old) and eight older males (52.9 +/- 2.1 yr old), matched for body weight and body composition. In a first experiment, the nonselective beta-agonist isoprenaline (ISO) was infuse

  18. 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

  19. 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

  20. Modeling beta-adrenergic control of cardiac myocyte contractility in silico

    Science.gov (United States)

    Saucerman, Jeffrey J.; Brunton, Laurence L.; Michailova, Anushka P.; McCulloch, Andrew D.; McCullough, A. D. (Principal Investigator)

    2003-01-01

    The beta-adrenergic signaling pathway regulates cardiac myocyte contractility through a combination of feedforward and feedback mechanisms. We used systems analysis to investigate how the components and topology of this signaling network permit neurohormonal control of excitation-contraction coupling in the rat ventricular myocyte. A kinetic model integrating beta-adrenergic signaling with excitation-contraction coupling was formulated, and each subsystem was validated with independent biochemical and physiological measurements. Model analysis was used to investigate quantitatively the effects of specific molecular perturbations. 3-Fold overexpression of adenylyl cyclase in the model allowed an 85% higher rate of cyclic AMP synthesis than an equivalent overexpression of beta 1-adrenergic receptor, and manipulating the affinity of Gs alpha for adenylyl cyclase was a more potent regulator of cyclic AMP production. The model predicted that less than 40% of adenylyl cyclase molecules may be stimulated under maximal receptor activation, and an experimental protocol is suggested for validating this prediction. The model also predicted that the endogenous heat-stable protein kinase inhibitor may enhance basal cyclic AMP buffering by 68% and increasing the apparent Hill coefficient of protein kinase A activation from 1.0 to 2.0. Finally, phosphorylation of the L-type calcium channel and phospholamban were found sufficient to predict the dominant changes in myocyte contractility, including a 2.6x increase in systolic calcium (inotropy) and a 28% decrease in calcium half-relaxation time (lusitropy). By performing systems analysis, the consequences of molecular perturbations in the beta-adrenergic signaling network may be understood within the context of integrative cellular physiology.

  1. Beta-adrenergic stimulation of skeletal muscle HSL can be overridden by AMPK signaling.

    Science.gov (United States)

    Watt, Matthew J; Steinberg, Gregory R; Chan, Stanley; Garnham, Andrew; Kemp, Bruce E; Febbraio, Mark A

    2004-09-01

    Hormone-sensitive lipase (HSL), an important regulatory enzyme for triacylglycerol hydrolysis within skeletal muscle, is controlled by beta-adrenergic signaling as well as intrinsic factors related to contraction and energy turnover. In the current study, we tested the capacity of 5'AMP-activated protein kinase (AMPK) to suppress beta-adrenergic stimulation of HSL activity. Eight male subjects completed 60 min of cycle exercise at 70% VO2 peak on two occasions: either with normal (CON) or low (LG) pre-exercise muscle glycogen content, which is known to enhance exercise-induced AMPK activity. Muscle samples were obtained before and immediately after exercise. Pre-exercise glycogen averaged 375 +/- 35 and 163 +/- 27 mmol x kg(-1) dm for CON and LG, respectively. AMPK alpha-2 was not different between trials at rest and was increased (3.7-fold, PHSL activity did not differ between trials at rest and increased (0 min: 1.67 +/- 0.13; 60 min: 2.60 +/- 0.26 mmol x min(-1) x kg(-1) dm) in CON. The exercise-induced increase in HSL activity was attenuated by AMPK alpha-2 activation in LG. The attenuated HSL activity during LG occurred despite higher plasma epinephrine levels (60 min: CON, 1.96 +/- 0.29 vs LG, 4.25 +/- 0.60 nM, PHSL activity in LG, IMTG was decreased by exercise (0 min: 27.1 +/- 2.0; 60 min: 22.5 +/- 2.0 mmol x kg(-1) dm, PHSL activity, we performed experiments in muscle cell culture. The epineprine-induced increase in HSL activity was totally attenuated (PHSL activity that can override beta-adrenergic stimulation. However, the increased IMTG degradation in LG suggests factors other than HSL activity are important for IMTG degradation.

  2. Beta-adrenergic stimulation of phagocytosis in the unicellular eukaryote Paramecium aurelia.

    Science.gov (United States)

    Wyroba, E

    1989-08-01

    Bete-adrenergic agonists isoproterenol and norepinephrine enhanced phagocytosis in Paramecium. Stimulation was stereospecific, dose-dependent and inhibited by the beta-agonists propranolol and alprenolol. Phorbol ester and forskolin potentiated the stimulatory effect of catecholamines on Paramecium phagocytosis. The dansyl analogue of propranolol (DAPN) was used for fluorescent visualization of the beta-adrenergic receptor sites in Paramecium which have been found to be localized at the cell membrane and within the membrane of the nascent digestive vacuoles. The appearance of the characteristic fluorescent pattern has been blocked by 1-propranolol.

  3. Defective beta adrenergic response of cystic fibrosis sweat glands in vivo and in vitro.

    OpenAIRE

    Sato, K.; Sato, F.

    1984-01-01

    Abnormal ductal NaCl absorption has been known as the only defect in cystic fibrosis (CF) sweat glands. We have fortuitously found that the secretory portion of CF sweat glands is also abnormal in that it failed to show a sweating response to beta adrenergic stimulation (isoproterenol, [ISO]) both in vivo and in vitro. For the in vitro sweat test, eccrine sweat glands were isolated from skin biopsy specimens of the forearm, cannulated, and stimulated to secrete sweat. All 14 isolated CF sweat...

  4. 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...

  5. 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.

  6. Indices of brain beta-adrenergic receptor signal transduction in the learned helplessness animal model of depression.

    Science.gov (United States)

    Gurguis, G N; Kramer, G; Petty, F

    1996-01-01

    Both stress response and antidepressant drug action may be mediated by beta-adrenergic receptors (beta AR). Since learned helplessness is a stress-induced animal model of depression, beta AR are relevant to investigate in this model. To date, studies have measured changes in total receptor density (RT), but have not examined more detailed aspects of signal transduction mechanisms such as coupling of the receptor to GS protein. We have investigated brain beta AR coupling in the frontal cortex, hippocampus and hypothalamus of rats exposed to inescapable shock and then tested for learned helplessness, and in both tested and naive controls using [125I]-iodocyanopindolol (ICYP) as the ligand. Both antagonist-saturation and agonist-displacement experiments were conducted, and the specificity for the beta AR was optimized by excluding ICYP binding to 5HT1B receptors. The percentage receptor density in the high-conformational state (%RH) and the ratio of agonist (isoproterenol) dissociation constant from the receptor in the low-/high-conformational states (KL/KH) were used as indices of coupling to GS protein. No significant differences were found between rats developing learned helplessness and non-helpless rats after inescapable stress in any parameter measured in any brain region. In the frontal cortex, exposure to inescapable shock induced beta AR uncoupling from GS protein as suggested by a low KL/KH ratio both in helpless and non-helpless rats but not in either control group. In the hypothalamus, there were trends for higher RL, RT and KL/KH ratio in helpless rats and stressed controls compared to naive controls. These findings suggest that beta AR binding parameters in frontal cortex, hippocampus or hypothalamus did not differentiate between helpless and non-helpless rats. Changes in beta AR coupling observed in these brain regions may reflect effects of stress, which appeared to be region-specific, rather than stress-induced behavioral depression.

  7. 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.

  8. Human adipose tissue blood flow during prolonged exercise, III. Effect of beta-adrenergic blockade, nicotinic acid and glucose infusion

    DEFF Research Database (Denmark)

    Bülow, J

    1981-01-01

    acid, during acute i.v. beta-adrenergic blockade by propranolol, and during continuous i.v. infusion of glucose. The most pronounced lipid mobilization and utilization during work was seen in the control experiments where ATBF rose 3-fold on average from the initial rest period to the third hour...

  9. 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.

  10. 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

  11. The relationship between some beta-adrenergic mediated responses and plasma concentrations of adrenaline and cyclic AMP in man

    DEFF Research Database (Denmark)

    Philipsen, E K; Myhre, John Gabriel; Larsen, S;

    1990-01-01

    concentrations at low adrenaline infusion rates was prevented, whereas a small increase in cyclic AMP was found at high adrenaline infusion rates, probably owing to incomplete beta-receptor blockade. Likewise, the adrenaline-induced increments in blood substrates (glucose, lactate, glycerol and beta......To test the hypothesis that increments in plasma cyclic AMP during beta-adrenergic stimulation reflect integrated second messenger function of the tissues activated by the agonist, graded adrenaline infusion resulting in plasma adrenaline concentrations within the physiological range was performed...... hydroxybutyric acid) were significantly reduced but not completely prevented by beta-blockade. We conclude that an altered relationship between beta-agonist concentrations and plasma cyclic AMP may provide evidence for the existence of differences in beta-adrenergic sensitivity in man....

  12. Ischemia- and agonist-induced changes in. alpha. - and. beta. -adrenergic receptor traffic in guinea pig hearts

    Energy Technology Data Exchange (ETDEWEB)

    Maisel, A.S.; Motulsky, H.J.; Ziegler, M.G.; Insel, P.A. (Univ. of California, La Jolla (USA))

    1987-11-01

    The authors have used radioligand binding techniques and subcellular fraction to assess whether changes in expression of myocardial {alpha}{sub 1}- and {beta}-adrenergic receptors are mediated by a redistribution of receptors between various membrane fractions. Three fractions were prepared from the left ventricles of guinea pigs that underwent either 1 h of ischemia or injection of epinephrine a crude membrane, a purified sarcolemma, and a light vesicle fraction. In control animals {alpha}{sub 1}-adrenergic receptors (({sup 3}H)prazosin binding) in light vesicles was only 25% of the total {alpha}{sub 1}-receptor density found in sarcolemmal and light vesicle fractions as compared with 50% for {beta}-adrenergic receptors (({sup 125}I)iodocyanopindolol binding sites). Although ischemia was associated with a 53% decrease in the number of light vesicle {beta}-adrenergic receptors and a 42% increase in the number of sarcolemma {beta}-receptors there was no change in the number of light vesicle {alpha}{sub 1}-receptors, even though the number of sarcolemmal {alpha}{sub 1}-receptors increased 34%. Epinephrine treatment promoted internalization of {beta}-adrenergic receptors. These results indicate that {alpha}{sub 1} and {beta}{sub 1}-adrenergic receptors may undergo a different cellular itinerary in guinea pig myocardium. Agonist and ischemia-induced changes in surface {beta}-receptors, but not {alpha}{sub 1}-receptors, appear to result from entry and exit of receptors from an intracellular pool that can be isolated in a light vesicle fraction. Changes in expression of {alpha}{sub 1}-adrenergic receptors may represent changes in the properties of receptors found in the sarcolemma or in a membrane fraction other than the light vesicle fraction that they have isolated.

  13. Immunoanalogue of vertebrate beta-adrenergic receptor in the unicellular eukaryote Paramecium.

    Science.gov (United States)

    Wiejak, Jolanta; Surmacz, Liliana; Wyroba, Elzbieta

    2002-01-01

    Cell fractionation, SDS-PAGE, quantitative Western blot, confocal immunolocalization and immunogold labelling were performed to find an interpretation of the physiological response of the unicellular eukaryote Paramecium to beta-adrenergic ligands. The 69 kDa polypeptide separated by SDS-PAGE in S2 and P2 Paramecium subcellular fractions cross-reacted with antibody directed against human beta2-adrenergic receptor. This was detected by Western blotting followed by chemiluminescent detection. Quantitative image analysis showed that beta-selective adrenergic agonist (-)-isoproterenol--previously shown to enhance phagocytic activity--evoked redistribution of the adrenergic receptor analogue from membraneous (P2) to cytosolic (S2) fraction. The relative increase in immunoreactive band intensity in S2 reached 80% and was paralleled by a 59% decrease in P2 fraction. Confocal immunofluorescence revealed beta2-adrenergic receptor sites on the cell surface and at the ridge of the cytopharynx--where nascent phagosomes are formed. This localization was confirmed by immunoelectron microscopy. These results indicate that the 69 kDa Paramecium polypeptide immunorelated to vertebrate beta2-adrenergic receptor appeared in this evolutionary ancient cell as a nutrient receptor.

  14. Age-associated alterations in hepatic. beta. -adrenergic receptor/adenylate cyclase complex

    Energy Technology Data Exchange (ETDEWEB)

    Graham, S.M.; Herring, P.A.; Arinze, I.J.

    1987-09-01

    The effect of age on catecholamine regulation of hepatic glycogenolysis and on hepatic adenylate cyclase was studied in male rats up to 24 mo of age. Epinephrine and norepinephrine stimulated glycogenolysis in isolated hepatocytes at all age groups studied. Isoproterenol, however, stimulated glycogenolysis only at 24 mo. In isolated liver membranes, usual activators of adenylate cyclase increased the activity of the enzyme considerably more in membranes from 24-mo-old rats than in membranes from either 3- or 22-mo-old rats. The Mn/sup 2 +/-dependent activity of the cyclase was increased by 2.9-fold in 3-mo-old animals and approx. 5.7-fold in 24-mo-old rats, indicating a substantial age-dependent increase in the intrinsic activity of the catalytic unit. The density of the ..beta..-adrenergic receptor, as measured by the binding of (/sup 125/I)-iodocyanopindolol to plasma membranes, was 5-8 fmol/mg protein in rats aged 3-12 mo but increased to 19 fmol/mg protein in 24-mo-old rats. Computer-aided analysis of isoproterenol competition of the binding indicated a small age-dependent increase in the proportion of ..beta..-receptors in the high-affinity state. These observations suggest that ..beta..-receptor-mediated hepatic glycogenolysis in the aged rat is predicated upon increases in the density of ..beta..-receptors as well as increased intrinsic activity of the catalytic unit of adenylate cyclase.

  15. 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

  16. 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.

  17. 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

  18. 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

  19. [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

  20. 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.

  1. 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...

  2. 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

  3. 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.

  4. Pavlovian conditioning of morphine-induced alterations of immune status: evidence for peripheral beta-adrenergic receptor involvement.

    Science.gov (United States)

    Coussons-Read, M E; Dykstra, L A; Lysle, D T

    1994-09-01

    The present studies examined the involvement of peripheral beta-adrenergic receptor activity in the establishment and expression of conditioned morphine-induced alterations of immune status. Previous work in our laboratory has shown that morphine's immunomodulatory effects can become conditioned to environmental stimuli which predict drug administration. These immune alterations include conditioned changes in natural killer cell activity, interleukin-2 production, and mitogen-induced lymphocyte proliferation. During the training phase of these experiments, Lewis rats received two conditioning sessions during which a subcutaneous injection of 15 mg/kg morphine sulfate was paired with exposure to a distinctive environment. On the test day, rats were reexposed to the conditioned stimulus prior to sacrifice. Saline or nadolol (0.002, 0.02, 0.2, or 2.0 mg/kg) was administered either prior to the training sessions or prior to the test session. Administration of nadolol prior to training did not affect the development of conditioned alterations of immune status. Conversely, nadolol administration prior to testing completely attenuated the expression of a subset of the conditioned morphine-induced changes in immune status. Taken together, these studies suggest that whereas peripheral beta-adrenergic receptor activity is not required for the establishment of conditioned morphine-induced alterations of immune status, it is involved in the expression of a subset of these conditioned immunomodulatory effects.

  5. 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

  6. 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

  7. Beta-adrenergic receptor agonists induce the release of granulocyte chemotactic protein-2, oncostatin M, and vascular endothelial growth factor from macrophages

    NARCIS (Netherlands)

    Verhoeckx, K.C.M.; Doornbos, R.P.; Witkamp, R.F.; Greef, de J.; Rodenburg, R.J.T.

    2006-01-01

    Vascular endothelial growth factor (VEGF), oncostatin M (OSM), and granulocyte chemotactic protein-2 (GCP-2/CXCL6) are up-regulated in U937 macrophages and peripheral blood macrophages exposed to LPS, beta-adrenergic receptor (ß2-AR) agonists (e.g. zilpaterol, and clenbuterol) and some other agents

  8. Beta-adrenergic receptor agonists induce the release of granulocyte chemotactic protein-2, oncostatin M, and vascular endothelial growth factor from macrophages

    NARCIS (Netherlands)

    Verhoeckx, K.C.; Doornbos, R.P.; Witkamp, R.F.; Greef, J. van der; Rodenburg, R.J.T.

    2006-01-01

    Vascular endothelial growth factor (VEGF), oncostatin M (OSM), and granulocyte chemotactic protein-2 (GCP-2/CXCL6) are up-regulated in U937 macrophages and peripheral blood macrophages exposed to LPS, beta-adrenergic receptor (beta2-AR) agonists (e.g. zilpaterol, and clenbuterol) and some other agen

  9. Beta-adrenergic receptor agonists induce the release of granulocyte chemotactic protein-2, oncostatin M, and vascular endothelial growth factor from macrophages

    NARCIS (Netherlands)

    Verhoeckx, K.C.M.; Doornbos, R.P.; Witkamp, R.F.; Greef, J. van der; Rodenburg, R.J.T.

    2006-01-01

    Vascular endothelial growth factor (VEGF), oncostatin M (OSM), and granulocyte chemotactic protein-2 (GCP-2/CXCL6) are up-regulated in U937 macrophages and peripheral blood macrophages exposed to LPS, beta-adrenergic receptor (β2-AR) agonists (e.g. zilpaterol, and clenbuterol) and some other agents

  10. 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

  11. 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....

  12. Dose-ranging study of the new beta-adrenergic antagonist nadolol in the treatment of essential hypertension.

    Science.gov (United States)

    Frithz, G

    1978-01-01

    A preliminary, single-blind, dose-ranging study was carried out in 30 patients with essential hypertension to assess the efficacy of nadolol, a new beta-adrenoceptor blocking agent without intrinsic sympathomimetic action and with an extremely long plasma half-life. After a 2-week period on placebo, patients were treated for 14 weeks with daily doses of 40 mg nadolol (20 mg twice daily). Dosage was increased every second week up to a maximum of 560 mg daily or until the patient was stabilized at an effective normotensive dose level. The results showed that at the end of the trial period there was a significant reduction in both systolic and diastolic blood pressure (approximately 34/21 mmHg) at an average daily dose of 110 mg nadolol. Apart from a tendency to bradycardia, explained by the drug's lack of sympathomimetic action, no other side-effects attributable to treatment were reported and no patient complained of sleep disturbance. PMID:26519

  13. 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...

  14. 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

  15. RT-PCR and Northern blot analysis in search for a putative Paramecium beta-adrenergic receptor.

    Science.gov (United States)

    Płatek, A; Wiejak, J; Wyroba, E

    1999-01-01

    RT-PCR and Northern blot analysis were performed in order to search for a putative beta-adrenergic receptor (beta-AR) in Paramecium using several beta2-adrenergic-specific molecular probes. Under strictly defined RT-PCR conditions DNA species of expected molecular size about 360 bp were generated with the primers corresponding to the universal mammalian beta2-AR sequence tagged sites (located within the 4th and the 6th transmembrane regions of the receptor). This RT-PCR product hybridized in Southern blot analysis with the oligonucleotide probe designed to the highly conservative beta2-AR region involved in G-proteins interaction and located within the amplified region. Northern hybridization was performed on Paramecium total RNA and mRNA with human beta2-AR cDNA and two oligonucleotide probes: the first included Phe 290 involved in agonist binding (Strader et al., 1995) and the second was the backward RT-PCR primer. All these probes revealed the presence of about 2 kb mRNA which is consistent with the size of beta2-AR transcripts found in higher eukaryotes.

  16. Dynamin-association with agonist-mediated sequestration of beta-adrenergic receptor in single-cell eukaryote Paramecium.

    Science.gov (United States)

    Wiejak, Jolanta; Surmacz, Liliana; Wyroba, Elzbieta

    2004-04-01

    Evidence that dynamin is associated with the sequestration of the Paramecium beta(2)-adrenergic receptor (betaAR) immunoanalogue is presented. We previously reported a dramatic change in the distribution of betaAR analogue in the subcellular fractions upon isoproterenol treatment: it is redistributed from the membraneous to the cytosolic fraction, as revealed by quantitative image analysis of western blots. Here we confirm and extend this observation by laser scanning confocal and immunogold electron microscopy. In the presence of isoproterenol (10 micro mol l(-1)) betaAR translocated from the cell surface into dynamin-positive vesicles in the cytoplasmic compartment, as observed by dual fluorochrome immunolabeling in a series of the confocal optical sections. Colocalization of betaAR and dynamin in the tiny endocytic vesicles was detected by further electron microscopic studies. Generally receptor sequestration follows its desensitization, which is initiated by receptor phosphorylation by G-protein-coupled receptor kinase. We cloned and sequenced the gene fragment of 407 nucleotides homologous to the beta-adrenergic receptor kinase (betaARK): its deduced amino acid sequence shows 51.6% homology in 126 amino acids that overlap with the human betaARK2 (GRK3), and may participate in Paramecium betaAR desensitization. These results suggest that the molecular machinery for the desensitization/sequestration of the receptor immunorelated to vertebrate betaAR exists in unicellular PARAMECIUM:

  17. 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.

  18. 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.

  19. 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.

  20. 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

  1. 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

  2. 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…

  3. 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.

  4. Personality effects on cardiovascular reactivity: need for closure moderates the impact of task difficulty on engagement-related myocardial beta-adrenergic activity.

    Science.gov (United States)

    Richter, Michael; Baeriswyl, Eric; Roets, Arne

    2012-05-01

    An experiment assessed the joint effect of dispositional need for closure (NFC) and task difficulty on engagement-related myocardial beta-adrenergic activity. Participants who scored either low or high on the NFC scale performed an ambiguous categorization task with either low or high difficulty. Confirming the theory-derived predictions, task difficulty effects on pre-ejection period (PEP) reactivity were moderated by NFC. If difficulty was low, PEP reactivity was low and independent of the participants' NFC level. If difficulty was high, participants with high NFC showed increased PEP reactivity compared to participants with low NFC. These results extend previous research on Wright's model of engagement-related cardiovascular reactivity and suggest that the model may provide a useful framework for assessing the impact of personality on cardiovascular response.

  5. Sympathetic nerve activity in normal and cystic follicles from isolated bovine ovary: local effect of beta-adrenergic stimulation on steroid secretion

    Directory of Open Access Journals (Sweden)

    Ortega Hugo H

    2011-05-01

    Full Text Available Abstract Cystic ovarian disease (COD is an important cause of abnormal estrous behavior and infertility in dairy cows. COD is mainly observed in high-yielding dairy cows during the first months post-partum, a period of high stress. We have previously reported that, in lower mammals, stress induces a cystic condition similar to the polycystic ovary syndrome in humans and that stress is a definitive component in the human pathology. To know if COD in cows is also associated with high sympathetic activity, we studied isolated small antral (5mm, preovulatory (10mm and cystic follicles (25mm. Cystic follicles which present an area 600 fold greater compared with preovulatory follicles has only 10 times less concentration of NE as compared with small antral and preovulatory follicles but they had 10 times more NE in follicular fluid, suggesting a high efflux of neurotransmitter from the cyst wall. This suggestion was reinforced by the high basal release of recently taken-up 3H-NE found in cystic follicles. While lower levels of beta-adrenergic receptor were found in cystic follicles, there was a heightened response to the beta-adrenergic agonist isoproterenol and to hCG, as measured by testosterone secretion. There was however an unexpected capacity of the ovary in vitro to produce cortisol and to secrete it in response to hCG but not to isoproterenol. These data suggest that, during COD, the bovine ovary is under high sympathetic nerve activity that in addition to an increased response to hCG in cortisol secretion could participate in COD development.

  6. 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.

  7. 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

  8. 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.

  9. 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.

  10. 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.

  11. 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

  12. 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

    1978-05-01

    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).

  13. 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.

  14. [Antifibrillatory activity of dipeptide antagonist of nerve growth factor].

    Science.gov (United States)

    Kryzhanovskiĭ, S A; Stoliarchuk, V N; Vititnova, M B; Tsorin, I B; Pekel'dina, E S; Gudasheva, T A

    2012-01-01

    In experiments on anesthetized rats were assessed antifibrillatoty action of dipeptide GK-1. This compound is the fragment of fourth loop of nerve growth factor (NGF) and manifests antagonistic activity in respect to TrkA receptor, that specified for NGF. It is shown that this compound is able to significantly increase the threshold of electrical fibrillation of the heart and its effectiveness is not inferior to the reference antiarrhythmics I and III class on Vaughan Williams classification. However, unlike the latter, antifibrillatory action of dipeptide GK-1 was delayed and realized within 40-60 minutes after its administration. It is discussed possible mechanisms underlying antifibrillatory action of dipeptide GK-1, that, to some extent, may be associated with its ability to change the reactivity of beta-adrenergic structures of the heart.

  15. Cooperative regulation of non-small cell lung carcinoma by nicotinic and beta-adrenergic receptors: a novel target for intervention.

    Directory of Open Access Journals (Sweden)

    Hussein A N Al-Wadei

    Full Text Available Lung cancer is the leading cause of cancer death; 80-85% of lung cancer cases are non-small cell lung cancer (NSCLC. Smoking is a documented risk factor for the development of this cancer. Although nicotine does not have the ability to initiate carcinogenic events, recent studies have implicated nicotine in growth stimulation of NSCLC. Using three NSCLC cell lines (NCI-H322, NCI-H441 and NCI-H1299, we identified the cooperation of nicotinic acetylcholine receptors (nAChRs and β-adrenergic receptors (β-ARs as principal regulators of these effects. Proliferation was measured by thymidine incorporation and MTT assays, and Western blots were used to monitor the upregulation of the nAChRs and activation of signaling molecules. Noradrenaline and GABA were measured by immunoassays. Nicotine-treated NSCLC cells showed significant induction of the α7nAChR and α4nAChR, along with significant inductions of p-CREB and p-ERK1/2 accompanied by increases in the stress neurotransmitter noradrenaline, which in turn led to the observed increase in DNA synthesis and cell proliferation. Effects on cell proliferation and signaling proteins were reversed by the α7nAChR antagonist α-BTX or the β-blocker propranolol. Nicotine treatment also down-regulated expression of the GABA synthesizing enzyme GAD 65 and the level of endogenous GABA, while treatment of NSCLC cells with GABA inhibited cell proliferation. Interestingly, GABA acts by reducing β-adrenergic activated cAMP signaling. Our findings suggest that nicotine-induced activation of this autocrine noradrenaline-initiated signaling cascade and concomitant deficiency in inhibitory GABA, similar to modulation of these neurotransmitters in the nicotine-addicted brain, may contribute to the development of NSCLC in smokers. Our data suggest that exposure to nicotine either by tobacco smoke or nicotine supplements facilitates growth and progression of NSCLC and that pharmacological intervention by β blocker may

  16. 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...

  17. 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

  18. ACTH antagonists

    Directory of Open Access Journals (Sweden)

    Adrian John Clark

    2016-08-01

    Full Text Available 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 whilst preparing for definitive treatment of a causative tumour, 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.

  19. 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

  20. 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

  1. 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.

  2. [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

  3. 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.

  4. Synthesis and pharmacological activity of adaprolol enantiomers: a new soft drug for treating glaucoma.

    Science.gov (United States)

    Boder, N; Elkoussi, A; Zuobi, K; Kovacs, P

    1996-01-01

    Adaprolol maleate is a new beta-adrenergic antagonist that is being developed to treat glaucoma. The soft drug was designed to minimize systemic activity through facile inactivation to an inactive metabolite. Studies with other potent beta-adrenergic antagonists indicated that tissue specific receptor differences might be more stringent for selected beta-adrenergic blocking activities and suggested that R enantiomers of traditional beta-blockers should be developed for controlling glaucoma. The present studies demonstrate that the potent ocular hypotensive effects of adaprolol are not stereoselective. In contrast, cardiac effects could be detected after intravenous S(+) adaprolol, but not R(-) adaprolol. The studies confirm that adaprolol functions as a potent beta-adrenergic antagonist. The negligible systemic beta-blocking activity detected with opthalmic administration of adaprolol is consistent with soft drug design.

  5. Studies on antagonistic marine streptomycetes

    Digital Repository Service at National Institute of Oceanography (India)

    Chandramohan, D.; Nair, S.

    Sixty nine strains of Streptomyces sp. isolated from the sediments of Andaman and Nicobar islands (Bay of Bengal) were screened for their antagonistic property against a number of test cultures (Vibrio sp., Klebsiella sp., Escherichia coli, Shigella...

  6. 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

  7. Glycyrrhizic Acid Reduces Heart Rate and Blood Pressure by a Dual Mechanism

    OpenAIRE

    Kailash Singh; Aung Moe Zaw; Revathi Sekar; Ahuja Palak; Allam, Ahmed A.; Jamaan Ajarem; Chow, Billy K. C.

    2016-01-01

    Beta adrenergic receptors are crucial for their role in rhythmic contraction of heart along with their role in the pathological conditions such as tachycardia and high risk of heart failure. Studies report that the levels of beta-1 adrenergic receptor tend to decrease by 50%, whereas, the levels of beta-2 adrenergic receptor remains constant during the risk of heart failure. Beta blockers—the antagonistic molecules for beta-adrenergic receptors, function by slowing the heart rate, which there...

  8. Antagonistic Interfa(e)ces

    DEFF Research Database (Denmark)

    Cox, Geoff; Jackson, Robert

    2011-01-01

    "lingering stink" so that it became purer and closer to authority. The paper will further link the purification of code to the structure of ideology inherent in Zizek’s psychoanalytical model between Symbolic reality, the antagonistic Real and ideological concealment. The purification is technical in so far...

  9. 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......)-phenylethylamine salt of N-BOC-(R)-ATAA. Like ATAA, neither (R)- nor (S)-ATAA significantly affected (IC50 > 100 microM) the receptor binding of tritiated AMPA, kainic acid, or (RS)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid, the latter being a competitive NMDA antagonist. Electrophysiological experiments......, using the rat cortical wedge preparation, showed the NMDA antagonist effect as well as the AMPA antagonist effect of ATAA to reside exclusively in the (R)-enantiomer (Ki = 75 +/- 5 microM and 57 +/- 1 microM, respectively). Neither (R)- nor (S)-ATAA significantly reduced kainic acid-induced excitation...

  10. Synthesis of potential mescaline antagonists.

    Science.gov (United States)

    DeSantis, F; Nieforth, K A

    1976-10-01

    1-[2-(3,4,5-Trimethoxyphenyl)ethyl]-3-pyrroline, 2-(3,4,5-trimethoxybenzyl)-1,2,3,6-tetrahydropyridine, N-n-propylmescaline, N-cyclopropylmethylmescaline, and N-allylmescaline were synthesized as potential mescaline antagonists. The ability of these compounds to antagonize mescaline-induced disruption of swim behavior is also given.

  11. Quantitative protein and fat metabolism in bull calves treated with beta-adrenergic agonist

    DEFF Research Database (Denmark)

    Chwalibog, André; Jensen, K; Thorbek, G

    1996-01-01

    matter, metabolizable energy and digestible protein was of the same magnitude for all groups. The beta-agonist had no significant effect on protein digestibility and metabolizability of energy, but daily live weight gain was significantly higher in the treated bulls. The utilization of digested protein......Protein and energy utilization and quantitative retention of protein, fat and energy was investigated with 12 Red Danish bulls during two subsequent 6 weeks trials (Sections A and B) at a mean live weight of 195 and 335 kg respectively. Treatments were control (Group 1) and beta-agonist (L-644......,969) treated animals (Group 2 and 3). Beta-agonist supplementation was 5 and 10 mg/d in Group 2 and 3 respectively in Section A and 10 and 20 mg/d in Section B. Measurements were performed by means of nitrogen and carbon balances and with use of indirect calorimetry. In each section the mean intake of dry...

  12. 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...

  13. beta. -adrenergic receptor-mediated hepatic glycogenolysis is increased in aged male rats

    Energy Technology Data Exchange (ETDEWEB)

    Herring, P.A.; Graham, S.M.; Arinze, I.J.

    1986-03-05

    The effect of age on catecholamine-stimulated glycogenolysis was studied in isolated hepatocytes prepared from 3, 12, and 24 month-old rats. Glucose release was stimulated by epinephrine and norepinephrine, this was inhibited by phentolamine and prazosin. Isoproterenol (ISO) stimulated glycogenolysis only in cells from 24 month-old rats, this was blocked by propranolol. In liver plasma membranes, binding of (/sup 3/H)yohimbine (100-130 fmol/mg protein) did not change with age, whereas (/sup 3/H)prazosin binding decreased from 870 fmol/mg at 3 months to 435 fmol/mg at 12 months, but subsequently rose to 656 fmol/mg at 24 months. (/sup 125/I)Cyanopindolol binding increased from 8 fmol/mg at 3 months to 19 fmol/mg at 24 months. The proportion of ..beta..-receptors in the high affinity state increased from 28% at 3 months to 42% at 24 months. ISO stimulated adenylate cyclase at 24 months but not at 3 months. Basal, fluoride-, GTP-, and Gpp(NH)p-stimulated activities were 1.4- to 2.4-fold greater at 24 months than at 3 months. These results suggest an age-related increase in the sensitivity of adenylate cyclase to ..beta..-receptor stimulation.

  14. 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 Chil...

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

    DEFF Research Database (Denmark)

    Chwalibog, André; Jensen, K; Thorbek, G

    1996-01-01

    , 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...

  16. 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.

  17. 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.

  18. 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.

  19. [Central effects of five beta-adrenergic receptor blockers in healthy volunteers: a quantitative EEG study].

    Science.gov (United States)

    Sabot, C; Pechadre, J C; Beudin, P; Lauxerois, M; Trolese, J F; Kantelip, J P; Ducher, J L; Gibert, J

    1989-03-01

    The effects of five beta blockers on the central nervous system of healthy subjects was studied by computerized EEG analysis. All subjects underwent continuous recording with a Holter magnetic type recorder during the experimental period. For 10 consecutive days, five groups of subjects received alternately placebo and the beta blockers acebutolol 600 mg, carteolol 20 mg, metoprolol 200 mg, pindolol 30 mg and sotalol 320 mg. EEG recordings (C4/P4, P4/02 and C3/P3, P3/01) lasting 5 min were made between 8.30 and 9.30 a.m. Subjects were at rest with eyes closed and there was no vigilance control. The signal was recorded on a magnetic tape recorder and then processed by Nicolet MED 80 system. Comparisons of absolute and relative powers and of average frequencies were then made between the different sequences and groups. The possible correlations between the changes observed in the power spectrum and the clinical, pharmacological and pharmacokinetic specific properties of each beta blocker are discussed.

  20. 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.

  1. 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...

  2. GABAA receptor partial agonists and antagonists

    DEFF Research Database (Denmark)

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

    2015-01-01

    antagonists and describes the development of potent antagonists from partial agonists originally derived from the potent GABAAR agonist muscimol. In this process, several heterocyclic aromatic systems have been used in combination with structural models in order to map the orthosteric binding site...... and to reveal structural details to be used for obtaining potency and subtype selectivity. The challenges connected to functional characterization of orthosteric GABAAR partial agonists and antagonists, especially with regard to GABAAR stoichiometry and alternative binding sites are discussed. GABAAR...

  3. New antagonist agents of neuropeptide y receptors

    Directory of Open Access Journals (Sweden)

    Ignacio Aldana

    2000-12-01

    Full Text Available In the CNS, NPY has been implicated in obesity and feeding, endocrine function and metabolism. Potent and selective rNPY antagonists will be able to probe the merits of this approach for the treatment of obesity. We report the synthesis and preliminary evaluation of some hydrazide derivatives as antagonists of rNPY.

  4. 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…

  5. 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.

  6. 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....

  7. 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.

  8. Antagonistic formation motion of cooperative agents

    Science.gov (United States)

    Lu, Wan-Ting; Dai, Ming-Xiang; Xue, Fang-Zheng

    2015-02-01

    This paper investigates a new formation motion problem of a class of first-order multi-agent systems with antagonistic 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 of the agents make an antagonistic formation motion in a distributed manner. It is shown that all of the agents can be spontaneously divided into several groups and that agents in the same group collaborate while agents in different groups compete. Finally, a numerical simulation is included to demonstrate our theoretical results. Project supported by the National Natural Science Foundation of China (Grant Nos. 61203080 and 61473051) and the Natural Science Foundation of Chongqing City (Grant No. CSTC 2011BB0081).

  9. 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

  10. 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

  11. Why are mineralocorticoid receptor antagonists cardioprotective?

    NARCIS (Netherlands)

    W. Chai (Wenxia); A.H.J. Danser (Jan)

    2006-01-01

    textabstractTwo clinical trials, the Randomized ALdosterone Evaluation Study (RALES) and the EPlerenone HEart failure and SUrvival Study (EPHESUS), have recently shown that mineralocorticoid receptor (MR) antagonists reduce mortality in patients with heart failure on top of ACE inhibition. This effe

  12. 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

  13. EFFECT OF ANGIOTENSIN II RECEPTOR ANTAGONIST AND ENDOTHELIN RECEPTOR ANTAGONIST ON NITROGLYCERIN TOLERANCE IN RATS

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Objective. To investigate whether angiotensin II receptor antagonist and endothelin receptor antagonist can improve the nitroglycerin (Nit) tolerance in vivo. Methods. Twenty-four rats were divided into 4 groups (n=6,each): Control group, Nitroglycerin (Nit) group, Nit+ bosentan group and Nit+ losartan group. Nitroglycerin tolerance was induced by 2-day treatment of nitroglycerin patch (0.05 mg/h). AngiotensinⅡ receptor antagonist losartan ( 10 mg· kg- 1· d- 1 ) and endothelin receptor antagonist bosentan ( 100 mg· kg- 1· d- 1 ) were given by gavage for 2 days respectively. Results. The least hypotensive response to sodium nitroprusside (SNP) was observed in Nit group . The effective percentages of hypotensive response to SNP were increased in both Nit+ losartan group and Nit+ bosentan group compared with Nit group [(31.95± 4.45 ) % vs (21.00± 3.69 ) % , P Conclusion. Endothelin receptor antagonist and angiotensin Ⅱ receptor antagonist could prevent against the Nit tolerance .

  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...

  16. Non-selective beta-adrenergic blockade prevents reduction of the cerebral metabolic ratio during exhaustive exercise in humans

    DEFF Research Database (Denmark)

    Larsen, T.S.; Rasmussen, P.; Overgaard, M.;

    2008-01-01

    .d.) and the arterial-jugular venous (a-v) difference from -0.02 +/- 0.03 mm at rest to 1.0 +/- 0.5 mm (P metabolic ratio decreased from 5.5 +/- 1.4 to 3.0 +/- 0.3 (P ...-v lactate difference (to 0.5 +/- 0.5 mm; P metabolic ratio remained at levels similar to those at rest. Together with the previous finding that the cerebral metabolic ratio is unaffected during exercise with administration of the beta(1......Intense exercise decreases the cerebral metabolic ratio of oxygen to carbohydrates [O(2)/(glucose + (1/2)lactate)], but whether this ratio is influenced by adrenergic stimulation is not known. In eight males, incremental cycle ergometry increased arterial lactate to 15.3 +/- 4.2 mm (mean +/- s...

  17. 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

  18. Beta-adrenergic activation of solute coupled water uptake by toad skin epithelium results in near-isosmotic transport

    DEFF Research Database (Denmark)

    Nielsen, Robert; Larsen, Erik Hviid

    2007-01-01

    of [Na+]out in agreement with Na+ self-inhibition of ENaC. Ouabain on the inside decreased I(SC)(Eqv) from 60+/-10 to 6.1+/-1.7 microA cm(-2), and J(V) from 3.34+/-0.47 to 1.40+/-0.24 nL cm(-2) x s(-1). Short-circuited preparations exhibited a linear relationship between short-circuit current and J...

  19. 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...

  20. Chronic stress accelerates pancreatic cancer growth and invasion: a critical role for beta-adrenergic signaling in the pancreatic microenvironment.

    Science.gov (United States)

    Kim-Fuchs, Corina; Le, Caroline P; Pimentel, Matthew A; Shackleford, David; Ferrari, Davide; Angst, Eliane; Hollande, Frédéric; Sloan, Erica K

    2014-08-01

    Pancreatic cancer cells intimately interact with a complex microenvironment that influences pancreatic cancer progression. The pancreas is innervated by fibers of the sympathetic nervous system (SNS) and pancreatic cancer cells have receptors for SNS neurotransmitters which suggests that pancreatic cancer may be sensitive to neural signaling. In vitro and non-orthotopic in vivo studies showed that neural signaling modulates tumour cell behavior. However the effect of SNS signaling on tumor progression within the pancreatic microenvironment has not previously been investigated. To address this, we used in vivo optical imaging to non-invasively track growth and dissemination of primary pancreatic cancer using an orthotopic mouse model that replicates the complex interaction between pancreatic tumor cells and their microenvironment. Stress-induced neural activation increased primary tumor growth and tumor cell dissemination to normal adjacent pancreas. These effects were associated with increased expression of invasion genes by tumor cells and pancreatic stromal cells. Pharmacological activation of β-adrenergic signaling induced similar effects to chronic stress, and pharmacological β-blockade reversed the effects of chronic stress on pancreatic cancer progression. These findings indicate that neural β-adrenergic signaling regulates pancreatic cancer progression and suggest β-blockade as a novel strategy to complement existing therapies for pancreatic cancer.

  1. 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

    ) of 17.8 mmHg, and responded to beta-blocker treatment with a significant reduction in the HVPG (-16%; P controls 1.01 ml/mmHg; P ... systemic vascular resistance increased substantially (1083 versus 1378 dyn x s x cm-5, +27%; P blood pressure (-6%; P blood flow (-22%; P ... with 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....

  2. Beta-adrenergic stimulation reverses the I Kr-I Ks dominant pattern during cardiac action potential.

    Science.gov (United States)

    Banyasz, Tamas; Jian, Zhong; Horvath, Balazs; Khabbaz, Shaden; Izu, Leighton T; Chen-Izu, Ye

    2014-11-01

    β-Adrenergic stimulation differentially modulates different K(+) channels and thus fine-tunes cardiac action potential (AP) repolarization. However, it remains unclear how the proportion of I Ks, I Kr, and I K1 currents in the same cell would be altered by β-adrenergic stimulation, which would change the relative contribution of individual K(+) current to the total repolarization reserve. In this study, we used an innovative AP-clamp sequential dissection technique to directly record the dynamic I Ks, I Kr, and I K1 currents during the AP in guinea pig ventricular myocytes under physiologically relevant conditions. Our data provide quantitative measures of the magnitude and time course of I Ks, I Kr, and I K1 currents in the same cell under its own steady-state AP, in a physiological milieu, and with preserved Ca(2+) homeostasis. We found that isoproterenol treatment significantly enhanced I Ks, moderately increased I K1, but slightly decreased I Kr in a dose-dependent manner. The dominance pattern of the K(+) currents was I Kr > I K1 > I Ks at the control condition, but reversed to I Kr Kr, and I K1 to cardiac repolarization during AP at different adrenergic states. In conclusion, the β-adrenergic stimulation fine-tunes the cardiac AP morphology by shifting the power of different K(+) currents in a dose-dependent manner. This knowledge is important for designing antiarrhythmic drug strategies to treat hearts exposed to various sympathetic tones.

  3. 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;

    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...

  4. 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…

  5. Effect of Cardiopulmonary Bypass on Beta Adrenergic ReceptorAdenylate Cyclase System on Surfaces of Peripheral Lymphocytes

    Institute of Scientific and Technical Information of China (English)

    LUO Ailin; TIAN Yuke; JIN Shiao

    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.

  6. 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...

  7. High affinity retinoic acid receptor antagonists: analogs of AGN 193109.

    Science.gov (United States)

    Johnson, A T; Wang, L; Gillett, S J; Chandraratna, R A

    1999-02-22

    A series of high affinity retinoic acid receptor (RAR) antagonists were prepared based upon the known antagonist AGN 193109 (2). Introduction of various phenyl groups revealed a preference for substitution at the para-position relative to the meta-site. Antagonists with the highest affinities for the RARs possessed hydrophobic groups, however, the presence of polar functionality was also well tolerated.

  8. [Cutaneous adverse effects of TNFalpha antagonists].

    Science.gov (United States)

    Failla, V; Sabatiello, M; Lebas, E; de Schaetzen, V; Dezfoulian, B; Nikkels, A F

    2012-01-01

    The TNFalpha antagonists, including adalimumab, etanercept and infliximab, represent a class of anti-inflammatory and immunosuppressive drugs. Although cutaneous adverse effects are uncommon, they are varied. There is no particular risk profile to develop cutaneous adverse effects. The principal acute side effects are injection site reactions and pruritus. The major long term cutaneous side effects are infectious and inflammatory conditions. Neoplastic skin diseases are exceptional. The association with other immunosuppressive agents can increase the risk of developing cutaneous adverse effects. Some adverse effects, such as lupus erythematosus, require immediate withdrawal of the biological treatment, while in other cases temporary withdrawal is sufficient. The majority of the other cutaneous adverse effects can be dealt without interrupting biologic treatment. Preclinical and clinical investigations revealed that the new biologics, aiming IL12/23, IL23 and IL17, present a similar profile of cutaneous adverse effects, although inflammatory skin reactions may be less often encountered compared to TNFalpha antagonists.

  9. 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.

  10. 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...

  11. 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

  12. 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......, pancreatic juice and serum demonstrated that the major component in serum is salivary amylase. This study has shown that beta-adrenergic agents stimulate secretion of amylase from the salivary glands in rats. Though the secretion is mainly exocrine small amounts of amylase is found in serum, which seems...

  13. 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.

  14. Limited Efficacy of Propranolol on the Reconsolidation of Fear Memories

    Science.gov (United States)

    Muravieva, Elizaveta V.; Alberini, Cristina M.

    2010-01-01

    Previous studies suggested that the beta-adrenergic receptor antagonist propranolol might be a novel, potential treatment for post-traumatic stress disorder (PTSD). This hypothesis stemmed mainly from rodent studies showing that propranolol interferes with the reconsolidation of Pavlovian fear conditioning (FC). However, subsequent investigations…

  15. 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…

  16. 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...

  17. EFFECT OF ANGIOTENSIN II RECEPTOR ANTAGONIST AND ENDOTHELIN RECEPTOR ANTAGONIST ON NITROGLYCERIN TOLERANCE IN RATS

    Institute of Scientific and Technical Information of China (English)

    张建梅; 陈永红; 王晓红; 唐朝枢

    2001-01-01

    Objective. To investigate whether angiotensin II receptor antagonist and endothelin receptor antagonist can improve the nitroglycerin (Nit) tolerance in vivo. Methods. Twenty-four rats were divided into 4 groups (n =6, each): Control group, Nitroglycerin (Nit) group, Nit + bosentan group and Nit + losartan group. Nitroglycerin tolerance was induced by 2-day treatment ofnitroglycerin patch (0. 05mg/h). Angiotensin I1 receptor antagonist losartan (10mg ·kg-1·d-1) and endothe-lin receptor antagonist bosentan ( 100 mg·kg-1· d-1 ) were given by gavage for 2 days respectively. Results. The least hypotensive response to sodium nitroprusside (SNP) was observed in Nit group. The effec-tive percentages of hypotensive response to SNP were increased in both Nit + losartan group and Nit + bosentangroup compared with Nit group [(31.95±4.45) % vs (21.00±3.69) %, P <0.01and (33. 18±6. 16)% vs (21.00±3.69 ) %, P < 0. 01 , respectivelyl. The maximal vessel relaxation induced by SNP was thesame in 4 different groups but the highest EC50 (concentration which produces 50% of the maximal response toSNP) was found in tolerant group[ (34 ±10) nmol/L, P < 0. 01 ]. The ET-1 amounts in plasma and vasculartissue were markedly increased by 54% and 60% in Nit group compared with those in control group( P<0. 01). The ET-1 amounts in plasma and vascular tissue were decreased by 30% and 37% in Nit + losartangroup compared with those in Nit group ( P < 0.01 ). Conclusion. Endothelin receptor antagonist and angiotensin Ⅱ receptor antagonist could prevent against the Nit tolerance.

  18. Evaluation of H2 receptor antagonists in chronic idiopathic urticaria

    Directory of Open Access Journals (Sweden)

    Minocha Y

    1995-01-01

    Full Text Available H1-antagonist (hydroxyzine hydrochloride in dosage of 10 mg-25 mg thrice a day failed to elicit satisfactory response in 60 out of 170 patients of chronic idiopathic urticaria. Additional administration of H2-antagonist (cimetidine in dosage of 200 mg four times a day, in patients not responding earlier to H1-antagonist alones exhibited moderate to good improvement of various parameters of urticaria in approximately 85% patients

  19. 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

  20. 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.

  1. Activins and activin antagonists in hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Alev Deli; Emanuel Kreidl; Stefan Santifaller; Barbara Trotter; Katja Seir; Walter Berger; Rolf Schulte-Hermann; Chantal Rodgarkia-Dara; Michael Grusch

    2008-01-01

    In many parts of the world hepatocellular carcinoma (HCC) is among the leading causes of cancer-related mortality but the underlying molecular pathology is still insufficiently understood. There is increasing evidence that activins, which are members of the transforming growth factor β (TGFβ) superfamily of growth and differentiation factors, could play important roles in liver carcinogenesis. Activins are disulphide-linked homo-or heterodimers formed from four different β subunits termed βA, βB, βC, and βE, respectively. Activin A, the dimer of two βA subunits, is critically involved in the regulation of cell growth, apoptosis, and tissue architecture in the liver, while the hepatic function of other activins is largely unexplored so far. Negative regulators of activin signals include antagonists in the extracellular space like the binding proteins follistatin and FLRG, and at the cell membrane antagonistic co-receptors like Cripto or BAMBI. Additionally, in the intracellular space inhibitory Smads can modulate and control activin activity. Accumulating data suggest that deregulation of activin signals contributes to pathologic conditions such as chronic inflammation, fibrosis and development of cancer. The current article reviews the alterations in components of the activin signaling pathway that have been observed in HCC and discusses their potential significance for liver tumorigenesis.

  2. Smoking, calcium, calcium antagonists, and aging.

    Science.gov (United States)

    Nicita-Mauro, V

    1990-01-01

    Aging is characterized, besides other changes, by a progressive increase in calcium content in the arterial wall, which is enhanced by diabetes mellitus, osteoporosis, arterial hypertension, and tabagism. As to tabagism, experiments in animals have shown that nicotine can increase calcium content of the arterial wall, and clinical studies have demonstrated that cigarette smoking induces peripheral vasoconstriction, with consequent increase in blood pressure levels. In order to study the role of calcium ions in the pathogenesis of the vasoconstrictive lesions caused by "acute" smoking, the author has studied the peripheral vascular effects of the calcium-channel antagonist nifedipine, a dihydropyridine derivative, and calcitonin, a hypocalcemizing hormone which possess vasoactive actions on 12 elderly regular smokers (mean age 65.8 years). The results demonstrated that both nifedipine (10 mg sublingually 20 min before smoking) and salmon calcitonin (100 MRC U/daily intramuscularly for three days) are able to prevent peripheral vasoconstriction evaluated by Doppler velocimetry, as well as the increase of blood pressure induced by smoking. On the basis of our results, the author proposes that cigarette smoking-induced vasoconstriction is a calcium-mediated process, which can be hindered by drugs with calcium antagonist action. PMID:2226675

  3. 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

  4. 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.

  5. 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.

  6. 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.

  7. ETA-receptor antagonists or allosteric modulators?

    DEFF Research Database (Denmark)

    De Mey, Jo G R; Compeer, Matthijs G; Lemkens, Pieter;

    2011-01-01

    The paracrine signaling peptide endothelin-1 (ET1) is involved in cardiovascular diseases, cancer and chronic pain. It acts on class A G-protein-coupled receptors (GPCRs) but displays atypical pharmacology. It binds tightly to ET receptor type A (ET(A)) and causes long-lasting effects. In resista......The paracrine signaling peptide endothelin-1 (ET1) is involved in cardiovascular diseases, cancer and chronic pain. It acts on class A G-protein-coupled receptors (GPCRs) but displays atypical pharmacology. It binds tightly to ET receptor type A (ET(A)) and causes long-lasting effects......(A) and that ERAs and the physiological antagonist allosterically reduce ET(A) functions. Combining the two-state model and the two-domain model of GPCR function and considering receptor activation beyond agonist binding might lead to better anti-endothelinergic drugs. Future studies could lead to compounds...

  8. 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

  9. Optimisation of GnRH antagonist use in ART

    NARCIS (Netherlands)

    Hamdine, O.

    2014-01-01

    This thesis focuses on the optimisation of controlled ovarian stimulation for IVF using exogenous FSH and GnRH antagonist co-treatment, by studying the timing of the initiation of GnRH antagonist co-medication and the role of ovarian reserve markers in optimising ovarian response and reproductive ou

  10. Serotonin 2A receptor antagonists for treatment of schizophrenia

    DEFF Research Database (Denmark)

    Ebdrup, Bjørn Hylsebeck; Rasmussen, Hans; Arnt, Jørn;

    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...

  11. 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…

  12. 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.

  13. 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

  14. 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

  15. Behavioural effects of histamine and its antagonists: a review.

    Science.gov (United States)

    White, J M; Rumbold, G R

    1988-01-01

    This review focuses on the behavioural effects of histamine and drugs which affect histaminergic function, particularly the H1- and H2-receptors antagonists. Research in this area has assumed considerable importance with increasing interest in the role of brain histamine, the clinical use of both H1 and H2 antagonists and evidence of nonmedical use of H1 antagonists. Results from a number of studies show that H1 and H2 antagonists have clear, but distinct subjective effects and that H1 antagonists have discriminative effects in animals. While H1 antagonists are reinforcers in certain conditions, histamine itself is a punisher. Moderate doses of H1 antagonists affect psychomotor performance in some situations, but the results are variable. The exceptions are terfenadine and astemizole, which do not seem to penetrate the blood-brain barrier readily. In studies of schedule-controlled behaviour, marked changes in response rate have been observed following administration of H1 antagonists, with the magnitude and direction dependent on the dose and the baseline behaviour. Histamine reduces avoidance responding, an effect mediated via H1-receptors. Changes in drinking and aggressive behaviour have also been observed following histamine administration and distinct roles for H1- and H2-receptors have been delineated. Separate H1- and H2-receptor mechanisms have also been suggested to account for changes in activity level. While the H2 antagonists do not always have strong behavioural effects when administered peripherally, there is evidence that cimetidine has a depressant effect on sexual function. These and other findings reveal an important role for histaminergic systems in a wide range of behaviour. PMID:3133686

  16. Leukotriene Receptor Antagonists and Related Compounds

    Directory of Open Access Journals (Sweden)

    Sally E Wenzel

    1999-01-01

    Full Text Available Leukotrienes (LTs, lipid mediators of inflammation, have proved to be important biochemicals involved in the symptoms and physiological changes of asthma. In the past year and a half, the development of three new drugs that modulate the LT pathway has been completed. The first subclass of these drugs, leukotriene receptor antagonists (LTRA (zafirlukast and montelukast, blocks the interaction of the cysteinyl form of the LTs with the cell type bearing the receptor. The second subclass, the 5-lipoxygenase (5-LO inhibitors (zileuton inhibits the 5-LO enzyme, which prevents the formation of both cysteinyl LTs and LTB4. The LT modulators have shown efficacy in inhibiting the physiological changes occurring after allergen, acetylsalicylic acid and exercise challenge in asthmatics. In addition, they have shown efficacy in improving symptoms, beta-agonist use and forced expiratory volume in 1 s (FEV1 in chronic, ‘day-to-day’ asthma in patients with mild disease. Comparison studies with low doses of inhaled corticosteroids suggest that LT modulators may have similar effects on symptom scores and beta-agonist use, but have lesser effects on FEV1. Finally, emerging data suggest that these drugs are beneficial in decreasing the dose of inhaled corticosteroids necessary to control more moderate to severe asthma. While long term studies will be helpful in determining the ‘disease modifying’ effects of these drugs, data suggest that these drugs are useful in the treatment of a broad range of asthmatic patients.

  17. Identification of a novel conformationally constrained glucagon receptor antagonist.

    Science.gov (United States)

    Lee, Esther C Y; Tu, Meihua; Stevens, Benjamin D; Bian, Jianwei; Aspnes, Gary; Perreault, Christian; Sammons, Matthew F; Wright, Stephen W; Litchfield, John; Kalgutkar, Amit S; Sharma, Raman; Didiuk, Mary T; Ebner, David C; Filipski, Kevin J; Brown, Janice; Atkinson, Karen; Pfefferkorn, Jeffrey A; Guzman-Perez, Angel

    2014-02-01

    Identification of orally active, small molecule antagonists of the glucagon receptor represents a novel treatment paradigm for the management of type 2 diabetes mellitus. The present work discloses novel glucagon receptor antagonists, identified via conformational constraint of current existing literature antagonists. Optimization of lipophilic ligand efficiency (LLE or LipE) culminated in enantiomers (+)-trans-26 and (-)-trans-27 which exhibit good physicochemical and in vitro drug metabolism profiles. In vivo, significant pharmacokinetic differences were noted with the two enantiomers, which were primarily driven through differences in clearance rates. Enantioselective oxidation by cytochrome P450 was ruled out as a causative factor for pharmacokinetic differences.

  18. 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.

  19. 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...

  20. 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

  1. 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...

  2. 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....

  3. 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...

  4. 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

  5. Identification of M-CSF agonists and antagonists

    Science.gov (United States)

    Pandit, Jayvardhan; Jancarik, Jarmila; Kim, Sung-Hou; Koths, Kirston; Halenbeck, Robert; Fear, Anna Lisa; Taylor, Eric; Yamamoto, Ralph; Bohm, Andrew

    2000-02-15

    The present invention is directed to methods for crystallizing macrophage colony stimulating factor. The present invention is also directed to methods for designing and producing M-CSF agonists and antagonists using information derived from the crystallographic structure of M-CSF. The invention is also directed to methods for screening M-CSF agonists and antagonists. In addition, the present invention is directed to an isolated, purified, soluble and functional M-CSF receptor.

  6. 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

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

    Directory of Open Access Journals (Sweden)

    Elizabeth R. Tuminello

    2011-01-01

    Full Text Available Research on apolipoprotein E (APOE has consistently revealed a relationship between the gene's ε4 allele and risk for development of Alzheimer's disease (AD. However, research with younger populations of ε4 carriers has suggested that the APOE ε4 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 evolutionary biology concept that proposes certain genes or alleles that may differentially impact fitness during different life stages. We critically review this hypothesis in light of new research of the impact of APOE on cognition and neural integrity across the lifespan. We provide recommendations for the revision of the antagonistic pleiotropy hypothesis of APOE and suggest important avenues for future research in this area.

  8. 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.

  9. 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.

  10. Development and characterization of high affinity leptins and leptin antagonists.

    Science.gov (United States)

    Shpilman, Michal; Niv-Spector, Leonora; Katz, Meirav; Varol, Chen; Solomon, Gili; Ayalon-Soffer, Michal; Boder, Eric; Halpern, Zamir; Elinav, Eran; Gertler, Arieh

    2011-02-11

    Leptin is a pleiotropic hormone acting both centrally and peripherally. It participates in a variety of biological processes, including energy metabolism, reproduction, and modulation of the immune response. So far, structural elements affecting leptin binding to its receptor remain unknown. We employed random mutagenesis of leptin, followed by selection of high affinity mutants by yeast surface display and discovered that replacing residue Asp-23 with a non-negatively charged amino acid leads to dramatically enhanced affinity of leptin for its soluble receptor. Rational mutagenesis of Asp-23 revealed the D23L substitution to be most effective. Coupling the Asp-23 mutation with alanine mutagenesis of three amino acids (L39A/D40A/F41A) previously reported to convert leptin into antagonist resulted in potent antagonistic activity. These novel superactive mouse and human leptin antagonists (D23L/L39A/D40A/F41A), termed SMLA and SHLA, respectively, exhibited over 60-fold increased binding to leptin receptor and 14-fold higher antagonistic activity in vitro relative to the L39A/D40A/F41A mutants. To prolong and enhance in vivo activity, SMLA and SHLA were monopegylated mainly at the N terminus. Administration of the pegylated SMLA to mice resulted in a remarkably rapid, significant, and reversible 27-fold more potent increase in body weight (as compared with pegylated mouse leptin antagonist), because of increased food consumption. Thus, recognition and mutagenesis of Asp-23 enabled construction of novel compounds that induce potent and reversible central and peripheral leptin deficiency. In addition to enhancing our understanding of leptin interactions with its receptor, these antagonists enable in vivo study of the role of leptin in metabolic and immune processes and hold potential for future therapeutic use in disease pathologies involving leptin.

  11. Development and Characterization of High Affinity Leptins and Leptin Antagonists*

    Science.gov (United States)

    Shpilman, Michal; Niv-Spector, Leonora; Katz, Meirav; Varol, Chen; Solomon, Gili; Ayalon-Soffer, Michal; Boder, Eric; Halpern, Zamir; Elinav, Eran; Gertler, Arieh

    2011-01-01

    Leptin is a pleiotropic hormone acting both centrally and peripherally. It participates in a variety of biological processes, including energy metabolism, reproduction, and modulation of the immune response. So far, structural elements affecting leptin binding to its receptor remain unknown. We employed random mutagenesis of leptin, followed by selection of high affinity mutants by yeast surface display and discovered that replacing residue Asp-23 with a non-negatively charged amino acid leads to dramatically enhanced affinity of leptin for its soluble receptor. Rational mutagenesis of Asp-23 revealed the D23L substitution to be most effective. Coupling the Asp-23 mutation with alanine mutagenesis of three amino acids (L39A/D40A/F41A) previously reported to convert leptin into antagonist resulted in potent antagonistic activity. These novel superactive mouse and human leptin antagonists (D23L/L39A/D40A/F41A), termed SMLA and SHLA, respectively, exhibited over 60-fold increased binding to leptin receptor and 14-fold higher antagonistic activity in vitro relative to the L39A/D40A/F41A mutants. To prolong and enhance in vivo activity, SMLA and SHLA were monopegylated mainly at the N terminus. Administration of the pegylated SMLA to mice resulted in a remarkably rapid, significant, and reversible 27-fold more potent increase in body weight (as compared with pegylated mouse leptin antagonist), because of increased food consumption. Thus, recognition and mutagenesis of Asp-23 enabled construction of novel compounds that induce potent and reversible central and peripheral leptin deficiency. In addition to enhancing our understanding of leptin interactions with its receptor, these antagonists enable in vivo study of the role of leptin in metabolic and immune processes and hold potential for future therapeutic use in disease pathologies involving leptin. PMID:21119198

  12. 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

  13. Hyperglycemia of Diabetic Rats Decreased by a Glucagon Receptor Antagonist

    Science.gov (United States)

    Johnson, David G.; Ulichny Goebel, Camy; Hruby, Victor J.; Bregman, Marvin D.; Trivedi, Dev

    1982-02-01

    The glucagon analog [l-Nα-trinitrophenylhistidine, 12-homoarginine]-glucagon (THG) was examined for its ability to lower blood glucose concentrations in rats made diabetic with streptozotocin. In vitro, THG is a potent antagonist of glucagon activation of the hepatic adenylate cyclase assay system. Intravenous bolus injections of THG caused rapid decreases (20 to 35 percent) of short duration in blood glucose. Continuous infusion of low concentrations of the inhibitor led to larger sustained decreases in blood glucose (30 to 65 percent). These studies demonstrate that a glucagon receptor antagonist can substantially reduce blood glucose levels in diabetic animals without addition of exogenous insulin.

  14. 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...

  15. 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

  16. Determinants of effective, safe and convenient vitamin K antagonist use

    NARCIS (Netherlands)

    Kooistra, Hilde Afra Margaretha

    2016-01-01

    Vitamin K antagonists (VKA) are frequently used anticoagulants. They are very effective in preventing atrial fibrillation related strokes and recurrent venous thrombosis. However, it can be difficult to achieve an optimal balance between the efficacy and side effects (bleeding), as the dose response

  17. The Effect of Antagonist Muscle Sensory Input on Force Regulation.

    Directory of Open Access Journals (Sweden)

    Tanya Onushko

    Full Text Available The purpose of this study was to understand how stretch-related sensory feedback from an antagonist muscle affects agonist muscle output at different contraction levels in healthy adults. Ten young (25.3 ± 2.4 years, healthy subjects performed constant isometric knee flexion contractions (agonist at 6 torque levels: 5%, 10%, 15%, 20%, 30%, and 40% of their maximal voluntary contraction. For half of the trials, subjects received patellar tendon taps (antagonist sensory feedback during the contraction. We compared error in targeted knee flexion torque and hamstring muscle activity, with and without patellar tendon tapping, across the 6 torque levels. At lower torque levels (5%, 10%, and 15%, subjects produced greater knee torque error following tendon tapping compared with the same torque levels without tendon tapping. In contrast, we did not find any difference in torque output at higher target levels (20%, 30%, and 40% between trials with and without tendon tapping. We also observed a load-dependent increase in the magnitude of agonist muscle activity after tendon taps, with no associated load-dependent increase in agonist and antagonist co-activation, or reflex inhibition from the antagonist tapping. The findings suggest that at relatively low muscle activity there is a deficiency in the ability to correct motor output after sensory disturbances, and cortical centers (versus sub-cortical are likely involved.

  18. 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.

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

    DEFF Research Database (Denmark)

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

    2007-01-01

    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...

  20. 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...

  1. Benzodiazepine receptor antagonists for acute and chronic hepatic encephalopathy

    DEFF Research Database (Denmark)

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

    2001-01-01

    The pathogenesis of hepatic encephalopathy is unknown. It has been suggested that liver failure leads to the accumulation of substances that bind to a receptor-complex in the brain resulting in neural inhibition which may progress to coma. Several trials have assessed benzodiazepine receptor...... antagonists for hepatic encephalopathy, but the results are conflicting....

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

    DEFF Research Database (Denmark)

    Henderson, Alan J; Guzzo, Peter R; Ghosh, Animesh;

    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 ...

  3. 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...

  4. 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.

  5. 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…

  6. 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

  7. 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

  8. 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

  9. Effects of alpha 1-adrenoceptor antagonists on male sexual function

    NARCIS (Netherlands)

    M.M. van Dijk; J.J.M.C.H. de la Rosette; M.C. Michel

    2006-01-01

    alpha(1)-Adrenoceptor antagonists such as alfuzosin, doxazosin, tamsulosin and terazosin are first-line agents for the treatment of lower urinary tract symptoms suggestive of benign prostatic hyperplasia (BPH), but are only second-line agents (doxazosin and terazosin only) for the treatment of arter

  10. Myofascial force transmission via extramuscular pathways occurs between antagonistic muscles.

    Science.gov (United States)

    Huijing, Peter A; Baan, Guus C

    2008-01-01

    Most often muscles (as organs) are viewed as independent actuators. To test if this is true for antagonistic muscles, force was measured simultaneously at: (1) the proximal and distal tendons of the extensor digitorum muscle (EDL) to quantify any proximo-distal force differences, as an indicator of myofascial force transmission, (2) at the distal tendons of the whole antagonistic peroneal muscle group (PER) to test if effects of EDL length changes are present and (3) at the proximal end of the tibia to test if myofascially transmitted force is exerted there. EDL length was manipulated either at the proximal or distal tendons. This way equal EDL lengths are attained at two different positions of the muscle with respect to the tibia and antagonistic muscles. Despite its relatively small size, lengthening of the EDL changed forces exerted on the tibia and forces exerted by its antagonistic muscle group. Apart from its extramuscular myofascial connections, EDL has no connections to either the tibia or these antagonistic muscles. Proximal EDL lengthening increased distal muscular forces (active PER DeltaF approximately +1.7%), but decreased tibial forces (passive from 0.3 to 0 N; active DeltaF approximately -5%). Therefore, it is concluded that these antagonistic muscles do not act independently, because of myofascial force transmission between them. Such a decrease in tibial force indicates release of pre-strained connections. Distal EDL lengthening had opposite effects (tripling passive force exerted on tibia; active PER force DeltaF approximately -3.6%). It is concluded that the length and relative position of the EDL is a co-determinant of passive and active force exerted at tendons of nearby antagonistic muscle groups. These results necessitate a new view of the locomotor apparatus, which needs to take into account the high interdependence of muscles and muscle fibres as force generators, as well as proximo-distal force differences and serial and parallel

  11. 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

  12. 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....

  13. 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.

  14. 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...

  15. 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

  16. 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.

  17. 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.

  18. 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.

  19. 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.

  20. 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...

  1. 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.

  2. Biological effects of growth hormone and its antagonist.

    Science.gov (United States)

    Okada, S; Kopchick, J J

    2001-03-01

    Serum levels of growth hormone (GH) can vary. Low levels of GH can result in a dwarf phenotype and have been positively correlated with an increased life expectancy. High levels of GH can lead to gigantism or a clinical syndrome termed acromegaly and has been implicated in diabetic eye and kidney damage. Additionally the GH/IGF-1 system has been postulated as a risk factor for several types of cancers. Thus both elevated and suppressed circulating levels of GH can have pronounced physiological effects. More than a decade ago the first drug of a new class, a GH antagonist, was discovered. This molecule is now being tested for its ability to combat the effects of high circulating levels of GH. Here, we discuss some of the detrimental actions of GH, and how a GH antagonist can be used to combat these effects. PMID:11286784

  3. 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.

  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. 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.

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

    DEFF Research Database (Denmark)

    Nielsen, Hans Jørgen

    1996-01-01

    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...... 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...

  7. 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.

  8. 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.

  9. 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...

  10. 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...

  11. 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 ...

  12. 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...

  13. Histamine H1 antagonists and clinical characteristics of febrile seizures

    Directory of Open Access Journals (Sweden)

    Zolaly MA

    2012-03-01

    Full Text Available Mohammed A ZolalyDepartment of Pediatrics, College of Medicine, Taibah University, Al-Madinah Al-Munawarah, Kingdom of Saudi ArabiaBackground: The purpose of this study was to determine whether seizure susceptibility due to antihistamines is provoked in patients with febrile seizures.Methods: The current descriptive study was carried out from April 2009 to February 2011 in 250 infants and children who visited the Madinah Maternity and Children's Hospital as a result of febrile convulsions. They were divided into two groups according to administration of antihistamines at the onset of fever.Results: Detailed clinical manifestations were compared between patients with and without administration of antihistamines. The time from fever detection to seizure onset was significantly shorter in the antihistamine group than that in the nonantihistamine group, and the duration of seizures was significantly longer in the antihistamine group than in the nonantihistamine group. No significant difference was found in time from fever detection to seizure onset or seizure duration between patients who received a first-generation antihistamine and those who received a second-generation antihistamine.Conclusion: Due to their central nervous system effects, H1 antagonists should not be administered to patients with febrile seizures and epilepsy. Caution should be exercised regarding the use of histamine H1 antagonists in young infants, because these drugs could potentially disturb the anticonvulsive central histaminergic system.Keywords: antihistamine, nonantihistamine, histamine H1 antagonist, febrile seizures

  14. Approaches to the rational design of selective melanocortin receptor antagonists

    Science.gov (United States)

    Hruby, Victor J; Cai, Minying; Nyberg, Joel; Muthu, Dhanasekaran

    2015-01-01

    Introduction When establishing the physiological roles of specific receptors in normal and disease states, it is critical to have selective antagonist ligands for each receptor in a receptor system with several subtypes. The melanocortin receptors have five subtypes referred to as the melanocortin 1 receptor, melanocortin 2 receptor, melanocortin 3 receptor, melanocortin 4 receptor and melanocortin 5 receptor, and they are of critical importance for many aspects of human health and disease. Areas covered This article reviews the current efforts to design selective antagonistic ligands for the five human melanocortin receptors summarizing the currently published orthosteric and allosteric antagonists for each of these receptors. Expert opinion Though there has been progress, there are still few drugs available that address the many significant biological activities and diseases that are associated with these receptors, which is possibly due to the lack of receptor selectivity that these designed ligands are currently showing. The authors believe that further studies into the antagonists’ 3D conformational and topographical properties in addition to future mutagenesis studies will provide greater insight into these ligands which could play a role in the treatment of various diseases in the future. PMID:22646078

  15. Twisted gastrulation, a BMP antagonist, exacerbates podocyte injury.

    Directory of Open Access Journals (Sweden)

    Sachiko Yamada

    Full Text Available Podocyte injury is the first step in the progression of glomerulosclerosis. Previous studies have demonstrated the beneficial effect of bone morphogenetic protein 7 (Bmp7 in podocyte injury and the existence of native Bmp signaling in podocytes. Local activity of Bmp7 is controlled by cell-type specific Bmp antagonists, which inhibit the binding of Bmp7 to its receptors. Here we show that the product of Twisted gastrulation (Twsg1, a Bmp antagonist, is the central negative regulator of Bmp function in podocytes and that Twsg1 null mice are resistant to podocyte injury. Twsg1 was the most abundant Bmp antagonist in murine cultured podocytes. The administration of Bmp induced podocyte differentiation through Smad signaling, whereas the simultaneous administration of Twsg1 antagonized the effect. The administration of Bmp also inhibited podocyte proliferation, whereas simultaneous administration of Twsg1 antagonized the effect. Twsg1 was expressed in the glomerular parietal cells (PECs and distal nephron of the healthy kidney, and additionally in damaged glomerular cells in a murine model of podocyte injury. Twsg1 null mice exhibited milder hypoalbuminemia and hyperlipidemia, and milder histological changes while maintaining the expression of podocyte markers during podocyte injury model. Taken together, our results show that Twsg1 plays a critical role in the modulation of protective action of Bmp7 on podocytes, and that inhibition of Twsg1 is a promising means of development of novel treatment for podocyte injury.

  16. 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.

  17. IAP antagonists sensitize murine osteosarcoma cells to killing by TNFα

    Science.gov (United States)

    Shekhar, Tanmay M.; Miles, Mark A.; Gupte, Ankita; Taylor, Scott; Tascone, Brianna; Walkley, Carl R.; Hawkins, Christine J.

    2016-01-01

    Outcomes for patients diagnosed with the bone cancer osteosarcoma have not improved significantly in the last four decades. Only around 60% of patients and about a quarter of those with metastatic disease survive for more than five years. Although DNA-damaging chemotherapy drugs can be effective, they can provoke serious or fatal adverse effects including cardiotoxicity and therapy-related cancers. Better and safer treatments are therefore needed. We investigated the anti-osteosarcoma activity of IAP antagonists (also known as Smac mimetics) using cells from primary and metastatic osteosarcomas that arose spontaneously in mice engineered to lack p53 and Rb expression in osteoblast-derived cells. The IAP antagonists SM-164, GDC-0152 and LCL161, which efficiently target XIAP and cIAPs, sensitized cells from most osteosarcomas to killing by low levels of TNFα but not TRAIL. RIPK1 expression levels and activity correlated with sensitivity. RIPK3 levels varied considerably between tumors and RIPK3 was not required for IAP antagonism to sensitize osteosarcoma cells to TNFα. IAP antagonists, including SM-164, lacked mutagenic activity. These data suggest that drugs targeting XIAP and cIAP1/2 may be effective for osteosarcoma patients whose tumors express abundant RIPK1 and contain high levels of TNFα, and would be unlikely to provoke therapy-induced cancers in osteosarcoma survivors. PMID:27129149

  18. Predictions of in vivo prolactin levels from in vitro k I values of d 2 receptor antagonists using an agonist-antagonist interaction model

    NARCIS (Netherlands)

    Petersson, K.J.; Vermeulen, A.M.J.; Friberg, L.E.

    2013-01-01

    Prolactin elevation is a side effect of all currently available D2 receptor antagonists used in the treatment of schizophrenia. Prolactin elevation is the result of a direct antagonistic D2 effect blocking the tonic inhibition of prolactin release by dopamine. The aims of this work were to assess th

  19. 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.

  20. Extra-helical binding site of a glucagon receptor antagonist.

    Science.gov (United States)

    Jazayeri, Ali; Doré, Andrew S; Lamb, Daniel; Krishnamurthy, Harini; Southall, Stacey M; Baig, Asma H; Bortolato, Andrea; Koglin, Markus; Robertson, Nathan J; Errey, James C; Andrews, Stephen P; Teobald, Iryna; Brown, Alastair J H; Cooke, Robert M; Weir, Malcolm; Marshall, Fiona H

    2016-05-12

    Glucagon is a 29-amino-acid peptide released from the α-cells of the islet of Langerhans, which has a key role in glucose homeostasis. Glucagon action is transduced by the class B G-protein-coupled glucagon receptor (GCGR), which is located on liver, kidney, intestinal smooth muscle, brain, adipose tissue, heart and pancreas cells, and this receptor has been considered an important drug target in the treatment of diabetes. Administration of recently identified small-molecule GCGR antagonists in patients with type 2 diabetes results in a substantial reduction of fasting and postprandial glucose concentrations. Although an X-ray structure of the transmembrane domain of the GCGR has previously been solved, the ligand (NNC0640) was not resolved. Here we report the 2.5 Å structure of human GCGR in complex with the antagonist MK-0893 (ref. 4), which is found to bind to an allosteric site outside the seven transmembrane (7TM) helical bundle in a position between TM6 and TM7 extending into the lipid bilayer. Mutagenesis of key residues identified in the X-ray structure confirms their role in the binding of MK-0893 to the receptor. The unexpected position of the binding site for MK-0893, which is structurally similar to other GCGR antagonists, suggests that glucagon activation of the receptor is prevented by restriction of the outward helical movement of TM6 required for G-protein coupling. Structural knowledge of class B receptors is limited, with only one other ligand-binding site defined--for the corticotropin-releasing hormone receptor 1 (CRF1R)--which was located deep within the 7TM bundle. We describe a completely novel allosteric binding site for class B receptors, providing an opportunity for structure-based drug design for this receptor class and furthering our understanding of the mechanisms of activation of these receptors. PMID:27111510

  1. 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...

  2. Non-Vitamin K Antagonist Oral Anticoagulants in Atrial Fibrillation.

    Science.gov (United States)

    Plitt, Anna; Ruff, Christian T; Giugliano, Robert P

    2016-10-01

    For more than 50 years, vitamin K antagonists (VKAs) have been the standard of care for treatment of atrial fibrillation (AF). However, the numerous limitations of VKAs have led to the development of non-VKA oral anticoagulants (NOACs). There are 4 NOACs currently approved for prevention of thromboembolism in patients with nonvalvular AF. This article provides an overview of AF, summarizes basic properties of NOACs, and reviews the landmark trials. Current data on use of NOACs in special populations and specific clinical scenarios are also presented. Lastly, recommendations from experts on controversial topics of bleeding management and reversal are described. PMID:27637305

  3. 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)

  4. 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. ...

  5. 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...

  6. 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.

  7. 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...

  8. 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...

  9. 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

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

    Science.gov (United States)

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

    2015-01-29

    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.

  11. 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.

  12. Suppression of Aldosterone Synthesis and Secretion by Channel Antagonists

    Directory of Open Access Journals (Sweden)

    Keiichi Ikeda

    2012-01-01

    Full Text Available Aldosterone, a specific mineralocorticoid receptor (MR agonist and a key player in the development of hypertension, is synthesized as a final product of renin-angiotensin-aldosterone system. Hypertension can be generally treated by negating the effects of angiotensin II through the use of angiotensin-converting enzyme inhibitors (ACE-Is or angiotensin II type 1 receptor antagonists (ARBs. However, the efficacy of angiotensin II blockade by such drugs is sometimes diminished by the so-called “aldosterone breakthrough” effect, by which ACE-Is or ARBs (renin-angiotensin system (RAS inhibitors gradually lose their effectiveness against hypertension due to the overproduction of aldosterone, known as primary aldosteronism. Although MR antagonists are used to antagonize the effects of aldosterone, these drugs may, however, give rise to life-threatening adverse actions, such as hyperkalemia, particularly when used in conjunction with RAS inhibitors. Recently, several groups have reported that some dihydropyridine Ca2+ channel blockers (CCBs have inhibitory actions on aldosterone production in in vitro and in the clinical setting. Therefore, the use of such dihydropyridine CCBs to treat aldosterone-related hypertension may prove beneficial to circumvent such therapeutic problems. In this paper, we discuss the mechanism of action of CCBs on aldosterone production and clinical perspectives for CCB use to inhibit MR activity in hypertensive patients.

  13. Growth hormone receptor antagonists: discovery and potential uses.

    Science.gov (United States)

    Kopchick, J J; Okada, S

    2001-06-01

    Serum levels of growth hormone (GH) in the human body vary and can influence the levels of insulin-like growth factor I (IGF-1). Low levels of GH can result in a dwarf phenotype and have been positively correlated with an increased life expectancy. High levels of GH can lead to gigantism or a clinical syndrome termed acromegaly, and also have been implicated in diabetic eye and kidney damage. Additionally, it has been postulated that the GH-IGF-I system can be involved in several types of cancers. Overall, both elevated and suppressed circulating levels of GH can have pronounced physiological effects. More than a decade ago a new class of drug, a GH antagonist, was discovered. It is now being tested for its ability to combat the effects of high circulating levels of GH. In this review, we will discuss some of the detrimental actions of GH and how a GH antagonist may be used to combat these effects. PMID:11527080

  14. 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.

  15. 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

  16. 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.

  17. 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

  18. 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

  19. Suvorexant: The first orexin receptor antagonist to treat insomnia

    Directory of Open Access Journals (Sweden)

    Ashok K Dubey

    2015-01-01

    Full Text Available Primary insomnia is mainly treated with drugs acting on benzodiazepine receptors and a few other classes of drugs used for different co-morbidities. A novel approach to treat insomnia has been introduced recently, with the approval of suvorexant, the first in a new class of orexin receptor antagonists. Orexin receptors in the brain have been found to play an important role in the regulation of various aspects of arousal and motivation. The drugs commonly used for insomnia therapy to date, have often been associated with adverse effects, such as, day-time somnolence, amnesia, confusion, and gait disturbance, apart from the risk of dependence on chronic use. Suvorexant has not shown these adverse effects because of its unique mechanism of action. It also appears to be suitable as a chronic therapy for insomnia, because of minimal physical dependence. The availability of this new drug as an effective and safe alternative is an important and welcome development in insomnia management.

  20. Suvorexant: The first orexin receptor antagonist to treat insomnia.

    Science.gov (United States)

    Dubey, Ashok K; Handu, Shailendra S; Mediratta, Pramod K

    2015-01-01

    Primary insomnia is mainly treated with drugs acting on benzodiazepine receptors and a few other classes of drugs used for different co-morbidities. A novel approach to treat insomnia has been introduced recently, with the approval of suvorexant, the first in a new class of orexin receptor antagonists. Orexin receptors in the brain have been found to play an important role in the regulation of various aspects of arousal and motivation. The drugs commonly used for insomnia therapy to date, have often been associated with adverse effects, such as, day-time somnolence, amnesia, confusion, and gait disturbance, apart from the risk of dependence on chronic use. Suvorexant has not shown these adverse effects because of its unique mechanism of action. It also appears to be suitable as a chronic therapy for insomnia, because of minimal physical dependence. The availability of this new drug as an effective and safe alternative is an important and welcome development in insomnia management. PMID:25969666

  1. Pharmacoepidemiological assessment of drug interactions with vitamin K antagonists

    DEFF Research Database (Denmark)

    Pottegård, Anton; Christensen, Rene dePont; Wang, Shirley V;

    2014-01-01

    PurposeWe present a database of prescription drugs and international normalized ratio (INR) data and the applied methodology for its use to assess drug-drug interactions with vitamin K antagonists (VKAs). We use the putative interaction between VKAs and tramadol as a case study. MethodsWe used...... a self-controlled case series to estimate the incidence rate ratio (IRR) comparing the rate of INR measurements of 4.0 in concomitant tramadol and VKA-exposed periods to VKA-only-exposed periods. Secondary analyses considered specific subgroups, alternative exposure criteria, alternative outcome...... definitions, and other drugs. ResultsWe identified 513 VKA users with at least 1 INR measurement 4.0 and concomitant tramadol and VKA exposure during the observation period. The overall IRR was 1.80 (95% confidence interval [CI], 1.53-2.10), with a stronger association among users of phenprocoumon compared...

  2. Pathological gambling induced by dopamine antagonists: a case report.

    Science.gov (United States)

    Grötsch, Philipp; Lange, Claudia; Wiesbeck, Gerhard A; Lang, Undine

    2015-03-01

    Pathological gambling is defined as inappropriate, persistent, and maladaptive gambling behaviour. It is a non-pharmacological addiction classified as an impulse control disorder. However, pathological gambling has been associated with dopamine agonist use. Here we report of a 28-year-old man with a first major depressive episode and a post-traumatic stress disorder who has been treated with a combination of the serotonine/noradrenaline reuptake inhibitor duloxetine and the tricyclic antidepressant maprotiline. The administration of antipsychotic flupentixole (up to 7 mg) turned this slight online poker gambler into an excessive gambler. Only after the discontinuation of the antidopaminergic agents and the switch to bupropion did this gambling behaviour stop which suggests a causal relationship between dopamine antagonists and pathological gambling.

  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. 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.

  5. 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.

  6. 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

  7. Comparison of GnRH Agonist, GnRH Antagonist, and GnRH Antagonist Mild Protocol of Controlled Ovarian Hyperstimulation in Good Prognosis Patients

    Directory of Open Access Journals (Sweden)

    Martin Stimpfel

    2015-01-01

    Full Text Available The reports on how to stimulate the ovaries for oocyte retrieval in good prognosis patients are contradictory and often favor one type of controlled ovarian hyperstimulation (COH. For this reason, we retrospectively analyzed data from IVF/ICSI cycles carried out at our IVF Unit in good prognosis patients (aged <38 years, first and second attempts of IVF/ICSI, more than 3 oocytes retrieved to elucidate which type of COH is optimal at our condition. The included patients were undergoing COH using GnRH agonist, GnRH antagonist or GnRH antagonist mild protocol in combination with gonadotrophins. We found significant differences in the average number of retrieved oocytes, immature oocytes, fertilized oocytes, embryos, transferred embryos, embryos frozen per cycle, and cycles with embryo freezing between studied COH protocols. Although there were no differences in live birth rate (LBR, miscarriages, and ectopic pregnancies between compared protocols, pregnancy rate was significantly higher in GnRH antagonist mild protocol in comparison with both GnRH antagonist and GnRH agonist protocols and cumulative LBR per cycle was significantly higher in GnRH antagonist mild protocol in comparison to GnRH agonist protocol. Our data show that GnRH antagonist mild protocol of COH could be the best method of choice in good prognosis patients.

  8. Agar composition affects in vitro screening of biocontrol activity of antagonistic microorganisms

    NARCIS (Netherlands)

    Bosmans, Lien; De Bruijn, I.; de Mot, Rene; Readers, Hans; Lievens, Bart

    2016-01-01

    Agar-based screening assays are the method of choice when evaluating antagonistic potential of bacterial biocontrol-candidates against pathogens.Weshowed thatwhen using the samemedium, but different agar compositions, the activity of a bacterial antagonist against Agrobacteriumwas strongly affected.

  9. Survivin mRNA antagonists using locked nucleic acid, potential for molecular cancer therapy

    DEFF Research Database (Denmark)

    Fisker, Niels; Westergaard, Majken; Hansen, Henrik Frydenlund;

    2007-01-01

    synergistic effect when combining the mRNA antagonists against Survivin with the chemotherapeutic Taxol. This effect was demonstrated at concentrations of antagonists far lower than any previously demonstrated, indicating the high potential of locked nucleic acid for therapeutic use. Further characterisations...

  10. Screening of Fungus Antagonists against Six Main Disease Pathogens in Crops

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    28 soil samples were collected from the rhizosphere of 16 plant species in six different districts in Hunan. As a result of isolation and purification, 122 fungus strains were obtained of which the antagonistic activity was tested against six fungus pathogens in tomato, cotton, cucumber, chilli, rice and rape, and 17 strains were found antagonistic to one or more pathogenic fungi.

  11. 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...

  12. 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

  13. 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,

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

    DEFF Research Database (Denmark)

    Klementiev, Boris; Li, Shizhong; Korshunova, Irina;

    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....

  15. 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...

  16. 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.

  17. Screening of antagonistic bacteria for biological control of nursery wilt of black pepper (Piper nigrum).

    Science.gov (United States)

    Anith, K N; Radhakrishnan, N V; Manomohandas, T P

    2003-01-01

    Bacterial antagonists of Phytophthora capsici were isolated from underground shoot portions of rooted cuttings of black pepper. Initially isolates were screened by dual culture on potato dextrose agar and carrot agar. Further, a screening was done on black pepper shoots for supression of lesion caused by the pathogen. Most of the antagonists showed varying levels of antagonism in the dual culture and the shoot assay. Isolate PN-026, showing the highest suppression of lesion development in the shoot assay was found to be the most efficient antagonist in reducing Phytophthora capsici induced nursery wilt of black pepper. This screening involving the host, pathogen, and the antagonist, performed on black pepper shoot (the planting material for this vegetatively propagated crop), could be used as a rapid and reliable method for the isolation of efficient bacterial antagonists of P. capsici.

  18. The NK1 receptor antagonist L822429 reduces heroin reinforcement.

    Science.gov (United States)

    Barbier, Estelle; Vendruscolo, Leandro F; Schlosburg, Joel E; Edwards, Scott; Juergens, Nathan; Park, Paula E; Misra, Kaushik K; Cheng, Kejun; Rice, Kenner C; Schank, Jesse; Schulteis, Gery; Koob, George F; Heilig, Markus

    2013-05-01

    Genetic deletion of the neurokinin 1 receptor (NK1R) has been shown to decrease the reinforcing properties of opioids, but it is unknown whether pharmacological NK1R blockade has the same effect. Here, we examined the effect of L822429, a rat-specific NK1R antagonist, on the reinforcing properties of heroin in rats on short (1 h: ShA) or long (12 h: LgA) access to intravenous heroin self-administration. ShA produces heroin self-administration rates that are stable over time, whereas LgA leads to an escalation of heroin intake thought to model important dependence-related aspects of addiction. L822429 reduced heroin self-administration and the motivation to consume heroin, measured using a progressive-ratio schedule, in both ShA and LgA rats. L822429 also decreased anxiety-like behavior in both groups, measured on the elevated plus maze, but did not affect mechanical hypersensitivity observed in LgA rats. Expression of TacR1 (the gene encoding NK1R) was decreased in reward- and stress-related brain areas both in ShA and LgA rats compared with heroin-naïve rats, but did not differ between the two heroin-experienced groups. In contrast, passive exposure to heroin produced increases in TacR1 expression in the prefrontal cortex and nucleus accumbens. Taken together, these results show that pharmacological NK1R blockade attenuates heroin reinforcement. The observation that animals with ShA and LgA to heroin were similarly affected by L822429 indicates that the SP/NK1R system is not specifically involved in neuroadaptations that underlie escalation resulting from LgA self-administration. Instead, the NK1R antagonist appears to attenuate acute, positively reinforcing properties of heroin and may be useful as an adjunct to relapse prevention in detoxified opioid-dependent subjects.

  19. 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

  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. 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

  2. [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

  3. 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.

  4. 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.

  5. Autoradiographic localization of beta-adrenoreceptors in rat uterus

    Energy Technology Data Exchange (ETDEWEB)

    Tolszczuk, M.; Pelletier, G.

    1988-12-01

    The inhibitory effects of catecholamines on uterine smooth muscle are known to be mediated through beta-adrenergic receptors. To investigate further the distribution of these receptors in the rat uterus, we utilized in vitro autoradiography using ( SVI)-cyanopindolol (CYP), a specific beta-receptor ligand that has equal activity for both beta 1- and beta 2-receptor subtypes. The specificity of the labeling and the characterization of receptor subtypes in different cell types were achieved by displacement of radioligand with increasing concentrations of zinterol, a beta-adrenergic agonist with preferential affinity for the beta 2-adrenoreceptor subtype, and practolol, a beta-adrenergic antagonist that binds preferentially to the beta 1-subtype. Quantitative estimation of ligand binding was performed by densitometry. It was shown that the vast majority of beta-adrenoreceptors were of the beta 2-subtype and were found in high concentration not only in the myometrium but also in the endometrial and serosal epithelia. Specific labeling was also observed in glandular elements. These results suggest that beta-adrenoreceptors might be involved in different functions in the uterus.

  6. Photodegradation products of propranolol: the structures and pharmacological studies.

    Science.gov (United States)

    Uwai, Koji; Tani, Marie; Ohtake, Yosuke; Abe, Shinya; Maruko, Akiko; Chiba, Takashi; Hamaya, Yoshiro; Ohkubo, Yasuhito; Takeshita, Mitsuhiro

    2005-12-12

    Recently, single-dose drug packaging systems, allowing the administration of multiple drugs in a single pill, have become popular for the convenience of the patient. The quality of drugs and an accurate measurement of their photostabilities within this system, however, have not been carefully addressed. Drugs that are unstable in light should be carefully handled to protect their potency and ensure their safety. Propranolol (1), a beta-adrenergic receptor antagonist, is widely used for angina pectoris, arrhythmia, and hypertension. Due to its naphthalene skeleton, this drug may be both light unstable and a photosensitizing agent. In this study, we isolated three photodegraded products of propranolol (1): 1-naphthol (2), N-acetylpropranolol (3), and N-formylpropranolol (4). The structures of these compounds were determined by spectroscopic methods and chemical syntheses. We also examined the acute toxicities of these substances in mice and their binding to beta-adrenergic receptors using rat cerebellum cortex membranes. Although the photoproducts isolated in this study did not exhibit any acute toxicity or significant binding to beta-adrenergic receptors, these results serve as a warning to single-dose packaging systems, as propranolol (1) must be handled carefully to protect the compound from light-induced degradation.

  7. 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

  8. 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.

  9. [Vascular calcifications, the hidden side effects of vitamin K antagonists].

    Science.gov (United States)

    Bennis, Youssef; Vengadessane, Subashini; Bodeau, Sandra; Gras, Valérie; Bricca, Giampiero; Kamel, Saïd; Liabeuf, Sophie

    2016-09-01

    Despite the availability of new oral anticoagulants, vitamin K antagonists (VKA, such as fluindione, acenocoumarol or warfarin) remain currently the goal standard medicines for oral prevention or treatment of thromboembolic disorders. They inhibit the cycle of the vitamin K and its participation in the enzymatic gamma-carboxylation of many proteins. The VKA prevent the activation of the vitamin K-dependent blood clotting factors limiting thus the initiation of the coagulation cascade. But other proteins are vitamin K-dependent and also remain inactive in the presence of VKA. This is the case of matrix Gla-protein (MGP), a protein that plays a major inhibitory role in the development of vascular calcifications. Several experimental and epidemiological results suggest that the use of the VKA could promote the development of vascular calcifications increasing thus the cardiovascular risk. This risk seems to be higher in patients with chronic kidney disease or mellitus diabetes who are more likely to develop vascular calcifications, and may be due to a decrease of the MGP activity. This review aims at summarizing the data currently available making vascular calcifications the probably underestimated side effects of VKA.

  10. 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

  11. 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.

  12. Antagonistic functions of two stardust isoforms in Drosophila photoreceptor cells.

    Science.gov (United States)

    Bulgakova, Natalia A; Rentsch, Michaela; Knust, Elisabeth

    2010-11-15

    Membrane-associated guanylate kinases (MAGUKs) are scaffolding proteins that organize supramolecular protein complexes, thereby partitioning the plasma membrane into spatially and functionally distinct subdomains. Their modular organization is ideally suited to organize protein complexes with cell type- or stage-specific composition, or both. Often more than one MAGUK isoform is expressed by one gene in the same cell, yet very little is known about their individual in vivo functions. Here, we show that two isoforms of Drosophila stardust, Sdt-H (formerly called Sdt-B2) and Sdt-D, which differ in their N terminus, are expressed in adult photoreceptors. Both isoforms associate with Crumbs and PATJ, constituents of the conserved Crumbs-Stardust complex. However, they form distinct complexes, localized at the stalk, a restricted region of the apical plasma membrane. Strikingly, Sdt-H and Sdt-D have antagonistic functions. While Sdt-H overexpression increases stalk membrane length and prevents light-dependent retinal degeneration, Sdt-D overexpression reduces stalk length and enhances light-dependent retinal degeneration. These results suggest that a fine-tuned balance of different Crumbs complexes regulates photoreceptor homeostasis.

  13. Preliminary investigations into triazole derived androgen receptor antagonists.

    Science.gov (United States)

    Altimari, Jarrad M; Niranjan, Birunthi; Risbridger, Gail P; Schweiker, Stephanie S; Lohning, Anna E; Henderson, Luke C

    2014-05-01

    A range of 1,4-substituted-1,2,3-N-phenyltriazoles were synthesized and evaluated as non-steroidal androgen receptor (AR) antagonists. The motivation for this study was to replace the N-phenyl amide portion of small molecule antiandrogens with a 1,2,3-triazole and determine effects, if any, on biological activity. The synthetic methodology presented herein is robust, high yielding and extremely rapid. Using this methodology a series of 17 N-aryl triazoles were synthesized from commercially available starting materials in less than 3h. After preliminary biological screening at 20 and 40 μM, the most promising three compounds were found to display IC50 values of 40-50 μM against androgen dependent (LNCaP) cells and serve as a starting point for further structure-activity investigations. All compounds in this work were the focus of an in silico study to dock the compounds into the human androgen receptor ligand binding domain (hARLBD) and compare their predicted binding affinity with known antiandrogens. A comparison of receptor-ligand interactions for the wild type and T877A mutant AR revealed two novel polar interactions. One with Q738 of the wild type site and the second with the mutated A877 residue.

  14. 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

  15. 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.

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

    Directory of Open Access Journals (Sweden)

    Gregory R. Tintinger

    2010-01-01

    Full Text Available 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 unrelated to conventional antagonism of cysteinyl leukotriene receptors. These novel activities enable montelukast to target eosinophils, monocytes, and, in particular, the corticosteroid-insensitive neutrophil, suggesting that this agent may have a broader spectrum of anti-inflammatory activities than originally thought. If so, montelukast is potentially useful in the chemotherapy of intermittent asthma, chronic obstructive pulmonary disease, cystic fibrosis, and viral bronchiolitis, which, to a large extent, involve airway epithelial cell/neutrophil interactions. The primary objective of this mini-review is to present evidence for the cysteinyl leukotrien–independent mechanisms of action of montelukast and their potential clinical relevance.

  17. 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

  18. Effect of platelet activating factor antagonist treatment on gentamicin nephrotoxicity

    Directory of Open Access Journals (Sweden)

    A. Rodriguez-Barbero

    1992-01-01

    Full Text Available To assess whether PAF could be involved in the gentamicin-induced nephrotoxicity, we have studied the effect of PAF antagonist BN-52021 on renal function in rats after gentamicin (GENTA treatment. Experiments were completed in 21 Wistar rats divided into three groups: group GENTA was injected with gentamicin 100 mg kg−1 body wt/day s.c. for 6 days. Group GENTA + BN received gentamicin and BN-52021 i.p. 5 mg kg−1 body wt/day. A third group served as control. Rats were placed in meta-bolic cages and plasma creatinine and creatinine clearance were measured daily. GENTA group showed a progressive increase in plasma creatinine, a drop in creatinine clearance and an increase in urinary excretion of N-acetyl-β-D-glucosaminidase and alkaline phosphatase. GENTA + BN group showed a lesser change in plasma creatinine and a creatinine clearance, but no difference with GENTA group in urinary excretion of NAG and AP were observed. Histological examination revealed a massive cortical tubular necrosis in rats treated with gentamicin, whereas in BN-52021 injected animals tubular damage was markedly attenuated. The present results suggest a role for PAF in the gentamicininduced nephro-toxicity.

  19. 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

  20. Agonists and Antagonists of TGF-β Family Ligands.

    Science.gov (United States)

    Chang, Chenbei

    2016-08-01

    The discovery of the transforming growth factor β (TGF-β) family ligands and the realization that their bioactivities need to be tightly controlled temporally and spatially led to intensive research that has identified a multitude of extracellular modulators of TGF-β family ligands, uncovered their functions in developmental and pathophysiological processes, defined the mechanisms of their activities, and explored potential modulator-based therapeutic applications in treating human diseases. These studies revealed a diverse repertoire of extracellular and membrane-associated molecules that are capable of modulating TGF-β family signals via control of ligand availability, processing, ligand-receptor interaction, and receptor activation. These molecules include not only soluble ligand-binding proteins that were conventionally considered as agonists and antagonists of TGF-β family of growth factors, but also extracellular matrix (ECM) proteins and proteoglycans that can serve as "sink" and control storage and release of both the TGF-β family ligands and their regulators. This extensive network of soluble and ECM modulators helps to ensure dynamic and cell-specific control of TGF-β family signals. This article reviews our knowledge of extracellular modulation of TGF-β growth factors by diverse proteins and their molecular mechanisms to regulate TGF-β family signaling.

  1. Iontophoresis of endothelin receptor antagonists in rats and men.

    Directory of Open Access Journals (Sweden)

    Matthieu Roustit

    Full Text Available INTRODUCTION: The treatment of scleroderma-related digital ulcers is challenging. The oral endothelin receptor antagonist (ERA bosentan has been approved but it may induce liver toxicity. The objective of this study was to test whether ERAs bosentan and sitaxentan could be locally delivered using iontophoresis. METHODS: Cathodal and anodal iontophoresis of bosentan and sitaxentan were performed on anaesthetized rat hindquarters without and during endothelin-1 infusion. Skin blood flow was quantified using laser-Doppler imaging and cutaneous tolerability was assessed. Iontophoresis of sitaxentan (20 min, 20 or 100 µA was subsequently performed on the forearm skin of healthy men (n = 5. RESULTS: In rats neither bosentan nor sitaxentan increased skin blood flux compared to NaCl. When simultaneously infusing endothelin-1, cathodal iontophoresis of sitaxentan increased skin blood flux compared to NaCl (AUC(0-20 were 44032.2 ± 12277 and 14957.5 ± 23818.8 %BL.s, respectively; P = 0.01. In humans, sitaxentan did not significantly increase skin blood flux as compared to NaCl. Iontophoresis of ERAs was well tolerated both in animals and humans. CONCLUSIONS: This study shows that cathodal iontophoresis of sitaxentan but not bosentan partially reverses endothelin-induced skin vasoconstriction in rats, suggesting that sitaxentan diffuses into the dermis. However, sitaxentan does not influence basal skin microvascular tone in rats or in humans.

  2. Pharmacology of glutamate receptor antagonists in the kindling model of epilepsy.

    Science.gov (United States)

    Löscher, W

    1998-04-01

    It is widely accepted that excitatory amino acid transmitters such as glutamate are involved in the initiation of seizures and their propagation. Most attention has been directed to synapses using NMDA receptors, but more recent evidence indicates potential roles for ionotropic non-NMDA (AMPA/kainate) and metabotropic glutamate receptors as well. Based on the role of glutamate in the development and expression of seizures, antagonism of glutamate receptors has long been thought to provide a rational strategy in the search for new, effective anticonvulsant drugs. Furthermore, because glutamate receptor antagonists, particularly those acting on NMDA receptors, protect effectively in the induction of kindling, it was suggested that they may have utility in epilepsy prophylaxis, for example, after head trauma. However, first clinical trials with competitive and uncompetitive NMDA receptor antagonists in patients with partial (focal) seizures, showed that these drugs lack convincing anticonvulsant activity but induce severe neurotoxic adverse effects in doses which were well tolerated in healthy volunteers. Interestingly, the only animal model which predicted the unfavorable clinical activity of competitive NMDA antagonists in patients with chronic epilepsy was the kindling model of temporal lobe epilepsy, indicating that this model should be used in the search for more effective and less toxic glutamate receptor antagonists. In this review, results from a large series of experiments on different categories of glutamate receptor antagonists in fully kindled rats are summarized and discussed. NMDA antagonists, irrespective whether they are competitive, high- or low-affinity uncompetitive, glycine site or polyamine site antagonists, do not counteract focal seizure activity and only weakly, if at all, attenuate propagation to secondarily generalized seizures in this model, indicating that once kindling is established, NMDA receptors are not critical for the expression of

  3. [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

  4. 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

    Anti-tumour necrosis factor (TNF) monoclonal antibodies or soluble TNF receptors have become an invaluable treatment against chronic inflammatory diseases, such as rheumatoid arthritis, inflammatory bowel disease and psoriasis. Individuals who are treated with TNF antagonists are at an increased...... 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...

  5. 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.

  6. HETEROGENEOUS RECEPTOR-BINDING OF CLASSICAL QUATERNARY MUSCARINIC ANTAGONISTS .1. BOVINE TISSUE DISTRIBUTION

    NARCIS (Netherlands)

    ROFFEL, AF; ENSING, K; INTHOUT, WG; DEZEEUW, RA; ZAAGSMA, J

    1991-01-01

    In competition experiments with the teritiary radioligand [H-3]dexetimide, classical quaternary muscarinic antagonists like ipratropium bromide and N-methylscopolamine bromide distinguished two muscarinic binding sites in bovine brain (total brain minus cerebellum) membranes, in contrast to their te

  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;

    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. General anaesthesia does not improve outcome in opioid antagonist detoxification treatment : a randomized controlled trial

    NARCIS (Netherlands)

    De Jong, Cor A J; Laheij, Robert J F; Krabbe, Paul F M

    2005-01-01

    AIM: Opioid detoxification by administering opioid-antagonists under general anaesthesia has caused considerable controversy. This study is conducted to determine whether rapid detoxification under general anaesthesia results in higher levels of opioid abstinence than rapid detoxification without an

  9. Epimuscular myofascial force transmission between antagonistic and synergistic muscles can explain movement limitation in spastic paresis

    NARCIS (Netherlands)

    Huijing, Peter A.

    2007-01-01

    Details and concepts of intramuscular, extramuscular and intermuscular myofascial force transmission are reviewed. Some new experimental data are added regarding myofascial force transmission between antagonistic muscles across the interosseal membrane of the lower hind limb of the rat. Combined wit

  10. 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.

  11. 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

  12. 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.

  13. 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.

  14. 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

  15. 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....

  16. Synthesis of phenylalaninol-derived oxazolopyrrolidone lactams and evaluation as NMDA receptor antagonists

    OpenAIRE

    Pereira, Nuno A.L.; Sureda, Francesc X; Turch, M.; Amat, Mercedes; van de Bosch, Joan; Santos, Maria M. M.

    2013-01-01

    N-Methyl-d-aspartate (NMDA) receptor antagonists are known to rescue neuronal cell death caused by excessive activation of glutamate receptors. This phenomenon, known as excitotoxicity, is implicated in the pathogenesis of several neurodegenerative disorders including ischemia, Alzheimer's disease, Parkinson's disease, and Huntington's disease. Unfortunately, some NMDA receptor antagonists have shown discouraging results when tested in clinical trials. However, recent advances in the physiolo...

  17. 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...

  18. 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.

  19. 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...

  20. 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...

  1. 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.

  2. 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...

  3. 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...

  4. 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

  5. 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...

  6. 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...

  7. Anti-idiotypic antibody: A new strategy for the development of a growth hormone receptor antagonist.

    Science.gov (United States)

    Lan, Hainan; Zheng, Xin; Khan, Muhammad Akram; Li, Steven

    2015-11-01

    In general, traditional growth hormone receptor antagonist can be divided into two major classes: growth hormone (GH) analogues and anti-growth hormone receptor (GHR) antibodies. Herein, we tried to explore a new class of growth hormone receptor (GHR) antagonist that may have potential advantages over the traditional antagonists. For this, we developed a monoclonal anti-idiotypic antibody growth hormone, termed CG-86. A series of experiments were conducted to characterize and evaluate this antibody, and the results from a competitive receptor-binding assay, Enzyme Linked Immunosorbent Assays (ELISA) and epitope mapping demonstrate that CG-86 behaved as a typical Ab2β. Next, we examined its antagonistic activity using in vitro cell models, and the results showed that CG-86 could effectively inhibit growth hormone receptor-mediated signalling and effectively inhibit growth hormone-induced Ba/F3-GHR638 proliferation. In summary, these studies show that an anti-idiotypic antibody (CG-86) has promise as a novel growth hormone receptor antagonist. Furthermore, the current findings also suggest that anti-idiotypic antibody may represent a novel strategy to produce a new class of growth hormone receptor antagonist, and this strategy may be applied with other cytokines or growth factors.

  8. 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

  9. 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.

  10. 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

  11. 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

  12. Effects of opiate antagonists on hormones and behavior of male and female rhesus monkeys.

    Science.gov (United States)

    Abbott, D H; Holman, S D; Berman, M; Neff, D A; Goy, R W

    1984-02-01

    Opiate antagonists, naloxone (100 micrograms/kg) and naltrexone (1 mg/kg) were given to singly housed adult male or female rhesus prior to a 20-minute behavioral test with an oppositely sexed stimulus monkey. Four of the intact adult males were socially and sexually experienced. The remaining two intact males and two castrated males had been reared in socially restricted conditions and were psychosexually deficient. Adult females were ovariectomized, and the effects of opiate antagonists were examined with or without concurrent estradiol treatment. Both antagonists inhibited sexual behavior of the socially reared, sexually active, intact males. No stimulatory effects on sexual behavior were observed for sexually deficient males, whether intact or castrated. Females showed little change in sexual behavior following opiate antagonist treatment, regardless of endocrine status. The proportion of approaches of the female to the male was increased when naloxone, but not naltrexone, was given. Specific endocrine effects of the opiate antagonists were only found in intact males. Naltrexone significantly increased LH concentrations in the two males tested, while the increase in LH in the four males receiving naloxone was not significant. In all intact males, increases in LH were accompanied by statistically significant increases in circulating concentrations of testosterone following naloxone and naltrexone. The gonadotropic stimulating effect of the opiate antagonists was specific to LH, and no changes were observed in circulating concentrations of FSH in either sex. PMID:6424632

  13. 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.

  14. 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;}

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

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    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

  16. 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.

  17. Genetic determinants of response and adverse effects following vitamin K antagonist oral anticoagulants

    Directory of Open Access Journals (Sweden)

    Parameshwar S.

    2016-06-01

    Full Text Available Background: Vitamin K antagonist anticoagulants (warfarin/acenocoumarol are commonly used anticoagulants that require careful clinical management to balance the risks of over anticoagulation and bleeding with those of under anticoagulation and clotting. Genetic variants of the enzyme that metabolizes vitamin K antagonist anticoagulant, cytochrome P-450 2C9 (CYP2C9, and of a key pharmacologic target of vitamin K antagonists anticoagulant, vitamin K epoxide reductase (VKORC1, contribute to differences in patients responses to various anticoagulant doses. Methods: In thirty patients on oral vitamin K antagonist anticoagulant therapy, presented with either clotting manifestations (valve thrombosis, pulmonary embolism and DVT or prolonged INR/bleeding manifestations, we assessed CYP2C9 genotypes, VKORC1 haplotypes, clinical characteristics, response to therapy (as determined by the international normalized ratio [INR], and bleeding events. Results: Of the thirty patients, thirteen patients INR was high and four patients presented with major bleeding and four with minor bleeding manifestations. Out of thirteen patients with high INR, ten patients showed CYP2C9 polymorphism ( 1/ 3 and 2/ 3 of poor metabolizer genotype. Most of the high INR patients were recently started on oral vitamin K antagonist anticoagulant. Most patients presented with clotting manifestations with below therapeutic INR are noncompliant with anticoagulants. Conclusions: The results of this study suggest that the CYP2C9 polymorphisms are associated with an increased risk of over anticoagulation and of bleeding events among patients on vitamin K antagonists' anticoagulant setting. Screening for CYP2C9 variants may allow clinicians to develop dosing protocols and surveillance techniques to reduce the risk of adverse drug reactions in patients receiving vitamin K antagonist anticoagulants. However the cost-effectiveness of genotyping of patients must be considered. [Int J Res Med Sci

  18. 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

  19. Evaluation of antagonist coactivation strategies elicited from electrically stimulated muscles under load-moving conditions.

    Science.gov (United States)

    Zhou, B H; Katz, S R; Baratta, R V; Solomonow, M; D'Ambrosia, R D

    1997-07-01

    Muscle coactivation strategies that produce ankle dorsiflexion and plantar flexion were elicited by electrical stimulation of the tibialis anterior (TA) and soleus (SOL) muscles of the cat, and examined under several loading conditions. Four different load types were used: free-limb motion (no load), fly-wheel, and two pendulums, each with a different lever arm. Three types of coactivation strategies were considered. The first coactivation strategy consisted of antagonist activity that decreased as the agonist activity increased. The second strategy consisted of increasing antagonist activity with increasing agonist activity. And, in the third strategy, antagonist coactivation decreased at low force levels, then increased at high force levels. The three strategies were evaluated based on the joint angle's peak-to-peak movement and its ability to track a linear input command given by the correlation coefficient of the output signal versus linear input. Results showed that increasing antagonist activity resulted in decreasing peak-to-peak angle and a decreased signal tracking capability for each load condition. The latter, however, was not as obvious in the flywheel load (as compared with free-moving and pendulum conditions). A decreasing peak-to-peak torque for pendulum loads was also observed with increasing antagonist activity. In all loading conditions, maximal peak-to-peak angle and torque were present when a moderate degree of antagonist activity was engaged, and signal tracking capability improved with earlier engagement of the antagonist muscles. It is suggested that strategies using a combination of low-level coactivation, as described in the physiological literature and previous functional electrical stimulation (FES) studies, could satisfactorily address the issues of controllability and efficiency while maintaining long-term joint integrity.

  20. 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

  1. 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

  2. Trichoderma viride Laccase Plays a Crucial Role in Defense Mechanism against Antagonistic Organisms.

    Science.gov (United States)

    Divya, Lakshmanan; Sadasivan, C

    2016-01-01

    Fungal laccases are involved in a variety of physiological functions such as delignification, morphogenesis, and parasitism. In addition to these functions, we suggest that fungal laccases are involved in defense mechanisms. When the laccase secreting Trichoderma viride was grown in the presence of a range of microorganisms including bacteria and fungi, laccase secretion was enhanced in response to antagonistic organisms alone. In addition, growth of antagonistic microbes was restricted by the secreting fungi. Besides, our study for the first time shows the inability of the secreting fungi (T. viride) to compete with antagonistic organism when laccase activity is inhibited, further emphasizing its involvement in rendering a survival advantage to the secreting organism. When laccase inhibitor was added to the media, the zone of inhibition exerted by the antagonist organism was more pronounced and consequently growth of T. viride was significantly restricted. Based on these observations we accentuate that, laccase plays an important role in defense mechanism and provides endurance to the organism when encountered with an antagonistic organism in its surrounding. PMID:27242756

  3. Evaluation of the protagonist-antagonist dichotomy in Spanish television content targeting children

    Directory of Open Access Journals (Sweden)

    José A. García-Castillo, Ph.D.

    2010-01-01

    Full Text Available The goal of this study is to analyse the profile of the protagonist-antagonist dichotomy in all children’s television content, of all genres, offered by Spanish television channels. The analysis of protagonist and antagonist characters focuses on variables such as: type and number, age, gender, nationality, skills, relationship between the characters, characterisation, means used to achieve goals, consequences of the action of the antagonist over the antagonist and vice versa. The sample consists of 168 series that were analysed using descriptive content analysis and multivariate analysis. The results showed that over 50% of the series do not have an antagonist and that when there is one the most common type is a single human, which appears in more than 15% of the analysed series, followed by the fantastic creature type, which is present in just 10%. In 80% of the series the skills of the protagonists are social and human, and in 45.24% the exhibited skill is intelligence.

  4. Dual action of neurokinin-1 antagonists on Mas-related GPCRs

    Science.gov (United States)

    Azimi, Ehsan; Reddy, Vemuri B.; Shade, Kai-Ting C.; Anthony, Robert M.; Pereira, Paula Juliana Seadi; Lerner, Ethan A.

    2016-01-01

    The challenge of translating findings from animal models to the clinic is well known. An example of this challenge is the striking effectiveness of neurokinin-1 receptor (NK-1R) antagonists in mouse models of inflammation coupled with their equally striking failure in clinical investigations in humans. Here, we provide an explanation for this dichotomy: Mas-related GPCRs (Mrgprs) mediate some aspects of inflammation that had been considered mediated by NK-1R. In support of this explanation, we show that conventional NK-1R antagonists have off-target activity on the mouse receptor MrgprB2 but not on the homologous human receptor MRGPRX2. An unrelated tripeptide NK-1R antagonist has dual activity on MRGPRX2. This tripeptide both suppresses itch in mice and inhibits degranulation from the LAD-2 human mast cell line elicited by basic secretagogue activation of MRGPRX2. Antagonists of Mrgprs may fill the void left by the failure of NK-1R antagonists. PMID:27734033

  5. Sphingosine-1-Phosphate Receptor-2 Antagonists: Therapeutic Potential and Potential Risks

    Science.gov (United States)

    Blankenbach, Kira V.; Schwalm, Stephanie; Pfeilschifter, Josef; Meyer zu Heringdorf, Dagmar

    2016-01-01

    The sphingosine-1-phosphate (S1P) signaling system with its specific G-protein-coupled S1P receptors, the enzymes of S1P metabolism and the S1P transporters, offers a multitude of promising targets for drug development. Until today, drug development in this area has nearly exclusively focused on (functional) antagonists at the S1P1 receptor, which cause a unique phenotype of immunomodulation. Accordingly, the first-in class S1P1 receptor modulator, fingolimod, has been approved for the treatment of relapsing-remitting multiple sclerosis, and novel S1P1 receptor (functional) antagonists are being developed for autoimmune and inflammatory diseases such as psoriasis, inflammatory bowel disease, lupus erythematodes, or polymyositis. Besides the S1P1 receptor, also S1P2 and S1P3 are widely expressed and regulate many diverse functions throughout the body. The S1P2 receptor, in particular, often exerts cellular functions which are opposed to the functions of the S1P1 receptor. As a consequence, antagonists at the S1P2 receptor have the potential to be useful in a contrasting context and different areas of indication compared to S1P1 antagonists. The present review will focus on the therapeutic potential of S1P2 receptor antagonists and discuss their opportunities as well as their potential risks. Open questions and areas which require further investigations will be emphasized in particular. PMID:27445808

  6. 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.

  7. 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.

  8. Rapid tolerance against focal cerebral ischemia induced by isoflurane anesthesia is attenuated by adenosine A1 receptor antagonist in rats

    Institute of Scientific and Technical Information of China (English)

    刘艳红; 熊利泽

    2003-01-01

    The brief anesthesia with isoflurane induces rapid tolerance against focal cerebral ischemia in rats and adenosine A1 receptor antagonist, DPCPX, attenuates the beneficial effect of isoflurane preconditioning.

  9. GnRH antagonist in in vitro fertilization: where we are now.

    Science.gov (United States)

    Shapiro, D B; Mitchell-Leef, D

    2003-10-01

    This review focuses on the recent literature concerning the use of GnRH antagonists in ovulation induction for in vitro fertilization (IVF). The GnRH antagonists, ganirelix acetate (Orgalutran/Antagon) and cetrorelix (Cetrotide), have come into increasingly common use since their release in the last 3 years. This class of GnRH analogue has several potential advantages over GnRH agonists. Among these advantages are: 1) shorter duration of injectable drug treatment, 2) decreased gonadotropin requirement per cycle, 3) improved patient convenience and 4) lower overall treatment cost. As clinicians gain experience with these drugs, optimal treatment paradigms will likely emerge. This review will discuss current strategies and potential applications for the GnRH antagonists.

  10. 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

  11. Opioid analgesics as noncompetitive N-methyl-D-aspartate (NMDA) antagonists

    DEFF Research Database (Denmark)

    Ebert, B; Thorkildsen, C; Andersen, S;

    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......, in order to obtain complete analgesia, a combination of an NMDA receptor antagonist and an opioid receptor agonist is needed. Recent in vitro data have demonstrated that methadone, ketobemidone, and dextropropoxyphene, in addition to being opioid receptor agonists, also are weak noncompetitive NMDA...... receptor antagonists. Clinical anecdotes suggest that the NMDA receptor antagonism of these opioids may play a significant role in the pharmacological action of these compounds; however, no clinical studies have been conducted to support this issue. In the present commentary, we discuss evidence...

  12. Dicentrine is preferentially antagonistic to rat aortic than splenic α1-adrenoceptor stimulation

    Institute of Scientific and Technical Information of China (English)

    MUSTAFA Mohd Rais; ACHIKE Francis Ifejika

    2000-01-01

    AIM: Dicentrine is a known α1-adrenoceptor antagonist, but its α1-adrenoceptor subtype selectivity has not yet been determined. We therefore, investigated the putative α1-adrenoceptor subtype selectivity of this agent. METHODS: Graded isometric contractile responses of rat aortic rings and spleen to phenylephrine were observed in the absence or presence of various concentrations of dicentrine. The pA2 values for dicentrine were determined.RESULTS: Aortic tissues were more sensitive to phenylephrine-induced connaction than the spleen tissues. Dicentrine was approximately 100 times more potent as an antagonist to the aortic contraction, than it was to the splenic contractions. CONCLUSION: Dicenuine is an a1-adrenoceptor antagonist which is more selective towards the putative α1D-adrenoceptor subtype of the rat aorta than the α1s-adrenoceptor of the spleen.

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

    DEFF Research Database (Denmark)

    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, ...... antagonists are additive with those of beta agonists. These data provide strong support for the use of leukotriene receptor antagonists for treating asthma.......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...... 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...

  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. Antagonists of sensory neuropeptides inhibit the secondary phase of increased circulation following thermally induced inflammation.

    Science.gov (United States)

    Löfgren, O; Qi, Y; Lundeberg, T; Gazelius, B

    1998-11-01

    A model of thermally induced inflammation in the anesthetized rat was used to measure acute microcirculatory reactions after heat exposure. The thermal injury was inflicted by dipping the right hindpaw into hot water at 60 degrees for 20 s. Local blood flow was recorded simultaneously in both hindpaws and continuously by laser Doppler flowmetry before, during and for 2 h after the thermal injury and the mean arterial blood pressure (MAP) was displayed on a chart recorder. To assess the contribution of the nervous system to the vascular changes seen, neuropeptide antagonists directed toward substance P (SP), neurokinin A (NKA), and calcitonin gene-related peptide (CGRP) were administered. The neurokinin antagonists (NK1, NK2) and the CGRP antagonist (CGRP8-37) were injected via a catheter into the jugular vein. During the first few minutes after thermal injury to the controls, an immediate increase in blood perfusion of about 351% was recorded, followed by a slow decrease of circulation. At 30 min after thermal injury, there was a secondary phase of increased microcirculation of approximately 329%. A slow decline of cutaneous circulation then followed and, after another 30 min, the value stabilized at a level about 100% above the level before injury. Pretreatment with intravenous injections of the NK1 antagonist, NK2 antagonist, and CGRP8-37 attenuated the first phase and almost abolished the secondary phase. No significant change of perfusion was observed on the unscalded paw. The MAP remained at a stable level throughout the experiment and was not affected by the thermal injury or by the administration of the antagonists as compared to controls. Our results show that sensory neuropeptides play a significant role in the blood flow increase seen following thermal injury. PMID:9828161

  16. 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.)

  17. 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.

  18. 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

  19. 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

  20. Antianxiety actions of Ca2+ channel antagonists with Vogel-type conflict test in rats.

    Science.gov (United States)

    Matsumoto, Y; Kataoka, Y; Watanabe, Y; Miyazaki, A; Taniyama, K

    1994-10-13

    We examined the effects of various derivatives of Ca2+ channel antagonists in a modified rat Vogel-type conflict model. Flunarizine (10 and 20 mg/kg), nicardipine (20 mg/kg), and verapamil (20 mg/kg), given as single i.p. injections, significantly increased punished lickings by 50-110%. Chronic administration of diltiazem, at 20 mg/kg i.p. for 8 days, a dose ineffective with a single i.p. injection, produced a significant anticonflict action. The possibility that Ca2+ channel antagonists have anxiolytic action should be considered.

  1. 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

  2. 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....

  3. 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.

  4. 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

  5. Chemogenomic discovery of allosteric antagonists at the GPRC6A receptor

    DEFF Research Database (Denmark)

    Gloriam, David E.; Wellendorph, Petrine; Johansen, Lars Dan;

    2011-01-01

    and 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...

  6. Development of prolactin receptor antagonists with reduced pH-dependence of receptor binding

    DEFF Research Database (Denmark)

    Hansen, Mathilde Johanne Kaas; Olsen, Johan Gotthardt; Bernichtein, Sophie;

    2011-01-01

    and thermodynamic characterization of receptor binding by isothermal titration calorimetry combined with in vitro bioactivity in living cells. Histidine residue 27 was recognized as a central hot spot for pH sensitivity and conservative substitutions at this site resulted in strong receptor binding at low pH. Pure...... antagonists were developed earlier and the histidine mutations were introduced within such background. The antagonistic properties were maintained and the high affinity at low pH conserved. The implications of these findings may open new areas of research in the field of prolactin cancer biology. Copyright...

  7. 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

  8. 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 ...

  9. Discovery of 2-substituted benzoxazole carboxamides as 5-HT3 receptor antagonists.

    Science.gov (United States)

    Yang, Zhicai; Fairfax, David J; Maeng, Jun-Ho; Masih, Liaqat; Usyatinsky, Alexander; Hassler, Carla; Isaacson, Soshanna; Fitzpatrick, Kevin; DeOrazio, Russell J; Chen, Jianqing; Harding, James P; Isherwood, Matthew; Dobritsa, Svetlana; Christensen, Kevin L; Wierschke, Jonathan D; Bliss, Brian I; Peterson, Lisa H; Beer, Cathy M; Cioffi, Christopher; Lynch, Michael; Rennells, W Martin; Richards, Justin J; Rust, Timothy; Khmelnitsky, Yuri L; Cohen, Marlene L; Manning, David D

    2010-11-15

    A new class of 2-substituted benzoxazole carboxamides are presented as potent functional 5-HT(3) receptor antagonists. The chemical series possesses nanomolar in vitro activity against human 5-HT(3)A receptors. A chemistry optimization program was conducted and identified 2-aminobenzoxazoles as orally active 5-HT(3) receptor antagonists with good metabolic stability. These novel analogues possess drug-like characteristics and have potential utility for the treatment of diseases attributable to improper 5-HT(3) receptor function, especially diarrhea predominant irritable bowel syndrome (IBS-D).

  10. Antagonists of the human A(2A) receptor. Part 6: Further optimization of pyrimidine-4-carboxamides.

    Science.gov (United States)

    Gillespie, Roger J; Bamford, Samantha J; Clay, Alex; Gaur, Suneel; Haymes, Tim; Jackson, Philip S; Jordan, Allan M; Klenke, Burkhard; Leonardi, Stefania; Liu, Jeanette; Mansell, Howard L; Ng, Sean; Saadi, Mona; Simmonite, Heather; Stratton, Gemma C; Todd, Richard S; Williamson, Douglas S; Yule, Ian A

    2009-09-15

    Antagonists of the human A(2A) receptor have been reported to have potential therapeutic benefit in the alleviation of the symptoms associated with neurodegenerative movement disorders such as Parkinson's disease. As part of our efforts to discover potent and selective antagonists of this receptor, we herein describe the detailed optimization and structure-activity relationships of a series of pyrimidine-4-carboxamides. These optimized derivatives display desirable physiochemical and pharmacokinetic profiles, which have led to promising oral activity in clinically relevant models of Parkinson's disease.

  11. 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

  12. 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...

  13. Identification of a novel NR2B-selective NMDA receptor antagonist using a virtual screening approach.

    Science.gov (United States)

    Mony, Laetitia; Triballeau, Nicolas; Paoletti, Pierre; Acher, Francine C; Bertrand, Hugues-Olivier

    2010-09-15

    We report the identification of a novel NR2B-selective NMDAR antagonist with an original scaffold, LSP10-0500. This compound was identified by a virtual high-throughput screening approach on the basis of a quantitative pharmacophore model of NR2B-specific NMDAR antagonists. A SAR study around LSP10-0500 is also described.

  14. Isolation from the Sorghum bicolor Mycorrhizosphere of a Bacterium Compatible with Arbuscular Mycorrhiza Development and Antagonistic towards Soilborne Fungal Pathogens

    Science.gov (United States)

    Budi, S. W.; van Tuinen, D.; Martinotti, G.; Gianinazzi, S.

    1999-01-01

    A gram-positive bacterium with antagonistic activity towards soilborne fungal pathogens has been isolated from the mycorrhizosphere of Sorghum bicolor inoculated with Glomus mosseae. It has been identified as Paenibacillus sp. strain B2 based on its analytical profile index and on 16S ribosomal DNA analysis. Besides having antagonistic activity, this bacterium stimulates mycorrhization. PMID:10543835

  15. 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

  16. 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

  17. 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

  18. 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.

  19. 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 ...

  20. 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...

  1. Antagonists of chemoattractants reveal separate receptors for cAMP, folic acid and pterin in Dictyostelium

    NARCIS (Netherlands)

    Haastert, Peter J.M. van; Wit, René J.W. de; Konijn, Theo M.

    1982-01-01

    Adenosine 3’,5’-monophosphate (cAMP), folic acid and pterin are chemoattractants in the cellular slime molds. The cAMP analog, 3’-amino-cAMP, inhibits a chemotactic reaction to cAMP at a concentration at which the analog is chemotactically inactive. The antagonistic effect of 3’-amino-cAMP on the ch

  2. Fatigue-related electromyographic coherence and phase synchronization analysis between antagonistic elbow muscles.

    Science.gov (United States)

    Wang, Lejun; Lu, Aiyun; Zhang, Shengnian; Niu, Wenxin; Zheng, Fanhui; Gong, Mingxin

    2015-03-01

    The aim of this study was to examine coherence and phase synchronization between antagonistic elbow muscles and thus to explore the coupling and common neural inputs of antagonistic elbow muscles during sustained submaximal isometric fatiguing contraction. Fifteen healthy male subjects sustained an isometric elbow flexion at 20 % maximal level until exhaustion, while surface electromyographic signals (sEMG) were collected from biceps brachii (BB) and triceps brachii (TB). sEMG signals were divided into the first half (stage 1 with minimal fatigue) and second half (stage 2 with severe fatigue) of the contraction. Coherence and phase synchronization analysis was conducted between sEMG of BB and TB, and coherence value and phase synchronization index in alpha (8-12 Hz), beta (15-35 Hz) and gamma (35-60 Hz) frequency bands were obtained. Significant increase in EMG-EMG coherence and phase synchronization index in alpha and beta frequency bands between antagonistic elbow flexion muscles was observed all increased in stage 2 compared to stage 1. Coupling of EMG activities between antagonistic muscles increased as a result of fatigue caused by 20 % maximal level sustained isometric elbow flexion, indicating the increased interconnection between synchronized cortical neurons and the motoneuron pool of BB and TB, which may be cortical in origin. This increased coupling may help to maintain coactivation level so as to ensure joint stability on the basis of maintaining the joint force output. PMID:25515087

  3. 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).

  4. 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...

  5. 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...

  6. Orally active vasopressin V1a receptor antagonist, SRX251, selectively blocks aggressive behavior.

    Science.gov (United States)

    Ferris, Craig F; Lu, Shi-Fang; Messenger, Tara; Guillon, Christophe D; Heindel, Ned; Miller, Marvin; Koppel, Gary; Robert Bruns, F; Simon, Neal G

    2006-02-01

    Arginine vasopressin functions as a neurochemical signal in the brain to affect social behavior. There is an expanding literature from animal and human studies showing that vasopressin, through the vasopressin 1A receptor (V1A), can stimulate aggressive behavior. Using a novel monocylic beta lactam platform, a series of orally active vasopressin V1a antagonists was developed with high affinity for the human receptor. SRX251 was chosen from this series of V1a antagonists to screen for effects on serenic activity in a resident-intruder model of offensive aggression. Resident, male Syrian golden hamsters were given oral doses of SRX251 or intraperitoneal Manning compound, a selective V1a receptor antagonist with reduced brain penetrance, at doses of 0.2 microg, 20 microg, 2 mg/kg or vehicle. When tested 90-120 min later, SRX251, but not Manning compound, caused a significant dose-dependent reduction in offensive aggression toward intruders as measured by latency to bite and number of bites. The reduction in aggression persisted for over 6 h and was no longer present 12 h post treatment. SRX251 did not alter the amount of time the resident investigated the intruder, olfactory communication, general motor activity, or sexual motivation. These data corroborate previous studies showing a role for vasopressin neurotransmission in aggression and suggest that V1a receptor antagonists may be used to treat interpersonal violence co-occurring with such illness as ADHD, autism, bipolar disorder, and substance abuse. PMID:16504276

  7. Population Pharmacokinetic Modeling of a Subcutaneous Depot for GnRH Antagonist Degarelix

    DEFF Research Database (Denmark)

    Tornøe, Christoffer Wenzel; Agersø, Henrik; Nielsen, Henrik Aalborg;

    2004-01-01

    Purpose. The objective of this study is to develop a population pharmacokinetic (PK) model that describes the subcutaneous (SC) depot formation of gonadotropin-releasing hormone ( GnRH) antagonist degarelix, which is being developed for treatment of prostate cancer, exhibiting dose-volume and dos...

  8. Predictors of Congestive Heart Failure after Treatment with an Endothelin Receptor Antagonist

    NARCIS (Netherlands)

    Hoekman, Jamo; Lambers Heerspink, Hiddo; Viberti, Giancarlo; Green, Damien; Mann, Johannes F. E.; de Zeeuw, Dick

    2014-01-01

    Background and objectives The Avosentan on Time to Doubling of Serum Creatinine, End Stage Renal Disease or Death (ASCEND) trial tested the renoprotective effect of the endothelin receptor antagonist avosentan in patients with diabetes and nephropathy, but the study was terminated due to an excess o

  9. Ovarian response prediction in GnRH antagonist treatment for IVF using anti-Mullerian hormone

    NARCIS (Netherlands)

    Hamdine, O.; Eijkemans, M.J.; Lentjes, E.W.; Torrance, H.L.; Macklon, N.S.; Fauser, B.C.; Broekmans, F.J.

    2015-01-01

    STUDY QUESTION: What is the clinical value of anti-Mullerian hormone (AMH) for the prediction of high or low ovarian response in controlled ovarian stimulation for IVF using GnRH antagonist treatment? SUMMARY ANSWER: AMH as a single test has substantial accuracy for ovarian response prediction in Gn

  10. Scintigraphic detection of pulmonary aspergillosis in rabbits with a radiolabeled leukotriene b4 antagonist.

    NARCIS (Netherlands)

    Eerd-Vismale, J.E.M. van; Rennen, H.J.J.M.; Oyen, W.J.G.; Harris, T.D.; Edwards, D.S.; Corstens, F.H.M.; Boerman, O.C.

    2004-01-01

    Radiolabeled chemotactic peptides have been studied for their applicability to the visualization of infectious and inflammatory foci. Because a radiolabeled leukotriene B4 (LTB4) antagonist allowed visualization of intramuscular E. coli abscesses in rabbits within a few hours after injection, we dec

  11. Imaging of infection and inflammation with an improved 99mTc-labeled LTB4 antagonist.

    NARCIS (Netherlands)

    Eerd-Vismale, J.E.M. van; Broekema, M.; Harris, T.D.; Edwards, D.S.; Oyen, W.J.G.; Corstens, F.H.M.; Boerman, O.C.

    2005-01-01

    Studies have demonstrated that the bivalent (111)In-labeled leukotriene B4 (LTB4) antagonist DPC11870 reveals infectious and inflammatory lesions in various rabbit models. The radioactive tracer accumulates quickly at the site of infection and clears rapidly from the circulation, resulting in high-q

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

    DEFF Research Database (Denmark)

    Goto, K.; Doessing, S.; Nielsen, R.H.;

    2009-01-01

    between the groups in terms of changes in serum free fatty acids, glycerol, (V) over dotO(2), or relative fat oxidation. Conclusion: GH might be an important determinant of exercise capacity during prolonged exercise, but GHR antagonist did not alter fat metabolism during exercise. (J Clin Endocrinol...... Metab 94: 3265-3272, 2009) Udgivelsesdato: 2009/9...

  13. 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

  14. 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...

  15. Probable interaction between an oral vitamin K antagonist and turmeric (Curcuma longa).

    Science.gov (United States)

    Daveluy, Amélie; Géniaux, Hélène; Thibaud, Lucile; Mallaret, Michel; Miremont-Salamé, Ghada; Haramburu, Françoise

    2014-01-01

    We report a probable interaction between a vitamin K antagonist, fluindione, and the herbal medicine turmeric that resulted in the elevation of the international normalized ratio (INR). The case presented here underlines the importance of considering potential exposure to herbal medications when assessing adverse effects.

  16. Infusions of alpha-2 noradrenergic agonists and antagonists into the amygdala: effects on kindling.

    Science.gov (United States)

    Pelletier, M R; Corcoran, M E

    1993-12-31

    We reported previously that activation of alpha-2 adrenoceptors with infusions of clonidine into the amygdala/pyriform region is sufficient to retard kindling. To characterize further the involvement in kindling of alpha-2 receptors in the amygdala/pyriform, we exposed rats to unilateral intraamygdaloid infusions of a variety of noradrenergic drugs followed by either low-frequency stimulation of the amygdala, to induce rapid kindling, or conventional high-frequency stimulation. Infusions and electrical stimulation were administered once every 48 h. The prophylactic effects of clonidine were blocked by simultaneous infusion of idazoxan, an alpha-2 adrenergic antagonist, which suggests strongly that these effects were produced at an alpha-2 receptor. Intraamygdaloid infusions of xylazine, another alpha-2 agonist, also significantly retarded low-frequency kindling. Unexpectedly, intraamygdaloid infusions of the alpha-2 antagonists idazoxan, yohimbine, and SK&F 104856 failed to accelerate kindling. Infusion of the alpha-1 antagonist corynanthine also failed to affect kindling. We propose that the alpha-2 adrenoceptors in the amygdala/pyriform region contribute to the prophylactic effects of systemically administered clonidine and that the facilitation of kindling observed after systemic administration of alpha-2 antagonists may be due to blockade of alpha-2 adrenoceptors outside of the amygdala/pyriform region.

  17. Dynamics of Antagonistic Potency of Rhodobacter capsulatus PG Lipopolysaccharide against Endotoxin-Induced Effects.

    Science.gov (United States)

    Kabanov, D S; Serov, D A; Zubova, S V; Grachev, S V; Prokhorenko, I R

    2016-03-01

    The dynamics of antagonistic potency of lipopolysaccharide (LPS) isolated from Rhodobacter capsulatus PG on the synthesis of proinflammatory (TNF-α, IL-1β, IL-8, IL-6, IFN-γ) and antiinflammatory (IL-10, IL-1Ra) cytokines induced by highly stimulatory endotoxins from Escherichia coli or Salmonella enterica have been studied. Using human whole blood, we have shown that R. capsulatus PG LPS inhibited most pronouncedly the endotoxin-induced synthesis of TNF-α, IL-1β, IL-8, and IL-6 during the first 6 h after endotoxin challenge. Similarly, the endotoxin-induced release of IFN-γ was abolished by R. capsulatus PG LPS as well (24 h). In contrast to the above-mentioned cytokines, the relatively weak antagonistic activity of R. capsulatus PG LPS against endotoxin-triggered production of IL-6 and IL-8 was revealed. Since R. capsulatus PG LPS displays more potent antagonistic activity against deleterious effects of S. enterica LPS than those of E. coli LPS in the cases of such cytokines as IL-1β (6 and 24 h), IL-6 and IL-8 (4 h), we conclude that the effectiveness of protective action of antagonist is mostly determined by the primary lipid A structure of the employed agonist.

  18. Montelukast, a leukotriene receptor antagonist, modulates lung CysLT1

    Institute of Scientific and Technical Information of China (English)

    ZHANGYan-Jun; ZHANGLei; WANGShao-Bin; SHENHua-Hao; WEIEr-Qing

    2004-01-01

    AIM: To determine the expressions of cysteinyl leukotriene receptors, CysLT, and CysLT2 , in airway eosinophilic inflammation of OVA-induced asthmatic mice and the modulation by montelukast, a CysLT1 receptor antagonist. METHODS: Asthma model was induced by chronic exposure to ovalbumin (OVA) in C57BL/6 mice. The eosinophils in

  19. 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

  20. Extended studies on the effect of glutamate antagonists on ischemic CA-1 damage

    DEFF Research Database (Denmark)

    Diemer, Nils Henrik; Balchen, T; Bruhn, T;

    1996-01-01

    Glutamate receptors are numerous on the ischemia vulnerable CA-1 pyramidal cells. Postischemic use of the AMPA antagonist NBQX has shown up to 80% protection against cell death. Three aspects of this were studied: In the first study, male Wistar rats were given NBQX (30 mg/kg x 3) either 20 hours...

  1. 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

  2. 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

  3. Leukotriene receptor antagonist ONO-1078 attenuate N-metyl-D-aspartate - mediated neurotoxicity in rats

    Institute of Scientific and Technical Information of China (English)

    ZHANGLi-Hui; WEIEr-Qing

    2004-01-01

    AIM: To investigate the possible effect of ONO-1078 t pranlukast, 4-oxo-8-[p-(4-phenylbutyloxy) benzoyl-amono]-2- (tetrazol-5-yl)-4H-1-benzopyran hemihydrate],a potent leukotriene receptor antagonist,on N-metyl-D-aspartate (NMDA)-mediated neurotoxicity in rats. METHODS: Brain injury was induced by NM-

  4. 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

    Anti-tumour necrosis factor (TNF) monoclonal antibodies or soluble TNF receptors have become an invaluable treatment against chronic inflammatory diseases, such as rheumatoid arthritis, inflammatory bowel disease and psoriasis. Individuals who are treated with TNF antagonists are at an increased...

  5. Long-term use of aldosterone-receptor antagonists in uncontrolled hypertension: A retrospective analysis

    NARCIS (Netherlands)

    P.M. Jansen (Pieter); K. Verdonk (Koen); B.P. Imholz (Ben); A.H.J. Danser (Jan); A.H. van den Meiracker (Anton)

    2011-01-01

    textabstractBackground. The long-term efficacy of aldosterone-receptor antagonists (ARAs) as add-on treatment in uncontrolled hypertension has not yet been reported. Methods. Data from 123 patients (21 with primary aldosteronism, 102 with essential hypertension) with difficult-to-treat hypertension

  6. Control of postharvest pathogens and colonization of the apple surface by antagonistic microorganisms in the field.

    Science.gov (United States)

    Leibinger, W; Breuker, B; Hahn, M; Mendgen, K

    1997-11-01

    ABSTRACT Selected isolates of Aureobasidium pullulans, Rhodotorula glutinis, and Bacillus subtilis reduced the size and number of lesions on wounded apples caused by the postharvest pathogens Penicillium expansum, Botrytis cinerea, and Pezicula malicorticis. Combinations of the antagonistic microorganisms were applied to apple trees in the field late in the growing season of two consecutive years. The population dynamics of the introduced microorganisms and the incidence of fruit decay were determined. Population sizes of introduced antagonists on apple surfaces increased in the field following application of treatments until harvest. After transfer of the fruit from the field into cold storage, the populations of the introduced antagonists remained higher than in the control treatments. Identification of the applied isolates of A. pullulans and R. glutinis during the experiments was achieved by isolate-specific DNA probes generated from random amplified polymorphic DNA. A combination of two strains of A. pullulans and one strain of R. glutinis suppressed rotting of apple to the same extent as the commonly used fungicide Euparen. Our data demonstrate that the application of antagonistic microorganisms in the field represents a promising alternative to fungicide treatments to control post-harvest diseases of apple.

  7. Evidence for homogeneity of thromboxane A2 receptor using structurally different antagonists.

    Science.gov (United States)

    Swayne, G T; Maguire, J; Dolan, J; Raval, P; Dane, G; Greener, M; Owen, D A

    1988-08-01

    Nine structurally dissimilar thromboxane antagonists (SQ 29548, ICI 185282, AH 23848, BM 13505 (Daltroban), BM 13177 (Sulotroban), SK&F 88046, L-636499, L-640035 and a Bayer compound SK&F 47821) were studied for activity as thromboxane A2 receptor antagonists. The assays used were inhibition of responses induced by the thromboxane mimetic, U46619, on human washed platelet aggregation, rabbit platelet aggregation, rabbit aortic strip contraction, anaesthetised guinea-pig bronchoconstriction, and a radio-labelled ligand (125I-PTA-OH) binding assay as a measure of affinity for the human platelet receptor. The results of the present study, with activities spanning at least four orders of magnitude along with statistically significant correlations (at least P less than 0.01), strongly suggests that between assays, antagonists and species a homogenous population of thromboxane A2 receptors exists. This finding is in contrast to those of a close series of 13-azapinane antagonists studied by other workers which have suggested receptor heterogeneity.

  8. Effect of the Urotensin Receptor Antagonist Palosuran in Hypertensive Patients With Type 2 Diabetic Nephropathy

    NARCIS (Netherlands)

    L. Vogt; C. Chiurchiu; H. Chadha-Boreham; P. Danaietash; J. Dingemanse; S. Hadjadj; H. Krum; G. Navis; E. Neuhart; A.I. Parvanova; P. Ruggenenti; A.J. Woittiez; R. Zimlichman; G. Remuzzi; D. de Zeeuw

    2010-01-01

    The urotensin system has been hypothesized to play an important role in the pathophysiology of diabetic nephropathy. In this multicenter, randomized, double-blind, placebo-controlled, 2-period crossover study, the effects of the urotensin receptor antagonist palosuran on urinary albumin excretion an

  9. Features of isolation and identification of phytopathogenic bacteria and search of their natural antagonists

    Directory of Open Access Journals (Sweden)

    O. S. Stonchyus

    2010-08-01

    Full Text Available Microflora of vegetables affected by bacteriosis was isolated and investigated. On the basis of morphological, cultural, physiological and biochemical characteristics of selected strains they were identified, and their plants pathogenicity was shown. The antagonistic influence of strain Bacillus thuringiensis var. thuringiensis IMV B-7186 on isolated bacterial culture was studied.

  10. Evolution of the Bifunctional Lead μ Agonist / δ Antagonist Containing the Dmt-Tic Opioid Pharmacophore.

    Science.gov (United States)

    Balboni, Gianfranco; Salvadori, Severo; Trapella, Claudio; Knapp, Brian I; Bidlack, Jean M; Lazarus, Lawrence H; Peng, Xuemei; Neumeyer, John L

    2010-02-17

    Based on a renewed importance recently attributed to bi- or multifunctional opioids, we report the synthesis and pharmacological evaluation of some analogues derived from our lead μ agonist / δ antagonist, H-Dmt-Tic-Gly-NH-Bzl. Our previous studies focused on the importance of the C-teminal benzyl function in the induction of such bifunctional activity. The introduction of some substituents in the para position of the phenyl ring (-Cl, -CH(3), partially -NO(2), inactive -NH(2)) was found to give a more potent μ agonist / antagonist effect associated with a relatively unmodified δ antagonist activity (pA(2) = 8.28-9.02). Increasing the steric hindrance of the benzyl group (using diphenylmethyl and tetrahydroisoquinoline functionalities) substantially maintained the μ agonist and δ antagonist activities of the lead compound. Finally and quite unexpectedly D-Tic2, considered as a wrong opioid message now; inserted into the reference compound in lieu of L-Tic, provided a μ agonist / δ agonist better than our reference ligand (H-Dmt-Tic-Gly-NH-Ph) and was endowed with the same pharmacological profile.

  11. 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

  12. 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

  13. A systematic review of prothrombin complex concentrate dosing strategies to reverse vitamin K antagonist therapy

    NARCIS (Netherlands)

    Khorsand, Nakisa; Kooistra, Hilde A. M.; van Hest, Reinier M.; Veeger, Nic J. G. M.; Meijer, Karina

    2015-01-01

    Management of patients with a major bleed while on vitamin K antagonist (VKA) is a common clinical challenge. Prothrombin Complex Concentrates (PCC) provide a rapid reversal of VKA induced coagulopathy. However, a well-defined PCC dosing strategy, especially in emergency setting, is still lacking. W

  14. Randomized controlled trial of the CGRP receptor antagonist telcagepant for migraine prevention

    DEFF Research Database (Denmark)

    Ho, Tony W; Connor, Kathryn M; Zhang, Ying;

    2014-01-01

    OBJECTIVE: To evaluate whether the calcitonin gene-related peptide (CGRP) receptor antagonist telcagepant might be effective for migraine prevention. METHODS: In this randomized, double-blind, placebo-controlled, multicenter trial (ClinicalTrials.gov NCT00797667), patients experiencing 3-14 migra...

  15. 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...

  16. A novel antagonist of CRTH2 blocks eosinophil release from bone marrow, chemotaxis and respiratory burst

    DEFF Research Database (Denmark)

    Royer, J F; Schratl, P; Lorenz, S;

    2007-01-01

    developed small molecule antagonist of CRTH2, Cay10471, on eosinophil function with respect to recruitment, respiratory burst and degranulation. METHODS: Chemotaxis of guinea pig bone marrow eosinophils and human peripheral blood eosinophils were determined using microBoyden chambers. Eosinophil release...

  17. 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

  18. Hydroxylated analogues of 5-aminovaleric acid as 4-aminobutyric acidB receptor antagonists

    DEFF Research Database (Denmark)

    Kristiansen, U; Hedegaard, A; Herdeis, C;

    1992-01-01

    The (R) and (S) forms of 5-amino-2-hydroxyvaleric acid (2-OH-DAVA) and 5-amino-4-hydroxyvaleric acid (4-OH-DAVA) were designed as structural hybrids of the 4-aminobutyric acidB (GABAB) agonist (R)-(-)-4-amino-3-hydroxybutyric acid [(R)-(-)-3-OH-GABA] and the GABAB antagonist 5-aminovaleric acid...

  19. 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

  20. 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.

  1. 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.

  2. 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.

  3. Design, synthesis, and biological evaluation of 4-phenylpyrrole derivatives as novel androgen receptor antagonists.

    Science.gov (United States)

    Yamamoto, Satoshi; Matsunaga, Nobuyuki; Hitaka, Takenori; Yamada, Masami; Hara, Takahito; Miyazaki, Junichi; Santou, Takashi; Kusaka, Masami; Yamaoka, Masuo; Kanzaki, Naoyuki; Furuya, Shuichi; Tasaka, Akihiro; Hamamura, Kazumasa; Ito, Mitsuhiro

    2012-01-01

    A series of 4-phenylpyrrole derivatives D were designed, synthesized, and evaluated for their potential as novel orally available androgen receptor antagonists therapeutically effective against castration-resistant prostate cancers. 4-Phenylpyrrole compound 1 exhibited androgen receptor (AR) antagonistic activity against T877A and W741C mutant-type ARs as well as wild-type AR. An arylmethyl group incorporated into compound 1 contributed to enhancement of antagonistic activity. Compound 4n, 1-{[6-chloro-5-(hydroxymethyl)pyridin-3-yl]methyl}-4-(4-cyanophenyl)-2,5-dimethyl-1H-pyrrole-3-carbonitrile exhibited inhibitory effects on tumor cell growth against the bicalutamide-resistant LNCaP-cxD2 cell line as well as the androgen receptor-dependent JDCaP cell line in a mouse xenograft model. These results demonstrate that this series of pyrrole compounds are novel androgen receptor antagonists with efficacy against prostate cancer cells, including castration-resistant prostate cancers such as bicalutamide-resistant prostate cancer.

  4. 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%

  5. EFFECTS OF THE ANGIOTENSIN-II ANTAGONIST LOSARTAN IN HYPERTENSIVE PATIENTS WITH RENAL-DISEASE

    NARCIS (Netherlands)

    GANSEVOORT, RT; DEZEEUW, D; SHAHINFAR, S; REDFIELD, A; DEJONG, PE

    1994-01-01

    Objective: To study the effects of the angiotensin II antagonist losartan in hypertensive patients with renal disease. Design: A single-blind longitudinal study was performed, lasting 4 months. Patients were treated once a day with placebo, 50 mg losartan, 100 mg losartan and placebo, each for 1 mon

  6. Therapeutic efficacy and immunological response of CCL5 antagonists in models of contact skin reaction.

    Directory of Open Access Journals (Sweden)

    Miriam Canavese

    Full Text Available Skin-infiltrating T-cells play a predominant role in allergic and inflammatory skin diseases such as atopic dermatitis, psoriasis and allergic contact dermatitis. These T-cells are attracted by several chemotactic factors including the chemokine CCL5/RANTES, a CC chemokine inducing both the migration and activation of specific leukocyte subsets. CCL5 has been found to be associated with various cell-mediated hypersensitive disorders such as psoriasis, atopic dermatitis and irritant contact dermatitis. We have used two antagonists, the first, Met-CCL5, a dual CCR1/CCR5 antagonist and the second, a variant in which GAG binding is abrogated, (44AANA(47-CCL5, which acts as a dominant negative inhibitor of CCL5. The antagonists were tested in two models of contact skin reaction. The first, irritant contact dermatitis (ICD is a pathological non-specific inflammatory skin condition arising from the release of pro-inflammatory cytokines by keratinocytes in response to haptens, usually chemicals. The second, contact hypersensitivity (CHS is a T-cell dependent model, mimicking in part the T-cell-mediated skin diseases such as psoriasis. In both models, the CCL5 antagonists showed therapeutic efficacy by reducing swelling by 50% as well as the reduction of soluble mediators in homogenates derived from challenged ears. These results demonstrate that blocking the receptor or the ligand are both effective strategies to inhibit skin inflammation.

  7. 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;

    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...

  8. 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;

    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...

  9. Pyrazolo Derivatives as Potent Adenosine Receptor Antagonists: An Overview on the Structure-Activity Relationships

    Directory of Open Access Journals (Sweden)

    Siew Lee Cheong

    2011-01-01

    Full Text Available In the past few decades, medicinal chemistry research towards potent and selective antagonists of human adenosine receptors (namely, A1, A2A, A2B, and A3 has been evolving rapidly. These antagonists are deemed therapeutically beneficial in several pathological conditions including neurological and renal disorders, cancer, inflammation, and glaucoma. Up to this point, many classes of compounds have been successfully synthesized and identified as potent human adenosine receptor antagonists. In this paper, an overview of the structure-activity relationship (SAR profiles of promising nonxanthine pyrazolo derivatives is reported and discussed. We have emphasized the SAR for some representative structures such as pyrazolo-[4,3-e]-1,2,4-triazolo-[1,5-c]pyrimidines; pyrazolo-[3,4-c] or -[4,3-c]quinolines; pyrazolo-[4,3-d]pyrimidinones; pyrazolo-[3,4-d]pyrimidines and pyrazolo-[1,5-a]pyridines. This overview not only clarifies the structural requirements deemed essential for affinity towards individual adenosine receptor subtypes, but it also sheds light on the rational design and optimization of existing structural templates to allow us to conceive new, more potent adenosine receptor antagonists.

  10. Hit to lead SAR study on benzoxazole derivatives for an NPY Y5 antagonist.

    Science.gov (United States)

    Omori, Naoki; Kouyama, Naoki; Yukimasa, Akira; Watanabe, Kana; Yokota, Yasunori; Tanioka, Hideki; Nambu, Hirohide; Yukioka, Hideo; Sato, Norihito; Tanaka, Yukari; Sekiguchi, Kazutaka; Okuno, Takayuki

    2012-03-01

    We report a hit to lead study on a novel benzoxazole NPY Y5 antagonist. Starting from HTS hit 1, structure-activity relationships were developed. Compound 12 showed reduction of food intake and a tendency to suppress body weight gain over the 21-day experimental period.

  11. 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...

  12. Effect of the cannabinoid receptor-1 antagonist rimonabant on lipolysis in rats

    DEFF Research Database (Denmark)

    Mølhøj, Signe; Hansen, Harald S; Schweiger, Martina;

    2010-01-01

    The cannabinoid receptor 1 antagonist, rimonabant, reduces food intake and body weight, but contradictory findings have been reported as to whether the weight-reducing effect is fully accounted for by the reduced food intake or if rimonabant also mediates a lipolytic effect. In the present study...

  13. Editing and Scaling of Instrument Packets for the Clinical Evaluation of Narcotic Antagonists. Final Report.

    Science.gov (United States)

    Boldt, Robert F.; Gitomer, Nancy L.

    Efforts of the National Academy of Sciences (NAS) as a contractor to the National Institute on Drug Abuse (NIDA) include: (1) assessment of the usefulness of naltrexone, a narcotic antagonist, in the rehabilitation of several types of opiate-dependent individuals; (2) assessment of any drawbacks to the use of naltrexone; and (3) appraisal of…

  14. Ionotropic excitatory amino acid receptor ligands. Synthesis and pharmacology of a new amino acid AMPA antagonist

    DEFF Research Database (Denmark)

    Madsen, U; Sløk, F A; Stensbøl, T B;

    2000-01-01

    We have previously described the potent and selective (RS)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor agonist, (RS)-2-amino-3-(3-carboxy-5-methyl-4-isoxazolyl)propionic acid (ACPA), and the AMPA receptor antagonist (RS)-2-amino-3-[3-(carboxymethoxy)-5-methyl-4-isoxa...

  15. Possible sites of action of the new calcitonin gene-related peptide receptor antagonists

    DEFF Research Database (Denmark)

    Eftekhari, Sajedeh; Edvinsson, Lars

    2010-01-01

    synapses CGRP results in vasodilatation via receptors on the smooth muscle cells. At central synapses, CGRP acts postjunctionally on second-order neurons to transmit pain centrally via the brainstem and midbrain to higher cortical pain regions. The recently developed CGRP-receptor antagonists have...

  16. TGF-.beta. antagonists as mitigators of radiation-induced tissue damage

    Science.gov (United States)

    Barcellos-Hoff, Mary H.

    1997-01-01

    A method for treating tissue damage caused by radiation is described by use of a TGF-.beta. antagonist, such as an anti-TGF-.beta. antibody or a TGF-.beta. latency associated protein. It is administered not more than a week after exposure, and is particularly useful in mitigating the side effects of breast cancer therapy.

  17. TGF-{beta} antagonists as mitigators of radiation-induced tissue damage

    Science.gov (United States)

    Barcellos-Hoff, M.H.

    1997-04-01

    A method for treating tissue damage caused by radiation is described by use of a TGF-{beta} antagonist, such as an anti-TGF-{beta} antibody or a TGF-{beta} latency associated protein. It is administered not more than a week after exposure, and is particularly useful in mitigating the side effects of breast cancer therapy.

  18. Therapeutic effect of pranlukast, a cysteinyl leukotriene receptor antagonist, on focal cerebral ischemia in mice

    Institute of Scientific and Technical Information of China (English)

    XUQiu-Qin; WEIEr-Qing; YUYue-Ping; ZHANGQi; ZHANGShi-Hong; ZHUChao-Yang

    2004-01-01

    AIM: To determine whether pranlukast (ONO-1078 ), a cysteinyl leukotriene receptor antagonist, possesses therapeutic effect when administered after focal cerebral ischemia in mice. METHODS: Persistent focal cerebral ischemia was induced by middle cerebral artery occlusion, pranlukast and edaravone, a positive control drug, were ip injected 1, 6 and

  19. Duration of treatment with vitamin K antagonists in symptomatic venous thromboembolism

    NARCIS (Netherlands)

    B.A. Hutten; M.H. Prins

    2006-01-01

    Background Currently, the most frequently used secondary treatment for patients with venous thromboembolism is vitamin K antagonists targeted at an INR of 2.5 (range 2.0 to 3.0). However, based on the continuing risk of bleeding and uncertainty regarding the risk of recurrent venous thromboembolism,

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

    NARCIS (Netherlands)

    Solovic, I.; Sester, M.; Gomez-Reino, J. J.; Rieder, H. L.; Ehlers, S.; Milburn, H. J.; Kampmann, B.; Hellmich, B.; Groves, R.; Schreiber, S.; Wallis, R. S.; Sotgiu, G.; Scholvinck, E. H.; Goletti, D.; Zellweger, J. P.; Diel, R.; Carmona, L.; Bartalesi, F.; Ravn, P.; Duarte, R.; Erkens, C.; Clark, J.; Migliori, G. B.; Lange, C.

    2010-01-01

    Anti-tumour necrosis factor (TNF) monoclonal antibodies or soluble TNF receptors have become an invaluable treatment against chronic inflammatory diseases, such as rheumatoid arthritis, inflammatory bowel disease and psoriasis. Individuals who are treated with TNF antagonists are at an increased ris

  1. 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

  2. 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....

  3. Antarlides: A New Type of Androgen Receptor (AR) Antagonist that Overcomes Resistance to AR-Targeted Therapy.

    Science.gov (United States)

    Saito, Shun; Fujimaki, Takahiro; Panbangred, Watanalai; Igarashi, Yasuhiro; Imoto, Masaya

    2016-02-18

    Prostate cancer is treated with androgen receptor (AR) antagonists but most patients experience disease progression after long-term treatment with these compounds. Therefore, new AR antagonists are required for patient follow-up treatment. In the course of screening for a new AR antagonist, we isolated the novel compounds antarlides A-E (1-5) from Streptomyces sp. BB47. Antarlides are mutually isomeric with respect to the double bond and have a 22-membered-ring macrocyclic structure. The full stereostructure of 1 was established by chemical modifications, including methanolysis, the Trost method, acetonide formation, and the PGME method. 1-5 inhibited the binding of androgen to ARs in vitro. In addition, 2 inhibited the transcriptional activity of not only wild-type AR but also mutant ARs, which are seen in patients with acquired resistance to clinically used AR antagonists. Therefore, antarlides are a potent new generation of AR antagonists that overcome resistance.

  4. 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

  5. Aldosterone and aldosterone receptor antagonists in patients with chronic heart failure

    Directory of Open Access Journals (Sweden)

    Nappi J

    2011-06-01

    Full Text Available Jean M Nappi, Adam SiegClinical Pharmacy and Outcome Sciences, South Carolina College of Pharmacy, Medical University of South Carolina Campus, Charleston, SC, USAAbstract: Aldosterone is a mineralocorticoid hormone synthesized by the adrenal glands that has several regulatory functions to help the body maintain normal volume status and electrolyte balance. Studies have shown significantly higher levels of aldosterone secretion in patients with congestive heart failure compared with normal patients. Elevated levels of aldosterone have been shown to elevate blood pressure, cause left ventricular hypertrophy, and promote cardiac fibrosis. An appreciation of the true role of aldosterone in patients with chronic heart failure did not become apparent until the publication of the Randomized Aldactone Evaluation Study. Until recently, the use of aldosterone receptor antagonists has been limited to patients with severe heart failure and patients with heart failure following myocardial infarction. The Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF study added additional evidence to support the expanded use of aldosterone receptor antagonists in heart failure patients. The results of the EMPHASIS-HF trial showed that patients with mild-to-moderate (New York Heart Association Class II heart failure had reductions in mortality and hospitalizations from the addition of eplerenone to optimal medical therapy. Evidence remains elusive about the exact mechanism by which aldosterone receptor antagonists improve heart failure morbidity and mortality. The benefits of aldosterone receptor antagonist use in heart failure must be weighed against the potential risk of complications, ie, hyperkalemia and, in the case of spironolactone, possible endocrine abnormalities, in particular gynecomastia. With appropriate monitoring, these risks can be minimized. We now have evidence that patients with mild-to-severe symptoms

  6. CysLT(1)R antagonists inhibit tumor growth in a xenograft model of colon cancer.

    Science.gov (United States)

    Savari, Sayeh; Liu, Minghui; Zhang, Yuan; Sime, Wondossen; Sjölander, Anita

    2013-01-01

    The expression of the inflammatory G-protein coupled receptor CysLT1R has been shown to be upregulated in colon cancer patients and associated with poor prognosis. The present study investigated the correlation between CysLT1R and colon cancer development in vivo using CysLT1R antagonists (ZM198,615 or Montelukast) and the nude mouse xenograft model. Two drug administration regimens were established. The first regimen was established to investigate the importance of CysLT1R in tumor initiation. Nude mice were inoculated with 50 µM CysLT1R antagonist-pretreated HCT-116 colon cancer cells and received continued treatment (5 mg/kg/day, intraperitoneally). The second regimen aimed to address the role of CysLT1R in tumor progression. Nude mice were inoculated with non-pretreated HCT-116 cells and did not receive CysLT1R antagonist treatment until recordable tumor appearance. Both regimens resulted in significantly reduced tumor size, attributed to changes in proliferation and apoptosis as determined by reduced Ki-67 levels and increased levels of p21(WAF/Cip1) (Pcolon cancer cell line HCT-116 and CysLT1R antagonists. In addition to significant reductions in cell proliferation, adhesion and colony formation, we observed induction of cell cycle arrest and apoptosis in a dose-dependent manner. The ability of Montelukast to inhibit growth of human colon cancer xenograft was further validated by using two additional colon cancer cell lines, SW-480 and HT-29. Our results demonstrate that CysLT1R antagonists inhibit growth of colon cancer xenografts primarily by reducing proliferation and inducing apoptosis of the tumor cells.

  7. 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).

  8. Similarities and Distinctions in Actions of Surface-Directed and Classic Androgen Receptor Antagonists.

    Directory of Open Access Journals (Sweden)

    Ji Ho Suh

    Full Text Available The androgen receptor (AR surface-directed antagonist MJC13 inhibits AR function and proliferation of prostate cancer (PC cells. These effects are related to arrest of an AR/chaperone complex in the cytoplasm. Here, we compared MJC13 and classic AR antagonists such as flutamide and bicalutamide. Microarray analysis and confirmatory qRT-PCR reveals that MJC13 and flutamide inhibit dihydrotestosterone (DHT-dependent genes in LNCaP PC cells. Both compounds are equally effective on a genome wide basis and as effective as second generation AR antagonists (MDV3100, ARN-509 at selected genes. MJC13 inhibits AR binding to the prostate specific antigen (PSA promoter more strongly than flutamide, consistent with different mechanisms of action. Examination of efficacy of MJC13 in conditions that reflect aspects castrate resistant prostate cancer (CRPC reveals that it inhibits flutamide activation of an AR mutant (ART877A that emerges during flutamide withdrawal syndrome, but displays greatly restricted gene-specific activity in 22Rv1 cells that express a constitutively active truncated AR and is inactive against glucocorticoid receptor (GR, which can co-opt androgen-dependent signaling networks in CRPC. Importantly, MJC13 inhibits AR interactions with SRC2 and β-catenin in the nucleus and, unlike flutamide, strongly inhibits amplification of AR activity obtained with transfected SRC2 and β-catenin. MJC13 also inhibits DHT and β-catenin-enhanced cell division in LNCaP cells. Thus, a surface-directed antagonist can block AR activity in some conditions in which a classic antagonist fails and may display utility in particular forms of CRPC.

  9. Similarities and Distinctions in Actions of Surface-Directed and Classic Androgen Receptor Antagonists.

    Science.gov (United States)

    Suh, Ji Ho; Chattopadhyay, Arundhati; Sieglaff, Douglas H; Storer Samaniego, Cheryl; Cox, Marc B; Webb, Paul

    2015-01-01

    The androgen receptor (AR) surface-directed antagonist MJC13 inhibits AR function and proliferation of prostate cancer (PC) cells. These effects are related to arrest of an AR/chaperone complex in the cytoplasm. Here, we compared MJC13 and classic AR antagonists such as flutamide and bicalutamide. Microarray analysis and confirmatory qRT-PCR reveals that MJC13 and flutamide inhibit dihydrotestosterone (DHT)-dependent genes in LNCaP PC cells. Both compounds are equally effective on a genome wide basis and as effective as second generation AR antagonists (MDV3100, ARN-509) at selected genes. MJC13 inhibits AR binding to the prostate specific antigen (PSA) promoter more strongly than flutamide, consistent with different mechanisms of action. Examination of efficacy of MJC13 in conditions that reflect aspects castrate resistant prostate cancer (CRPC) reveals that it inhibits flutamide activation of an AR mutant (ART877A) that emerges during flutamide withdrawal syndrome, but displays greatly restricted gene-specific activity in 22Rv1 cells that express a constitutively active truncated AR and is inactive against glucocorticoid receptor (GR), which can co-opt androgen-dependent signaling networks in CRPC. Importantly, MJC13 inhibits AR interactions with SRC2 and β-catenin in the nucleus and, unlike flutamide, strongly inhibits amplification of AR activity obtained with transfected SRC2 and β-catenin. MJC13 also inhibits DHT and β-catenin-enhanced cell division in LNCaP cells. Thus, a surface-directed antagonist can block AR activity in some conditions in which a classic antagonist fails and may display utility in particular forms of CRPC.

  10. 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.)

  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

    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.)

  13. 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

  14. Testosterone dynamics and psychopathic personality traits independently predict antagonistic behavior towards the perceived loser of a competitive interaction.

    Science.gov (United States)

    Geniole, Shawn N; Busseri, Michael A; McCormick, Cheryl M

    2013-11-01

    Few studies have investigated the influence of changes in testosterone on subsequent competitive, antagonistic behavior in humans. Further, little is known about the extent to which such effects are moderated by personality traits. Here, we collected salivary measures of testosterone before and after a rigged competition. After the competition, participants were given the opportunity to act antagonistically against the competitor (allocate a low honorarium). We hypothesized that changes in testosterone throughout the competition would predict antagonistic behavior such that greater increases would be associated with the allocation of lower honorariums. Further, we investigated the extent to which personality traits related to psychopathy (fearless dominance, FD; self-centered impulsivity, SCI; and coldheartedness) moderated this relationship. In men (n=104), greater increases in testosterone and greater FD were associated with more antagonistic behavior, but testosterone concentrations did not interact with personality measures. In women (n=97), greater FD and SCI predicted greater antagonistic behavior, but there were no significant endocrine predictors or interactions with personality measures. In a secondary set of analyses, we found no support for the dual-hormone hypothesis that the relationship between baseline testosterone concentrations and behavior is moderated by cortisol concentrations. Thus, results are consistent with previous findings that in men, situation-specific testosterone reactivity rather than baseline endocrine function is a better predictor of future antagonistic behavior. The results are discussed with respect to the Challenge Hypothesis and the Biosocial Model of Status, and the possible mechanisms underlying the independent relations of testosterone and personality factors with antagonistic behavior.

  15. Xerostomia: prevalence and pharmacotherapy. With special reference to beta-adrenoceptor antagonists.

    Science.gov (United States)

    Nederfors, T

    1996-01-01

    The main objective of this thesis was to estimate the prevalence of subjectively perceived dry mouth, xerostomia, in a representative general adult population, and the possible co-morbidity between xerostomia and on-going pharmacotherapy. Further, to evaluate the effects of beta-adrenoceptor antagonists on saliva flow rate and composition. The prevalence of xerostomia was evaluated by means of a questionnaire mailed to a random sample of 4.200 adult subjects living in the southern part of the province of Halland, Sweden. Three hundred men and equally many women aged 20, 30, 40, 50, 60, 70 and 80 years were selected from the national census register. From 3311 (81%) evaluable questionnaires was concluded that, in the studied population, 21.3% of the men and 27.3% of the women reported xerostomia. The difference between the sexes was statistically significant, women reporting higher prevalence of dry mouth than men. It was also found that xerostomia was significantly age-related. Further, it was demonstrated that there was a strong co-morbidity between reported prevalence of dry mouth and on-going pharmacotherapy. Generally, no specific drug or drug-group proved to be especially xerogenic, rather, polypharmacy was strongly correlated to reported symptoms of dry mouth, and it was also a significant correlation between increasing xerostomia and the number of medications taken. The effects of beta-adrenoceptor antagonists on saliva flow rate and composition were evaluated both in healthy volunteers and in hypertensive patients. The effects of one week of treatment with the non-selective (propranolol) and the beta 1-selective (atenolol) adrenoceptor antagonists were compared with that of placebo in three different clinical trials, including 38, 11 and 19 healthy volunteers, respectively. Two of these studies were focused on the effects on whole saliva secretion rate and composition and the third study on the secretions from the parotid and the submandibular

  16. 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

  17. 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...

  18. Cardiovascular studies with SK&F 93319, an antagonist of histamine at both H1- and H2-receptors.

    OpenAIRE

    Harvey, C A; Owen, D A

    1984-01-01

    Cardiovascular studies have been made in anaesthetized cats with SK&F 93319, an antagonist of histamine at both H1- and H2-receptors. SK&F 93319, 8 X 10(-8) and 4 X 10(-7) mol kg-1 min-1 antagonized depressor responses to injections of histamine and the maximum displacement of histamine dose-response curves exceeded that which can be obtained with either an H1-receptor antagonist or an H2-receptor antagonist alone. SK&F 93319, 8 X 10(-8) and 4 X 10(-7) mol kg-1 min-1, also caused dose-depende...

  19. 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

  20. Insights into cardio-oncology:Polypharmacology of quinazoline-based α1-adrenoceptor antagonists

    Institute of Scientific and Technical Information of China (English)

    Salvatore; Patanè

    2015-01-01

    New uses of cardiovascular drugs with proven experience are emerging,including for treating cancer.Quinazoline is a compound made up of two fused six member simple aromatic rings,benzene and pyrimidine rings,with several biological effects.Cardiologists first used quinazoline-based α1-adrenoceptor antagonists prazosin,doxazosin,and terazosin; currently available data support their use as safe,well tolerated,and effective add-on therapy in uncontrolled hypertension with additional favourable metabolic effects.Recent findings highlight the anticancer effects of quinazoline-based α1-adrenoceptor antagonists,indicating that they may have a significant role in uncontrolled hypertensive cancer patients without signs of ischemia.

  1. P2Y12 Receptor Antagonists and Morphine: A Dangerous Liaison?

    Science.gov (United States)

    Giannopoulos, Georgios; Deftereos, Spyridon; Kolokathis, Fotios; Xanthopoulou, Ioanna; Lekakis, John; Alexopoulos, Dimitrios

    2016-09-01

    P2Y12 receptor antagonists, concurrently administered with aspirin in what has come to be commonly called dual antiplatelet therapy, are a mainstay of treatment for patients with acute coronary syndromes. Morphine, on the contrary, is a commonly used drug in the acute phase of acute coronary syndromes to relieve pain-with the added potential benefit of attenuating acutely raised sympathetic tone. In current guidelines, though, morphine is recommended with decreasing strength of recommendation. One reason is that it raises concern regarding the potentially significant interaction with antiplatelet agents, leading to impaired inhibition of platelet activation. In any case, it is still considered a mandatory part of the inventory of available medications in prehospital acute myocardial infarction management. The goal of the present review is to present published evidence on morphine and its potential interactions with P2Y12 receptor antagonists, as well as on the central issue of whether such interactions may underlie clinically significant effects on patient outcomes.

  2. 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.

  3. 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.

  4. 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

  5. Synthesis, Optimization, and Evaluation of Novel Small Molecules as Antagonists of WDR5-MLL Interaction.

    Science.gov (United States)

    Bolshan, Yuri; Getlik, Matthäus; Kuznetsova, Ekaterina; Wasney, Gregory A; Hajian, Taraneh; Poda, Gennadiy; Nguyen, Kong T; Wu, Hong; Dombrovski, Ludmila; Dong, Aiping; Senisterra, Guillermo; Schapira, Matthieu; Arrowsmith, Cheryl H; Brown, Peter J; Al-Awar, Rima; Vedadi, Masoud; Smil, David

    2013-03-14

    The WD40-repeat protein WDR5 plays a critical role in maintaining the integrity of MLL complexes and fully activating their methyltransferase function. MLL complexes, the trithorax-like family of SET1 methyltransferases, catalyze trimethylation of lysine 4 on histone 3, and they have been widely implicated in various cancers. Antagonism of WDR5 and MLL subunit interaction by small molecules has recently been presented as a practical way to inhibit activity of the MLL1 complex, and N-(2-(4-methylpiperazin-1-yl)-5-substituted-phenyl) benzamides were reported as potent and selective antagonists of such an interaction. Here, we describe the protein crystal structure guided optimization of prototypic compound 2 (K dis = 7 μM), leading to identification of more potent antagonist 47 (K dis = 0.3 μM).

  6. Blockade of the stimulus properties of mescaline by a serotonin antagonist.

    Science.gov (United States)

    Winter, J C

    1975-04-01

    It is known that the effects of mescaline (3, 4, 5-trimethoxyphenylethylamine), a hallucinogen, can function as a discriminative stimulus. The present investigation examined the ability of cinanserin, a serotinin antagonist, to block the stimulus properties of mescaline in the rat. After a reliable discrimination was established between the effects following the injection of mescaline (10 mg/kg) and those following administration of saline, subjects were pretreated with cinanserin HC1 (3 mg/kg) and then treated with mescaline. Such pretreatment was found to block discrimination, i.e., the response rate following the administration of mescaline plus cinanserin was appropriate for the saline condition. The present data suggest that antagonists of serotonin may be useful in furthering our understanding of phenethylamine hallucinogens.

  7. [6]-gingerol: a novel AT₁ antagonist for the treatment of cardiovascular disease.

    Science.gov (United States)

    Liu, Qing; Liu, Jinjin; Guo, Haili; Sun, Shengnan; Wang, Shifeng; Zhang, Yanling; Li, Shiyou; Qiao, Yanjiang

    2013-03-01

    Considering the prevalence of cardiovascular disease in public health and the limited validated therapeutic options, this study aimed to find novel compounds targeting the angiotensin II type 1 receptor, accepted as a therapeutic target in cardiovascular disease. A small library consisting of 89 compounds from 39 Chinese herbs was profiled using a cell-based calcium mobilization assay which was developed and characterized for high-throughput screening. [6]-Gingerol derived from Zingiber officinale Roscoe (ginger) was identified as a novel angiotensin II type 1 receptor antagonist, with an IC50 value of 8.173 µM. The hit was further tested by a specificity assay indicating that it had no antagonistic effects on other evaluated GPCRs, such as endothelin receptors. The major ingredient of ginger, [6]-gingerol, could inhibit angiotensin II type 1 receptor activation, which partially clarified the mechanism of ginger regulating blood pressure and strengthening heart in the cardiovascular system. PMID:23479389

  8. 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

  9. 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.

  10. 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. .

  11. 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

  12. 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.

  13. 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

  14. 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;

    2008-01-01

    Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that plays a critical role in angiogenesis, survival, metastasis, drug resistance, and glucose metabolism. Elevated expression of the alpha-subunit of HIF-1 (HIF-1alpha), which occurs in response to hypoxia or activation of growth factor...... 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...... the expression of HIF-1alpha mRNA. In vitro, in human prostate (15PC3, PC3, and DU145) and glioblastoma (U373) cells, EZN-2968 induced a potent, selective, and durable antagonism of HIF-1 mRNA and protein expression (IC(50), 1-5 nmol/L) under normoxic and hypoxic conditions associated with inhibition of tumor...

  15. 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...

  16. Therapeutic Opportunities for Caffeine and A2A Receptor Antagonists in Retinal Diseases.

    Science.gov (United States)

    Boia, Raquel; Ambrósio, António Francisco; Santiago, Ana Raquel

    2016-01-01

    Caffeine, the major component of coffee, is the most consumed psychostimulant in the world. Caffeine is an adenosine analog and acts as a nonselective adenosine receptor antagonist. The majority of the effects of caffeine are mainly mediated by the blockade of adenosine receptors, and the proved neuroprotective effects of caffeine in brain disorders have been mimicked by the blockade of adenosine A2A receptor (A2AR). A growing body of evidence demonstrates that microglia-mediated neuroinflammation plays a key role in the pathophysiology of brain and retinal diseases. Moreover, the control of microglia reactivity by blocking A2AR has been proposed to be the mechanism underlying the observed protective effects of caffeine. Hence, it is conceivable that caffeine and A2AR antagonists offer therapeutic value for the treatment of retinal diseases, mainly those involving microglia-mediated neuroinflammation.

  17. 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....

  18. 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.

  19. 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 ).

  20. 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

    2015-09-09

    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.

  1. The effect of purging on sexually selected traits through antagonistic pleiotropy with survival

    OpenAIRE

    Bolstad, Geir H.; Pélabon, Christophe; Larsen, Line-K; Fleming, Ian A; Viken, Åslaug; Rosenqvist, Gunilla

    2012-01-01

    Sexually selected traits are expected to evolve to a point where their positive effect on reproductive success is counterbalanced by their negative effect on survival. At the genetic level, such a trade-off implies antagonistic pleiotropy between survival and the expression of sexually selected traits. Yet, the consequences of such a genetic architecture have been largely overlooked in studies examining how inbreeding influences sexually selected traits. These studies have solely interpreted ...

  2. Risk assessment in contemporary outpatients with non-valvular atrial fibrillation recently on vitamin K antagonists

    OpenAIRE

    Abumuaileq, Rami Riziq Yousef

    2016-01-01

    Atrial Fibrillation increases the risk of embolic stroke by five fold. Vitamin K antagonists (VKAs) are still the most used oral anticoagulants in patients with nonvalvular atrial fibrillation (NVAF) and are highly effective for the prevention of thromboembolic (TE) complications in these patients. However, achieving the best benefit and safety from VKAs in the clinical practice remains a major challenge mainly because of their unpredictable anticoagulant response. In this thes...

  3. 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...

  4. 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...

  5. 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...

  6. Genetic and functional diversity among the antagonistic potential fluorescent pseudomonads isolated from tea rhizosphere.

    Science.gov (United States)

    Saikia, Ratul; Sarma, Rupak K; Yadav, Archana; Bora, Tarun C

    2011-02-01

    Twenty-five fluorescent pseudomonads from rhizospheric soil of six tea gardens in four district of Upper Assam, India were isolated and screened for antagonistic activity against fungal pathogens such as Fusarium oxysporum f. sp. raphani (For), Fusarium oxysporum f. sp. ciceri (Foc), Fusarium semitectum (Fs), and Rhizoctonia solani (Rs); and bacterial pathogens-Staphylococcus aureus (Sa), Escherichia coli (Ec), and Klebsiella pneumoniae (Kp). Most of the isolates exhibited strong antagonistic activity against the fungal pathogens and gram-positive bacterium i.e. Staphylococcus aureus. Productions of siderophore, salicylic acid (SA), hydrogen cyanide (HCN), and cell wall-degrading enzyme (chitinase) were studied to observe the possible mechanisms of antagonistic activity of the isolates. Correlation between the antagonistic potentiality of some isolates and their levels of production of siderophore, salicylic acid, and hydrogen cyanide was observed. Out of the 25 isolates, antibiotic-coding genes, 2,4-diacetylphloroglucinol (DAPG) and pyoluteorin (PLT) were detected in the isolates, Pf12 and Pf373, respectively. Genetic diversity of these fluorescent pseudomonads were analyzed with reference to four strains of Pseudomonas fluorescens NICM 2099(T), P. aeruginosa MTCC 2582(T), P. aureofaciens NICM 2026(T), and P. syringae MTCC 673(T). 16S rDNA-RFLP analysis of these isolates using three tetra cutter restriction enzymes (HaeIII, AluI and MspI) revealed two distinct clusters. Cluster A comprised only two isolates Pf141 and 24-PfM3, and cluster B comprised 23 isolates along with four reference strains. PMID:20689953

  7. Inter-genomic sexual conflict drives antagonistic coevolution in harvester ants.

    Science.gov (United States)

    Herrmann, Michael; Cahan, Sara Helms

    2014-12-22

    The reproductive interests of males and females are not always aligned, leading to sexual conflict over parental investment, rate of reproduction and mate choice. Traits that increase the genetic interests of one sex often occur at the expense of the other, selecting for counter-adaptations leading to antagonistic coevolution. Reproductive conflict is not limited to intraspecific interactions; interspecific hybridization can produce pronounced sexual conflict between males and females of different species, but it is unclear whether such conflict can drive sexually antagonistic coevolution between reproductively isolated genomes. We tested for hybridization-driven sexually antagonistic adaptations in queens and males of the socially hybridogenetic 'J' lineages of Pogonomyrmex harvester ants, whose mating system promotes hybridization in queens but selects against it in males. We conducted no-choice mating assays to compare patterns of mating behaviour and sperm transfer between inter- and intra-lineage pairings. There was no evidence for mate discrimination on the basis of pair type, and the total quantity of sperm transferred did not differ between intra- and inter-lineage pairs; however, further dissection of the sperm transfer process into distinct mechanistic components revealed significant, and opposing, cryptic manipulation of copulatory investment by both sexes. Males of both lineages increased their rate of sperm transfer to high-fitness intra-lineage mates, with a stronger response in the rarer lineage for whom mating mistakes are the most likely. By contrast, the total duration of copulation for intra-lineage mating pairs was significantly shorter than for inter-lineage crosses, suggesting that queens respond to prevent excessive sperm loading by prematurely terminating copulation. These findings demonstrate that sexual conflict can lead to antagonistic coevolution in both intra-genomic and inter-genomic contexts. Indeed, the resolution of sexual conflict

  8. 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

  9. Classification of 5-HT1A receptor agonists and antagonists using GA-SVM method

    Institute of Scientific and Technical Information of China (English)

    Xue-lian ZHU; Hai-yan CAI; Zhi-jian XU; Yong WANG; He-yao WANG; Ao ZHANG; Wei-liang ZHU

    2011-01-01

    Aim:To construct a reliable computational model for the classification of agonists and antagonists of 5-HT1A receptor.Methods:Support vector machine (SVM),a well-known machine learning method,was employed to build a prediction model,and genetic algorithm (GA) was used to select the most relevant descriptors and to optimize two important parameters,C and r of the SVM model.The overall dataset used in this study comprised 284 ligands of the 5-HT1A receptor with diverse structures reported in the literatures.Results:A SVM model was successfully developed that could be used to predict the probability of a ligand being an agonist or antagonist of the 5-HT1A receptor.The predictive accuracy for training and test sets was 0.942 and 0.865,respectively.For compounds with probability estimate higher than 0.7,the predictive accuracy of the model for training and test sets was 0.954 and 0.927,respectively.To further validate our model,the receiver operating characteristic (ROC) curve was plotted,and the Area-Under-the-ROC-Curve (AUC) value was calculated to be 0.883 for training set and 0.906 for test set.Conclusion:A reliable SVM model was successfully developed that could effectively distinguish agonists and antagonists among the ligands of the 5-HT1A receptor.To our knowledge,this is the first effort for the classification of 5-HT1A receptor agonists and antagonists based on a diverse dataset.This method may be used to classify the ligands of other members of the GPCR family.

  10. An agonist–antagonist cerebellar nuclear system controlling eyelid kinematics during motor learning

    Directory of Open Access Journals (Sweden)

    Raudel eSánchez-Campusano

    2012-03-01

    Full Text Available The presence of two antagonistic groups of deep cerebellar nuclei neurons has been reported as necessary for a proper dynamic control of learned motor responses. Most models of cerebellar function seem to ignore the biomechanical need for a double activation–deactivation system controlling eyelid kinematics, since most of them accept that, for closing the eyelid, only the activation of the orbicularis oculi muscle (via the red nucleus to the facial motor nucleus is necessary, without a simultaneous deactivation of levator palpebrae motoneurons (via unknown pathways projecting to the perioculomotor area. We have analyzed the kinetic neural commands of two antagonistic types of cerebellar posterior interpositus neuron (types A and B, the electromyographic activity of the orbicularis oculi muscle, and eyelid kinematic variables in alert behaving cats during classical eyeblink conditioning, using a delay paradigm. We addressed the hypothesis that the interpositus nucleus can be considered an agonist–antagonist system controlling eyelid kinematics during motor learning. To carry out a comparative study of the kinetic–kinematic relationships, we applied timing and dispersion pattern analyses. We concluded that, in accordance with a dominant role of cerebellar circuits for the facilitation of flexor responses, type A neurons fire during active eyelid downward displacements ─ i.e., during the active contraction of the orbicularis oculi muscle. In contrast, type B neurons present a high tonic rate when the eyelids are wide open, and stop firing during any active downward displacement of the upper eyelid. From a functional point of view, it could be suggested that type B neurons play a facilitative role for the antagonistic action of the levator palpebrae muscle. From an anatomical point of view, the possibility that cerebellar nuclear type B neurons project to the perioculomotor area ─ i.e., more or less directly onto levator palpebrae

  11. 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 ...

  12. 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 ...

  13. 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...

  14. 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.

  15. Antagonistic Activities of Purple Non-sulfur Bacterial Extracts Against Antibiotic Resistant Vibrio sp.

    OpenAIRE

    Chandrasekaran, R.; Ashok Kumar, G. V.

    2011-01-01

    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...

  16. Social Memory in Mice: Disruption with an NMDA Antagonist and Attenuation with Antipsychotic Drugs

    OpenAIRE

    Gao, Xue-Min; Elmer, Gregory I.; Adams-Huet, Beverley; Tamminga, Carol A.

    2008-01-01

    Social recognition reflects the ability of one animal to learn and remember the identity of another. Animal models of social learning and memory are pertinent to several different CNS diseases involving disruptions in cognition. Moreover, the increased understanding of the basic biology of memory increases the likelihood of discovery of memory-enhancing treatments in these human diseases. In the present study, we investigated the effects of the non-competitive NMDA antagonist ketamine on soci...

  17. (−) Arctigenin and (+) Pinoresinol Are Antagonists of the Human Thyroid Hormone Receptor β

    OpenAIRE

    Ogungbe, Ifedayo Victor; Crouch, Rebecca A.; Demeritte, Teresa

    2014-01-01

    Lignans are important biologically active dietary polyphenolic compounds. Consumption of foods that are rich in lignans is associated with positive health effects. Using modeling tools to probe the ligand-binding pockets of molecular receptors, we found that lignans have high docking affinity for the human thyroid hormone receptor β. Follow-up experimental results show that lignans (−) arctigenin and (+) pinoresinol are antagonists of the human thyroid hormone receptor β. The modeled complexe...

  18. 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

  19. 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...

  20. Quantitative Structure-Activity Relationships and Docking Studies of Calcitonin Gene-Related Peptide Antagonists

    DEFF Research Database (Denmark)

    Jenssen, Håvard; Mehrabian, Mohadeseh; Kyani, Anahita

    2012-01-01

    calcitonin gene-related peptide antagonists was performed using a panel of physicochemical descriptors. The computational studies evaluated different variable selection techniques and demonstrated shuffling stepwise multiple linear regression to be superior over genetic algorithm-multiple linear regression....... The linear quantitative structure-activity relationship model revealed better statistical parameters of cross-validation in comparison with the non-linear support vector regression technique. Implementing only five peptide descriptors into this linear quantitative structure-activity relationship model...

  1. Opioid receptor antagonists increase [Ca2+]i in rat arterial smooth muscle cells in hemorrhagic shock

    Institute of Scientific and Technical Information of China (English)

    Li KAI; Zhong-feng WANG; Yu-liang SHI; Liang-ming LIU; De-yao HU

    2004-01-01

    AIM: To examine the effects of opioid receptor antagonists and norepinephrine on intracellular free Ca2+ concentration ([Ca2+]i) in mesenteric arterial (MA) smooth muscle cells (SMC) isolated from normal and hemorrhagic shocked rats in the vascular hyporesponse stage. METHODS: The rat model of hemorrhagic shock was made by withdrawing blood to decrease the artery mean blood pressure to 3.73-4.26 kPa and keeping at the level for 3 h.[Ca2+]i of vascular smooth muscle cells (VSMC) were detected by the laser scan confocal microscopy. RESULTS:In the hyporesponse VMSC of rats in hemorrhagic shock, selective δ-, κ-, and μ-opioid receptor antagonists (naltrindole, nor-binaltorphimine, and β-funaltrexamine, 100 nmol/L) as well as norepinephrine 5 μmol/L significantly increased [Ca2+]i by 47 %±13 %, 37 %±14 %, 33 %±10 %, and 54 %±17 %, respectively, although their effects were lower than those in the normal rat cells (the increased values were 148 %±54 %, 130 %±44 %, 63 %±17 %and 110 %±38 %, respectively); and the norepinephrine-induced increase in [Ca2+]i was further augmented by three δ-, κ-, and μ-opioid receptor antagonists (50 nmol/L, respectively) application (from 52 %± 16 % to 99 %±29 %,146 %±54 % and 137 %±47 %, respectively). CONCLUSION: The disorder of [Ca2+]i regulation induced by hemorrhagic shock was mediated by opioid receptor and α-adrenoceptor, which may be partly responsible for the vascular hyporesponse, and the opioid receptor antagonists improved the response of resistance arteries to vascular stimulants in decompensatory stage of hemorrhagic shock.

  2. 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

  3. A novel series of glucagon receptor antagonists with reduced molecular weight and lipophilicity.

    Science.gov (United States)

    Filipski, Kevin J; Bian, Jianwei; Ebner, David C; Lee, Esther C Y; Li, Jian-Cheng; Sammons, Matthew F; Wright, Stephen W; Stevens, Benjamin D; Didiuk, Mary T; Tu, Meihua; Perreault, Christian; Brown, Janice; Atkinson, Karen; Tan, Beijing; Salatto, Christopher T; Litchfield, John; Pfefferkorn, Jeffrey A; Guzman-Perez, Angel

    2012-01-01

    A novel series of glucagon receptor antagonists has been discovered. These pyrazole ethers and aminopyrazoles have lower molecular weight and increased polarity such that the molecules fall into better drug-like property space. This work has culminated in compounds 44 and 50 that were shown to have good pharmacokinetic attributes in dog, in contrast to rats, in which clearance was high; and compound 49, which demonstrated a dose-dependent reduction in glucose excursion in a rat glucagon challenge experiment.

  4. Does route of administration affect the outcome of TNF antagonist therapy?

    OpenAIRE

    Schwartzman, Sergio; Morgan, G James

    2004-01-01

    The tumor necrosis factor (TNF) antagonists are parenterally administered biologic response modifiers indicated for the management of rheumatoid arthritis. Although infliximab, etanercept, and adalimumab are all members of this class, they differ in route of administration and dosing regimen. In the USA and in Europe, infliximab, in combination with oral methotrexate, is administered intravenously, initially at a dose of 3 mg/kg at weeks 0, 2, and 6, then every 8 weeks thereafter. The US Food...

  5. "Mirror image" antagonists of thrombin-induced platelet activation based on thrombin receptor structure.

    OpenAIRE

    Hung, D. T.; Vu, T K; Wheaton, V I; Charo, I F; Nelken, N A; Esmon, N; Esmon, C T; Coughlin, S R

    1992-01-01

    Platelet activation by thrombin plays a critical role in hemostasis and thrombosis. Based on structure-activity studies of a cloned platelet thrombin receptor, we designed two "mirror image" antagonists of thrombin and thrombin receptor function. First, "uncleavable" peptides mimicking the receptor domain postulated to interact with thrombin were found to be potent thrombin inhibitors. Second, proteolytically inactive mutant thrombins designed to bind but not cleave the thrombin receptor were...

  6. Using a Cocontraction Ratio to Predict Antagonistic Behavior During Elbow Motion

    CERN Document Server

    Pontonnier, Charles

    2012-01-01

    Inverse dynamics methods for muscle forces prediction are globally unable to predict antagonistic activity during a joint motion. This is due to a lack of physiological information describing how forces are shared between flexors and extensors. The aim of this study is the definition and the use of a new EMG-based cocontraction ratio in an inverse dynamics muscle forces prediction approach applied to the elbow flexion motion. Results show the relevance of the ratio.

  7. Isolation and characterization of actinomycete antagonists of a fungal root pathogen.

    Science.gov (United States)

    Crawford, D L; Lynch, J M; Whipps, J M; Ousley, M A

    1993-11-01

    By use of selective media, 267 actinomycete strains were isolated from four rhizosphere-associated and four non-rhizosphere-associated British soils. Organic media with low nutrient concentrations were found to be best for isolating diverse actinomycetes while avoiding contamination and overgrowth of isolation media by eubacteria and fungi. While all isolates grew well at pHs 6.5 to 8.0, a few were unable to grow at pH 6.0 and a significant number failed to grow at pH 5.5. Eighty-two selected isolates were screened for in vitro antagonism towards Pythium ultimum by use of a Difco cornmeal agar assay procedure. Five isolates were very strong antagonists of the fungus, four were strong antagonists, and ten others were weakly antagonistic. The remaining isolates showed no antagonism by this assay. Additional studies showed that several of the P. ultimum antagonists also strongly inhibited growth of other root-pathogenic fungi. Twelve isolates showing antifungal activity in the in vitro assay were also tested for their effects on the germination and short-term growth of lettuce plants in glasshouse pot studies in the absence of pathogens. None of the actinomycetes prevented seed germination, although half of the isolates retarded seed germination and outgrowth of the plants by 1 to 3 days. During 18-day growth experiments, biomass yields of some actinomycete-inoculated plants were reduced in comparison with untreated control plants, although all plants appeared healthy and well rooted. None of the actinomycetes significantly enhanced plant growth over these short-term experiments. For some, but not all, actinomycetes, some correlations between delayed seed germination and reduced 18-day plant biomass yields were seen. For others, plant biomass yields were not reduced despite an actinomycete-associated delay in seed germination and plant outgrowth. Preliminary glasshouse experiments indicated that some of the actinomycetes protect germinating lettuce seeds against

  8. 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

  9. 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...

  10. Melanin concentrating hormone receptor 1 (MCHR1) antagonists - Still a viable approach for obesity treatment?

    DEFF Research Database (Denmark)

    Högberg, T.; Frimurer, T.M.; Sasmal, P.K.

    2012-01-01

    Obesity is a global epidemic associated with multiple severe diseases. Several pharmacotherapies have been investigated including the melanin concentrating hormone (MCH) and its receptor 1. The development of MCHR1 antagonists are described with a specific perspective on different chemotypes inve...... and recent X-ray structures of GPCRs invoked in selectivity issues indicate a way to support future drug design. © 2012 Elsevier Ltd. All rights reserved....

  11. Agonistic and Antagonistic Interactions between Chlorhexidine and Other Endodontic Agents: A Critical Review

    OpenAIRE

    Mohammadi, Zahed; Giardino, Luciano; Palazzi, Flavio; Asgary, Saeed

    2014-01-01

    Root canal irrigants play a significant role in elimination of the microorganisms, tissue remnants, and removal of the debris and smear layer. No single solution is able to fulfill all these actions completely; therefore, a combination of irrigants may be required. The aim of this investigation was to review the agonistic and antagonistic interactions between chlorhexidine (CHX) and other irrigants and medicaments. An English-limited Medline search was performed for articles published from 20...

  12. Dihydromorphine-peptide hybrids with delta receptor agonistic and mu receptor antagonistic actions

    Energy Technology Data Exchange (ETDEWEB)

    Smith, C.B.; Medzihradsky, F.; Woods, J.H.

    1986-03-05

    The actions of two morphine derivatives with short peptide side chains were evaluated upon the contraction of the isolated mouse vas deferens and upon displacement of /sup 3/H-etorphine from rat brain membranes. NIH-9833 (N-(6,14-endoetheno-7,8-dihydromorphine-7-alpha-carbonyl)-L-phenylalanyl-L-leucine ethyl ester HCl) was a potent agonist upon the vas deferens. Its EC50 for inhibition of the twitch was 1.2 +/- 0.1 nM. Both naltrexone (10/sup -7/ M) a relatively nonselective opioid antagonist, and ICI-174864 (10/sup -/' M) a highly selective delta receptor antagonist, blocked the actions of NIH-9833 which indicates that this drug is a delta receptor agonist. In contrast, NIH-9835 (N-(6,14-endoetheno-7,8-dihydromorphine-7-alpha-carbonyl)-L-glycyl-L-phenylalanyl-L-leucine ethyl ester HCl), which differs from NIH-9835 by the presence of a single amino acid residue, was devoid of opioid agonistic activity but was a potent antagonist of the inhibitory actions on the vas deferens of morphine and sufentanil. NIH-9833 and NIH-9835 were potent displacers of /sup 3/H-etorphine from rat cerebral membranes with EC50's of 0.58 nM and 1.7 nM, respectively. The observation that addition of a single glycyl group changes a dihydromorphine-peptide analog from a potent delta receptor agonist to an equally potent mu receptor antagonist suggests that the two receptor sites might be structurally quite similar.

  13. Impact of selected antagonistic fungi on Fusarium species – toxigenic cereal pathogens

    OpenAIRE

    Delfina Popiel; Hanna Kwaśny; Jerzy Chełkowski; Łukasz Stępień; Magdalena Laskowska

    2013-01-01

    Fusarium-ear blight is a destructive disease in various cereal-growing regions and leads to significant yield and quality losses for farmers and to contamination of cereal grains with mycotoxins, mainly deoxynivalenol and derivatives, zearalenone and moniliformin. Fusarium pathogens grow well and produce significant inoculum on crop resiudues. Reduction of mycotoxins production and pathogen sporulation may be influenced by saprophytic fungi, exhibiting antagonistic effect. Dual culture bioass...

  14. Synthesis and antitumor activity of nitric oxide releasing derivatives of AT1 antagonist

    Institute of Scientific and Technical Information of China (English)

    Yan Chun Zhang; Jin Pei Zhou; Xiao Ming Wu; Wei Hong Pan

    2009-01-01

    A series of novel nitric oxide-donating derivatives (7a-e, 8a-e) were synthesized by coupling furoxan and nitric oxide with irbesartan analogue and their cytotoxicity against BEL7402 cells in vitro were evaluated by MTI" method. It was found that 8c exhibits the most cytotoxic activities with IC.so value of 12.5 umol/L. The hybrids of ATI antagonist and nitric oxide donor appear to have beneficial effects on antitumor.

  15. Gingival hyperplasia in renal allograft recipients receiving cyclosporin-A and calcium antagonists.

    Science.gov (United States)

    King, G N; Fullinfaw, R; Higgins, T J; Walker, R G; Francis, D M; Wiesenfeld, D

    1993-04-01

    Although it is established that the immunosuppressant cyclosporin-A (CsA) and calcium antagonists [Nifedipine (Nif) and Diltiazem (Dz)] can independently induce gingival enlargement, little has been documented on the significance of the salivary CsA levels and the combined effect of CsA and a calcium antagonist upon gingival tissues. In the present cross-sectional investigation, clinical periodontal parameters and the pharmacologic profiles of CsA, Nif, and Dz were determined for 66 renal transplant recipients. Subjects were divided into the following groups: Group (Gp) 1: CsA [n = 18]; Gp 2: CsA + Nif [n = 15]; Gp 3: CsA + Dz [n = 12] and a negative Control Gp 4: azathioprine [n = 21]. A gingival enlargement score was assessed for each patient from study models using a hyperplastic index (HI). Pharmacologic profiles included CsA whole blood and whole saliva levels as measured by fluorescence polarization immunoassay. The HI scores between Gp 1, 2 and 3 were not significantly different. However, when compared with controls (Gp 4), there was a significant difference in HI and all individual groups (Gp 1, 2, 3) (p < 0.05). Gingival hyperplasia was only weakly related to plaque and calculus but was unrelated to CsA dose (mg/kg/day), duration of CsA therapy (months), CsA blood or saliva levels (ng/ml), or the concurrent administration of a Nif or Dz. Gingival enlargement was found to occur in 49% of subjects who were either on CsA or CsA and a calcium antagonist. It is concluded that CsA alone or in combination with a calcium antagonist caused a significant increase in gingival enlargement compared with controls.(ABSTRACT TRUNCATED AT 250 WORDS)

  16. Evaluation of the beta 2 adrenoceptor agonist/antagonist activity of formoterol and salmeterol.

    OpenAIRE

    Grove, A.; Lipworth, B J

    1996-01-01

    BACKGROUND: Salmeterol and formoterol have a lower intrinsic activity at beta 2 receptors than isoprenaline in human bronchus in vitro. The aim of the present study was to evaluate in vivo the beta 2 agonist/antagonist activity of salmeterol and formoterol at rest with low endogenous adrenergic tone, on exercise with raised endogenous adrenergic tone, and in the presence of fenoterol, an exogenous full beta 2 receptor agonist. METHODS: Eight normal subjects were randomised to receive single d...

  17. Ovarian hyperstimulation syndrome prevention strategies: use of gonadotropin-releasing hormone antagonists.

    Science.gov (United States)

    Griesinger, Georg

    2010-11-01

    The most serious complication of ovarian stimulation for in vitro fertilization is severe ovarian hyperstimulation syndrome (OHSS), a rare but potentially life-threatening condition. The present review discusses the place of gonadotropin-releasing hormone antagonists (GnRH-ant) in primary, secondary, and tertiary prevention of OHSS. Sound evidence indicates that the routine use of GnRH-ant instead of GnRH agonists (GnRHa) during ovarian stimulation drastically reduces the relative risk of OHSS. GnRH-ant are therefore useful for primary OHSS prevention, and an increased use of antagonists should help reduce the overall incidence of severe OHSS with its associated risks and complications. In patients on antagonist protocols identified to be at risk of developing severe OHSS, replacing human chorionic gonadotropin with GnRHa as a trigger of final oocyte maturation has been proposed as an effective measure of secondary prevention. A concept of combining GnRHa triggering with cryopreservation of all oocytes or embryos has yielded promising results as far as total avoidance of OHSS is concerned while providing a good chance of pregnancy for the patient in later frozen-thawed embryo transfers. In patients with early onset of OHSS, reinitiation of GnRH-ant in the luteal phase as a measure of tertiary prevention might lead to rapid regression of the syndrome; however only limited data on this new concept are available in the literature.

  18. The evolution of P2X7 antagonists with a focus on CNS indications.

    Science.gov (United States)

    Rech, Jason C; Bhattacharya, Anindya; Letavic, Michael A; Savall, Brad M

    2016-08-15

    The P2X7 receptor is an ATP-gated nonselective cation channel that has been linked to a number of inflammatory diseases. Activation of the P2X7 receptor by elevated levels of ATP results in the release of proinflammatory cytokines and elevated levels of these cytokines has been associated with a variety of disease states. A number of research groups in both industry and academia have explored the identification of P2X7R antagonists as therapeutic agents. Much of this early effort focused on the treatment of diseases related to peripheral inflammation and resulted in several clinical candidates, none of which were advanced to market. The emerging role of the P2X7 receptor in neuroinflammation and related diseases has resulted in a shift in medicinal chemistry efforts toward the development of centrally penetrant antagonists. This review will highlight the biology supporting the role of P2X7 in diseases related to neuroinflammation and review the recent medicinal chemistry efforts to identify centrally penetrant antagonists. PMID:27426304

  19. Pharmacology of JB-9315, a new selective histamine H2-receptor antagonist.

    Science.gov (United States)

    Palacios, B; Montero, M J; Sevilla, M A; San Román, L

    1998-02-01

    1. The histamine H2-receptor antagonistic activity and antisecretory and antiulcer effects of JB-9315 were studied in comparison with the standard H2 blocker ranitidine. 2. In vitro, JB-9315 is a competitive antagonist of histamine H2 receptors in the isolated, spontaneously beating guinea-pig right atrium, with a pA2 value of 7.30 relative to a value of 7.36 for ranitidine. JB-9315 was specific for the histamine H2 receptor because, at high concentration, it did not affect histamine- or acetylcholine-induced contractions in guinea-pig isolated ileum or rat isolated duodenum, respectively. 3. JB-9315 dose dependently inhibited histamine-, pentagastrin- or carbachol-stimulated acid secretion and basal secretion in the perfused stomach preparation of the anesthetized rat. In the pylorus-ligated rat after intraperitoneal administration, total acid output over 4 h was inhibited by JB-9315 with an ID50 of 32.8 mg/kg, confirming its H2-receptor antagonist properties. 4. JB-9315 showed antiulcer activity against cold stress plus indomethacin-induced lesions with an ID50 of 6.8 mg/kg. 5. JB-9315, 50 and 100 mg/kg, inhibited macroscopic gastric hemorrhagic lesions induced by ethanol. In contrast, ranitidine (50 mg/kg) failed to reduce these lesions. 6. These results indicate that JB-9315 is a new antiulcer drug that exerts a cytoprotective effect in addition to its gastric antisecretory activity.

  20. Plasma DNA methylation of Wnt antagonists predicts recurrence of esophageal squamous cell carcinoma

    Institute of Scientific and Technical Information of China (English)

    Ji-Bin Liu; Fu-Lin Qiang; Jing Dong; Jin Cai; Shu-Hui Zhou; Min-Xin Shi; Ke-Ping Chen; Zhi-Bin Hu

    2011-01-01

    AIM: To detect the effects of plasma DNA methylation of Wnt antagonists/inhibitors on recurrence of esophageal squamous cell carcinoma (ESCC).METHODS: We used methylation-specific polymerase chain reaction to detect hypermethylation of the promoter of four Wnt antagonists/inhibitors (SFRP-1, WIF-1, DKK-3 and RUNX3) using DNA from the plasma of ESCC patients (n = 81) and analyzed the association between promoter hypermethylation of Wnt pathway modulator genes and the two-year recurrence of ESCC.RESULTS: Hypermethylation of SFRP-1, DKK-3 and RUNX-3 was significantly associated with an increased risk of ESCC recurrence (P = 0.001, 0.003 and 0.001 for SFRP-1, DKK-3 and RUNX3, respectively). Patients carrying two to three methylated genes had a significantly elevated risk of recurrence compared with those not carrying methylated genes (odds ratio = 15.69, 95% confidential interval: 2.97-83). The area under the receiver operating characteristic curve (AUC) was 77.1 for ESCC recurrence prediction (sensitivity = 66.67 and specificity = 83.3). When combining methylated genes and the clinical stage, the AUC was 83.69, with a sensitivity of 76.19 and a specificity of 83.3.CONCLUSION: The status of promoter hypermethylation of Wnt antagonists/inhibitors in plasma may serve as a non-invasive prognostic biomarker for ESCC.