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Sample records for alpha adrenoceptor antagonists

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

    NARCIS (Netherlands)

    van Dijk, Marleen M.; de La Rosette, Jean J. M. C. H.; Michel, Martin C.

    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

  2. The effect of beta-adrenoceptor antagonists on the alpha-adrenoceptor blockade produced by phenoxybenzamine.

    Science.gov (United States)

    Sankaranarayanan, A; Sharma, P L

    1977-05-01

    The effect of beta-adrenoceptor antagonists on the irreversible alpha-adrenoceptor blockade produced by phenoxybenzamine was studied in dogs. The pressor effects of adrenaline were revived after the inhibition by the alpha-receptor block by (+/-) propranolol, (-) INPEA, (+/-) MJ 1999 and (+/-) butoxamine. The enantiomers (+) propranolol and (+) INPEA were ineffective in this regard. (+/-) Practolol also did not revive the pressor effect of the amines. The alpha-receptor mediated effect of the amines, in the nictitating membrana-receptor blockade. It is concluded that (1) blockade of the peripheral (beta-2) receptors is essential for the revival of the pressor effects, (2) local anesthetic effect of the beta-antagonists is not involved. Further work using a series of doses of agonists and antagonists of alpha-and beta-receptors is indicated to clarify the nature of this drug-interaction.

  3. The effects of SB 216469, an antagonist which discriminates between the alpha 1A-adrenoceptor and the human prostatic alpha 1-adrenoceptor

    NARCIS (Netherlands)

    Chess-Williams, R.; Chapple, C. R.; Verfurth, F.; Noble, A. J.; Couldwell, C. J.; Michel, M. C.

    1996-01-01

    1. The affinity of the alpha 1-adrenoceptor antagonist SB 216469 (also known as REC 15/2739) has been determined at native and cloned alpha 1-adrenoceptor subtypes by radioligand binding and at functional alpha 1-adrenoceptor subtypes in isolated tissues. 2. In radioligand binding studies with

  4. An overview of the pharmacodynamic properties and therapeutic potential of combined alpha- and beta-adrenoceptor antagonists

    NARCIS (Netherlands)

    van Zwieten, P. A.

    1993-01-01

    Haemodynamically, the combination of alpha 1- and beta-adrenoceptor antagonists is a logical one. alpha 1-Adrenoceptor blockade causes vasodilatation and hence counteracts elevated peripheral vascular resistance, the most consistent haemodynamic derangement in established essential hypertension.

  5. alpha2-Adrenoceptor antagonists reverse the 5-HT2 receptor antagonist suppression of head-twitch behavior in mice.

    Science.gov (United States)

    Matsumoto, K; Mizowaki, M; Thongpraditchote, S; Murakami, Y; Watanabe, H

    1997-03-01

    The alpha2-adrenoceptor agonist clonidine, as well as 5-HT2 receptor antagonists, reportedly suppress 5-HT2 receptor-mediated head-twitch behavior. We investigated the effect of alpha2-adrenoceptor antagonists on the suppressive action of 5-HT2 receptor antagonists in mice pretreated with the noradrenaline toxin 6-hydroxydopamine (6-OHDA) or the 5-HT synthesis inhibitor p-chlorophenylalanine (p-CPA). In normal mice, idazoxan (0.08-0.2 mg/kg, IP) or yohimbine (0.2-2.0 mg/kg, IP), both alpha2-adrenoceptor antagonists, had no effect on the head-twitch response caused by 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT; 16 mg/kg, IP), but idazoxan significantly enhanced the response at 0.5 mg/kg. On the other hand, these alpha2-adrenoceptor antagonists, at doses that had no effect on the basal number of head-twitches (idazoxan 0.2 mg/kg and yohimbine 0.5 mg/kg), significantly attenuated not only the suppressive effect of clonidine (0.01 mg/kg, IP) on head-twitch response but also that of the 5-HT2 receptor antagonist ritanserin (0.03 mg/kg, IP). Moreover, idazoxan (0.2 mg/kg) also significantly reversed the inhibition by 0.01 mg/kg (IP) ketanserin, a selective 5-HT2 receptor antagonist. Pretreatment with 6-OHDA plus nomifensine but not with p-CPA significantly attenuated the effect of idazoxan (0.2-0.5 mg/kg) on the ritanserin inhibition of the head-twitch response. Prazosin, an alpha1-adrenoceptor antagonist, dose-dependently suppressed the response, and the effect of prazosin (1.25 mg/kg) was significantly attenuated by 0.5 mg/kg idazoxan. These results indicate that endogenous noradrenaline is involved in the apparent antagonistic interaction between selective alpha2-adrenoceptor antagonists and 5-HT2 receptor antagonists in the head-twitch response, and suggest that noradrenaline stimulation of alpha1-adrenoceptors may be involved in this apparent antagonism.

  6. Apoptosis induction by doxazosin and other quinazoline alpha(1)-adrenoceptor antagonists: a new mechanism for cancer treatment?

    NARCIS (Netherlands)

    Kyprianou, Natasha; Vaughan, Taylor B.; Michel, Martin C.

    2009-01-01

    Doxazosin and related, quinazoline-based alpha(1)-adrenoceptor antagonists can induce apoptosis in prostate and various other normal, benign, smooth muscle, endothelial and malignant cells. Such apoptosis-inducing effects occur independently of alpha(1)-adrenoceptor antagonism and typically require

  7. An overview of the pharmacodynamic properties and therapeutic potential of combined alpha- and beta-adrenoceptor antagonists.

    Science.gov (United States)

    van Zwieten, P A

    1993-04-01

    Haemodynamically, the combination of alpha 1- and beta-adrenoceptor antagonists is a logical one. alpha 1-Adrenoceptor blockade causes vasodilatation and hence counteracts elevated peripheral vascular resistance, the most consistent haemodynamic derangement in established essential hypertension. beta-Blockers, which lower elevated blood pressure by a different (not yet clearly understood) mechanism, suppress the reflex tachycardia triggered by vasodilatation. Combined alpha/beta-adrenoceptor blockade can be obtained by the simultaneous administration of both types of adrenoceptor antagonists, but also by giving drugs that possess alpha- and beta-adrenoceptor antagonistic activity in the same molecule. Carvedilol and labetalol are the best known examples of such combined alpha/beta-adrenoceptor antagonists, although their pharmacodynamic profile is a result of different receptor selectivity of their component stereoisomers, rather than combined alpha/beta-blocking activity in a single chemical entity. Both compounds have been investigated clinically in the treatment of essential hypertension in moderate-to-large scale trials. A few newer combined alpha/beta-adrenoceptor antagonists, such as amosulalol, arotinolol and medroxalol have been developed, but clinical data on these compounds are relatively scarce.

  8. The antagonistic effect of antipsychotic drugs on a HEK293 cell line stably expressing human alpha(1A1)-adrenoceptors

    DEFF Research Database (Denmark)

    Nourian, Zahra; Mulvany, Michael J; Nielsen, Karsten Bork

    2008-01-01

    Antipsychotic drugs often cause orthostatic hypotension, probably through antagonist action on resistance vessel alpha(1A)-adrenoceptors. Here we have tested this possibility directly using cells transfected with a relevant human alpha(1A)-adrenoceptor splice variant. To determine a splice variant...... a cell line stably expressing a functional form of this splice variant. The expression of recombinant alpha(1A1)-adrenoceptor subtype was confirmed by Western immunoblot analysis, and its functionality demonstrated using a Fura-2 assay by a rise in intracellular calcium concentration ([Ca(2+)](i)) when...... human alpha(1A1)-adrenoceptors in competition binding studies confirmed much higher antagonist affinity of sertindole and risperidone than haloperidol for these receptors. In summary, it can be concluded that there is an approximately 10-fold higher adrenoceptor affinity of risperidone and sertindole...

  9. Inhibition of [11C]mirtazapine binding by alpha2-adrenoceptor antagonists studied by positron emission tomography in living porcine brain

    DEFF Research Database (Denmark)

    Smith, Donald F; Dyve, Suzan; Minuzzi, Luciano

    2006-01-01

    Inhibition of [11C]mirtazapine binding by alpha2-adrenoceptor antagonists studied by positron emission tomography in living porcine brain......Inhibition of [11C]mirtazapine binding by alpha2-adrenoceptor antagonists studied by positron emission tomography in living porcine brain...

  10. Characterization of the adrenoceptor antagonistic and antihypertensive activity of oral amosulalol, a combined alpha- and beta-adrenoceptor antagonist, in hypertensive rats.

    Science.gov (United States)

    Inagaki, O; Sudoh, K; Shibasaki, M; Nakagawa, C; Honda, K

    1994-11-01

    The adrenoceptor antagonistic and antihypertensive effects of amosulalol, 5-[1-hydroxy-2-[[2-(o- methoxy)ethyl]-2-ethylbenzenesulfonamide HCl, a combined alpha- and beta-adrenoceptor antagonist, were examined in hypertensive rats. Oral administration of amosulalol (1-30 mg/kg) produced a dose-dependent antihypertensive effect without reflex tachycardia in conscious spontaneously hypertensive rats (SHR) with a duration > 10 h after the higher doses (10 and 30 mg/kg). Amosulalol was approximately threefold more potent than labetalol and arotinolol in decreasing blood pressure (BP) in conscious SHR. Oral (p.o.) administration of amosulalol 10 mg/kg produced equally potent reductions in mean arterial BP (MBP) without reflex tachycardia in deoxycorticosterone acetate-salt rats (DHR) and renal hypertensive rats (RHR) as it did in SHR. Repeated oral administration (1, 4, 8, or 12 weeks) of amosulalol 10 mg/kg elicited an antihypertensive effect without evidence of tolerance in conscious SHR and produced a rightward shift in phenylephrine (PE)-induced vasopressor and isoproterenol (ISO)-induced positive chronotropic responses with dose ratios of 3.3-12.5 and 3.7-6.4, respectively, in pithed SHR. In addition, single p.o. administration of amosulalol 10 mg/kg produced a rightward shift in these responses with dose ratios of 12.1 and 3.5, respectively, in pithed SHR. Amosulalol exerted antihypertensive activity without tachycardia through blockade of vascular alpha- and cardiac beta-adrenoceptors, and its activities were constant even after repeated p.o. administration.

  11. The inhibitory effect of newer calcium antagonists (nimodipine and PY-108-068) on vasoconstriction in vivo mediated by postsynaptic alpha 2-adrenoceptors

    NARCIS (Netherlands)

    Van Meel, J. C. A.; Wilffert, B; De Zoeten, K; Timmermans, P B; Van Zwieten, P A

    1982-01-01

    In the pithed rat, stimulation of postsynaptic alpha 1 as well as alpha 2-adrenoceptors is known to cause vasoconstriction. The two newer nifedipine-related calcium antagonistic agents nimodipine and PY-108-068 proved potent inhibitors of pressor responses induced by the selective alpha 2-receptor

  12. Effects of alpha-adrenoceptor antagonist doxazosin on MDR1-mediated multidrug resistance and transcellular transport.

    Science.gov (United States)

    Takara, Kohji; Sakaeda, Toshiyuki; Kakumoto, Mikio; Tanigawara, Yusuke; Kobayashi, Hironao; Okumura, Katsuhiko; Ohnishi, Noriaki; Yokoyama, Teruyoshi

    2009-01-01

    The purpose of this study is to examine the effects of doxazosin, an alpha-adrenoceptor antagonist, on P-glycoprotein/MDR1-mediated multidrug resistance (MDR) and the transport of anticancer drugs. The effects of doxazosin, prazosin, and terazosin on MDR1-mediated MDR were assessed in human cervical carcinoma HeLa cells and the MDR1-overexpressing derivative Hvrl00-6, established by stepwise increases of the vinblastine concentration in the culture medium. The effects of doxazosin on the transcellular transport and intracellular accumulation of [3H]vinblastine, [3H]daunorubicin, and [3H]digoxin, all MDR1 substrates, were evaluated using LLC-GA5-COL150 cell monolayers, established by transfection of human MDR1 cDNA into porcine kidney epithelial LLC-PK1 cells. The sensitivity to vinblastine and paclitaxel of Hvrl00-6 cells was increased at 3.4- and 17.5-fold, respectively, by the addition of 1 microM doxazosin, whereas prazosin and terazosin had weaker or no such effects. Prazosin at 1 microM had a reversal effect on the sensitivity to vinblastine, whereas terazosin had no effect. In transport experiments, doxazosin concentration dependently increased the apical-to-basal transport of radiolabeled drugs in LLC-GA5-COL150 cells, but did not show remarkable effects on the basal-to-apical transport. In addition, doxazosin restored the intracellular accumulation in a concentration-dependent manner in LLC-GA5-COL150 cells. Doxazosin may partly reverse MDR by inhibiting MDR1-mediated transport, making it a candidate lead compound in the development of a reversing agent for MDR.

  13. Evidence for activation of both adrenergic and cholinergic nervous pathways by yohimbine, an alpha 2-adrenoceptor antagonist.

    Science.gov (United States)

    Bagheri, H; Chale, J J; Guyen, L N; Tran, M A; Berlan, M; Montastruc, J L

    1995-01-01

    Adrenoceptors are involved in the control of the activity of the autonomic nervous system and especially the sympathetic nervous system. Activation of alpha 2-adrenoceptors decreases sympathetic tone whereas their blockade has an opposite effect. However, previous investigations have shown that yohimbine (a potent alpha 2-adrenoceptor antagonist) increases salivary secretion through activation of cholinergic pathways. The aim of the present experiment was to investigate the involvement of both the sympathetic and the parasympathetic system in several pharmacological effects of yohimbine. For this purpose, salivary secretion and various endocrino-metabolic parameters (noradrenaline and insulin secretions, lipomobilization) were evaluated in conscious fasting dogs before and after blockade of either the sympathetic (with the beta-adrenoceptor antagonist agent nadolol) or the parasympathetic (with the anticholinergic agent atropine) systems. Yohimbine alone (0.4 mg.kg-1, i.v.) increased within 5-15 minutes, plasma noradrenaline (600%), insulin levels (300%), free-fatty acids (79%) and salivary secretion (143%). Atropine (0.2 mg.kg-1, i.v.) suppressed yohimbine-induced salivary secretion (90%) but did not significantly modify the yohimbine induced changes in noradrenaline (312%), insulin (277%) and free-fatty acids (102%) plasma levels. Administration of nadolol (1 mg.kg-1, i.v.) did not change the magnitude of the increase in both noradrenaline plasma levels (550%) and salivary secretion (300%) induced by yohimbine. However, nadolol totally blunted the increase in insulin (15%) and free-fatty acids (4%) plasma levels. These results show that yohimbine-induced increase in salivary secretion is a cholinergic effect whereas the increase in insulin and free fatty acids can be explained by an increase in sympathetic tone.(ABSTRACT TRUNCATED AT 250 WORDS)

  14. Adrenoceptor blocking effects of arotinolol, a new combined alpha- and beta-adrenoceptor blocking agent.

    Science.gov (United States)

    Miyagishi, A; Nakahara, H; Hara, Y

    1984-10-01

    In isolated tissues and anesthetized animals, beta- and alpha-adrenoceptor blocking properties of arotinolol were studied in comparison with those of other typical adrenoceptor antagonists. The following order of beta-adrenoceptor blocking activities were obtained in isolated tissues: arotinolol = pindolol greater than propranolol = oxprenolol = alprenolol greater than or equal to labetalol for beta 1-adrenoceptors (guinea-pig right atrium) and pindolol = oxprenolol = arotinolol greater than propranolol greater than labetalol for beta 2-adrenoceptors (guinea-pig trachea). In anesthetized cats, arotinolol was about 9 and 25 times more potent than propranolol, about 30 and 100 times more potent than labetalol in blocking beta 1- and beta 2-adrenoceptors, respectively. Furthermore arotinolol showed a competitive antagonistic effect on phenylephrine-induced contraction of isolated rat aortic strips. The relative order of alpha 1-adrenoceptor blocking potencies was as follows: prazosin greater than phentolamine greater than labetalol greater than arotinolol = yohimbine. Presynaptic alpha 2-adrenoceptor blocking action of arotinolol was also assessed in isolated rat vas deferens and arotinolol was revealed to be a much weaker presynaptic alpha 2-adrenoceptor antagonist. In anesthetized rats arotinolol was 4-5 times less potent than labetalol and about 26 times less potent than phentolamine in blocking alpha 1-adrenoceptors. Thus, as for the selectivity for 2 subtypes of alpha-adrenoceptors, arotinolol showed a selectivity for alpha 1-adrenoceptors over presynaptic alpha 2-adrenoceptors.

  15. Effects of arotinolol, an alpha- and beta-adrenoceptor antagonist, on renin release from rat kidney cortical slices.

    Science.gov (United States)

    Morimoto, S; Miyawaki, N; Sasaki, Y; Matsumura, Y

    1986-06-01

    The effects of arotinolol on changes in renin release in rat kidney cortical slices in response to isoproterenol (IP) or norepinephrine (NE), were studied in comparison with those of AC-623, a main metabolite of arotinolol, and other typical adrenoceptor antagonists. Arotinolol, at concentrations of 10(-8) to 10(-4) mol/l, inhibited the increasing effect of 10(-6) mol/l IP on renin release, in a concentration-dependent manner. Similar results were observed with AC-623, propranolol or labetalol, although the inhibitory potencies of these agents were considerably lower than that of arotinolol. The blocking effect of arotinolol on the 10(-5) mol/l NE-induced decrease in renin release was much less potent than seen with other alpha-adrenoceptor blocking agents such as prazosin, phenoxybenzamine and labetalol. These data suggest that the potent blocking effects of arotinolol and its metabolite on the increased renin release in response to beta-adrenoceptor stimulation may contribute to the antihypertensive effect of this agent.

  16. 5-Methoxy-N,N-dimethyltryptamine-induced analgesia is blocked by alpha-adrenoceptor antagonists in rats.

    Science.gov (United States)

    Archer, T.; Danysz, W.; Jonsson, G.; Minor, B. G.; Post, C.

    1986-01-01

    The effects of the alpha-adrenoceptor antagonists prazosin, phentolamine and yohimbine upon 5-methoxy-N,N-dimethyltryptamine (5-MeODMT)-induced analgesia were tested in the hot-plate, tail-flick and shock-titration tests of nociception with rats. Intrathecally injected yohimbine and phentolamine blocked or attenuated the analgesia produced by systemic administration of 5-MeODMT in all three nociceptive tests. Intrathecally administered prazosin attenuated the analgesic effects of 5-MeODMT in the hot-plate and tail-flick tests, but not in the shock titration test. Intrathecal yohimbine showed a dose-related lowering of pain thresholds in saline and 5-MeODMT-treated animals. Phentolamine and prazosin produced normal dose-related curves in the hot-plate test and biphasic effects in the shock titration and tail-flick tests. These results demonstrate a functional interaction between alpha 2-adrenoceptors and 5-HT agonist-induced analgesia at a spinal level in rats. PMID:2877697

  17. THE EFFECT OF SOME ALPHA-ADRENOCEPTOR ANTAGONISTS ON SPONTANEOUS MYOGENIC ACTIVITY IN THE RAT PORTAL-VEIN AND THE PUTATIVE INVOLVEMENT OF ATP-SENSITIVE K+ CHANNELS

    NARCIS (Netherlands)

    SCHWIETERT, R; WILHELM, D; WILFFERT, B; VANZWIETEN, PA

    1992-01-01

    In the present study we showed that the alpha-adrenoceptor antagonists phentolamine, yohimbine, prazosin, corynanthine and idazoxan, when cumulatively applied in high concentrations (1-100-mu-mol/l), can increase spontaneous myogenic activity in the rat portal vein. 5-Methyl-urapidil and rauwolscine

  18. Identification of human platelet alpha 2-adrenoceptors with a new antagonist [3H]-RX821002, a 2-methoxy derivative of idazoxan.

    Science.gov (United States)

    Galitzky, J.; Senard, J. M.; Lafontan, M.; Stillings, M.; Montastruc, J. L.; Berlan, M.

    1990-01-01

    1. The binding of a new alpha 2-adrenoceptor antagonist, [3H]-RX821002 (2-(2-methoxy-1,4-benzodioxan-2-yl)-2-imidazoline), was investigated in human platelet membranes and compared with [3H]-yohimbine binding parameters. 2. Analysis of kinetic data revealed association and dissociation time courses consistent with a simple biomolecular reaction. Saturation isotherms showed that [3H]-RX821002 labelled a higher total number of alpha 2-binding sites (224 +/- 31 vs 168 +/- 24 fmol mg-1 protein) than [3H]-yohimbine and with higher affinity (Kd: 0.92 +/- 0.06 vs 1.51 +/- 0.08 nM). Moreover [3H]-RX821002 exhibited a lower percentage of nonspecific binding 3. The difference in total binding is due to a better labelling of the alpha 2-adrenoceptors in the low affinity state by [3H]-RX821002 since the labelled receptors number in high affinity state was identical with the two radioligands. 4. [3H]-RX821002 binding displayed a specificity similar to that obtained with [3H]-yohimbine. The potency of various compounds acting on adrenoceptors was: yohimbine greater than oxymetazoline greater than UK14304 greater than (-)-adrenaline greater than prazosin greater than or equal to (+)-adrenaline greater than isoprenaline. This order of potency is classical for an alpha 2A-adrenoceptor. 5. RX821002 is a more potent alpha 2-adrenoceptor antagonist than yohimbine on adrenaline-induced platelet aggregation. 6. These results indicate that [3H]-RX821002 is a suitable ligand for the identification of human platelet alpha 2-adrenoceptors. PMID:1976403

  19. Differential vascular alpha1-adrenoceptor antagonism by tamsulosin and terazosin

    NARCIS (Netherlands)

    Schäfers, R. F.; Fokuhl, B.; Wasmuth, A.; Schumacher, H.; Taguchi, K.; de Mey, C.; Philipp, T.; Michel, M. C.

    1999-01-01

    AIMS: In patients with lower urinary tract symptoms suggestive of benign prostatic obstruction the alpha1-adrenoceptor antagonist terazosin lowers blood pressure whereas only very small if any alterations were reported with the alpha1-adrenoceptor antagonist tamsulosin. Therefore, we have compared

  20. Effects of alpha1-adrenoceptor antagonist (tamsulosin) on incident of ejaculation and semen quality in the goat.

    Science.gov (United States)

    Kimsakulvech, S; Suttiyotin, P; Pinyopummin, A

    2015-04-01

    Male temporary contraception is occasionally required in some animals. Alpha1-adrenoceptor antagonist (tamsulosin) can cause ejaculation disorder. Two sets of Latin square were applied to six male goats to received either normal saline, dimethylsulphoxide or tamsulosin (179.8 nmol kg(-1) ) at 1-week interval. Semen collection and libido scoring were undertaken at 3, 6 and 24 h post-injection. For ejaculated semen, its quality was evaluated. Physiological measurements including body temperature, respiration and heart rates were measured before injection and at 30 min before semen collection. The results showed that libido score and physiological changes were not affected by treatments and time periods. Anejaculation was observed in 11 (91.7%), 5 (41.7%) and 1 (8.3%) males at 3, 6 and 24 h post-tamsulosin injection respectively. The incidence returned to normal when compared with control groups at 24 h. The percentages of motile and live spermatozoa at 6 h post-tamsulosin injection were significantly lower (P tamsulosin had temporary effects on ejaculation and semen quality without reducing sex desire and physiological functions in male goats. © 2014 Blackwell Verlag GmbH.

  1. Anti-Parkinson effects of a selective alpha2C-adrenoceptor antagonist in the MPTP marmoset model.

    Science.gov (United States)

    Philippens, Ingrid H C H M; Joosen, Marloes J A; Ahnaou, Abdellah; Andres, Ignacio; Drinkenburg, Wilhelmus Pim H I M

    2014-08-01

    Current dopamine replacement therapies, in Parkinson's disease (PD), result in aversive side effects and rapid drug dose escalation over time. Therefore, a non-dopaminergic treatment would be an advantageous supplement to lower the dose of dopamine replacement treatment postponing the occurrence of side effects. The noradrenergic system plays an important role in the facilitation or maintenance of the activity of the nigrostriatal dopamine pathways. Here the putative anti-Parkinson effects of the oral selective alpha2C-adrenoceptor antagonist (JNJ27063699 0.1-10mg/kg p.o.) and of vehicle (fruit syrup) were evaluated in the MPTP-marmoset model. Dose-related anti-Parkinson effects were assessed by means of a behavioural rating scale covering parkinsonian symptoms, body weight and body temperature, and two test systems assessing locomotor activity and complex motor skills of hand-eye coordination for controlled movements in MPTP- or saline-pretreated marmosets. JNJ27063699, at the middle and higher doses, consistently improved locomotor activity and hand-eye coordination capabilities, which indicates an improvement in the coordination of motor control -or movements- in MPTP-pretreated monkeys. No additional effects on the parkinsonian symptoms or side effects were observed on other test systems. Overall, the findings link deficit in motor coordination with dysfunctional adrenergic signalling and it suggest that selective alpha2C adrenergic antagonism may contribute to behavioural improvement in the MPTP-monkey model of PD. In multi-drug medication JNJ27063699 might have potential in the treatment of motor deficit in PD. Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.

  2. Evidence that catecholamines stimulate renal gluconeogenesis through an alpha 1-type of adrenoceptor.

    Science.gov (United States)

    Kessar, P; Saggerson, E D

    1980-01-01

    1. Noradrenaline stimulates gluconeogenesis through an alpha-adrenoceptor in renal cortical tubule fragments from fed rats incubated with 5 mM-lactate. 2. The selective alpha 1-adrenoreceptor agonist methoxamine stimulated gluconeogenesis, but the selective alpha 2-adrenoceptor agonist clonidine was ineffective. 3. The selective alpha 1-adrenoceptor antagonist thymoxamine blocked the stimulatory effects on gluconeogenesis of noradrenaline and of oxymetazoline (a synthetic alpha-agonist). The selective alpha 2-adrenoceptor antagonist yohimbine was ineffective in this respect. 4. It is concluded that noradrenaline and oxymetazoline stimulate gluconeogenesis in rat kidney via an alpha 1-rather than an alpha 2-type of adrenoceptor. PMID:6255939

  3. Classification of alpha 1-adrenoceptor subtypes

    NARCIS (Netherlands)

    Michel, M. C.; Kenny, B.; Schwinn, D. A.

    1995-01-01

    Two alpha 1-adrenoceptor subtypes (alpha 1A and alpha 1B) have been detected in various tissues by pharmacological techniques, and three distinct cDNAs encoding alpha 1-adrenoceptor subtypes have been cloned. The profile of an increasing number of subtype-selective compounds at cloned and endogenous

  4. New {alpha}{sub 1}-adrenoceptor antagonists derived from the antipsychotic sertindole - carbon-11 labelling and pet examination of brain uptake in the cynomolgus monkey

    Energy Technology Data Exchange (ETDEWEB)

    Balle, Thomas E-mail: tb@dfuni.dk; Halldin, Christer; Andersen, Linus; Hjorth Alifrangis, Lene; Badolo, Lassina; Gjervig Jensen, Klaus; Chou, Y.-W.; Andersen, Kim; Perregaard, Jens; Farde, Lars

    2004-04-01

    Central {alpha}{sub 1}-adrenergic receptors are potential targets for recently developed antipsychotic drugs. Two new 11C labeled potent and selective {alpha}{sub 1}-adrenoceptor antagonists, 1- [2- [4-[1-(4-fluorophenyl)-5-(2-[{sup 11}C]methyl-tetrazol-5-yl)-1H-indol-3-yl]-1- pipridinyl]ethyl]-imidazolidin-2-one ([{sup 11}C]2) and 1- [2- [4-[1-(4-fluorophenyl)-5-(1-[{sup 11}C]methyl-(1,2,3-triazol-4-yl) -1H-indol-3-yl]- 1-piperidinyl]ethyl]-imidazolidin-2-one ([{sup 11}C]3) were prepared and evaluated for imaging of central {alpha}{sub 1}-adrenergic receptors in the cynomolgus monkey brain. For both compounds, the total brain radioactivity was only about 0.6% of the radioactivity injected i.v. There was no evident binding in regions known to contain {alpha}{sub 1}-adrenoceptors. This observation suggests that the affinity of the radioligands in primates in vivo is not sufficient to provide a signal for specific binding that can be differentiated from the background. In addition, active efflux by P-glycoprotein may be responsible for the low total brain-uptake of the two radioligands. Both compounds showed a highly polarised and verapamile sensitive transport across monolayers of Caco-2 cells. The total brain-uptake of [{sup 3}H]2 was 6 times higher in mdr1a(-/-) knock-out mice lacking the gene encoding P-glycoprotein compared to wild type mice. Pretreatment of one monkey with Cyclosporin A (15 mg/kg) resulted in 40% higher brain uptake for [{sup 11}C]3 when compared with baseline. These observations support the view that efflux by P-glycoprotein can be of quantitative importance for the total brain-uptake of some PET radioligands.

  5. Central and peripheral alpha-adrenoceptors

    NARCIS (Netherlands)

    van Zwieten, P A; van Meel, J. C. A.; de Jonge, A; Wilffert, B; Timmermans, P B

    1982-01-01

    The recent interest in the characterization and functional, role of alpha-adrenoceptors has prompted us to study the following different, although interdigitated, lines of research: (a) The functional role of calcium ions in the process of vasoconstriction, induced by alpha 2-adrenoceptor

  6. Alpha 1-adrenoceptor subtypes in the rat ventricular muscle.

    Science.gov (United States)

    Kinami, J; Tsuchihashi, H; Baba, S; Mano, F; Maruyama, K; Nagatomo, T

    1992-02-01

    Scatchard analyses of [3H]prazosin binding in rat ventricular muscle membranes showed biphasic curves, which identified alpha 1High- and alpha 1Low-affinity sites. The alpha 1High-affinity site was completely inhibited by 1 microM phenoxybenzamine. The displacement potencies of alpha 1-adrenergic antagonists were characterized by [3H]prazosin binding to alpha 1High- and alpha 1Low-affinity sites in the absence and presence of 1 microM phenoxybenzamine. The affinities of most chemicals for alpha 1Low-affinity sites were significantly lower than those for alpha 1High-affinity sites, but WB-4101 (2-(2,6-dimethoxy-phenoxyethyl)aminomethyl-1,4-benzodioxane), arotinolol, cinanserin, nifedipine, and p-aminoclonidine had the same affinities for both alpha 1Low- and alpha 1High-affinity sites. These results show that two alpha 1-adrenoceptor subtypes, alpha 1High- and alpha 1Low-affinity, are present in the rat heart, and that there are physical variations in alpha 1-adrenoceptor binding sites, based on their selectivity to antagonists.

  7. Alpha 1 B- but not alpha 1 A-adrenoceptors mediate inositol phosphate generation

    NARCIS (Netherlands)

    Michel, M. C.; Hanft, G.; Gross, G.

    1990-01-01

    We used novel highly subtype-selective antagonists to study whether alpha 1A- and/or alpha 1B-adrenoceptors mediate the stimulation of inositol phosphate generation by noradrenaline in rat cerebral cortex. Phentolamine (10 microM) and prazosin (100 nM) completely abolished the stimulated inositol

  8. Molecular characterization of alpha 1- and alpha 2-adrenoceptors.

    Science.gov (United States)

    Harrison, J K; Pearson, W R; Lynch, K R

    1991-02-01

    Three 'alpha 1-adrenoceptors' and three 'alpha 2-adrenoceptors' have now been cloned. How closely do these receptors match the native receptors that have been identified pharmacologically? What are the properties of these receptors, and how do they relate to other members of the cationic amine receptor family? Kevin Lynch and his colleagues discuss these questions in this review.

  9. Inhibition of human prostate cancer cells proliferation by a selective alpha1-adrenoceptor antagonist labedipinedilol-A involves cell cycle arrest and apoptosis

    International Nuclear Information System (INIS)

    Liou, S.-F.; Lin, H.-H.; Liang, J.-C.; Chen, I.-J.; Yeh, J.-L.

    2009-01-01

    In this research, we conducted an in vitro analysis to evaluate the prostate cancer cells response to labedipinedilol-A in order to determine the effect of this selective α 1 -adrenoceptor antagonist to suppress prostate cancer cell growth by affecting cell proliferation and apoptosis. Here, we report that treatment of androgen-sensitive (LNCaP) and androgen-insensitive (PC-3) prostate cancer cells with labedipinedilol-A inhibited cell proliferation in concentration-dependent and time-dependent manners. Moreover, norepinephrine-stimulated proliferation of both cell lines are markedly inhibited by labedipinedilol-A. The probable involvement of α 1 -adrenoceptors in this cellular response is suggested. Labedipinedilol-A-induced growth inhibition was associated with G 0 /G 1 arrest, and G 2 /M arrest depending upon concentrations. Cell cycle blockade was associated with reduced amounts of cyclin D1/2, cyclin E, Cdk2, Cdk4, and Cdk6 and increased levels of the Cdk inhibitory proteins (Cip1/p21 and Kip1/p27). In addition, labedipinedilol-A also induced apoptosis in PC-3 cells, as determined by using Hoechst 33342 staining, DNA fragmentation, and Annexin V staining assay. Furthermore, labedipinedilol-A triggered the mitochondrial apoptotic pathway, as indicated by increasing the expression of Bax, but decreasing the level of Bcl-2, resulting in mitochondrial membrane potential loss, cytochrome c release, and activation of caspase-9 and -3. We further investigated the role of MAPK cascades in the anti-proliferative and apoptosis effects of labedipinedilol-A, and confirmed that labedipinedilol-A could activate JNK1/2 but not p38 in both cell lines. Unlike JNK1/2, however, labedipinedilol-A treatment resulted in down-regulation of phospho-ERK1/2 expression. We concluded that labedipinedilol-A possessed the growth-suppressive and apoptotic effects on LNCaP and PC-3 cells by its α 1 -adrenoceptor blockade, and the apoptotic effects of labedipinedilol-A primarily through

  10. Selective regulation of beta 1- and beta 2-adrenoceptors in the human heart by chronic beta-adrenoceptor antagonist treatment

    NARCIS (Netherlands)

    Michel, M. C.; Pingsmann, A.; Beckeringh, J. J.; Zerkowski, H. R.; Doetsch, N.; Brodde, O. E.

    1988-01-01

    1. In 44 patients undergoing coronary artery bypass grafting, the effect of chronic administration of the beta-adrenoceptor antagonists sotalol, propranolol, pindolol, metoprolol and atenolol on beta-adrenoceptor density in right atria (containing 70% beta 1- and 30% beta 2-adrenoceptors) and in

  11. Effects of silodosin, a selective alpha-1A adrenoceptor antagonist, on erectile function in a rat model of partial bladder outlet obstruction.

    Science.gov (United States)

    Bastaskın, Tugce; Kaya, Ecem; Ozakca, Isıl; Yilmaz, Didem; Bayatlı, Nur; Akdemir, Alp Ozgur; Gur, Serap

    2017-03-01

    We investigated the effects of silodosin (selective α 1A -adrenoceptor antagonist) on erectile dysfunction (ED) in a rat model of bladder outlet obstruction. Adult male Sprague-Dawley rats (n = 32) were divided into four groups: (i) sham-operated control; (ii) silodosin-treated (sham) control (0.1 mg/kg/day); (iii) partial bladder outlet obstruction (PBOO); and (iv) silodosin-treated with PBOO. PBOO was induced by ligation of the urethra for 6 weeks. In vivo, erectile responses were monitored by evaluating ratios of intracavernosal pressure (ICP)/mean arterial pressure (MAP). Organ-bath studies were performed on corpus cavernosum (CC) strips. Penises were assessed at baseline for protein expression of neuronal nitric oxide synthase (nNOS) and Rho-associated protein kinase (ROCK2) by Western blot. Immunohistochemistry and Masson trichrome staining were performed for analysis of nNOS protein levels and tissue alterations. The ratio of ICP/MAP was significantly decreased in obstructed rats (0.26 ± 0.043, P < 0.01) compared to sham-control rats (0.64 ± 0.10), which was restored by the treatment (0.59 ± 0.14, P < 0.01) compared with obstructed rats. Relaxation responses were significantly reduced in strips from the obstructed group. Silodosin restored nitrergic relaxant responses. nNOS expression in the obstructed group decreased, which was improved by treatment. The decreased smooth muscle/collagen ratio in the bladder obstructed group was reversed by the treatment. Silodosin improves erectile function in obstructed rats. Further clinical trials are needed to explore fully the potential benefits of silodosin in patients with benign prostatic hyperplasia (BPH)/lower urinary tract symptoms (LUTS) in association with ED. Neurourol. Urodynam. 36:597-603, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  12. Saw palmetto extracts potently and noncompetitively inhibit human alpha1-adrenoceptors in vitro

    NARCIS (Netherlands)

    Goepel, M.; Hecker, U.; Krege, S.; Rübben, H.; Michel, M. C.

    1999-01-01

    BACKGROUND: We wanted to test whether phytotherapeutic agents used in the treatment of lower urinary tract symptoms have alpha1-adrenoceptor antagonistic properties in vitro. METHODS: Preparations of beta-sitosterol and extracts of stinging nettle, medicinal pumpkin, and saw palmetto were obtained

  13. Characterization of postsynaptic alpha-adrenoceptors in rat aortic strips and portal veins.

    Science.gov (United States)

    Digges, K. G.; Summers, R. J.

    1983-01-01

    Postsynaptic alpha-adrenoceptors in rat isolated aortic strips and portal veins have been examined using a number of agonist and antagonist drugs which have varying selectivity for alpha 1- and alpha 2-adrenoceptors. In both tissues (-)-noradrenaline [-)-NA), (-)-adrenaline [-) Adr) (-)-alpha-methyl noradrenaline [-)-alpha-Me-NA) and (-)-phenylephrine [-)-PE) were full agonists, while clonidine, oxymetazoline and (2-(2,6-dichlorophenyl)-5,6-dihydroimidazo(2,1,b) thiazole (44,549) were partial agonists. Guanfacine was a full agonist in aortic strips but only a partial agonist in portal veins. In aortic strips, pA2 values for prazosin and yohimbine were not significantly different using (-)-NA, (-)-PE or guanfacine as the agonist, suggesting a single population of alpha-adrenoceptors. The order of potency of the antagonists, prazosin = 2-(beta-(4-hydroxyphenyl)-ethylaminomethyl)-tetralone (BE2254) greater than phentolamine greater than yohimbine greater than rauwolscine, is indicative of an alpha 1-type of receptor. In portal veins, the order of potency of the antagonists was prazosin greater than BE2254 greater than phentolamine greater than yohimbine greater than rauwolscine, again indicating an alpha 1-type of receptor. The mean pA2 value for yohimbine was not significantly different in either tissue. However, mean pA2 values for prazosin, BE-2254 and phentolamine were approximately one order of magnitude lower in portal veins than in aortic strips, suggesting that the receptors in the two tissues may not be identical. PMID:6140044

  14. Alpha 1-adrenoceptor subtype affinities of drugs for the treatment of prostatic hypertrophy. Evidence for heterogeneity of chloroethylclonidine-resistant rat renal alpha 1-adrenoceptor

    NARCIS (Netherlands)

    Michel, M. C.; Büscher, R.; Kerker, J.; Kraneis, H.; Erdbrügger, W.; Brodde, O. E.

    1993-01-01

    We have used radioligand binding and inositol phosphate accumulation studies to determine the affinity at mixed alpha 1A- and alpha 1B-adrenoceptors (rat cerebral cortex and kidney), alpha 1A-adrenoceptors (rat cerebral cortex and kidney following inactivation of alpha 1B-adrenoceptors by

  15. Selectivity of the imidazoline alpha-adrenoceptor agonists (oxymetazoline and cirazoline) for human cloned alpha 1-adrenoceptor subtypes.

    Science.gov (United States)

    Horie, K.; Obika, K.; Foglar, R.; Tsujimoto, G.

    1995-01-01

    1. To investigate the structure-activity relationships of alpha-adrenoceptor agonists for the alpha 1-adrenoceptor subtypes, we have compared the imidazoline class of compounds, oxymetazoline and cirazoline, with the phenethylamine, noradrenaline, in their affinities and also in their intrinsic activities in Chinese hamster ovary (CHO) cells stably expressing the cloned human alpha 1-adrenoceptor subtypes (alpha 1a-, alpha 1b-, and alpha 1d-subtypes). 2. Radioligand binding studies with [125I]-HEAT showed that cirazoline and oxymetazoline had higher affinities at alpha 1a-subtype than at alpha 1b- and alpha 1d-subtypes, while noradrenaline had higher affinity at the alpha 1d-subtype than at alpha 1a- and alpha 1b-subtypes. 3. In functional studies, cirazoline caused transients of cytosolic Ca2+ concentrations ([Ca2+]i response) in a concentration-dependent manner and developed a maximal response similar to that to noradrenaline in CHO cells expressing the alpha 1a-subtype, while it acted as a partial agonist at alpha 1b- and alpha 1d-adrenoceptors. Oxymetazoline, on the other hand, was a weak agonist at alpha 1a-adrenoceptors, and has no intrinsic activity at the other subtypes. 4. Using the phenoxybenzamine inactivation method, the relationships between receptor occupancy and noradrenaline-induced [Ca2+]i response for alpha 1a- and alpha 1d-subtypes were found to be linear, whereas it was moderately hyperbolic for the alpha 1b-subtype, indicating the absence of receptor reserves in CHO cells expressing alpha 1a- and alpha 1d-subtypes while there exists a small receptor reserve for CHO cells expressing the alpha 1b-subtype.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8564227

  16. Alpha-adrenoceptor agonistic activity of oxymetazoline and xylometazoline.

    Science.gov (United States)

    Haenisch, Britta; Walstab, Jutta; Herberhold, Stephan; Bootz, Friedrich; Tschaikin, Marion; Ramseger, René; Bönisch, Heinz

    2010-12-01

    Oxymetazoline and xylometazoline are both used as nasal mucosa decongesting α-adrenoceptor agonists during a common cold. However, it is largely unknown which of the six α-adrenoceptor subtypes are actually present in human nasal mucosa, which are activated by the two alpha-adrenoceptor agonists and to what extent. Therefore, mRNA expression in human nasal mucosa of the six α-adrenoceptor subtypes was studied. Furthermore, the affinity and potency of the imidazolines oxymetazoline and xylometazoline at these α-adrenoceptor subtypes were examined in transfected HEK293 cells. The rank order of mRNA levels of α-adrenoceptor subtypes in human nasal mucosa was: α(2A) > α(1A) ≥ α(2B) > α(1D) ≥ α(2C) > α(1B) . Oxymetazoline and xylometazoline exhibited in radioligand competition studies higher affinities than the catecholamines adrenaline and noradrenaline at most α-adrenoceptor subtypes. Compared to xylometazoline, oxymetazoline exhibited a significantly higher affinity at α(1A) - but a lower affinity at α(2B) -adrenoceptors. In functional studies in which adrenoceptor-mediated Ca(2+) signals were measured, both, oxymetazoline and xylometazoline behaved at α(2B) -adrenoceptors as full agonists but oxymetazoline was significantly more potent than xylometazoline. Furthermore, oxymetazoline was also a partial agonist at α(1A) -adrenoceptors; however, its potency was relatively low and it was much lower than its affinity. The higher potency at α(2B) -adrenoceptors, i.e. at receptors highly expressed at the mRNA level in human nasal mucosa, could eventually explain why in nasal decongestants oxymetazoline can be used in lower concentrations than xylometazoline.

  17. Does treatment with beta-adrenoceptor antagonists in vivo alter human adenylate cyclase responsiveness in vitro?

    NARCIS (Netherlands)

    Michel, M. C.; Klüppel, M.; Philipp, T.; Brodde, O. E.

    1991-01-01

    1. Treatment with beta-adrenoceptor antagonists in vivo can alter adenylate cyclase responsiveness in the human heart. We have determined the effects of treatment with four different beta-adrenoceptor antagonists in vivo on the responsiveness of lymphocyte and platelet adenylate cyclase in vitro in

  18. Inhibition of K+ permeability diminishes alpha 2-adrenoceptor mediated effects on norepinephrine release

    International Nuclear Information System (INIS)

    Zimanyi, I.; Folly, G.; Vizi, E.S.

    1988-01-01

    The effect of two different potassium channel blockers, 4-aminopyridine (4-AP) and quinine, on the alpha 2-adrenoceptor mediated modulation of norepinephrine (NE) release was investigated. Pairs of mouse vasa deferentia were loaded with 3 H-norepinephrine ( 3 H-NE), superfused continuously, and stimulated electrically. 4-AP (5.3 x 10(-4) M), and quinine (10(-5) M) enhanced the stimulation-evoked release of tritium significantly. The electrically induced release of radioactivity was reduced by alpha 2-adrenoceptor agonists (1-NE and xylazine) and enhanced by the alpha 2-adrenoceptor antagonist yohimbine. Both effects were affected markedly by 4-AP or quinine: the depressant action of 1-NA and xylazine was partially antagonized and the facilitatory effect of yohimbine was completely abolished during the blockade of the potassium channels. It is suggested that the blockade of the potassium permeability counteracts negative feedback modulation; therefore, it seems likely that the stimulation of alpha 2-adrenoceptors leads to an enhanced potassium permeability and hyperpolarization of varicose axon terminals

  19. Effects of alpha-adrenoceptor and of combined sympathetic and parasympathetic blockade on cardiac performance and vascular resistance

    DEFF Research Database (Denmark)

    Kelbaek, H; Frandsen, Henrik Lund; Hilsted, J

    1992-01-01

    1. Cardiac performance and vascular resistance was studied in seven healthy men by radionuclide cardiography and venous plethysmography before and after alpha-adrenoceptor blockade with phentolamine and after combined alpha-adrenoceptor, beta-adrenoceptor (propranolol) and parasympathetic (atropine...

  20. Evidence that two stereochemically different alpha-2 adrenoceptors modulate norepinephrine release in rat cerebral cortex

    Energy Technology Data Exchange (ETDEWEB)

    Harsing, L.G. Jr.; Vizi, E.S. (Institute of Experimental Medicine, Budapest (Hungary))

    1991-01-01

    Cerebral cortex slices from the rat were loaded with (3H)norepinephrine ((3H)NE) and superfused in order to measure the release of radioactivity at rest and in response to electrical stimulation. The (-)-isomer and the (+)-isomer of CH-38083 (7,8-(methylenedioxy)-14- alpha-hydroxyalloberbane HCl), a selective alpha-2-adrenoceptor antagonist with an alloberbane skeleton, increased the electrically induced release of (3H)NE in a concentration-dependent manner, and a similar effect was observed with racemic CH-38083 and idazoxan. The stereoisomers of CH-38083 applied in a concentration range of 10(-8) to 10(-6) mol/l were equipotent in facilitating stimulation-evoked (3H)NE release: concentrations needed to enhance tritium outflow by 50% were 1.3 X 10(-7) mol/l for (-)-CH-38083 and 1.4 X 10(-7) mol/l for (+)-CH-38083. Exogenous NE decreased the electrically stimulated release of (3H)NE, and the stereoisomers of CH-38083 antagonized this inhibition with different potencies: the dissociation constant (KB) values for (-)-isomer and for (+)-isomer of CH-38083 were 14.29 and 97.18 nmol/l. These data indicate that presynaptic alpha-2 adrenoceptors that are available for NE released from axon terminals do not show stereospecificity toward enantiomers of CH-38083, whereas those that are occupied by exogenous NE are much more sensitive toward (-)-CH-38083. The alpha-1 adrenoceptor antagonist prazosin also differentiated between the alpha-2 adrenoceptor subtypes: prazosin (10(-6) mol/l) did not alter the increase of electrically induced (3H)NE release evoked by (-)- and (+)-CH-38083; however, in its presence, the stereoisomers of CH-38083 failed to antagonize the inhibitory effect of exogenous NE on its own release.

  1. Effects of tamsulosin metabolites at alpha-1 adrenoceptor subtypes

    NARCIS (Netherlands)

    Taguchi, K.; Saitoh, M.; Sato, S.; Asano, M.; Michel, M. C.

    1997-01-01

    We have investigated the affinity and selectivity of tamsulosin and its metabolites, M1, M2, M3, M4 and AM1, at the tissue and the cloned alpha-1 adrenoceptor subtypes in the radioligand binding and the functional studies. In the radioligand binding studies, the compounds competed for [3H]prazosin

  2. Alpha-1 Adrenoceptor Hyperresponsiveness in Three Neuropathic Pain States: Complex Regional Pain Syndrome 1, Diabetic Peripheral Neuropathic Pain and Central Pain States Following Spinal Cord Injury

    Directory of Open Access Journals (Sweden)

    Robert W Teasell

    2004-01-01

    Full Text Available The pathophysiology of the pain associated with complex regional pain syndrome, spinal cord injury and diabetic peripheral neuropathy is not known. The pain of complex regional pain syndrome has often been attributed to abnormal sympathetic nervous system activity based on the presence of vasomotor instability and a frequently reported positive response, albeit a temporary response, to sympathetic blockade. In contrast, the pain below the level of spinal cord injury and diabetic peripheral neuropathy are generally seen as deafferentation phenomena. Each of these pain states has been associated with abnormal sympathetic nervous system function and increased peripheral alpha-1 adrenoceptor activity. This increased responsiveness may be a consequence of alpha-1 adrenoceptor postsynaptic hypersensitivity, or alpha-2 adrenoceptor presynaptic dysfunction with diminished noradrenaline reuptake, increased concentrations of noradrenaline in the synaptic cleft and increased stimulation of otherwise normal alpha-1 adrenoceptors. Plausible mechanisms based on animal research by which alpha-1 adrenoceptor hyperresponsiveness can lead to chronic neuropathic-like pain have been reported. This raises the intriguing possibility that sympathetic nervous system dysfunction may be an important factor in the generation of pain in many neuropathic pain states. Although results to date have been mixed, there may be a greater role for new drugs which target peripheral alpha-2 adrenoceptors (agonists or alpha-1 adrenoceptors (antagonists.

  3. Effects of alpha-adrenoceptor and of combined sympathetic and parasympathetic blockade on cardiac performance and vascular resistance

    DEFF Research Database (Denmark)

    Kelbaek, H; Frandsen, Henrik Lund; Hilsted, J

    1992-01-01

    1. Cardiac performance and vascular resistance was studied in seven healthy men by radionuclide cardiography and venous plethysmography before and after alpha-adrenoceptor blockade with phentolamine and after combined alpha-adrenoceptor, beta-adrenoceptor (propranolol) and parasympathetic (atropine......) blockade. 2. During alpha-adrenoceptor blockade heart rate and cardiac output increased considerably and left ventricular ejection fraction increased because of increased contractility. Systemic vascular resistance fell both during alpha-adrenoceptor blockade alone and during combined blockade...

  4. DYSFUNCTIONAL PRESYNAPTIC ALPHA-2-ADRENOCEPTORS EXPOSE FACILITATORY BETA-2-ADRENOCEPTORS IN THE VASCULATURE OF SPONTANEOUSLY HYPERTENSIVE RATS

    NARCIS (Netherlands)

    REMIE, R; VANROSSUM, JXM; COPPES, RP; ZAAGSMA, J

    1992-01-01

    Previous studies on spontaneously hypertensive rats (SHR) have yielded inconsistent information about functional aberrations of the presynaptic alpha(2)- and beta(2)-adrenoceptor-mediated modulation of sympathetic neurotransmitter release. In the present investigation we studied the capacity of

  5. Alpha 1A and alpha 1B-adrenoceptors enhance inositol phosphate generation in rat renal cortex

    NARCIS (Netherlands)

    Michel, M. C.; Büscher, R.; Philipp, T.; Brodde, O. E.

    1993-01-01

    We have studied the role of alpha 1A- and alpha 1B-adrenoceptors in noradrenaline- and methoxamine-stimulated inositol phosphate accumulation in rat renal cortical slices. [3H]Prazosin binding studies with and without inactivation of alpha 1B-adrenoceptors by chloroethylclonidine treatment suggested

  6. Comparison of alpha 1A- and alpha 1B-adrenoceptor coupling to inositol phosphate formation in rat kidney

    NARCIS (Netherlands)

    Büscher, R.; Erdbrügger, W.; Philipp, T.; Brodde, O. E.; Michel, M. C.

    1994-01-01

    We have compared the coupling mechanisms of rat renal alpha 1A- and alpha 1B-like adrenoceptors to inositol phosphate formation. The experiments were performed in parallel in native renal tissue preparations and in those where alpha 1B-adrenoceptors had been inactivated by treatment with 10 mumol/l

  7. The pharmacological rationale for combining muscarinic receptor antagonists and beta-adrenoceptor agonists in the treatment of airway and bladder disease

    NARCIS (Netherlands)

    Dale, Philippa R.; Cernecka, Hana; Schmidt, Martina; Dowling, Mark R.; Charlton, Steven J.; Pieper, Michael P.; Michel, Martin C.

    Muscarinic receptor antagonists and beta-adrenoceptor agonists are used in the treatment of obstructive airway disease and overactive bladder syndrome. Here we review the pharmacological rationale for their combination. Muscarinic receptors and beta-adrenoceptors are physiological antagonists for

  8. Comparison of guinea-pig, bovine and rat alpha 1-adrenoceptor subtypes

    NARCIS (Netherlands)

    Büscher, R.; Heeks, C.; Taguchi, K.; Michel, M. C.

    1996-01-01

    1. To elucidate a possible role of species differences in the classification of alpha 1-adrenoceptor subtypes, we have characterized the alpha 1-adrenoceptors in guinea-pig spleen, kidney and cerebral cortex and in bovine cerebral cortex using concentration-dependent alkylation by

  9. Characterization of alpha-adrenoceptor subtypes in the corpus cavernosum of patients undergoing sex change surgery

    NARCIS (Netherlands)

    Goepel, M.; Krege, S.; Price, D. T.; Michelotti, G. A.; Schwinn, D. A.; Michel, M. C.

    1999-01-01

    PURPOSE: To characterize the subtypes of alpha1- and alpha2-adrenoceptors in the human corpus cavernosum from patients undergoing sex change surgery. MATERIALS AND METHODS: Saturation and competition radioligand binding studies were performed for characterization at the protein level.

  10. METABOLIC AND HORMONAL RESPONSES TO ADRENOCEPTOR ANTAGONISTS IN 48-HOUR-STARVED EXERCISING RATS

    NARCIS (Netherlands)

    BENTHEM, L; VANDERLEEST, J; STEFFENS, AB; ZIJLSTRA, WG

    1995-01-01

    The influence of 48 hours of starvation on sympathoadrenal regulation of nutrient utilization was investigated in rats. To assess the role of alpha- and beta-adrenoceptors, rats were studied during alpha- and beta-blockade. Energy metabolism was measured using indirect calorimetry before, during,

  11. Imidazoline2 (I2) receptor- and alpha2-adrenoceptor-mediated modulation of hypothalamic-pituitary-adrenal axis activity in control and acute restraint stressed rats.

    Science.gov (United States)

    Finn, David P; Hudson, Alan L; Kinoshita, Hiroshi; Coventry, Toni L; Jessop, David S; Nutt, David J; Harbuz, Michael S

    2004-03-01

    Central noradrenaline regulates the activity of the hypothalamic-pituitary-adrenal (HPA) axis and the neuroendocrine response to stress. alpha2-adrenoceptors and imidazoline2 (I2) receptors modulate the activity of the central noradrenergic system. The present set of experiments investigated the role of alpha2-adrenoceptors and I2 receptors in the regulation of HPA axis activity under basal conditions and during exposure to the acute psychological stress of restraint. Three separate experiments were carried out in which rats were given an i.p. injection of either saline vehicle, the combined alpha2-adrenoceptor antagonist and I2 receptor ligand idazoxan (10 mg/kg), the selective I2 receptor ligand BU224 (2.5 or 10 mg/kg) or the selective alpha2-adrenoceptor antagonist RX821002 (2.5 mg/kg) with or without restraint stress. Drugs were administered immediately prior to restraint of 60 min duration. Blood was sampled pre-injection, 30, 60 and 240 min post-injection and plasma corticosterone was measured by radioimmunoassay. In experiment 1, idazoxan increased plasma corticosterone levels in naive animals and potentiated the corticosterone response to acute restraint stress. In experiment 2, BU224 administration increased plasma corticosterone levels in a dose-related manner in naive rats. The results of experiment 3 indicated that RX821002 also elevated plasma corticosterone levels in naive rats, however, only BU224 potentiated the corticosterone response to restraint stress. These studies suggest that both alpha2-adrenoceptors and I2 receptors play a role in modulating basal HPA axis activity and that I2 receptors may play a more important role than alpha2-adrenoceptors in modulating the HPA axis response to the acute psychological stress of restraint.

  12. Effects of α-adrenoceptor antagonists on ABCG2/BCRP-mediated resistance and transport.

    Science.gov (United States)

    Takara, Kohji; Yamamoto, Kazuhiro; Matsubara, Mika; Minegaki, Tetsuya; Takahashi, Minoru; Yokoyama, Teruyoshi; Okumura, Katsuhiko

    2012-01-01

    Acquired resistance of cancer cells to various chemotherapeutic agents is known as multidrug resistance, and remains a critical factor in the success of cancer treatment. It is necessary to develop the inhibitors for multidrug resistance. The aim of this study was to examine the effects of eight α-adrenoceptor antagonists on ABCG2/BCRP-mediated resistance and transport. Previously established HeLa/SN100 cells, which overexpress ABCG2/BCRP but not ABCB1/MDR1, were used. The effects of the antagonists on sensitivity to mitoxantrone and the transport activity of Hoehst33342, both substrates for ABCG2/BCRP, were evaluated using the WST-1 assay and cellular kinetics, respectively. ABCG2/BCRP mRNA expression and the cell cycle were also examined by real-time RT-PCR and flow cytometry, respectively. Sensitivity to mitoxantrone was reversed by the α-adrenoceptor antagonists in a concentration-dependent manner, although such effects were also found in the parental HeLa cells. Levels of ABCG2/BCRP mRNA expression were not influenced by the antagonists. The transport activity of Hoechst33342 was decreased by doxazosin and prazosin, but unaffected by the other antagonists. In addition, doxazosin and prazosin increased the proportion of S phase cells in the cultures treated with mitoxantrone, whereas the other α-adrenoceptor antagonists increased the percentage of cells in G(2)/M phase. These findings suggested that doxazosin and prazosin reversed resistance mainly by inhibiting ABCG2/BCRP-mediated transport, but the others affected sensitivity to mitoxantrone via a different mechanism.

  13. Effects of α-adrenoceptor antagonists on ABCG2/BCRP-mediated resistance and transport.

    Directory of Open Access Journals (Sweden)

    Kohji Takara

    Full Text Available Acquired resistance of cancer cells to various chemotherapeutic agents is known as multidrug resistance, and remains a critical factor in the success of cancer treatment. It is necessary to develop the inhibitors for multidrug resistance. The aim of this study was to examine the effects of eight α-adrenoceptor antagonists on ABCG2/BCRP-mediated resistance and transport. Previously established HeLa/SN100 cells, which overexpress ABCG2/BCRP but not ABCB1/MDR1, were used. The effects of the antagonists on sensitivity to mitoxantrone and the transport activity of Hoehst33342, both substrates for ABCG2/BCRP, were evaluated using the WST-1 assay and cellular kinetics, respectively. ABCG2/BCRP mRNA expression and the cell cycle were also examined by real-time RT-PCR and flow cytometry, respectively. Sensitivity to mitoxantrone was reversed by the α-adrenoceptor antagonists in a concentration-dependent manner, although such effects were also found in the parental HeLa cells. Levels of ABCG2/BCRP mRNA expression were not influenced by the antagonists. The transport activity of Hoechst33342 was decreased by doxazosin and prazosin, but unaffected by the other antagonists. In addition, doxazosin and prazosin increased the proportion of S phase cells in the cultures treated with mitoxantrone, whereas the other α-adrenoceptor antagonists increased the percentage of cells in G(2/M phase. These findings suggested that doxazosin and prazosin reversed resistance mainly by inhibiting ABCG2/BCRP-mediated transport, but the others affected sensitivity to mitoxantrone via a different mechanism.

  14. Subtype-selective modulation of human beta 1- and beta 2-adrenoceptor function by beta-adrenoceptor agonists and antagonists

    NARCIS (Netherlands)

    Brodde, O. E.; Daul, A.; Michel, M. C.

    1990-01-01

    In healthy volunteers a 14-day treatment with the selective beta 1-adrenoceptor agonist xamoterol (2 x 200 mg/day) desensitized beta 1-adrenoceptor-mediated physiological effects, but did not affect beta 2-adrenoceptor-mediated effects; in contrast, a 9-day treatment with the selective beta

  15. alpha2 adrenoceptors are involved in the regulation of the gripping-induced immobility episodes in taiep rats.

    Science.gov (United States)

    Eguibar, José R; Cortés, Ma Del Carmen; Valencia, Jaime; Arias-Montaño, José A

    2006-10-01

    In 1989 Holmgren et al. (Holmgren et al. 1989 Lab Anim Sci 39:226-228) described a new mutant rat that developed a progressive motor disturbance during its lifespan. The syndrome is characterized by a tremor in the hind limbs followed by ataxia, episodes of tonic immobility, epilepsy, and paralysis. The acronym of these symptoms (taiep) became the name of this autosomic, recessive mutant rat. The taiep rats are neurological mutant animals with a hypomyelination, followed by a progressive demyelination process. At 7-8 months of age, taiep rats develop immobility episodes (IEs) characterized by a cortical desynchronization, associated with the theta rhythm in the hippocampus and changes of the nucal electromyogram (EMG), whose pattern is like rapid-eye-movement (REM) sleep. These rats also show an altered sleep pattern with an equal REM sleep distribution. This study analyzed therole of alpha(2) adrenoceptors in the expression of gripping-induced IEs in 8-month-old male taiep rats. The alpha(2) adrenoceptor agonists clonidine and xylacine increased the frequency of gripping-induced IEs whereas the alpha(2) antagonists yohimbine and idazoxandecreased or prevented such episodes. These findings correlate with the pharmacological observations in narcoleptic dogs and humans in which alpha(2) adrenergic mechanisms are involved in the modulation of cataplexy. Unexpectedly, the repetitive administration of clonidine resulted in jumping behavior, indicative of phasic activation of extensor musculature. Taken together, our results show that alpha(2) adrenoceptors are involved in the modulation in gripping-induced IEs and after the administration of several doses of clonidine produced phasic motor activation.

  16. Comparison of cloned and pharmacologically defined rat tissue alpha 1-adrenoceptor subtypes

    NARCIS (Netherlands)

    Michel, M. C.; Insel, P. A.

    1994-01-01

    Multiple alpha 1-adrenoceptor subtypes have been defined by pharmacological and receptor cloning techniques, but the precise alignment of cloned and pharmacologically-defined subtypes is still unclear. We have compared the affinities of 8 subtype-selective compounds at three cloned alpha

  17. Alpha- and beta-adrenoceptors in hypertension. II. Platelet alpha 2- and lymphocyte beta 2-adrenoceptors in children of parents with essential hypertension. A model for the pathogenesis of the genetically determined hypertension

    NARCIS (Netherlands)

    Michel, M. C.; Galal, O.; Stoermer, J.; Bock, K. D.; Brodde, O. E.

    1989-01-01

    To study whether changes in alpha- and beta-adrenoceptors in human essential hypertension (EHT) might be genetically determined, we assessed platelet alpha 2- and lymphocyte beta 2-adrenoceptor density in 48 normotensive children of normotensive parents (NT) and in 41 normotensive children with one

  18. Radiosynthesis and evaluation of new α1-adrenoceptor antagonists as PET radioligands for brain imaging

    International Nuclear Information System (INIS)

    Airaksinen, Anu J.; Finnema, Sjoerd J.; Balle, Thomas; Varnäs, Katarina; Bang-Andersen, Benny; Gulyás, Balázs; Farde, Lars; Halldin, Christer

    2013-01-01

    Introduction: Evaluation of the α 1 -adrenoceptors in relation to brain pathophysiology and drug treatment has been hindered by lack of α 1 -adrenoceptor specific radioligands with sufficient brain exposure. Our aim was to develop an α 1 -adrenoceptor specific PET radioligand for brain imaging. Methods: Two sertindole analogues 1-(4-fluorophenyl)-5-(1-methyl-1H-1,2,4-triazol-3-yl)-3-(1-[ 11 C] methylpiperidin-4-yl)-1H-indole [ 11 C]3 and 1-(4-fluorophenyl)-3-(1-[ 11 C]methylpiperidin-4-yl)-5-(pyrimidin-5-yl) -1H-indole ([ 11 C]Lu AA27122) [ 11 C]4 were synthesized and evaluated as α 1 -adrenoceptor PET radioligands in cynomolgus monkey. Compounds 3 and 4 were selected due to their promising in vitro preclinical profile; high affinity and selectivity for the α 1 -adrenoceptor, favourable blood brain barrier permeability rates in Caco-2 monolayers and promising brain tissue/plasma ratio, assessed by equilibrium dialysis of free fraction in plasma and brain homogenate. Results: Compounds [ 11 C]3 and [ 11 C]4 were synthesized from their desmethyl piperidine precursors with high specific radioactivity (> 370 GBq/μmol) using [ 11 C]methyl iodide. The 1,2,4-triazole analogue [ 11 C]3 exhibited poor brain uptake, but the corresponding pyrimidyl analogue [ 11 C]4 exhibited high brain exposure and binding in α 1 -adrenoceptor rich brain regions. However, the binding could not be inhibited by pretreatment with prazosin (0.1 mg/kg and 0.3 mg/kg). The results were extended by autoradiography of [ 11 C]4 binding in human brain sections and competition with antagonists from different structural families, revealing that only a minor portion of the observed binding of [ 11 C]4 in brain was α 1 -adrenoceptor specific. Conclusion: Though [ 11 C]3 and [ 11 C]4 proved not suitable as PET radioligands, the study provided further understanding of structural features influencing brain exposure of the chemical class of compounds related to the antipsychotic drug sertindole. It

  19. Alpha2B-adrenoceptors couple to Ca2+ increase in both endogenous and recombinant expression systems

    NARCIS (Netherlands)

    Holmberg, C. I.; Kukkonen, J. P.; Bischoff, A.; Näsman, J.; Courtney, M. J.; Michel, M. C.; Akerman, K. E.

    1998-01-01

    The ability of cloned human alpha2B-adrenoceptors heterologously expressed in Sf9 cells and endogenous alpha2B-adrenoceptors in NG 108-15 neuroblastoma x glioma cells to couple to increase of intracellular Ca2+ was studied. Ca2+ increases in NG 108-15 cells were detectable but slight, whereas those

  20. Functional characterization of neuronal pre and postsynaptic alpha 2-adrenoceptor subtypes in guinea-pig submucosal plexus.

    Science.gov (United States)

    Shen, K. Z.; Barajas-Lopez, C.; Surprenant, A.

    1990-01-01

    1. The alpha 2-adrenoceptors on cell bodies of submucosal neurones, on presynaptic cholinergic nerve terminals innervating submucosal neurones, and on presynaptic sympathetic fibres innervating submucosal arterioles were characterized in functional studies by use of subtype selective ligands. 2. Both membrane hyperpolarization and presynaptic inhibition of nicotinic excitatory synaptic potentials (e.p.s.ps) produced by UK 14304 were similarly antagonized by idazoxan, yohimbine. SKF 104078, WB 4101 and ARC-239. Antagonism was competitive and dissociation equilibrium constants were the same for both effects. 3. Vasoconstriction of submucosal arterioles in response to stimulation of the sympathetic nerves (20 Hz for 2 s) was inhibited by UK 14304 and clonidine: concentrations producing half-maximum responses were 6 nm and 10 nM respectively. Idazoxan, yohimbine, WB 4101 and SKF 104078 antagonized this action, with dissociation constants similar to those for antagonism of the postsynaptic membrane hyperpolarization and presynaptic inhibition of nicotinic e.p.s.ps. 4. Oxymetazoline was a partial agonist when membrane hyperpolarization or presynaptic inhibition of nicotinic e.p.s.ps were measured but a full agonist when presynaptic inhibition of sympathetically-mediated arteriolar vasoconstriction was measured. As an agonist, oxymetazoline produced half maximum responses at 80-120 nM; the dissociation constant for oxymetazoline as an antagonist was 130 nM. 5. Neither prazosin nor chlorpromazine (up to 30 microM) altered any of the three responses to alpha 2-adrenoceptor agonists. 6. It is concluded that alpha 2-adrenoceptors present on submucosal neuronal cell bodies, on presynaptic cholinergic nerve terminals and on presynaptic sympathetic nerve terminals are the alpha 2A subtype. However, functional characterization of this subtype differs from that provided by ligand binding studies. PMID:1982232

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

    Directory of Open Access Journals (Sweden)

    Mallory Batty

    2016-08-01

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

  2. Thyroid hormone modulates inotropic responses, alpha-adrenoceptor density and catecholamine concentrations in the rat heart

    NARCIS (Netherlands)

    Zwaveling, J.; Batink, H. D.; de Jong, J.; Winkler Prins, E. A.; Pfaffendorf, M.; van Zwieten, P. A.

    1996-01-01

    We investigated the influence of hyper- and hypothyroidism on basal parameters of isolated perfused hearts of rats. In addition the effects of different extracellular calcium concentrations ([Ca2+]o), the calcium entry promoter Bay K8644 and the alpha 1-adrenoceptor agonist methoxamine were

  3. Enhanced inotropic responsiveness to alpha 1-adrenoceptor stimulation in isolated working hearts from diabetic rats

    NARCIS (Netherlands)

    Heijnis, J. B.; van Zwieten, P. A.

    1992-01-01

    We compared the inotropic responsiveness to the alpha 1-adrenoceptor agonist cirazoline and the calcium entry promoter Bay K 8644 in isolated working hearts from streptozotocin (STZ) diabetic rats and age-matched controls. The maximal rate of contraction and cardiac output (CO) were unaffected by

  4. Differential labeling of platelet alpha 2 adrenoceptors by 3H dihydroergocryptine and 3H yohimbine in patients with myeloproliferative disorders

    International Nuclear Information System (INIS)

    Swart, S.S.; Wood, J.K.; Barnett, D.B.

    1985-01-01

    Platelet alpha adrenoceptor status was examined using the radioligands 3 H-yohimbine ( 3 H-YOH) and 3 H-dihydroergocryptine ( 3 H-DHE) in 14 patients with myeloproliferative disorder (MPD) and 10 normal controls. Platelets from normal controls and MPD patients sensitive to adrenaline induced aggregation exhibited approximately 50% more binding sites identified by 3 H-DHE than 3 H-YOH, whereas MPD platelets insensitive to adrenaline showed selective loss of these extra 3 H-DHE sites. In functional studies after 30 minutes preincubation with the unlabelled antagonists, DHE was more potent than YOH at inhibiting adrenaline induced aggregation in normal platelets. In addition, the affinity constant for DHE was virtually identical in binding and functional experiments, whereas for YOH the affinity constant for binding was approximately 10 fold more potent than that for aggregation. These results suggest that the alpha adrenoceptor binding site on human platelets labelled by 3 H-DHE may be of more functional relevance than that labelled by 3 H-YOH alone

  5. Stimulation of prostaglandin synthesis in rat cerebral cortex via a beta-adrenoceptor.

    Science.gov (United States)

    Hillier, K; Templeton, W W

    1982-01-01

    1. Synthesis of prostaglandin E2 (PGE2) and prostaglandin F2 alpha (PGF2 alpha) in rat cerebral cortex slices is increased by beta-adrenoceptor agonists. 2. Phenylephrine, an alpha-adrenoceptor agonist, has no effect while oxymetazoline increased PGF2 alpha only. 3. PG synthesis stimulation by noradrenaline (NA) was prevented by beta- but not by alpha-adrenoceptor antagonists. 4. Dibutyryl cyclic AMP and inhibitors of cyclic nucleotide phosphodiesterase augment PG synthesis. 5. Stimulation of PG synthesis in rat cerebral cortex by NA is mediated by a beta-adrenoceptor.

  6. Tesofensine, a novel triple monoamine reuptake inhibitor, induces appetite suppression by indirect stimulation of alpha1 adrenoceptor and dopamine D1 receptor pathways in the diet-induced obese rat

    DEFF Research Database (Denmark)

    Axel, Anne Marie Dixen; Mikkelsen, Jens D; Hansen, Henrik H

    2010-01-01

    in the DIO rat. Tesofensine (0.5-3.0 mg/kg, s.c.) induced a dose-dependent and marked decline in food intake with an ED(50) of 1.3 mg/kg. The hypophagic response of tesofensine (1.5 mg/kg, s.c.) was almost completely reversed by co-administration of prazosin (1.0 mg/kg, alpha(1) adrenoceptor antagonist......) and partially antagonized by co-administration of SCH23390 (0.03 mg/kg, DA D(1) receptor antagonist). In contrast, tesofensine-induced hypophagia was not affected by RX821002 (0.3 mg/kg, alpha(2) adrenoceptor antagonist), haloperidol (0.03 mg/kg, D(2) receptor antagonist), NGB2904 (0.1 mg/kg, D(3) receptor...... antagonist), or ritanserin (0.03 mg/kg, 5-HT(2A/C) receptor antagonist). Hence, the mechanism underlying the suppression of feeding by tesofensine in the obese rat is dependent on the drug's ability to indirectly stimulate alpha(1) adrenoceptor and DA D(1) receptor function....

  7. Quantification of in vivo binding of [[sup 3]H]RX 821002 in rat brain: evaluation as a radioligand for central [alpha][sub 2]-adrenoceptors

    Energy Technology Data Exchange (ETDEWEB)

    Hume, S.P.; Lammertsma, A.A.; Opacka-Juffry, J.; Ahier, R.G.; Myers, R., Cremer, J.E.; Pike, V.W. (Hammersmith Hospital, London (United Kingdom). M.R.C. Cyclotron Unit); Hudson, A.L.; Nutt, D.J. (Bristol Univ. (United Kingdom). Reckitt and Coleman Psychopharmacology Unit)

    1992-11-01

    On the basis of its established in vitro characteristics, [[sup 3]H]RX 821002 was evaluated in rats as an in vivo radioligand for central [alpha][sub 2]-adrenoceptors. Estimates for in vivo binding potential, obtained by compartmental analyses of time-radioactivity data, ranged between 1.9 for hypothalamus and 0.2 for cerebellum, with a regional distribution in brain which was similar to that observed in vitro. Selectivity and specificity of the signal were checked by predosing with either the [alpha][sub 2]-antagonists, idazoxan or yohimbine, the [alpha][sub 2]-agonist, clonidine, or the [alpha][sub 1]-antagonist, prazosin. Pretreatment of the rats with the selective neurotoxin, DSP-4, had no significant effect on [[sup 3]H]RX 821002 binding, suggesting that the majority of labelled sites were situated post-junctionally. The studies indicate that [[sup 3]H]RX 821002 can be used experimentally as an in vivo marker for central [alpha][sub 2]-adrenoceptors. The size and rate of expression of the specific signal encourage the development and assessment of [[sup 11]C]RX 821002 for clinical PET studies. (author).

  8. Chemical stimulation of the ST36 acupoint reduces both formalin-induced nociceptive behaviors and spinal astrocyte activation via spinal alpha-2 adrenoceptors.

    Science.gov (United States)

    Kang, Suk-Yun; Kim, Chi-Young; Roh, Dae-Hyun; Yoon, Seo-Yeon; Park, Ji-Ho; Lee, Hye-Jung; Beitz, Alvin J; Lee, Jang-Hern

    2011-11-25

    Spinal astrocytes have emerged as important mechanistic contributors to pathological and chronic pain. Recently, we have demonstrated that injection of diluted bee venom (DBV) into the Zusanli (ST36) acupoint produces a potent anti-nociceptive effect via the activation of spinal alpha-2 adrenoceptors. However, it is unclear if this anti-nociceptive effect is associated with alterations in spinal astrocytes. Thus, the present study was designed to determine: (1) whether DBV's anti-nociceptive effect in the formalin test involves suppression of spinal astrocyte activation; (2) whether DBV-induced astrocyte inhibition is mediated by spinal alpha-2 adrenoceptors; and (3) whether this glial modulation is potentiated by intrathecal administration of the glial metabolic inhibitor, fluorocitrate (FC) in combination with DBV injection. DBV was injected directly into the ST36 acupoint, and spinal expression of the astrocytic marker, glial fibrillary acidic protein (GFAP), was assessed together with effects on formalin-induced nociception. DBV treatment reduced pain responses in the late phase of the formalin test and significantly blocked the formalin-evoked increase in spinal GFAP expression. These effects of DBV were prevented by intrathecal pretreatment with selective alpha-2A and alpha-2C adrenoceptor antagonists. Moreover, low dose intrathecal injection of FC in conjunction with low dose DBV injection into the ST36 acupoint synergistically suppressed pain responses and GFAP expression. These results demonstrate that DBV stimulation of the ST36 acupoint inhibits the formalin-induced activation of spinal astrocytes and nociceptive behaviors in this inflammatory pain model and this inhibition is associated with the activation of spinal alpha-2 adrenoceptors. Copyright © 2011 Elsevier Inc. All rights reserved.

  9. Enhanced bradycardia induced by beta-adrenoceptor antagonists in rats pretreated with isoniazid.

    Science.gov (United States)

    Vidrio, H; Sánchez-Salvatori, M A; Medina, M

    1998-12-01

    High doses of isoniazid increase hypotension induced by vasodilators and change the accompanying reflex tachycardia to bradycardia, an interaction attributed to decreased synthesis of brain gamma-aminobutyric acid (GABA). In the present study, the possible enhancement by isoniazid of bradycardia induced by beta-adrenoceptor antagonists was determined in rats anaesthetised with chloralose-urethane. Isoniazid significantly increased bradycardia after propranolol, pindolol, labetalol and atenolol, as well as after clonidine, but not after hexamethonium or carbachol. Enhancement was not observed in rats pretreated with methylatropine or previously vagotomised. These results are compatible with interference by isoniazid with GABAergic inhibition of cardiac parasympathetic tone. Such interference could be exerted centrally, possibly at the nucleus ambiguus, or peripherally at the sinus node.

  10. Cingulate Alpha-2A Adrenoceptors Mediate the Effects of Clonidine on Spontaneous Pain Induced by Peripheral Nerve Injury

    Directory of Open Access Journals (Sweden)

    Yong-Jie Wang

    2017-09-01

    Full Text Available The anterior cingulate cortex (ACC is an important brain area for the regulation of neuropathic pain. The α2A adrenoceptor is a good target for pain management. However, the role of cingulate α2A adrenoceptors in the regulation of neuropathic pain has been less studied. In this study, we investigated the involvement of cingulate α2A adrenoceptors in the regulation of neuropathic pain at different time points after peripheral nerve injury in mice. The application of clonidine, either systemically (0.5 mg/kg intraperitoneally or specifically to the ACC, increased paw withdrawal thresholds (PWTs and induced conditioned place preference (CPP at day 7 after nerve injury, suggesting that cingulate α2 adrenoceptors are involved in the regulation of pain-like behaviors. Quantitative real-time PCR data showed that α2A adrenoceptors are the dominant α2 adrenoceptors in the ACC. Furthermore, the expression of cingulate α2A adrenoceptors was increased at day 3 and day 7 after nerve injury, but decreased at day 14, while no change was detected in the concentration of adrenaline or noradrenaline. BRL-44408 maleate, a selective antagonist of α2A adrenoceptors, was microinfused into the ACC. This blocking of cingulate α2A adrenoceptors activity abolished the CPP induced by clonidine (0.5 mg/kg intraperitoneally but not the effects on PWTs at day 7. However, clonidine applied systemically or specifically to the ACC at day 14 increased the PWTs but failed to induce CPP; this negative effect was reversed by the overexpression of cingulate α2A adrenoceptors. These results suggest that cingulate α2A adrenoceptors are necessary for the analgesic effects of clonidine on spontaneous pain.

  11. Estrogen increases smooth muscle expression of alpha2C-adrenoceptors and cold-induced constriction of cutaneous arteries.

    Science.gov (United States)

    Eid, A H; Maiti, K; Mitra, S; Chotani, M A; Flavahan, S; Bailey, S R; Thompson-Torgerson, C S; Flavahan, N A

    2007-09-01

    Raynaud's phenomenon, which is characterized by intense cold-induced constriction of cutaneous arteries, is more common in women compared with men. Cold-induced constriction is mediated in part by enhanced activity of alpha(2C)-adrenoceptors (alpha(2C)-ARs) located on vascular smooth muscle cells (VSMs). Experiments were therefore performed to determine whether 17beta-estradiol regulates alpha(2C)-AR expression and function in cutaneous VSMs. 17beta-Estradiol (0.01-10 nmol/l) increased expression of the alpha(2C)-AR protein and the activity of the alpha(2C)-AR gene promoter in human cultured dermal VSMs, which was assessed following transient transfection of the cells with a promoter-reporter construct. The effect of 17beta-estradiol was associated with increased accumulation of cAMP and activation of the cAMP-responsive Rap2 GTP-binding protein. Transient transfection of VSMs with a dominant-negative mutant of Rap2 inhibited the 17beta-estradiol-induced activation of the alpha(2C)-AR gene promoter, whereas a constitutively active mutant of Rap2 increased alpha(2C)-AR promoter activity. The effects of 17beta-estradiol were inhibited by the estrogen receptor (ER) antagonist, ICI-182780 (1 micromol/l), and were mimicked by a cell-impermeable form of the hormone (estrogen:BSA) or by the selective ER-alpha receptor agonist 4,4',4'''-(4-propyl-[(1)H]-pyrazole-1,3,5-triyl)tris-phenol (PPT; 10 nmol/l) or the selective ER-beta receptor agonist 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN; 10 nmol/l). Therefore, 17beta-estradiol increased expression of alpha(2C)-ARs by interacting with cell surface receptors to cause a cAMP/Rap2-dependent increase in alpha(2C)-AR transcription. In mouse tail arteries, 17beta-estradiol (10 nmol/l) increased alpha(2C)-AR expression and selectively increased the cold-induced amplification of alpha(2)-AR constriction, which is mediated by alpha(2C)-ARs. An estrogen-dependent increase in expression of cold-sensitive alpha(2C)-ARs may contribute

  12. Radiolabelling and PET brain imaging of the a1-adrenoceptor antagonist Lu AE43936

    DEFF Research Database (Denmark)

    Risgaard, Rune; Ettrup, Anders Janusz; Balle, Thomas

    2013-01-01

    Cerebral α₁-adrenoceptors are a common target for many antipsychotic drugs. Thus, access to positron emission tomography (PET) brain imaging of α₁-adrenoceptors could make important contributions to the understanding of psychotic disorders as well as to the pharmacokinetics and occupancy of drugs...

  13. Presynaptic alpha2-adrenoceptor-mediated modulation of adenosine 5' triphosphate and noradrenaline corelease: differences in canine mesenteric artery and vein.

    Science.gov (United States)

    Bobalova, J; Mutafova-Yambolieva, V N

    2001-02-01

    1. The modulatory effects of agonists and antagonists of prejunctional alpha2-adrenoceptors on the electrical field stimulation (EFS, 0.3 ms, 12 V)-induced release of endogenous noradrenaline (NA) and the cotransmitter adenosine 5' triphosphate (ATP) were measured in endothelium-denuded segments of canine inferior mesenteric artery and compared with effects in mesenteric vein. The overflow of NA and ATP was evoked by long-duration (2 min) EFS at low frequency (4 Hz) and high frequency (16 Hz) of stimulation and was analysed using HPLC techniques with electrochemical detection and fluorescence detection, respectively. 2. The EFS-evoked overflow of both NA and ATP was significantly reduced by tetrodotoxin (1 microM) and guanethidine (10 microM) in the artery and vein. Desipramine (10 microM), a blocker of neuronal uptake of NA, increased the EFS (4 and 16 Hz)-evoked overflow of NA in both artery and vein. EFS-evoked overflow of NA in vein exceeded the NA overflow in artery at both 4 and 16 Hz in control preparations as well as in the presence of desipramine. However, the EFS-evoked overflow of ATP was equal in the artery and vein. 3. Stimulation of alpha2-adrenoceptors with clonidine (0.1 microM) and oxymethazoline (0.3 microM) reduced the EFS evoked overflow of NA in both artery and vein at 4 Hz, whereas the NA overflow at 16 Hz remained unchanged in both blood vessels. The overflow of ATP as well as of ADP (and hence ATP:ADP ratio) was unaffected by the alpha2-adrenoceptor agonists in the artery and vein. 4. In artery, blockade of alpha2-adrenoceptors with yohimbine at a concentration of 0.1 microM caused no effect on the NA overflow neither at 4 Hz nor at 16 Hz of EFS. Yohimbine at a concentration of 1 microM increased the overflow of NA at 4 Hz but not 16 Hz of EFS. In vein, however, yohimbine (0.1 and 1 microM) increased NA overflow at both 4 and 16 Hz of stimulation. Idazoxan (1 microM) increased the NA overflow in artery only at 4 Hz, whereas in vein idazoxan

  14. Effects of alpha-adrenoceptor and of combined sympathetic and parasympathetic blockade on cardiac performance and vascular resistance

    DEFF Research Database (Denmark)

    Kelbaek, H; Frandsen, Henrik Lund; Hilsted, J

    1992-01-01

    . The increase in calf blood flow was of the same magnitude after combined blockade and after alpha-adrenoceptor blockade alone, and was considerably higher than the fall in systemic vascular resistance. Plasma catecholamine concentrations increased after phentolamine, but the changes were blunted when...... propranolol and atropine were added. 3. These results indicate that peripheral vasoconstriction especially that exerted by alpha-adrenoceptor nervous tone in skeletal muscle restricts left ventricular emptying of the intact heart. During pharmacologic blockade of the sympathetic and parasympathetic nervous...

  15. Up-regulation of α1a and α1d-adrenoceptors in the prostate by administration of subtype selective α1-adrenoceptor antagonist tamsulosin in patients with benign prostatic hyperplasia.

    Science.gov (United States)

    Kojima, Yoshiyuki; Sasaki, Shoichi; Kubota, Yasue; Imura, Makoto; Oda, Nobuyuki; Kiniwa, Mamoru; Hayashi, Yutaro; Kohri, Kenjiro

    2011-10-01

    We examined the change in α(1)-adrenoceptor subtype expression in the prostate due to chronic tamsulosin administration in a benign prostatic hyperplasia rat model and in patients. We measured α(1)-adrenoceptor subtype expression after tamsulosin administration in the prostate of the benign prostatic hyperplasia rat model using TaqMan® reverse transcriptase-polymerase chain reaction. We also measured expression before and after 12-week tamsulosin treatment in the prostate of patients with benign prostatic hyperplasia. We examined the correlation between the change in α(1)-adrenoceptor expression due to tamsulosin treatment and acute urinary retention during long-term followup. The expression of α(1a) and α(1d)-adrenoceptors was significantly increased in dose dependent fashion by tamsulosin in the benign prostatic hyperplasia rat model. Median mRNA expression of subtypes α(1a) and α(1d)-adrenoceptors was 1.4 (IQR 0.6, 3.0) and 1.7 × 1,000 copies per 1 ng β-actin (IQR 0.9, 2.4) before treatment, and 6.0 (IQR 2.0, 8.0) and 2.2 × 1,000 copies per 1 ng β-actin (IQR 1.7, 3.6), respectively, after treatment. The expression of α(1a) and α(1d)-adrenoceptors significantly increased after tamsulosin treatment (p <0.01 and <0.05, respectively). This increase was observed in 10 patients in whom acute urinary retention did not develop during long-term followup but not in 4 in whom acute urinary tract retention developed. Tamsulosin up-regulated α(1a) and α(1d)-adrenoceptors, suggesting that it has clinical selectivity for α(1a) and α(1d)-adrenoceptors. Up-regulation of α(1)-adrenoceptors subtype expression is considered an adaptive response to chronic tamsulosin administration. The difference in the response to α(1)-adrenoceptors antagonists among patients may contribute to the diversity in the long-term efficiency of α(1)-adrenoceptor antagonists. Copyright © 2011 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All

  16. Studies on concurrent alpha- and beta-adrenoceptor blocking action of S-596 (arotinolol).

    Science.gov (United States)

    Takekoshi, N; Murakami, E; Matsui, S; Murakami, H; Emoto, J; Hashimoto, A

    1983-11-01

    The effects of a therapeutic dose of oral S-596 upon the cardiovascular response to intravenous isoproterenol and noradrenaline were studied in 2 hypertensive and 4 normotensive subjects in order to evaluate the drug's mode of action. After oral administration of S-596, mean blood pressure rose slightly and the heart rate decreased. In addition, cardiac output decreased considerably and total peripheral resistance increased. However pulmonary arterial end-diastolic pressure and right atrial pressure were not affected by S-596 administration. Before S-596, intravenous isoproterenol increased both heart rate and pulse pressure in a dose-dependent manner. Similarly, intravenous noradrenaline increased both systolic and diastolic pressures. Following 15 mg of S-596, the effects of isoproterenol were antagonized such that the cumulative log-dose-response curves of the mean isoproterenol-induced increases in heart rate and reductions in diastolic pressure were shifted in parallel to the right. At the same time, the mean noradrenaline-induced increases in blood pressure were also antagonized in a competitive manner. The mean ratio of alpha- and beta-components was calculated as: (formula: see text) From this result it can be suggested that the alpha-adrenoceptor blockade potency of this drug is approximately one-eight of its beta-adrenoceptor blockade potency.

  17. Chronic beta-adrenoceptor antagonist treatment modulates human cardiac and vascular beta-adrenoceptor density in a subtype-selective fashion

    NARCIS (Netherlands)

    Brodde, O. E.; Michel, M. C.; Wang, X. L.; Zerkowski, H. R.

    1988-01-01

    In order to study the regulation of human cardiac and vascular beta-adrenoceptors as induced by beta-adrenoceptor antagonism we determined beta-adrenoceptor density and subtype distribution in right atria, saphenous veins and lymphocytes from 60 patients undergoing coronary artery bypass grafting;

  18. Possible alpha-adrenoceptor blocking activity of arotinolol (S-596), a new beta-adrenoceptor blocking agent in isolated dog coronary artery.

    Science.gov (United States)

    Sakanashi, M; Miyamoto, Y; Ito, H; Takeo, S; Noguchi, K; Higa, T

    1984-01-01

    Effects of arotinolol on dog coronary arteries were investigated in vitro. In distal portions of left circumflex coronary arteries contracted with 3 X 10(-2)M KCl, norephinephrine relaxed the strips in a concentration-dependent fashion. Propranolol (10(-6)M) converted the norepinephrine-induced relaxations to contractions, and arotinolol (10(-6)-10(-5)M) inhibited the relaxations induced by norepinephrine in a concentration-dependent manner. In proximal portions of the strips after potassium-contracture, norephinephrine produced concentration-dependent contractions which were augmented by propranolol (10(-6)M) and inhibited by arotinolol (10(-6)-10(-5)M). These results suggest that arotinolol has an alpha-adrenoceptor blocking activity in addition to a beta-adrenoceptor blocking action in dog coronary arteries.

  19. Different roles of alpha2-adrenoceptor subtypes in non-pregnant and late-pregnant uterine contractility in vitro in the rat.

    Science.gov (United States)

    Gáspár, Róbert; Gál, Adrienn; Gálik, Márta; Ducza, Eszter; Minorics, Renáta; Kolarovszki-Sipiczki, Zoltán; Klukovits, Anna; Falkay, George

    2007-10-01

    The roles of the alpha2-adrenoceptor (alpha2-AR) subtypes (alpha2A-, alpha2B- and alpha2C-AR) in uterine contractility have not been investigated. The aims of this study were to identify these receptors in the non-pregnant and the late-pregnant rat myometrium and to determine their roles in contractions. We found that the myometrial alpha2-AR subtypes are involved differently in the control of late-pregnant contractions, while they have no influence on the contractions of the non-pregnant myometrium. The myometrial expressions of the alpha2-AR subtypes were determined by RT-PCR and Western blotting techniques. In vitro contractions were stimulated with noradrenaline, and its effect was modified with the selective antagonists BRL 44408 (alpha2A), ARC 239 (alpha2B/C) and spiroxatrine (alpha2C). cAMP production was followed by noradrenaline stimulation in the presence of isobutylmethylxanthine and forskolin, and alterations induced in it by the antagonists were determined with an Enzyme Immunoassay Kit. The most effective antagonist was tested on labour-induced uteri in vitro. All the alpha2-AR subtypes were identified in both non-pregnant and pregnant uteri. Noradrenaline was not able to contract the non-pregnant tissue in the presence of propranolol and doxazosin, while its contracting effect in the pregnant uteri was enhanced by BRL 44408, spiroxatrine and the combination BRL 44408+spiroxatrine. ARC 239 exerted a strong inhibitory effect on noradrenaline-stimulated contractions. The increasing and the decreasing effects of the compounds were confirmed by the changes in the intracellular cAMP levels. The effect of ARC 239 on the labour-induced myometrium was similar to that on the 22-day-pregnant myometrium. The stimulation of alpha2-ARs does not evoke contractions in the non-pregnant uterus. The alpha2A- and alpha2C-ARs mediate decreases, while the alpha2B-AR mediates an increase in the contractions in the 22-day-pregnant myometrium. These differences may offer new

  20. Heterogeneity of alpha 2-adrenoceptors in rat cortex but not human platelets can be defined by 8-OH-DPAT, RU 24969 and methysergide.

    Science.gov (United States)

    Brown, C. M.; MacKinnon, A. C.; McGrath, J. C.; Spedding, M.; Kilpatrick, A. T.

    1990-01-01

    1. Saturation experiments indicated that [3H]-yohimbine binding was specific, saturable and labelled a single population of sites in rat cerebral cortex (Kd 5.3 +/- 0.9 nM, Bmax 121 +/- 10 fmol mg-1 protein) and human platelets (Kd 0.7 +/- 0.1 nM, Bmax 152 +/- 10 fmol mg-1 protein). 2. The alpha 2-adrenoceptor antagonists, yohimbine, rauwolscine, WY 26703, idazoxan and BDF 6143 displaced [3H]-yohimbine binding to each tissue in a simple manner, with high affinity and Hill slopes close to unity. 3. The alpha 1-adrenoceptor agonist, oxymetazoline and the antagonist prazosin inhibited the binding of [3H]-yohimbine to rat in a complex manner consistent with an interaction at more than one site. However, indoramin and WB 4101 only appeared to interact with one site. In contrast, in human platelets, all antagonists gave rise to monophasic displacement curves with Hill slopes close to unity suggesting a single site of interaction. 4. The 5-hydroxytryptamine (5-HT) receptor ligands, 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), RU 24969, and methysergide inhibited the binding of [3H]-yohimbine to rat cortex with high and low affinity, consistent with an interaction with two populations of binding sites. However, inhibition of [3H]-yohimbine binding to human platelets suggested a single site of interaction. The low affinity of 5-HT, 5-carboxyamidotryptamine (5-CT) and dipropyl-5-CT indicated that [3H]-yohimbine was not labelling a 5-HT1-like site in rat cortex.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1970497

  1. The effect of some α-adrenoceptor antagonists on spontaneous myogenic activity in the rat portal vein and the putative involvement of ATP-sensitive K+channels

    NARCIS (Netherlands)

    Schwietert, R.; Wilhelm, D.; Wilffert, B.; Van Zwieten, P.A.

    1992-01-01

    In the present study we showed that the α-adrenoceptor antagonists phentolamine, yohimbine, prazosin, corynanthine and idazoxan, when cumulatively applied in high concentrations (1-100 μmol/l), can increase spontaneous myogenic activity in the rat portal vein. 5-Methyl-urapidil and rauwolscine were

  2. Lack of effect of chronic calcium antagonist treatment on beta 1- and beta 2-adrenoceptors in right atria from patients with or without heart failure

    NARCIS (Netherlands)

    Brodde, O. E.; Hundhausen, H. J.; Zerkowski, H. R.; Michel, M. C.

    1992-01-01

    1. We studied the effects of chronic calcium antagonist (calcium entry blocker, CEB; nifedipine, verapamil, diltiazem) treatment on beta-adrenoceptor density (assessed by (-)-[125I]-iodocyanopindolol [ICYP] binding) and subtype distribution in right atria from 65 patients without apparent heart

  3. Alpha- and beta-adrenoceptor cross-talk in the regulation of glycogenolysis in dog and guinea-pig liver.

    Science.gov (United States)

    Maroto, R; Calvo, S; Sancho, C; Esquerro, E

    1992-01-01

    The dog liver glycogenolytic response to isoprenaline (EC50 = 3 x 10(-9) M) was selectively blocked by 10(-5) M of practolol, but not by butoxamine. In contrast, the glycogenolytic response to isoprenaline (EC50 = 3 x 10(-7) M) was inhibited by 10(-6) M of butoxamine, but not by practolol, in the guinea-pig liver. This suggests that, in the dog, the isoprenaline response is dominated by beta 1-adrenoceptors, while in the guinea-pig beta 2-receptors control such response. Glucose release from dog and guinea-pig liver slices was also stimulated by amidephrine (EC50 = 10(-6) M in the dog and 4 x 10(-5) M in the guinea-pig). Both prazosin and yohimbine blocked this response. The effectiveness of clonidine as a glucose-mobilizing agent could only be established in the dog liver. Prazosin showed greater activity than yohimbine in antagonizing the response to both agonists. In the dog, low concentrations of alpha-adrenoceptor agonists (10(-9) M), that failed to modify the basal glucose release per se, selectively depressed the isoprenaline response. Prazosin, but not yohimbine, reversed this inhibitory effect. It is concluded that glucose release from the dog liver is regulated by two opposite mechanisms that seem to be associated to alpha 1-adrenoceptors (inhibitory) and to beta 1-adrenoceptors (stimulatory).

  4. Role of alpha1- and alpha2-adrenoceptors in the regulation of locomotion and spatial behavior in the active place avoidance task: A dose–response study

    Czech Academy of Sciences Publication Activity Database

    Stuchlík, Aleš; Valeš, Karel

    2008-01-01

    Roč. 433, č. 3 (2008), s. 235-240 ISSN 0304-3940 R&D Projects: GA ČR(CZ) GA309/07/0341; GA MZd(CZ) NR9178; GA MŠk(CZ) 1M0517; GA MŠk(CZ) LC554 Institutional research plan: CEZ:AV0Z50110509 Keywords : alpha1- alpha2 adrenoceptors * avoidance * memory Subject RIV: FH - Neurology Impact factor: 2.200, year: 2008

  5. Partial to complete antagonism by putative antagonists at the wild-type α2C-adrenoceptor based on kinetic analyses of agonist : antagonist interactions

    Science.gov (United States)

    Pauwels, Petrus J; Colpaert, Francis C

    2000-01-01

    Activation of the recombinant human α2C-adrenoceptor (α2C AR) by (−)-adrenaline in CHO-K1 cells transiently co-expressing a chimeric Gαq/i1 protein induced a rapid, transient Ca2+ response with a high-magnitude followed by a low-magnitude phase which continued throughout the recorded time period (15 min). Activation of the α2C AR by various α2 AR agonists revealed the following rank order of high-magnitude Ca2+ response [Emax (%) versus 10 μM (−)-adrenaline]: UK 14304 (102±4)=talipexole (101±3)=(−)-adrenaline (100)=d-medetomidine (98±1)>oxymetazoline (81±4)⋍clonidine (75±5). The methoxy- (RX 821002) and ethoxy-derivatives (RX 811059) of idazoxan and the dexefaroxan analogue atipamezole were fully effective as antagonists of both the high- and the low-magnitude Ca2+ response. However, though acting as full antagonists of the high-magnitude response, the further putative α2 AR antagonists idazoxan (27%), SKF 86466 (29%) and dexefaroxan (59%) reversed the low-magnitude response only partially. In conclusion, kinetic analyses of agonist : antagonist interactions at the α2C AR demonstrate a wide spectrum of partial to complete antagonism of the low-magnitude Ca2+ response for structurally related α2 AR ligands. PMID:11090111

  6. Dopamine D2 receptors and alpha1-adrenoceptors synergistically modulate locomotion and behavior of rats in a place avoidance task

    Czech Academy of Sciences Publication Activity Database

    Stuchlík, Aleš; Petrásek, Tomáš; Valeš, Karel

    2008-01-01

    Roč. 189, č. 1 (2008), s. 139-144 ISSN 0166-4328 R&D Projects: GA ČR(CZ) GA309/07/0341; GA MZd(CZ) NR9178; GA MŠk(CZ) 1M0517; GA MŠk(CZ) LC554 Institutional research plan: CEZ:AV0Z50110509 Keywords : D2 receptors * alpha1-adrenoceptors * behavior Subject RIV: FH - Neurology Impact factor: 3.171, year: 2008

  7. Membrane potential responses to ionophoretically applied alpha-adrenoceptor agonists in the mouse anococcygeus muscle.

    Science.gov (United States)

    Large, W. A.

    1983-01-01

    1 Noradrenaline phenylephrine, naphazoline and oxymetazoline were applied by ionophoresis to the mouse anococcygeus muscle and the membrane potential was recorded with an intracellular microelectrode. 2 The ionophoretic application of noradrenaline and phenylephrine produced dose-related depolarizations in 96% of the cells tested; in contrast, naphazoline and oxymetazoline depolarized only 62% of the cells although contraction was always seen. 3 The depolarizations produced by all four drugs had similar characteristics in shape and time course except that the latency of responses induced by the imidazoline-related drugs was significantly longer than the value obtained with the phenylethanolamines. This discrepancy was not due to the difference in susceptibility to neuronal uptake of the two groups of drugs. 4 The time to peak depolarization for naphazoline and oxymetazoline was longer than that for noradrenaline and phenylephrine but was not sufficient to account for the considerably slower contraction produced by the former drugs. 5 At room temperature the sensitivity of the mouse anococcygeus to ionophoretically applied naphazoline and oxymetazoline was significantly lower than that to noradrenaline and phenylephrine but at 35 degrees C the sensitivity was similar for all drugs. 6 These results suggest that there might be two subclasses of alpha 1-adrenoceptor in the mouse anococcygeus; stimulation of one type leads to depolarization and contraction and activation of the other class produces contraction with no change in membrane potential. PMID:6135476

  8. Alpha-1 adrenoceptors in brown adipose tissue of lean and ob/ob mice

    International Nuclear Information System (INIS)

    Behrens-Zaror, G.; Himms-Hagen, J.

    1986-01-01

    Obese (ob/ob) mice have a low capacity to increase thyroxine 5'-deiodinase (T4 5'-D) in brown adipose tissue (BAT) when exposed to cold. This effect is mediated by alpha-1 (A-1) adrenoceptors. The authors objective was to find out whether BAT of the ob/ob mouse has normal A-1 receptors. Saturation analysis of binding of [3H]-WB4101 at 0.05 nM to 10 μM to crude membrane preparations (100,000 g pellets from Polytron homogenates) using the LIGAND program of Munson and Rodbard, showed two populations of binding sites in BAT of lean (+/+, 11-15 wk old) mice. Acute exposure (12 h, 14 0 C) or acclimation to cold (3 wk, 14 0 C) did not alter affinity or concentration of sites. Displacement with yohimbine and prazosin indicated binding of WB4101 to A-1 receptors. Very young (5 wk) lean (+/.) and obese mice had similar affinity constants (lean 0.13 +/- 0.043 and 34.2 +/- 14.9; obese, 0.12 +/- 0.028 and 20.9 +/- 5.48 nM) and concentrations (lean 22.4 +/- 3.8 and 647 +/- 137; obese, 28.6 +/- 4.6 and 547 +/- 105 fmol/mg protein) of sites. Old (1 yr) mice had high affinity sites similar to those in younger animals (KD lean 0.19 +/- 0.028, obese, 0.25 +/- 0.075; Bmax lean, 60.2 +/- 12.1; obese, 63.1 +/- 13.5 fmol/mg protein). The authors conclude that the ob/ob mouse has normal high affinity A-1 receptors in BAT. Anomalous properties of low affinity binding in old ob/ob mice could not be characterized because of high nonspecific binding. BAT of the ob/ob mouse does not lack A-1 receptors but may have a post-receptor alteration in the A-1 adrenoceptor-mediated response

  9. Clinical experience in Europe with uroselective alpha1-antagonists.

    Science.gov (United States)

    Debruyne, F M; Van der Poel, H G

    1999-01-01

    alpha1-Adrenoreceptors are thought to be involved in prostate smooth muscle contractions and could hence play a role in the dynamic component of intravesical obstruction associated with symptomatic BPH. Consequently, since the mid-eighties alpha receptor blocking agents have been used for the treatment of BPH. Non-selective alpha blockers are usually associated with systemic side-effects which resulted in an exclusion or withdrawal of many patients from this form of treatment. With the availability of so-called uroselective alpha blockers the management picture has changed since it was anticipated that these compounds cause lesser side-effects with at least the same, or even better, efficacy. Comparative clinical studies are essential for determining the eventual advantages of the uroselective alpha1-antagonists and a large number of such studies have been performed worldwide studying the various available compounds. European studies with terazosin showed clear superiority of the drug over the placebo while causing only limited side-effects. Various other studies using alpha-blocking agents such as doxazosin, tamsulosin and alfuzosin yielded identical results. Especially with tamsulosin and alfuzosin, the side-effects were comparable with those encountered in the placebo group. About 7% of the patients using tamsulosin experienced retrograde ejaculation in one study which did not occur in the alfuzosin studies. Important studies in Europe have also investigated the value of a combination of an alpha blocker with a 5alpha-reductase inhibitor. Comparable studies in which both alfuzosin and doxazosin were combined with the 5alpha-reductase inhibitor Proscar have shown that a combination is not superior to a blocker monotherapy and especially in the ALFIN study the results show that alfuzosin monotherapy is superior to Proscar in the management of symptomatic BPH. European studies have evaluated Quality of Life, sexuality as well as socio-economical outcome of the

  10. Regarding the unitary theory of agonist and antagonist action at presynaptic adrenoceptors.

    Science.gov (United States)

    Kalsner, S; Abdali, S A

    2001-06-01

    1. The linkage between potentiation of field stimulation-induced noradrenaline release and blockade of the presynaptic inhibitory effect of exogenous noradrenaline by a presynaptic antagonist was examined in superfused rabbit aorta preparations. 2. Rauwolscine clearly potentiated the release of noradrenaline in response to 100 pulses at 2 Hz but reduced the capacity of noradrenaline to inhibit transmitter release to a questionable extent, and then only when comparisons were made with untreated, rather then to rauwolscine-treated, controls. 3. Aortic preparations exposed for 60 min to rauwolscine followed by superfusion with antagonist-free Krebs for 60 min retained the potentiation of stimulation-induced transmitter release but no antagonism of the noradrenaline-induced inhibition could be detected at either of two noradrenaline concentrations when comparisons were made with rauwolscine treated controls. 4. Comparisons of the inhibitory effect of exogenous noradrenaline (1.8 x 10-6 M) on transmitter efflux in the presence and absence of rauwolscine pretreatment revealed that the antagonist enhanced rather than antagonized the presynaptic inhibition by noradrenaline. 5 It is concluded that the unitary hypothesis that asserts that antagonist enhancement of transmitter release and its blockade of noradrenaline induced inhibition are manifestations of a unitary event are not supportable.

  11. Evidence against the unitary hypothesis of agonist and antagonist action at presynaptic adrenoceptors.

    Science.gov (United States)

    Kalsner, S.

    1982-01-01

    1 The concept that presynaptic receptors regulate noradrenergic transmitter release via a system of inhibitory receptors mediating negative feedback relies on a supposed association between increases in stimulation-induced efflux of [3H]-noradrenaline by antagonists and blockade by them of the inhibitory effects of exogenous noradrenaline. 2 It was shown in guinea-pig ureter, that yohimbine (3 X 10(-7)M), a presumed selective presynaptic antagonist, increased transmitter efflux substantially at 1 Hz and 5 Hz with 100 pulses, purportedly representing antagonism of the inhibitory effect of locally released noradrenaline but did not reduce the inhibitory effect of exogenous noradrenaline (1.8 X 10(-6)M or 1.8 X 10(-7)M) except in one case. 3 Additionally, the inhibitory effect of oxymetazoline (1.0 X 10(-7)M or 1.0 X 10(-8)M) on stimulation-induced efflux was in no way antagonized by yohimbine (3 X 10(-7)M). 4 It is concluded that the increased efflux of [3H]-noradrenaline produced by antagonists and the decreased efflux produced by exogenous agonists may represent actions at different loci and that the hypothesis of presynaptic feedback regulatory sites is still not substantiated. PMID:6128040

  12. Effect of alpha 1-adrenoceptor blockade on maximal VO2 and endurance capacity in well-trained athletic hypertensive men.

    Science.gov (United States)

    Tomten, S E; Kjeldsen, S E; Nilsson, S; Westheim, A S

    1994-07-01

    The effect of alpha 1-adrenoceptor blockade (doxazosin, 4 mg daily) on maximal VO2 and physical endurance capacity in 16 mildly hypertensive, athletic men was investigated in a randomized, placebo-controlled, double-blind, two-period of 4 weeks, cross-over study. The maximal workload obtained during graded bicycle ergometer exercise and the corresponding maximal VO2 were reduced by 16 +/- 3 W (mean +/- SE), (P = .00003) and 3 +/- 1 mL/(kg.min) (P = .0004), respectively, on doxazosin compared with placebo. The running time on a 5000 m track increased by 43 +/- 12 sec on doxazosin (P = .04). Heart rate was unchanged during the running session. Systolic blood pressure was reduced by 9 +/- 4.1 mm Hg (P = .04) immediately after finishing 5000 m. Six subjects reported side effects from doxazosin (headache, fatigue, and leg pain). Thus, antihypertensive treatment with alpha 1-selective adrenoceptor blockade moderately, but significantly, reduces maximal O2 consumption and high intensity physical endurance capacity in mildly hypertensive athletic men. Significantly reduced systolic blood pressure and unchanged heart rate immediately after running, combined with unchanged heart rate during the race may, however, suggest a safer exercise performance.

  13. Co-release of endogenous ATP and [{sup 3}H]noradrenaline from rat hypothalamic slices: origin and modulation by {alpha}{sub 2}-adrenoceptors

    Energy Technology Data Exchange (ETDEWEB)

    Vizi, E.S. [Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest (Hungary); Lajtha, A.; Sershen, H. [Center for Neurochemistry, The N.S. Kline Institute for Psychiatric Research, Orangeburg, New York (United States); Sperlagh, B. [Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest (Hungary)

    1997-10-17

    was without effect. In contrast, neither of the {alpha}{sub 2}-antagonists significantly affected the evoked-release of ATP.In summary, we report here that endogenous ATP and [{sup 3}H]noradrenaline are co-released stimulation-dependently from superfused rat hypothalamic slices. A significant part of the release of both compounds is derived from the nerve terminals, originating from the A1 catecholaminergic cell group of brainstem nuclei. Unlike that from the peripheral sympathetic transmission, noradrenaline and {alpha}{sub 1}-adrenoceptor agonists were unable to promote the release of ATP. Conversely, parallel ATP and noradrenaline release could be induced by nicotine receptor activation, but this release does not originate from the same nerve endings. The evoked-release of [{sup 3}H]noradrenaline is inhibited by endogenous noradrenaline via {alpha}{sub 2AD} subtype of adrenoreceptors, while the release of ATP is not subject to this autoinhibitory modulation. In conclusion, our results support the view that ATP is involved in the neurotransmission in the hypothalamus, but the sources of the released ATP and noradrenaline seem to be not identical under different stimulatory and modulatory conditions. (Copyright (c) 1997 Elsevier Science B.V., Amsterdam. All rights reserved.)

  14. ALPHA-ADRENOCEPTOR REGULATION OF INOSITOL PHOSPHATES, INTERNAL CALCIUM AND MEMBRANE CURRENT IN DDT1 MF-2 SMOOTH-MUSCLE CELLS

    NARCIS (Netherlands)

    NELEMANS, A; HOITING, B; MOLLEMAN, A; DUIN, M; DENHERTOG, A

    1990-01-01

    The effect of alpha-1-adrenoceptor stimulation on inositol phosphates (InsPs), intracellular Ca2+ and membrane current was measured in vas deferens DDT1 MF-2 cells. The InsPs were analyzed after labelling the cells with [H-3]myo-inositol using high performance liquid chromatography and the internal

  15. Rapid eye movement sleep loss induces neuronal apoptosis in the rat brain by noradrenaline acting on alpha 1-adrenoceptor and by triggering mitochondrial intrinsic pathway

    Directory of Open Access Journals (Sweden)

    Bindu I Somarajan

    2016-03-01

    Full Text Available Many neurodegenerative disorders are associated with rapid eye movement sleep (REMS-loss, however the mechanism was unknown. As REMS-loss elevates noradrenaline (NA level in the brain as well as induces neuronal apoptosis and degeneration, in this study we have delineated the intracellular molecular pathway involved in REMS deprivation (REMSD associated NA-induced neuronal apoptosis. Rats were REMS deprived for 6 days by the classical flower-pot method, suitable controls were conducted and the effects on apoptosis markers evaluated. Further, the role of NA was studied by one, intraperitoneal (i.p. injection of NA-ergic alpha1-adrenoceptor antagonist prazosin (PRZ and two, by down-regulation of NA synthesis in locus coeruleus (LC neurons by local microinjection of tyrosine hydroxylase siRNA (TH-siRNA. Immunoblot estimates showed that the expressions of pro-apoptotic proteins viz. Bcl2-associated death promoter (BAD protein, apoptotic protease activating factor-1 (Apaf-1, cytochrome c, caspase9, caspase3 were elevated in the REMS-deprived rat brains, while caspase8 level remained unaffected; PRZ treatment did not allow elevation of these pro-apoptotic factors. Further, REMSD increased cytochrome c expression, which was prevented if the NA synthesis from the LC neurons was blocked by microinjection of TH-siRNA in vivo into the LC during REMSD in freely moving normal rats. Mitochondrial damage was re-confirmed by transmission electron microscopy (TEM, which showed distinctly swollen mitochondria with disintegrated cristae, chromosomal condensation and clumping along the nuclear membrane and all these changes were prevented in PRZ treated rats. Combining findings of this study along with earlier reports we propose that upon REMSD NA level increases in the brain as the LC NA-ergic REM-OFF neurons do not cease firing and TH is up-regulated in those neurons. This elevated NA acting on alpha1-adrenoceptors damages mitochondria causing release of

  16. "Ejaculatory disorders and α1-adrenoceptor antagonists therapy: clinical and experimental researches"

    Directory of Open Access Journals (Sweden)

    Lania Caterina

    2006-07-01

    Full Text Available Abstract Background It is well known that the use of the α-adrenergic receptor antagonists in the BPH therapy may induce ejaculatory disorder. A review of clinical literature shows a greater incidence of ejaculatory disorder during the use of tamsulosin compared with alfuzosin. Anejaculation has been until now referred to retrograde ejaculation due to relaxation of prostatic and bladder neck smooth muscle tone. In a recent researches was evaluated the effect of tamsulosin and alfuzosin on rat vas deferent "in vitro", concluding that tamsulosin may "cause ejaculatory dysfunction by altering the progression and emission of sperm". An abnormal increase of contraction would be the cause of ejaculatory disorder. The aim of our paper is to compare human and rat vas deferens contractile activity and to evaluate with a clinical study if tamsulosin causes retrograde ejaculation disorder. Methods We have revaluated the human and rat vas deferens contractile activity in vitro according to our experience and literature. We have also performed a clinical study on 10 patients (48–72 y affected by anejaculation. Post-coital urine was examined to search spermatozoa. Results Human and rat vas deferens activity is not comparable. Contractile activity induced by norepinephrin after tamsulosin incubation in rat prostatic vas deferens strips is similar to the contractile activity evoked by norepinephrin in human strips. Spermatozoa were found in post coital urine of 6 patients. Conclusion In our opinion the treatment with tamsulosin may induce retrograde ejaculation but not other ejaculatory disorder due to abnormal sperm progression.

  17. Aortic barodenervation up-regulates {alpha}{sub 2}-adrenoceptors in the nucleus tractus solitarius and rostral ventrolateral medulla: an autoradiographic study

    Energy Technology Data Exchange (ETDEWEB)

    Abdel-Rahman, A.A.; El-Mas, M.M. [Department of Pharmacology, School of Medicine, East Carolina, University Greenville, NC (United States)

    1997-05-12

    Earlier findings have shown that {alpha}{sub 2}-adrenoceptors in the nucleus tractus solitarius and rostral ventrolateral medulla modulate baroreflexes. The present study investigated whether attenuation of baroreflexes induced by surgical interruption of aortic baroafferents is related to an alteration of {alpha}{sub 2}-adrenoceptor binding in these regions of the brainstem. In vitro autoradiography was utilized to assess the density and binding dissociation constant (affinity) of {alpha}{sub 2}-adrenoceptors in the rostral ventrolateral medulla and in the middle and rostral portions of the nucleus tractus solitarius of aortic-barodenervated and sham-operated rats. Compared to sham operation, aortic barodenervation caused an acute rise in mean arterial pressure and heart rate and a significant reduction in baroreflex sensitivity. Two days later, mean arterial pressure and heart rate of conscious aortic-barodenervated rats subsided to sham-operated levels, whereas the baroreflex sensitivity remained significantly (P<0.05) reduced when measured by phenylephrine (0.55{+-}0.08 vs 1.26{+-}0.07 ms/mmHg) or nitroprusside (0.43{+-}0.06 vs 1.01{+-}0.09 ms/mmHg). Examination of brainstem coronal sections obtained from separate groups of rats 48 h after surgery and preincubated with [{sup 3}H]rauwolscine (0.5-16 nM) revealed that labeling of {alpha}{sub 2} binding sites was saturable and of high affinity. Scatchard analysis of the saturation isotherms obtained from the three brain areas of sham-operated rats showed an uneven distribution of {alpha}{sub 2} binding sites; the rostral nucleus tractus solitarius exhibited the highest density and lowest affinity. Aortic barodenervation caused region-dependent changes in the binding activity of {alpha}{sub 2}-adrenoceptors. These changes comprised significant (P<0.05) increases in the density of {alpha}{sub 2}-adrenoceptors in the middle nucleus tractus solitarius (436{+-}60 vs 240{+-}50 fmol/mg protein) and rostral ventrolateral

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

    Directory of Open Access Journals (Sweden)

    Sharif A Issa

    2008-07-01

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

  19. A Comparison of the Anorectic Effect and Safety of the Alpha2-Adrenoceptor Ligands Guanfacine and Yohimbine in Rats with Diet-Induced Obesity.

    Directory of Open Access Journals (Sweden)

    Magdalena Dudek

    Full Text Available The search for drugs with anorectic activity, acting within the adrenergic system has attracted the interest of researchers. Partial α2-adrenoceptor agonists might offer the potential for effective and safe treatment of obesity. We compared the effectiveness and safety of α2-adrenoceptor ligands in reducing body mass. We also analyzed if antagonist and partial agonists of α2-adrenoceptor--yohimbine and guanfacine--act similarly, and determined which course of action is connected with anorectic activity. We tested intrinsic activity and effect on the lipolysis of these compounds in cell cultures, evaluated their effect on meal size, body weight in Wistar rats with high-fat diet-induced obesity, and determined their effect on blood pressure, heart rate, lipid profile, spontaneous locomotor activity, core temperature and glucose, as well as glycerol and cortisol levels. Both guanfacine and yohimbine showed anorectic activity. Guanfacine was much more effective than yohimbine. Both significantly reduced the amount of intraperitoneal adipose tissue and had a beneficial effect on lipid profiles. Decreased response of α2A-adrenoceptors and partial stimulation of α2B-receptors seem to be responsible for the anorectic action of guanfacine. The stimulation of α1-adrenoceptors by guanfacine is responsible for cardiovascular side effects but may also be linked with improved anorexic effect. α1-adrenoceptor blockade is connected with the side effects of yohimbine, but it is also associated with the improvement of lipid profiles. Guanfacine has been approved by the Food and Drug Administration (FDA to treat hypertension and conduct disorder, but as it reduces body weight, it is worth examining its effectiveness and safety in models of obesity.

  20. Structural flexibility of the G alpha s alpha-helical domain in the beta2-adrenoceptor Gs complex

    DEFF Research Database (Denmark)

    Westfield, Gerwin H; Rasmussen, Søren Gøgsig Faarup; Su, Min

    2011-01-01

    The active-state complex between an agonist-bound receptor and a guanine nucleotide-free G protein represents the fundamental signaling assembly for the majority of hormone and neurotransmitter signaling. We applied single-particle electron microscopy (EM) analysis to examine the architecture...... of agonist-occupied β(2)-adrenoceptor (β(2)AR) in complex with the heterotrimeric G protein Gs (Gαsβγ). EM 2D averages and 3D reconstructions of the detergent-solubilized complex reveal an overall architecture that is in very good agreement with the crystal structure of the active-state ternary complex...

  1. Effects of the selective β1-adrenoceptor antagonist, nebivolol, on cardiovascular parameters in the pithed normotensive rat

    NARCIS (Netherlands)

    Schneider, J.; Fruh, C.; Wilffert, B.; Peters, Thies

    1990-01-01

    In the pithed rat we investigated the cardiovascular properties of d,l-nebivolol and its enantiomers. We used the increase in heart rate elicited by (-)-adrenaline and (-)-noradrenaline as a model for studying β1-adrenoceptors. A leftward shift of the logarithmic dose-pressor response curve of

  2. Accumbal noradrenaline that contributes to the alpha-adrenoceptor-mediated release of dopamine from reserpine-sensitive storage vesicles in the nucleus accumbens is derived from alpha-methyl-para-tyrosine-sensitive pools.

    NARCIS (Netherlands)

    Verheij, M.M.M.; Cools, A.R.

    2009-01-01

    Alpha-adrenoceptors in the nucleus accumbens are known to inhibit accumbal dopamine release from reserpine-sensitive pools. The aim of this study was to test our previously reported hypothesis that accumbal noradrenaline that controls the dopamine release from these storage vesicles is derived from

  3. The alpha(2)-adrenoceptor agonist dexmedetomidine suppresses memory formation only at doses attenuating the perception of sensory input.

    Science.gov (United States)

    van Oostrom, Hugo; Stienen, Peter J; Doornenbal, Arie; Hellebrekers, Ludo J

    2010-03-10

    It was investigated whether continuous rate infusion of the alpha(2)-adrenoceptor agonist dexmedetomidine can suppress memory formation by mechanisms other than reducing perception of sensory input in a fear-conditioning paradigm. Different groups of rats infused with either saline or dexmedetomidine (2.0, 4.0 or 10.0microg/kg bolus, followed by 2.0, 4.0 or 10.0microg/kg/h continuous rate infusion respectively), were subjected to a somatosensory-evoked potential (SEP) fear-conditioning paradigm. This paradigm combined the pairing of an innoxious conditioned stimulus (CS) and a noxious unconditioned stimulus (US), of which the latter was used to generate the SEPs (training phase).The following day, the perception of the US during the training phase was assessed by presenting the CS only and subsequently scoring the resulting duration of freezing behaviour (testing phase). Freezing behaviour was reduced only in those groups which demonstrated reduced SEPs. Based on these findings, it is concluded that dexmedetomidine suppresses memory formation only at doses reducing central nervous system activity in response to sensory input. Copyright (c) 2009 Elsevier B.V. All rights reserved.

  4. Bindings of 3H-prazosin and 3H-yohimbine to alpha adrenoceptors in the guinea-pig stomach

    International Nuclear Information System (INIS)

    Taniguchi, T.; Nishikawa, H.

    1988-01-01

    Alpha adrenoceptor subtypes have been investigated by radioligand binding study in guinea-pig stomach using 3 H-prazosin and 3 H-yohimbine. The specific 3 H-prazosin binding to guinea-pig stomach was saturable and of high affinity with a Bmax of 33 fmol/mg protein. Specific 3 H-yohimbine binding to the tissue was also saturable and of high affinity with a Bmax of 150 fmol/mg protein. Adrenergic drugs competed for 3 H-prazosin binding in order of prazosin > phentolamine > methoxamine > norepinephrine > clonidine > epinephrine > yohimbine. These drugs competed for 3 H-yohimbine binding in order of yohimbine > phentolamine > clonidine > epinephrine > norepinephrine > prazosin > methoxamine. They also examined whether dopamine receptors exist in guinea-pig stomach, using radioligand binding study. Specific binding of 3 H-spiperone, 3 H-apomorphine, 3 H-dopamine and 3 H-domperidone was not detectable in the stomach. Dopaminergic drugs such as dopamine, haloperidol, domperidone and sulpiride competed for 3 H-prazosin binding in order of haloperidol > domperidone > dopamine > sulpiride. Metoclopramide, sulpiride and dopamine competed for 3 H-yohimbine binding in order of metoclopramide > sulpiride > dopamine

  5. Noradrenergic lesion of the locus coeruleus increases the firing activity of the medial prefrontal cortex pyramidal neurons and the role of alpha2-adrenoceptors in normal and medial forebrain bundle lesioned rats.

    Science.gov (United States)

    Wang, Yong; Zhang, Qiao Jun; Liu, Jian; Ali, Umar; Gui, Zhen Hua; Hui, Yan Ping; Wang, Tao; Chen, Li; Li, Qiang

    2010-04-09

    Degeneration of noradrenergic neurons in the locus coeruleus (LC) and dysfunction of the prefrontal cortex were regarded as playing a specific role in the occurrence of non-motor symptoms in Parkinson's disease. The present study examined the spontaneous firing rate and firing pattern of medial prefrontal cortex (mPFC) pyramidal neurons, and effects of alpha(2)-adrenoceptor agonist UK-14,304 and antagonist yohimbine on the neuronal activity in rats with 6-hydroxydopamine lesions of the LC, medial forebrain bundle (MFB) and with combined MFB and LC lesions. The firing rate of mPFC pyramidal neurons in rats with lesions of the LC and with combine LC and MFB lesions is significantly higher than that of normal and MFB-lesioned rats and the firing pattern of these neurons in rats with lesions of the LC and with combine LC and MFB lesions also changed significantly towards more regular compared with normal and MFB-lesioned rats. The local administration of UK-14,304 in the mPFC inhibited the firing activity of the pyramidal neurons in normal rats and rats with lesions of the LC, MFB and with combined LC and MFB lesions, while yohimbine increased the firing activity of the pyramidal neurons. These results indicate that the lesions of the LC lead to hyperactivity of mPFC pyramidal neurons in normal and MFB-lesioned rats, and the postsynaptic alpha(2)-adrenoceptors may partially mediate the inhibitory effects of LC-noradrenergic system on the firing activity of pyramidal neurons in the mPFC, suggesting that LC-noradrenergic system plays an important role in the functional disorders of mPFC in Parkinson's disease. Copyright (c) 2010 Elsevier B.V. All rights reserved.

  6. Alpha-2A Adrenoceptor Agonist Guanfacine Restores Diuretic Efficiency in Experimental Cirrhotic Ascites: Comparison with Clonidine.

    Directory of Open Access Journals (Sweden)

    Giovanni Sansoè

    Full Text Available In human cirrhosis, adrenergic hyperfunction causes proximal tubular fluid retention and contributes to diuretic-resistant ascites, and clonidine, a sympatholytic drug, improves natriuresis in difficult-to-treat ascites.To compare clonidine (aspecific α2-adrenoceptor agonist to SSP-002021R (prodrug of guanfacine, specific α2A-receptor agonist, both associated with diuretics, in experimental cirrhotic ascites.Six groups of 12 rats were studied: controls (G1; controls receiving furosemide and potassium canrenoate (G2; rats with ascitic cirrhosis due to 14-week CCl4 treatment (G3; cirrhotic rats treated (over the 11th-14th CCl4 weeks with furosemide and canrenoate (G4, furosemide, canrenoate and clonidine (G5, or diuretics and SSP002021R (G6. Three rats of each group had their hormonal status and renal function assessed at the end of 11th, 12th, 13th, and 14th weeks of respective treatments.Cirrhotic rats in G3 and G4 gained weight over the 12th-14th CCl4 weeks. In G4, brief increase in sodium excretion over the 11th-12th weeks preceded worsening of inulin clearance and natriuresis (diuretic resistance. In comparison with G4, the addition of clonidine (G5 or guanfacine (G6 to diuretics improved, respectively, sodium excretion over the 11th-12th CCl4 weeks, or GFR and electrolytes excretion over the 13th-14th CCl4 weeks. Natriuretic responses in G5 and G6 were accompanied by reduced catecholamine serum levels.α2A-receptor agonists restore glomerular filtration rate and natriuresis, and delay diuretic-resistant ascites in experimental advanced cirrhosis. Clonidine ameliorates diuretic-dependent natriuresis just for a short time.

  7. Olfactory Bulb [alpha][subscript 2]-Adrenoceptor Activation Promotes Rat Pup Odor-Preference Learning via a cAMP-Independent Mechanism

    Science.gov (United States)

    Shakhawat, Amin MD.; Harley, Carolyn W.; Yuan, Qi

    2012-01-01

    In this study, three lines of evidence suggest a role for [alpha][subscript 2]-adrenoreceptors in rat pup odor-preference learning: olfactory bulb infusions of the [alpha][subscript 2]-antagonist, yohimbine, prevents learning; the [alpha][subscript 2]-agonist, clonidine, paired with odor, induces learning; and subthreshold clonidine paired with…

  8. Validation of [(11) C]ORM-13070 as a PET tracer for alpha2c -adrenoceptors in the human brain.

    Science.gov (United States)

    Lehto, Jussi; Hirvonen, Mika M; Johansson, Jarkko; Kemppainen, Jukka; Luoto, Pauliina; Naukkarinen, Tarja; Oikonen, Vesa; Arponen, Eveliina; Rouru, Juha; Sallinen, Jukka; Scheinin, Harry; Vuorilehto, Lauri; Finnema, Sjoerd J; Halldin, Christer; Rinne, Juha O; Scheinin, Mika

    2015-03-01

    This study explored the use of the α2C -adrenoceptor PET tracer [(11) C]ORM-13070 to monitor α2C -AR occupancy in the human brain. The subtype-nonselective α2 -AR antagonist atipamezole was administered to eight healthy volunteer subjects to determine its efficacy and potency (Emax and EC50 ) at inhibiting tracer uptake. We also explored whether the tracer could reveal changes in the synaptic concentrations of endogenous noradrenaline in the brain, in response to several pharmacological and sensory challenge conditions. We assessed occupancy from the bound-to-free ratio measured during 5-30 min post injection. Based on extrapolation of one-site binding, the maximal extent of inhibition of striatal [(11) C]ORM-13070 uptake (Emax ) achievable by atipamezole was 78% (95% CI 69-87%) in the caudate nucleus and 65% (53-77%) in the putamen. The EC50 estimates of atipamezole (1.6 and 2.5 ng/ml, respectively) were in agreement with the drug's affinity to α2C -ARs. These findings represent clear support for the use of [(11) C]ORM-13070 for monitoring drug occupancy of α2C -ARs in the living human brain. Three of the employed noradrenaline challenges were associated with small, approximately 10-16% average reductions in tracer uptake in the dorsal striatum (atomoxetine, ketamine, and the cold pressor test; P tracer uptake. The tracer is suitable for studying central nervous system receptor occupancy by α2C -AR ligands in human subjects. [(11) C]ORM-13070 also holds potential as a tool for in vivo monitoring of synaptic concentrations of noradrenaline, but this remains to be further evaluated in future studies. © 2014 Wiley Periodicals, Inc.

  9. Long-term motor improvement after stroke is enhanced by short-term treatment with the alpha-2 antagonist, atipamezole.

    Science.gov (United States)

    Beltran, Erik J; Papadopoulos, Catherine M; Tsai, Shih-Yen; Kartje, Gwendolyn L; Wolf, William A

    2010-07-30

    Drugs that increase central noradrenergic activity have been shown to enhance the rate of recovery of motor function in pre-clinical models of brain damage. Less is known about whether noradrenergic agents can improve the extent of motor recovery and whether such improvement can be sustained over time. This study was designed to determine if increasing central noradrenergic tone using atipamezole, an alpha-2 adrenoceptor antagonist, could induce a long-term improvement in motor performance in rats subjected to ischemic brain damage caused by permanent middle cerebral artery occlusion. The importance of pairing physical "rehabilitation" with enhanced noradrenergic activity was also investigated. Atipamezole (1 mg/kg, s.c.) or vehicle (sterile saline) was administered once daily on Days 2-8 post-operatively. Half of each drug group was housed under enriched environment conditions supplemented with daily focused activity sessions while the other half received standard housing with no focused activity. Skilled motor performance in forelimb reaching and ladder rung walking was assessed for 8 weeks post-operatively. Animals receiving atipamezole plus rehabilitation exhibited significantly greater motor improvement in both behavioral tests as compared to vehicle-treated animals receiving rehabilitation. Interestingly, animals receiving atipamezole without rehabilitation exhibited a significant motor improvement in the ladder rung walk test but not the forelimb reaching test. These results suggest that a short-term increase in noradrenergic activity can lead to sustained motor improvement following stroke, especially when paired with rehabilitation. Published by Elsevier B.V.

  10. Characterization and regional distribution of alpha 2-adrenoceptors in postmortem human brain using the full agonist (/sup 3/H)UK 14304

    Energy Technology Data Exchange (ETDEWEB)

    Meana, J.J.; Barturen, F.; Garcia-Sevilla, J.A.

    1989-04-01

    The full agonist (3H)UK 14304 (5-bromo-6-(2-imidazolin-2-yl-amino)-quinoxaline) was used to characterize alpha 2-adrenoceptors in postmortem human brain. The binding at 25 degrees C was rapid (t1/2, 4.6 min) and reversible (t1/2, 14.1 min), and the KD determined from the kinetic studies was 0.48 nM. In frontal cortex, the rank order of potency of adrenergic drugs competing with (3H)UK 14304 or (3H)clonidine showed the specificity for an alpha 2A-adrenoceptor: UK 14304 approximately equal to yohimbine approximately equal to oxymetazoline approximately equal to clonidine greater than phentolamine approximately equal to (-)-adrenaline greater than idazoxan approximately equal to (-)-noradrenaline greater than phenylephrine greater than (+/-)-adrenaline much greater than corynanthine greater than prazosin much greater than (+/-)-propranolol. GTP induced a threefold decrease in the affinity of (3H)UK 14304, with no alteration in the maximum number of binding sites, suggesting that the radioligand labelled the high-affinity state of the alpha 2-adrenoceptor. In the frontal cortex, analyses of saturation curves indicated the existence of a single population of noninteracting sites for (3H)UK 14304 (KD = 0.35 +/- 0.13 nM; Bmax = 74 +/- 9 fmol/mg of protein). In other brain regions (hypothalamus, hippocampus, cerebellum, brainstem, caudate nucleus, and amygdala) the Bmax ranged from 68 +/- 7 to 28 +/- 4 fmol/mg of protein. No significant changes in the KD values were found in the different regions examined. The binding of (3H)UK 14304 was not affected by age, sex or postmortem delay.

  11. The alpha(2)-adrenoceptors do not modify the activity of tyrosine hydroxylase, corticoliberine, and neuropeptide Y producing hypothalamic magnocellular neurons ion the Long Evans and Brattleboro rats

    DEFF Research Database (Denmark)

    Bundzikova, J; Pirnik, Z; Zelena, D

    2010-01-01

    The hypothalamic supraoptic (SON) and paraventricular (PVN) nuclei are activated by body salt-fluid variations. Stimulation of alpha(2)-adrenoceptors by an agonist-xylazine (XYL) activates oxytocinergic but not vasopressinergic magnocellular neurons. In this study, tyrosine hydroxylase (TH...... sections of 30 mum thickness double immunolabeled with Fos/neuropeptide were evaluated under light microscope. Under basal conditions, di/di in comparison with control Long Evans rats, displayed significantly higher number of TH, CRH, and NPY immunoreactive neurons in the SON and PVN (except NPY cells...

  12. The costo-uterine muscle of the rat contains a homogeneous population of beta-adrenoceptors.

    Science.gov (United States)

    Hartley, M. L.; Pennefather, J. N.

    1985-01-01

    The effects of two selective beta-adrenoceptor antagonists on the inhibitory responses to some sympathomimetic amines of electrically-stimulated preparations of costo-uterine muscle, taken from virgin rats, have been examined quantitatively. pA2 values for the antagonist, atenolol (beta 1-selective) and ICI 118,551 (beta 2-selective) were obtained using as agonists, fenoterol (beta 2-selective agonist) and noradrenaline (alpha- and beta-adrenoceptor agonist, beta 1-selective); and in addition, with ICI 118,551 only, isoprenaline (beta-agonist, non-selective) and adrenaline (alpha- and beta-adrenoceptor agonist, beta 2-selective). Catecholamine uptake mechanisms and alpha-adrenoceptors were not blocked in any of these experiments. Atenolol competitively antagonized the effects of fenoterol and noradrenaline to a similar extent, the pA2 values being 5.4 and 5.7, respectively. ICI 118,551 competitively antagonized the effects of fenoterol, isoprenaline, adrenaline and noradrenaline to a similar extent; pA2 values ranged from 8.7 with noradrenaline to 9.1 with isoprenaline. These results extend our previous observations which indicated that the adrenoceptors mediating inhibition of electrically-evoked contractions of costo-uterine muscle of the virgin rat are homogeneous and of the beta 2-subtype. The potency of the beta 1-selective agonist RO 363 in producing inhibition of electrically-evoked contractions of this tissue was also examined. RO 363 was 200 times less potent than isoprenaline but was a full agonist. This indicates that there is efficient coupling between beta 2-adrenoceptor activation and tissue response in this non-innervated preparation. PMID:2858239

  13. Comparison of vascular alpha(1)-adrenoceptor antagonism of tamsulosin in oral controlled absorption system (OCAS) and modified release (MR) formulations

    NARCIS (Netherlands)

    Michel, M. C.; Korstanje, C.; Krauwinkel, W.; Shear, M.; Davies, J.; Quartel, A.

    2005-01-01

    Objective: The cardiovascular a-l-adrenoceptor (AR) antagonism of the new oral controlled absorption system (OCAS) 0.4 mg tablet formulation of tamsulosin was compared with that of the modified release (MR) 0.4 mg capsule formulation in healthy male volunteers after a single dose in the fasted

  14. Design, Synthesis, and Biological Evaluation of Novel Tetrahydroprotoberberine Derivatives (THPBs) as Selective α1A-Adrenoceptor Antagonists.

    Science.gov (United States)

    Guo, Diliang; Li, Jing; Lin, Henry; Zhou, Yu; Chen, Ying; Zhao, Fei; Sun, Haifeng; Zhang, Dan; Li, Honglin; Shoichet, Brian K; Shan, Lei; Zhang, Weidong; Xie, Xin; Jiang, Hualiang; Liu, Hong

    2016-10-27

    A novel series of tetrahydroprotoberberine derivatives (THPBs) were designed, synthesized, and evaluated as selective α 1A -adrenergic receptors (AR) antagonists for the treatment of benign prostatic hyperplasia. On the basis of the pharmacophore model of the marketed drug silodosin, THPBs were modified by introducing an indole segment into their core scaffolds. In calcium assays, 7 out of 32 compounds displayed excellent antagonistic activities against α 1A -ARs, with IC 50 less than 250 nM. Among them, compound (S)-27 had the most potent biological activity; its IC 50 toward α 1A -AR was 12.8 ± 2.2 nM, which is 781 and 20 times more selective than that toward α 1B - and α 1D -AR, respectively. In the functional assay using isolated rat tissues, compound (S)-27 inhibited norepinephrine-induced urethra smooth muscle contraction potently (IC 50 = 0.5 ± 0.3 nM), without inhibiting the aortic contraction (IC 50 > 1000 nM), displaying a better tissue selectivity than the marketed drug silodosin. Additional results of preliminary safety studies (acute toxicity and hERG inhibition) and pharmacokinetics studies indicated the potential druggability for compound (S)-27 which is a promising lead for the development of selective α 1A -AR antagonists for the treatment of BPH.

  15. Corticotropin-releasing factor in the basolateral amygdala enhances memory consolidation via an interaction with the beta-adrenoceptor-cAMP pathway: dependence on glucocorticoid receptor activation.

    Science.gov (United States)

    Roozendaal, Benno; Schelling, Gustav; McGaugh, James L

    2008-06-25

    Extensive evidence indicates that stress hormone effects on the consolidation of emotionally influenced memory involve noradrenergic activation of the basolateral complex of the amygdala (BLA). The present experiments examined whether corticotropin-releasing factor (CRF) modulates memory consolidation via an interaction with the beta-adrenoceptor-cAMP system in the BLA. In a first experiment, male Sprague Dawley rats received bilateral infusions of the CRF-binding protein ligand inhibitor CRF(6-33) into the BLA either alone or together with the CRF receptor antagonist alpha-helical CRF(9-41) immediately after inhibitory avoidance training. CRF(6-33) induced dose-dependent enhancement of 48 h retention latencies, which was blocked by coadministration of alpha-helical CRF(9-41), suggesting that CRF(6-33) enhances memory consolidation by displacing CRF from its binding protein, thereby increasing "free" endogenous CRF concentrations. In a second experiment, intra-BLA infusions of atenolol (beta-adrenoceptor antagonist) and Rp-cAMPS (cAMP inhibitor), but not prazosin (alpha(1)-adrenoceptor antagonist), blocked CRF(6-33)-induced retention enhancement. In a third experiment, the CRF receptor antagonist alpha-helical CRF(9-41) administered into the BLA immediately after training attenuated the dose-response effects of concurrent intra-BLA infusions of clenbuterol (beta-adrenoceptor agonist). In contrast, alpha-helical CRF(9-41) did not alter retention enhancement induced by posttraining intra-BLA infusions of either cirazoline (alpha(1)-adrenoceptor agonist) or 8-br-cAMP (cAMP analog). These findings suggest that CRF facilitates the memory-modulatory effects of noradrenergic stimulation in the BLA via an interaction with the beta-adrenoceptor-cAMP cascade, at a locus between the membrane-bound beta-adrenoceptor and the intracellular cAMP formation site. Moreover, consistent with evidence that glucocorticoids enhance memory consolidation via a similar interaction with the

  16. The role of adrenoceptors in circulatory and metabolic regulation

    NARCIS (Netherlands)

    van Zwieten, P. A.

    1988-01-01

    This survey covers the classification and subdivisions of alpha- and beta-adrenoceptors, including alpha 1 and alpha 2, beta 1 and beta 2, and pre-and postsynaptic receptor subtypes, together with the distribution and functional relevance of the various adrenoceptor subtypes. The emphasis will be on

  17. Tricyclic pharmacophore-based molecules as novel integrin alpha(v)beta3 antagonists. Part 2: synthesis of potent alpha(v)beta3/alpha(IIb)beta3 dual antagonists.

    Science.gov (United States)

    Ishikawa, Minoru; Kubota, Dai; Yamamoto, Mikio; Kuroda, Chizuko; Iguchi, Maki; Koyanagi, Akihiro; Murakami, Shoichi; Ajito, Keiichi

    2006-04-01

    We synthesized 4-aminopiperidine derivatives of our prototype integrin alpha(v)beta3 antagonist 1 in an attempt to increase the activity and water solubility. Introduction of one or two hydrophilic moieties into the central aromatic ring and/or the benzene ring at the C-terminus of 1 increased water solubility and enhanced inhibition of cell adhesion. The results of a structure-activity relationships (SAR) study indicated that the torsion angle between the central aromatic ring and the piperidine ring, and the acidity at the sulfonamide moiety, might be important for alpha(v)beta3 receptor binding activity. Some of these compounds are novel and potent alpha(v)beta3/alpha(IIb)beta3 dual antagonists with acceptable water solubility and a satisfactory early absorption, distribution, metabolism, excretion, and toxicity (ADMET) profile.

  18. Sympathetic vascular control of the pig nasal mucosa: adrenoceptor mechanisms in blood flow and volume control.

    Science.gov (United States)

    Lacroix, J. S.; Lundberg, J. M.

    1989-01-01

    1. The adrenoceptor mechanisms influencing the total blood flow, volume and superficial blood flow in the nasal mucosa of pigs anaesthetized with pentobarbitone have been characterized by use of various agonists and antagonists. 2. Local intra-arterial bolus injection of the selective alpha 1-agonist phenylephrine, the selective alpha 2-agonist UK 14.304, the mixed alpha 1/alpha 2-agonist oxymetazoline and the mixed alpha/beta-agonists noradrenaline (NA) and adrenaline induced dosed-related reduction of nasal arterial blood flow (BF), nasal mucosal volume (V, reflecting capacitance vessel function) and the laser Doppler flowmetry signal (LDF, reflecting superficial movement of blood cells). The rank order of alpha-agonist potency regarding BF reduction was UK 14.304 greater than oxymetazoline greater than phenylephrine = adrenaline. For the volume response the potency order was UK 14.304 greater than oxymetazoline = NA = adrenaline greater than phenylephrine while for the reduction of the LDF signal the potency was UK 14.304 = NA = adrenaline greater than oxymetazoline greater than phenylephrine. The selective beta 2-agonist terbutaline caused dose-dependent increase of BF whereas only a small augmentation of the V was obtained upon the highest dose (40 nmol) while no modification of the LDF signal was observed. 3. After pretreatment with the selective alpha 1-antagonist prazosin, the response to phenylephrine was abolished while the selective alpha 2-antagonist idazoxan attenuated the effect of UK 14.304. After pretreatment with alpha-antagonists, both NA and adrenaline caused biphasic effects with constriction followed by vasodilatation for BF, but not for V or LDF. This vasodilatation was blocked by the beta-antagonist propranolol. 4. The reduction in nasal BF and V upon sympathetic nerve stimulation was attenuated both by prazosin and idazoxan. Propranolol enhanced the remaining reduction of BF but not of V in the presence of alpha-antagonists. 5. It is

  19. The cytotoxicity of the α1-adrenoceptor antagonist prazosin is linked to an endocytotic mechanism equivalent to transport-P

    International Nuclear Information System (INIS)

    Fuchs, Robert; Stracke, Anika; Ebner, Nadine; Zeller, Christian Wolfgang; Raninger, Anna Maria; Schittmayer, Matthias; Kueznik, Tatjana; Absenger-Novak, Markus; Birner-Gruenberger, Ruth

    2015-01-01

    Since the α1-adrenergic antagonist prazosin (PRZ) was introduced into medicine as a treatment for hypertension and benign prostate hyperplasia, several studies have shown that PRZ induces apoptosis in various cell types and interferes with endocytotic trafficking. Because PRZ is also able to induce apoptosis in malignant cells, its cytotoxicity is a focus of interest in cancer research. Besides inducing apoptosis, PRZ was shown to serve as a substrate for an amine uptake mechanism originally discovered in neurones called transport-P. In line with our hypothesis that transport-P is an endocytotic mechanism also present in non-neuronal tissue and linked to the cytotoxicity of PRZ, we tested the uptake of QAPB, a fluorescent derivative of PRZ, in cancer cell lines in the presence of inhibitors of transport-P and endocytosis. Early endosomes and lysosomes were visualised by expression of RAB5-RFP and LAMP1-RFP, respectively; growth and viability of cells in the presence of PRZ and uptake inhibitors were also tested. Cancer cells showed co-localisation of QAPB with RAB5 and LAMP1 positive vesicles as well as tubulation of lysosomes. The uptake of QAPB was sensitive to transport-P inhibitors bafilomycin A1 (inhibits v-ATPase) and the antidepressant desipramine. Endocytosis inhibitors pitstop ® 2 (general inhibitor of endocytosis), dynasore (dynamin inhibitor) and methyl-β-cyclodextrin (cholesterol chelator) inhibited the uptake of QAPB. Bafilomycin A1 and methyl-β-cyclodextrin but not desipramine were able to preserve growth and viability of cells in the presence of PRZ. In summary, we confirmed the hypothesis that the cellular uptake of QAPB/PRZ represents an endocytotic mechanism equivalent to transport-P. Endocytosis of QAPB/PRZ depends on a proton gradient, dynamin and cholesterol, and results in reorganisation of the LAMP1 positive endolysosomal system. Finally, the link seen between the cellular uptake of PRZ and cell death implies a still unknown pro

  20. Lower lid entropion secondary to treatment with alpha-1a receptor antagonist: a case report

    Directory of Open Access Journals (Sweden)

    Simcock Peter

    2010-03-01

    Full Text Available Abstract Introduction The use of alpha-1a receptor antagonists (tamsulosin is widely accepted in the treatment of benign prostatic hypertrophy (BPH. It has previously been implicated as a causative agent in intra-operative floppy iris syndrome due to its effects on the smooth muscle. We report a case of lower lid entropion that may be related to a patient commencing treatment of tamsulosin. Case presentation A 74-year-old Caucasian man was started on alpha 1-a receptor antagonist (Tamsulosin treatment for benign prostatic hypertrophy. Eight days later, he presented to the ophthalmology unit with a right lower lid entropion which was successfully treated surgically with a Weiss procedure. Conclusion We report a case of lower lid entropion that may be secondary to the recent use of an alpha-1a blocker (tamsulosin. This can be explained by considering the effect of autonomic blockade on alpha-1 receptors in the Muller's muscle on a patient that may already have an anatomical predisposition to entropion formation due to a further reduction in muscle tone.

  1. Relaxation Responses of Trigonal Smooth Muscle from Rabbit by Alpha1-Adrenoceptor Antagonists Alfuzosin, Doxazosin and Tamsulosin

    Directory of Open Access Journals (Sweden)

    A. Karadeniz

    2008-01-01

    Full Text Available This study was performed to investigate the effects of alfuzosin, doxazosin and tamsulosin in vitro on trigone smooth muscle of rabbit. In this study, fifteen rabbits weighing 2.5 - 3 kg were used. One strip in the shape of a trigone was prepared for each of the isolated bladders. Firstly, an initial tension of 1 g was placed on each segment, and we waited for equilibration by constantly bubbling with 95% O2 and 5% CO2. Next, the determination level of electrical stimulation which created submaximal contraction and effective dosage were found for trigone and they were determined by applying different concentrations of phenylephrine (10-8 M, 10-7 M, 10-6 M, 10-5 M, respectively. Firstly 10-8 M dosage of alfuzosin (10-8 M, 10-7 M, 10-6 M, 10-5 M was added, then we waited for 20 min. Then, an effective dosage of phenylephrine (10-5 M was added into the solution and we waited for 7 min again. After this process, electrical stimulation was applied for the contraction of the tissue. After stimulation, the tissue was washed twice every two minutes and rested; we waited until the tissue reached its starting stretching value. The same processes were performed for the other dosages of alfuzosin (10-7 M, 10-6 M, 10-5 M, doxazosin (10-7 M, 10-6 M, 10-5 M and tamsulosin (10-7 M, 10-6 M, 10-5 M, respectively. In conclusion, when we compared the amplitudes of the responses of all concentrations of doxazosin, alfuzosin and tamsulosin in the trigone smooth muscle with amplitude of a response of effective concentration of phenylephrine, it was determined that the prevention level of contractions occurred after tamsulosin hydrochloride was higher than after alfuzosin hydrochloride and doxazosin mesylate. With these results, we showed that alfuzosin, doxazosin and tamsulosin inhibited noradrenalin-based contractions in the rabbit trigone smooth muscle and this result can be used both for in vitro and in vivo future studies.

  2. Highly Potent, Water Soluble Benzimidazole Antagonist for Activated (alpha)4(beta)1 Integrin

    Energy Technology Data Exchange (ETDEWEB)

    Carpenter, R D; Andrei, M; Lau, E Y; Lightstone, F C; Liu, R; Lam, K S; Kurth, M J

    2007-08-29

    The cell surface receptor {alpha}{sub 4}{beta}{sub 1} integrin, activated constitutively in lymphoma, can be targeted with the bisaryl urea peptidomimetic antagonist 1 (LLP2A). However, concerns on its preliminary pharmacokinetic (PK) profile provided an impetus to change the pharmacophore from a bisaryl urea to a 2-arylaminobenzimidazole moiety resulting in improved solubility while maintaining picomolar potency [5 (KLCA4); IC{sub 50} = 305 pM]. With exceptional solubility, this finding has potential for improving PK to help diagnose and treat lymphomas.

  3. Comparison of adrenoceptor subtype expression in porcine and human bladder and prostate

    NARCIS (Netherlands)

    Goepel, M.; Wittmann, A.; Rübben, H.; Michel, M. C.

    1997-01-01

    We have quantified and characterized alpha 1-, alpha 2- and beta-adrenoceptor subtypes in porcine bladder detrusor and bladder neck, human bladder detrusor, and porcine and human prostate. alpha 1-, alpha 2- and beta-adrenoceptor were identified in radioligand binding studies using [3H]prazosin,

  4. Preliminary Molecular Dynamic Simulations of the Estrogen Receptor Alpha Ligand Binding Domain from Antagonist to Apo

    Directory of Open Access Journals (Sweden)

    Adrian E. Roitberg

    2008-06-01

    Full Text Available Estrogen receptors (ER are known as nuclear receptors. They exist in the cytoplasm of human cells and serves as a DNA binding transcription factor that regulates gene expression. However the estrogen receptor also has additional functions independent of DNA binding. The human estrogen receptor comes in two forms, alpha and beta. This work focuses on the alpha form of the estrogen receptor. The ERα is found in breast cancer cells, ovarian stroma cells, endometrium, and the hypothalamus. It has been suggested that exposure to DDE, a metabolite of DDT, and other pesticides causes conformational changes in the estrogen receptor. Before examining these factors, this work examines the protein unfolding from the antagonist form found in the 3ERT PDB crystal structure. The 3ERT PDB crystal structure has the estrogen receptor bound to the cancer drug 4-hydroxytamoxifen. The 4-hydroxytamoxifen ligand was extracted before the simulation, resulting in new conformational freedom due to absence of van der Waals contacts between the ligand and the receptor. The conformational changes that result expose the binding clef of the co peptide beside Helix 12 of the receptor forming an apo conformation. Two key conformations in the loops at either end of the H12 are produced resulting in the antagonist to apo conformation transformation. The results were produced over a 42ns Molecular Dynamics simulation using the AMBER FF99SB force field.

  5. Quantification of [{sup 11}C]GB67 binding to cardiac {alpha}{sub 1}-adrenoceptors with positron emission tomography: validation in pigs

    Energy Technology Data Exchange (ETDEWEB)

    Park-Holohan, So-Jin; Turton, David R.; Hume, Susan P. [Hammersmith Hospital, Hammersmith Imanet Ltd., GE HealthCare, Cyclotron Building, London (United Kingdom); Asselin, Marie-Claude [Hammersmith Hospital, Hammersmith Imanet Ltd., GE HealthCare, Cyclotron Building, London (United Kingdom); The University of Manchester, Wolfson Molecular Imaging Centre, Manchester (United Kingdom); Williams, Sharron L.; Camici, Paolo G. [Hammersmith Hospital, MRC Clinical Sciences Centre, Cyclotron Building, London (United Kingdom); Rimoldi, Ornella E. [Hammersmith Hospital, MRC Clinical Sciences Centre, Cyclotron Building, London (United Kingdom); New York Medical College, Cardiovascular Research Institute Department of Medicine, Valhalla, NY (United States)

    2008-09-15

    An increase in human cardiac {alpha}{sub 1}-adrenoceptor ({alpha}{sub 1}-AR) density is associated with various diseases such as myocardial ischemia, congestive heart failure, hypertrophic cardiomyopathy and hypertension. Positron emission tomography (PET) with an appropriate radioligand offers the possibility of imaging receptor function in the normal and diseased heart. [{sup 11}C]GB67, an analogue of prazosin, has been shown in rats to have potential as a PET ligand with high selectivity to {alpha}{sub 1}-AR. However, {alpha}{sub 1}-AR density is up to ten times higher in rat heart compared to that in man. The aim of the present preclinical study was to extend the previous evaluation to a large mammal heart, where the {alpha}{sub 1}-AR density is comparable to man, and to validate a method for quantification before PET studies in man. Seven [{sup 11}C]GB67 PET studies, with weight-adjusted target dose of either 5.29 MBq kg{sup -1} (pilot, test-retest and baseline-predose studies) or 8.22 MBq kg{sup -1} (baseline-displacement studies), were performed in four anaesthetised pigs (39.5 {+-} 3.9 kg). Total myocardial volume of distribution (V{sub T}) was estimated under different pharmacological conditions using compartmental analysis with a radiolabelled metabolite-corrected arterial plasma input function. A maximum possible blocking dose of 0.12 {mu}mol kg{sup -1} of unlabeled GB67 was given 20 min before [{sup 11}C]GB67 administration in the predose study and 45 min after administration of [{sup 11}C]GB67 in the displacement study. In addition, [{sup 15}O]CO (3,000 MBq) and [{sup 15}O]H{sub 2}O, with weight adjusted target dose of 10.57 MBq kg{sup -1}, were also administered for estimation of blood volume recovery (RC) of the left ventricular cavity and myocardial perfusion (MBF), respectively. [{sup 11}C]GB67 V{sub T} values (in ml cm{sup -3}) were estimated to be 24.2 {+-} 5.5 (range, 17.3-31.3), 10.1 (predose) and 11.6 (displacement). MBF did not differ within

  6. Evidence for a non-adrenoceptor, imidazoline-mediated contractile response to oxymetazoline in the porcine isolated rectal artery.

    Science.gov (United States)

    Minyan, W; Dunn, W R; Blaylock, N A; Chan, S L; Wilson, V G

    2001-04-01

    Imidazoline derivatives are known to elicit responses through both alpha(2)-adrenoceptor and non-adrenoceptor, imidazoline sites, though as yet there are no examples of the latter on vascular smooth muscle. In the presence of 0.3 microM prazosin, neither UK-14304 (0.01 - 3 microM) nor oxymetazoline (0.01 - 30 microM) caused a significant contraction of the porcine isolated rectal artery, a preparation with a low density of alpha(2)-adrenoceptors. In the presence of a combination of U46619 and forskolin, however, both agonists produced concentration-dependent contractions. Pretreatment with phenoxybenzamine (3 microM) abolished responses to UK-14304, but left those elicited by oxymetazoline largely unaffected. The putative I(3) imidazoline antagonist 2-(2,3 dihydro-2-benzofuranyl)-2-imidazole (KU-14R, 10 microM) caused a 6 fold rightward displacement of the phenoxybenzamine-insensitive concentration - response curve to oxymetazoline. Our data indicates that non-adrenoceptor, imidazoline sites, pharmacologically similar to the I(3) imidazoline site on islet cells, mediate vasoconstriction in the porcine isolated rectal artery.

  7. The alpha7 nicotinic acetylcholine receptor-selective antagonist, methyllycaconitine, partially protects against beta-amyloid1-42 toxicity in primary neuron-enriched cultures.

    Science.gov (United States)

    Martin, Shelley E; de Fiebre, Nancy Ellen C; de Fiebre, Christopher M

    2004-10-01

    Studies have suggested that the neuroprotective actions of alpha7 nicotinic agonists arise from activation of receptors and not from the extensive desensitization which rapidly follows activation. Here, we report that the alpha7-selective nicotinic antagonist, methyllycaconitine (MLA), protects against beta-amyloid-induced neurotoxicity; whereas the alpha4beta2-selective antagonist, dihydro-beta-erythroidine, does not. These findings suggest that neuroprotective actions of alpha7-acting agents arise from receptor inhibition/desensitization and that alpha7 antagonists may be useful neuroprotective agents.

  8. Iris morphologic changes related to alpha(1)-adrenergic receptor antagonists implications for intraoperative floppy iris syndrome.

    Science.gov (United States)

    Prata, Tiago Santos; Palmiero, Pat-Michael; Angelilli, Allison; Sbeity, Zaher; De Moraes, Carlos Gustavo V; Liebmann, Jeffrey M; Ritch, Robert

    2009-05-01

    To identify iris structural alterations associated with intraoperative floppy iris syndrome (IFIS) in patients using systemic alpha(1)-adrenergic receptor antagonists (alpha-1ARA). Cross-sectional study. Twenty-nine patients with current or past treatment with any systemic alpha-1ARA and 22 untreated controls. Consecutive eligible patients underwent slit-lamp-adapted optical coherence tomography in a masked fashion under standardized lighting conditions. Iris thickness at the dilator muscle region (DMR; measured at half of the distance between the scleral spur and the pupillary margin) and at the sphincter muscle region (SMR; 0.75 mm from the pupillary margin), the ratio between the DMR/SMR (to compensate for possible intersubject variability), and pupillary diameter. Most treated patients were on tamsulosin (27/29). Mean age was similar in study and control groups (70.6+/-7.6 vs 67.1+/-9.1 years; P = 0.061). Photopic pupil diameter was reduced in the study group (2.06+/-0.5 vs 2.5+/-0.6 mm; P = 0.001). The SMR was similar between groups (P = 0.53). Significantly lower values were found in treated subjects for the DMR and the DMR/SMR ratio (Pcolor were not significant in this model. Patients using systemic alpha-1ARA have significantly lower values of DMR thickness and DMR/SMR ratio and smaller pupil diameter when compared with age-matched controls. These differences seem to be related to the duration of drug exposure and provide evidence of structural alterations to the iris dilator muscle from this class of agents in IFIS. Proprietary or commercial disclosure may be found after the references.

  9. Neuroprotective and memory-related actions of novel alpha-7 nicotinic agents with different mixed agonist/antagonist properties.

    Science.gov (United States)

    Meyer, E M; Tay, E T; Zoltewicz, J A; Meyers, C; King, M A; Papke, R L; De Fiebre, C M

    1998-03-01

    The goals of this study were to develop compounds that were selective and highly efficacious agonists at alpha-7 receptors, while varying in antagonist activity; and to test the hypothesis that these compounds had memory-related and neuroprotective actions associated with both agonist and antagonist alpha-7 receptor activities. Three compounds were identified; E,E-3-(cinnamylidene)anabaseine (3-CA), E,E-3-(2-methoxycinnamylidene) anabaseine (2-MeOCA) and E,E-3-(4-methoxycinnamylidene) anabaseine (4-MeOCA) each displaced [125I]alpha-bungarotoxin binding from rat brain membranes and activated rat alpha-7 receptors in a Xenopus oocyte expression system fully efficaciously. The potency series for binding and receptor activation was 2-MeOCA > 4-MeOCA = 3-CA and 2-MeOCA = 3-CA > 4-MeOCA, respectively. No compound significantly activated oocyte-expressed alpha-4beta-2 receptors. Although each cinnamylidene-anabaseine caused a long-term inhibition of alpha-7 receptors, as measured by ACh-application 5 min later, this inhibition ranged considerably, from less than 20% (3-CA) to 90% (2-MeOCA) at an identical concentration (10 microM). These compounds improved passive avoidance behavior in nucleus basalis lesioned rats, with 2-MeOCA most potent in this respect. In contrast, only 3-CA was neuroprotective against neurite loss during nerve growth factor deprivation in differentiated rat pheochromocytoma (PC12) cells. Choline, an efficacious alpha-7 agonist without antagonist activity, was also protective in this model. These results suggest that the neurite-protective action of alpha-7 receptor agonists may be more sensitive to potential long-term antagonist properties than acute behavioral actions are.

  10. Genetically engineered bacteriophage delivers a tumor necrosis factor alpha antagonist coating on neural electrodes

    International Nuclear Information System (INIS)

    Kim, Young Jun; Nam, Chang-Hoon; Jin, Young-Hyun; Stieglitz, Thomas; Salieb-Beugelaar, Georgette B

    2014-01-01

    This paper reports a novel approach for the formation of anti-inflammatory surface coating on a neural electrode. The surface coating is realized using a recombinant f88 filamentous bacteriophage, which displays a short platinum binding motif and a tumor necrosis factor alpha antagonist (TNF-α antagonist) on p3 and p8 proteins, respectively. The recombinant bacteriophages are immobilized on the platinum surface by a simple dip coating process. The selective and stable immobilization of bacteriophages on a platinum electrode is confirmed by quartz crystal microbalance with dissipation monitoring, atomic force microscope and fluorescence microscope. From the in vitro cell viability test, the inflammatory cytokine (TNF-α) induced cell death was prevented by presenting recombinant bacteriophage coating, albeit with no significant cytotoxic effect. It is also observed that the bacteriophage coating does not have critical effects on the electrochemical properties such as impedance and charge storage capacities. Thus, this approach demonstrates a promising anti-apoptotic as well as anti-inflammatory surface coating for neural implant applications. (paper)

  11. The inhibitory effects of presynaptic alpha-adrenoceptor agonists on contractions of guinea-pig ileum and mouse vas deferens in the morphine-dependent and withdrawn states produced in vitro.

    Science.gov (United States)

    Gillan, M. G.; Kosterlitz, H. W.; Robson, L. E.; Waterfield, A. A.

    1979-01-01

    1 Isolated ilea from guinea-pigs implanted with morphine pellets were stimulated coaxially, either with or without morphine present in the bath fluid, and the longitudinal contractions recorded. 2 In the absence of morphine the inhibitory effects of the presynaptic alpha-adrenoceptor agonists, clonidine and oxymetazoline were much reduced and the dose-response curve was flat. This state of 'withdrawal' was readily reversed by morphine and levorphanol but not its inactive (+)-isomer, dextrophan. 3 The kappa-agonists, ketazocine and ethylketazocine, also restored the effects of clonidine as did the opioid peptides Tyr-D-Ala-Gly-Phe-D-Leu, acting preferentially on delta-receptors, and Tyr-D-Ala-Gly-MePhe-Met(O)-ol, acting mainly on micro-receptors. 4 The inhibitory effects of adrenaline and adenosine 3',5'-diphosphate were reduced at low but not at high concentrations. 5 In contrast, the inhibitory effect of clonidine on the electrically evoked contractions of vasa deferentia from mice implanted with morphine pellets was not abolished by the lack of morphine in the bath fluid or by addition of naloxone. 6 A possible explanation is suggested for the loss of the inhibitory effects of presynaptic alpha-adrenoceptor agonists in the withdrawn state of the dependent ileum. PMID:37965

  12. Chronic intermittent hypoxia affects the cytosolic phospholipase A(2)alpha/cyclooxygenase 2 pathway via beta(2)-adrenoceptor-mediated ERK/p38 stimulation

    Czech Academy of Sciences Publication Activity Database

    Míčová, P.; Hahnová, K.; Hlaváčková, Markéta; Elsnicová, B.; Chytilová, Anna; Holzerová, Kristýna; Žurmanová, J.; Neckář, Jan; Kolář, František; Nováková, Olga; Novotný, J.

    2016-01-01

    Roč. 423, 1-2 (2016), s. 151-163 ISSN 0300-8177 R&D Projects: GA ČR(CZ) GA13-10267S Institutional support: RVO:67985823 Keywords : heart * hypoxia * ischemia/reperfusion * phospholipase A2 * cyclooxygenase 2 * beta-adrenoceptor * MAPK Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery Impact factor: 2.669, year: 2016

  13. Pathological prolongation of action potential duration as a cause of the reduced alpha-adrenoceptor-mediated negative inotropy in streptozotocin-induced diabetic mice myocardium.

    Science.gov (United States)

    Kanae, Haruna; Hamaguchi, Shogo; Wakasugi, Yumi; Kusakabe, Taichi; Kato, Keisuke; Namekata, Iyuki; Tanaka, Hikaru

    2017-11-01

    Effect of pathological prolongation of action potential duration on the α-adrenoceptor-mediated negative inotropy was studied in streptozotocin-induced diabetic mice myocardium. In streptozotocin-treated mouse ventricular myocardium, which had longer duration of action potential than that in control mice, the negative inotropic response induced by phenylephrine was smaller than that in control mice. 4-Aminopyridine prolonged the action potential duration and decreased the negative inotropy in control mice. Cromakalim shortened the action potential duration and increased the negative inotropy in streptozotocin-treated mice. These results suggest that the reduced α-adrenoceptor-mediated inotropy in the diabetic mouse myocardium is partly due to its prolonged action potential. Copyright © 2017 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

  14. Effect of the endothelin receptor antagonist tezosentan on alpha-naphthylthiourea-induced lung injury in rats

    Directory of Open Access Journals (Sweden)

    Figen Atalay

    2012-02-01

    Full Text Available Acute lung injury is an inflammatory syndrome that increases the permeability of the blood-gas barrier, resulting in high morbidity and mortality. Despite intensive research, treatment options remain limited. We investigated the protective efficacy of tezosentan, a novel, dual endothelin receptor antagonist, in an experimental model of alpha-naphthylthiourea (ANTU-induced acute lung injury in rats. ANTU was intraperitoneally (i.p. injected into rats at a dose of 10 mg/kg. Tezosentan was injected 30 minutes before ANTU was subcutaneously (s.c. injected at doses of 2, 10, or 30 mg/kg, 60 minutes before ANTU was injected at doses of 2, 10, or 30 mg/kg (i.p., and 90 minutes before ANTU at a dose of 10 mg/kg (i.p.. Four hours later, the lung weight/body weight (LW/BW ratio and pleural effusion (PE were measured. When injected 30 minutes before ANTU at doses of 2, 10, or 30 mg/kg (s.c., tezosentan had no effect on lung pathology. When injected 60 minutes before ANTU at doses of 2, 10, or 30 mg/kg (i.p. or 90 minutes before ANTU (10 mg/kg, i.p., tezosentan significantly decreased the PE/BW ratio and had a prophylactic effect on PE formation at all doses. Therefore, tezosentan may attenuate lung injury. Furthermore, its acute and inhibitory effects on fluid accumulation were more effective in the pleural cavity than in the interstitial compartment in this experimental model.

  15. Lack of evidence that nebivolol is a β(3)-adrenoceptor agonist

    NARCIS (Netherlands)

    Frazier, Elfaridah P.; Michel-Reher, Martina B.; van Loenen, Pieter; Sand, Carsten; Schneider, Tim; Peters, Stephan L. M.; Michel, Martin C.

    2011-01-01

    Nebivolol is a selective β(1)-adrenoceptor antagonist which, in addition, displays endothelium-dependent vasodilating properties in humans and other species. β(3)-Adrenoceptors have been proposed to be a molecular target of nebivolol-induced vasodilatation. Therefore, we have investigated possible

  16. β(3)-Adrenoceptor Antagonist SR59230A Attenuates the Imbalance of Systemic and Myocardial Oxygen Transport Induced by Dopamine in Newborn Lambs.

    Science.gov (United States)

    Gill, Richdeep S; Cheung, Po-Yin; Yu, Xiaoyang; Aklabi, Mohammed Al; Nagendran, Jeevan; Quinonez, Luis G; Li, Ying Qian; Miller, John; Ross, David B; Rebeyka, Ivan M; Li, Jia

    2012-01-01

    In neonates, the increase in O(2)-delivery (DO(2)) by dopamine is offset by a greater increase in O(2)-consumption (VO(2)). This has been attributed to β(3)-adrenergic receptors in neonatal brown fat tissue. β(3) receptors in the heart have negative inotropic properties. We evaluated the effects of SR59230A, a β(3)-antagonist, on the balance of systemic and myocardial O(2)-transport in newborn lambs treated with dopamine. Lambs (2-5 days old, n = 12) were anesthetized and mechanically ventilated. Heart rate (HR) and rectal temperature were monitored. VO(2) was measured by respiratory mass spectrometry and cardiac output (CO) by a pulmonary artery transonic flowmeter. Arterial, jugular bulb venous and coronary sinus blood gases and lactate were measured to calculate DO(2), O(2) extraction ratio (ERO(2)), myocardial O(2) and lactate extraction ratios (mERO(2), mERlac). After baseline measurements, lambs were randomized to receive SR59230A at 5 mg/kg iv (SRG) or placebo. Both groups received incremental doses of a dopamine infusion (0-5-10-15-20 mcg/kg/min) every 15 min. Measurements were repeated at the end of each dose. After SR59230A infusion, CO and HR trended to decrease (P = 0.06), but no significant changes occurred in other parameters. Over the incremental doses of dopamine, temperature increased in both groups (P 0.1). DO(2) trended to a small increase (P = 0.08). VO(2) increased in both groups (P transport induced by dopamine at higher doses. Studies are warranted to examine the effect of SR59230A in cases of cardiac dysfunction and increased VO(2), observed after cardiac surgery.

  17. Minimally-invasive Sampling of Interleukin-1alpha and Interleukin-1 Receptor Antagonist from the Skin: A Systematic Review of In vivo Studies in Humans

    NARCIS (Netherlands)

    Falcone, D.; Spee, P.; Kerkhof, P.C.M. van de; Erp, P.E.J. van

    2017-01-01

    Interleukin-1alpha (IL-1alpha) and its receptor antagonist IL-1RA play a pivotal role in skin homeostasis and disease. Although the use of biopsies to sample these cytokines from human skin is widely employed in dermatological practice, knowledge about less invasive, in vivo sampling methods is

  18. Closed headpiece of integrin [alpah]IIb[beta]3 and its complex with an [alpha]IIb[beta]3-specific antagonist that does not induce opening

    Energy Technology Data Exchange (ETDEWEB)

    Zhu, Jieqing; Zhu, Jianghai; Negri, Ana; Provasi, Davide; Filizola, Marta; Coller, Barry S.; Springer, Timothy A. (Sinai); (Rockefeller); (CH-Boston)

    2011-08-24

    The platelet integrin {alpha}{sub IIb}{beta}{sub 3} is essential for hemostasis and thrombosis through its binding of adhesive plasma proteins. We have determined crystal structures of the {alpha}{sub IIb}{beta}{sub 3} headpiece in the absence of ligand and after soaking in RUC-1, a novel small molecule antagonist. In the absence of ligand, the {alpha}{sub IIb}{beta}{sub 3} headpiece is in a closed conformation, distinct from the open conformation visualized in presence of Arg-Gly-Asp (RGD) antagonists. In contrast to RGD antagonists, RUC-1 binds only to the {alpha}{sub IIb} subunit. Molecular dynamics revealed nearly identical binding. Two species-specific residues, {alpha}{sub IIb} Y190 and {alpha}{sub aIIb} D232, in the RUC-1 binding site were confirmed as important by mutagenesis. In sharp contrast to RGD-based antagonists, RUC-1 did not induce {alpha}{sub IIb}{beta}{sub 3} to adopt an open conformation, as determined by gel filtration and dynamic light scattering. These studies provide insights into the factors that regulate integrin headpiece opening, and demonstrate the molecular basis for a novel mechanism of integrin antagonism.

  19. Effect of compound D-600 (methoxyverapamil) on gluconeogenesis and on acceleration of the process by alpha-adrenergic stimuli in rat kidney tubules.

    Science.gov (United States)

    Saggerson, E D; Carpenter, C A

    1980-01-01

    1. Tubule fragments were isolated from renal cortex of fed rats and glucose formation was measured after incubation with 5 mM-sodium lactate. 20 Compound D-600 (10-100 microM) decreased gluconeogenesis from lactate. This inhibition of the process by compound D-600 increased with increasing extracellular Ca2+ concentration, was overridden by noradrenaline and diminished by starvation for 24 h. 3. Inhibition of lactate-supported gluconeogenesis by compound D-600 was not prevented by the alpha 1-adrenoceptor antagonist thymoxamine. 4. Compound D-600 had little effect on gluconeogenesis from 2-oxoglutarate and increased gluconeogenesis from succinate. 5. Compound D-600 opposed stimulation of gluconeogenesis by noradrenaline or oxymetazoline (a selective alpha-adrenoceptor agonist) in a manner suggesting that compound D-600 is an alpha-adrenoceptor blocker. Oxymetazoline was more sensitive than noradrenaline to blockade by both compound D-600 and by the conventional alpha-adrenoceptor antagonist phentolamine. Noradrenaline became more sensitive to blockade by compound D-600 when extracellular Ca2+ was decreased. 6. Compound D-600 did not block stimulation of gluconeogenesis by angiotensin or cyclic AMP. PMID:6258565

  20. Synthesis of 1,2-benzisothiazolyloxypropanolamine derivatives and investigation of their activity at beta-adrenoceptors.

    Science.gov (United States)

    Morini, Giovanni; Pozzoli, Cristina; Menozzi, Alessandro; Comini, Mara; Poli, Enzo

    2005-10-01

    The synthesis of 3-methoxy-1,2-benzisothiazole derivatives, substituted in position 5- (compounds 1-7) or 7- (compounds 8-14), with oxypropanolaminic side chains and the pharmacological investigation on their activity at beta-adrenoceptors are described. Compounds were prepared in an attempt to explore the ability of the benzisothiazole ring to interact with the beta-adrenoceptor site and to establish whether oxypropanolaminic derivatives recognise the beta3-adrenoceptor subtype. All the products were tested on rat atria, bladder and small intestine, which preferentially (but not exclusively) express beta1-, beta2- and beta3-adrenoceptors, respectively. When compared with the reference, non-specific, beta-adrenoceptor agonist isoprenaline, the products tested did not show any consistent beta-adrenoceptor agonistic activity in the different models. Most compounds relaxed smooth muscle preparations, but such effect was resistant to the blockade by propranolol (1 micromol/l), ICI 118,551 (1 micromol/l) or bupranolol (1-10 micromol/l), thus excluding that the spasmolytic effect involves any beta-adrenoceptors. When tested as antagonists, some of these products showed a concentration-dependent attenuation of the isoprenaline-induced effects in rat atria, without affecting beta-adrenoceptor-mediated relaxation in smooth muscle. These data confirm the ability of the benzisothiazole ring to interact with beta-adrenoceptors, but the substitution in 5- or 7-positions with oxypropanolaminic groups does not generate compounds endowed with specific activity at beta3-adrenoceptors. Conversely, most of these compounds behave as (specific) antagonists at beta1- (cardiac) adrenoceptors. At the maximum concentrations tested (1-100 micromol/l), these compounds also exert direct spasmolytic and negative chronotropic effects, which could be related to a blockade of Ca2+-dependent mechanisms at an intracellular level and/or an anaesthetic-like activity at plasma membranes.

  1. How important is the α1-adrenoceptor in primate and rodent proximal urethra? Sex differences in the contribution of α1-adrenoceptor to urethral contractility.

    Science.gov (United States)

    Alexandre, Eduardo C; de Oliveira, Mariana G; Campos, Rafael; Kiguti, Luiz R; Calmasini, Fabiano B; Silva, Fábio H; Grant, Andrew D; Yoshimura, Naoki; Antunes, Edson

    2017-06-01

    Urethral smooth muscle (USM) contributes to urinary continence by contracting during the urine storage phase, which is mainly mediated by activation of postjunctional α 1 -adrenoceptors. Males and females show differences in the functioning of the lower urinary tract and the most common urinary tract symptoms (LUTS). LUTS in men typically occur in association with bladder outlet obstruction, whereas in women urinary urge-incontinence symptoms are more common. Therefore, this study aimed to evaluate sex differences in α 1 -adrenoceptor subtype expression and their importance in proximal urethra contraction in the mouse (C57BL6/J) and marmoset ( Callithrix jacchus ). Contractile responses to phenylephrine, norepinephrine, potassium chloride (KCl), and electrical-field stimulation (EFS) were evaluated. Phenylephrine, norepinephrine, KCl, and EFS produced markedly greater contractions in male mice and marmoset USM compared with females. The sex differences remained unchanged by N ω -nitro-l-arginine (l-NAME; nitric oxide synthase inhibitor), atropine (muscarinic receptor antagonist), and PPADS (P2X1-purinoceptor antagonist). Additionally, selective α 1A (but not α 1B - and α 1D -)-adrenoceptor antagonists significantly reduced phenylephrine-induced USM contractions. qRT-PCR for α 1A -, B -, and D -adrenoceptor subtypes revealed a marked presence of the α 1A -adrenoceptor subtype in male USM, but not females. Male mouse urethra also exhibited a higher tyrosine hydroxylase mRNA expression. Histomorphometric analysis showed a greater USM area in male than female mice. In conclusion, male mouse and marmoset proximal USM shows strong α 1A - adrenoceptor-induced contractions and abundant α 1A -adrenoceptor expression, whereas α 1A -adrenoceptor-mediated mechanisms are much less important in females. The differential expression of α 1 -adrenoceptors in the proximal urethra may contribute to the higher incidence of urinary incontinence in women and obstructed

  2. Computer-Assisted Determination of Minimum Energy Conformations. 7. A pharmacophore Model of the Active Region of the Alpha2-Adrenoceptor.

    Science.gov (United States)

    1992-09-01

    helpful discussions on the adrenergic system; Fu-Lian Hsu, Research Directorate, CRDEC, for his advice on synthesis and chemical interactions; Duane...Miller and Yoshiya Amomiya, Ohio State University, Columbus, OH, for their assistance in the synthesis of suggested alpha2- adrenergic compounds...Preferred Conformations of Ephedrine Isomers and the Nature of the Alpha Adrenergic Receptor," J. Pharmacol. Exp. Ther. Vol. 164 (1), pp 75-81 (1968). 24

  3. 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...... 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......-regulation of endogenous HIF-1alpha and vascular endothelial growth factor in the liver. The effect can last for days after administration of single dose of EZN-2968 and is associated with long residence time of locked nucleic acid in certain tissues. In efficacy studies, tumor reduction was found in nude mice implanted...

  4. Preservation of the positive lusitropic effect of beta-adrenoceptors stimulation in diabetic cardiomyopathy.

    Science.gov (United States)

    Amour, Julien; Loyer, Xavier; Michelet, Pierre; Birenbaum, Aurélie; Riou, Bruno; Heymes, Christophe

    2008-10-01

    In diabetic cardiomyopathy, diastolic dysfunction results in part from sarcoplasmic reticulum abnormalities affecting both phospholamban and sarcoplasmic reticulum Ca2+ uptake (SERCA2a). Consequently, the positive lusitropic effect of beta-adrenoceptors stimulation could be altered, and beta3-adrenoceptor over-expression may play a role, as previously demonstrated with an altered positive inotropic effect. In this study, we tested the hypothesis that the beta-adrenergic positive lusitropic effect is altered in diabetic cardiomyopathy, and that beta3-adrenoceptor over-expression is involved. beta-adrenergic responses were investigated in vivo (dobutamine-echocardiography) and in vitro (papillary muscle preparation) in healthy and diabetic rats killed 4 (4W) and 12 (12W) wk after IV streptozotocin injection. The effect of beta3-adrenoceptor pathway inhibition by S-cyanopindolol (selective beta3-adrenoceptor antagonist) or by NG-nitro-L-arginine-methyl-ester (nonselective nitric oxide synthase inhibitor) on the lusitropic response to isoproterenol (nonselective beta-adrenoceptors agonist) was studied in vitro. Western blots were performed to quantify the protein expressions of beta1- and beta3-adrenoceptors, phospholamban, and SERCA2a. Data are presented as mean percentages of baseline+/-sd. Despite the increased phospholamban/SERCA2a protein ratio and documented diastolic dysfunction, the positive lusitropic effect of beta-adrenoceptors stimulation was preserved in vivo (dobutamine) and in vitro (isoproterenol) in 4W and 12W diabetic, compared with healthy, rats. The beta3-adrenoceptor was up-regulated whereas beta1-adrenoceptor was down-regulated in 4W and 12W diabetic, compared with healthy, rats. Nevertheless, S-cyanopindolol or NG-nitro-L-arginine-methyl-ester had no lusitropic effect. The positive lusitropic effect of beta-adrenoceptor stimulation was preserved in diabetic cardiomyopathy. beta3-adrenoceptor over-expression does not seem to affect this process.

  5. Identification of an endogenous alpha-adrenergic receptor antagonist: studies on its possible role in endocrine and cardiovascular function

    International Nuclear Information System (INIS)

    Dunbar, J.C.; Wider, M.; House, F.; Campbell, R.

    1986-01-01

    The concept of α and β adrenergic receptors that are regulated by epinephrine or norepinephrine (NE) is well established. The reported receptor antagonists have been synthetic. A peptide extracted from the duodenal mucosa with α-2 antagonist properties has been identified. It specifically inhibits 3 H-yohimbine binding (α-2) but not 3 H dihydroalprenolol (β) binding in whole brain membranes. Partially purified preparations of the alpha receptor binding inhibitor (ABI) were tested for endocrine pancreatic and cardiovascular effects. When isolated islets were incubated in the presence of ABI with and without NE, ABI along did not alter insulin secretion but completely reversed the NE suppression of glucose stimulated insulin release. Glucagon secretion by these same islets was enhanced by ABI and augmented the stimulatory effect of NE. Intravenous (I.V.) infusion of ABI increased serum insulin in the presence of NE and decreased the serum glucose response to a glucose load. Infusion of ABI into the 4th ventricle, or I.V. resulted in a decrease (50-60%) in systolic and diastolic blood pressure as well as a decrease (10-20%) in heart rate. From these studies the authors conclude that a duodenal peptide with the capacity to inhibit α-2 agonist binding may play a role in endocrine and cardiovascular functions

  6. Comparison of the Intravenous and Epidural Administration of Tumor Necrosis Factor-alpha Antagonists in an Experimental Rat Pain Model

    Science.gov (United States)

    Beyaz, Serbülent Gökhan; İnanmaz, Mustafa Erkan; Ergönenç, Tolga; Palabıyık, Onur; Tomak, Yakup; Tuna, Ayça Taş

    2017-01-01

    Introduction: Inflammatory cytokines secreted from the nucleus pulposus are thought to lead to lumbar nerve root compression-like symptoms. Tumor necrosis factor-alpha (TNF-α), an inflammatory cytokine, likely plays an important role in lumbar disc hernia-related leg pain. In this experimental study, we compared the effectiveness of TNF-α antagonists administered through the intravenous or epidural route in lumbar spine pathologies. Materials and Methods: After ethics committee approval had been obtained, 24 Sprague Dawley male rats aged 70–90 days and weighing 250–300 g each were allocated to four groups. In Group I, only the surgical procedure was performed; in Group II, 1 ml of saline solution was administered into the epidural field; in Group III, 10 mg/kg of infliximab was administered into the coccygeal vein; and in Group IV (epidural group), 25 mg of etanercept was administered into the epidural region. Results: When the left leg pull values were analyzed on day 14, whereas there was not a significant difference among the three groups, a decreasing difference was observed in Group IV (P discopathy, TNF-α antagonists administered epidurally led to earlier recovery from radiculopathy-related allodynia compared to intravenous administration. PMID:29284846

  7. alpha2- to beta3-Adrenoceptor switch in 3T3-L1 preadipocytes and adipocytes: modulation by testosterone, 17beta-estradiol, and progesterone.

    Science.gov (United States)

    Monjo, Marta; Pujol, Esperanza; Roca, Pilar

    2005-07-01

    Sex steroid hormones are important factors in the determination of fat distribution and accumulation. The aim of this study was to investigate the effect of testosterone (T), 17beta-estradiol (17betaE), and progesterone (P) on adrenergic receptor (AR) gene expression in 3T3-L1 preadipocytes and adipocytes and their relation to the proliferation and differentiation processes. Our data clearly show that alpha(2A)-AR was the highest AR subtype expressed in preadipocytes, whereas in mature adipocytes was by far beta(3)-AR. In the differentiation process to adipocytes, alpha(2A)-AR expression was decreased to 0.3-fold (P distribution.

  8. Reactivation of pulmonary tuberculosis (TBC) with the use of antagonist of the tumor necrosis factor alpha (FNTα) in rheumatoid arthritis: On purpose of a case

    International Nuclear Information System (INIS)

    Martinez V, Jose B; Medina V, Yimy F; Parga, Roberto; Restrepo, Jose Felix; Iglesias G, Antonio; Rondon, Federico

    2005-01-01

    Woman 56 years old, with history of rheumatoid arthritis who develops reactivation of pulmonary tuberculosis (TBC) after 1 year of treatment with biological therapy (antagonist of the tumor necrosis factor alpha). It is discussed pathophysiologic mechanisms, diagnostic approach, treatment of TBC and some recommendations for the use of biological therapy in patients with rheumatic disease

  9. Inhibition of [(11)C]mirtazapine binding by alpha(2)-adrenoceptor antagonists studied by positron emission tomography in living porcine brain

    DEFF Research Database (Denmark)

    Smith, Donald F.; Dyve, Suzan; Minuzzi, Luciano

    2006-01-01

    We have developed [(11)C]mirtazapine as a ligand for PET studies of antidepressant binding in living brain. However, previous studies have determined neither optimal methods for quantification of [(11)C]mirtazapine binding nor the pharmacological identity of this binding. To obtain that informati...

  10. Combined administration of alpha1-adrenoceptor antagonist prazosin and beta-blocker propranolol impairs spatial avoidance learning on a dry arena

    Czech Academy of Sciences Publication Activity Database

    Petrásek, Tomáš; Doulames, Vanessa; Prokopová, Iva; Valeš, Karel; Stuchlík, Aleš

    2010-01-01

    Roč. 208, č. 2 (2010), s. 402-407 ISSN 0166-4328 R&D Projects: GA ČR(CZ) GA309/07/0341; GA ČR(CZ) GA309/09/0286; GA MŠk(CZ) 1M0517; GA MŠk(CZ) LC554; GA ČR(CZ) GCP303/10/J032 Institutional research plan: CEZ:AV0Z50110509 Keywords : Prazosin * propranolol * learning Subject RIV: FH - Neurology Impact factor: 3.393, year: 2010

  11. β2-Adrenoceptors and non-β-adrenoceptors mediate effects of BRL37344 and clenbuterol on glucose uptake in soleus muscle: studies using knockout mice

    Science.gov (United States)

    Ngala, Robert A; O'Dowd, Jacqueline; Wang, Steven J; Stocker, Claire; Cawthorne, Michael A; Arch, Jonathan RS

    2009-01-01

    Background and purpose: In previous work, 10 pM BRL37344 and 10 pM clenbuterol stimulated glucose uptake in mouse soleus muscle. Ten nM BRL37344 also stimulated uptake but 100 nM clenbuterol inhibited uptake. Antagonist studies suggested that the opposite effects of 10 nM BRL37344 and 100 nM clenbuterol are mediated by the β2-adrenoceptor. BRL37344 and clenbuterol have been studied in muscles that lack β3-, β2- or all three β-adrenoceptors. Effects of β-adrenoceptor antagonists on responses to the agonists have been studied further using muscles from wild-type mice. Experimental approach: Soleus muscles of wild-type or β-adrenoceptor knockout mice were incubated with 2-deoxy[1-14C]-glucose, and β-adrenoceptor ligands. Formation of 2-deoxy[1-14C]-glucose-6-phosphate was measured. Key results: Concentration–response relationships were similar for BRL37344 and clenbuterol in normal muscle and muscle lacking β3-adrenoceptors. Ten pM BRL37344 and clenbuterol stimulated glucose uptake in muscle lacking β2-adrenoceptors or all three β-adrenoceptors, but 10 nM BRL37344 did not stimulate uptake in either case, and 100 nM clenbuterol stimulated, rather than inhibited, uptake in muscle lacking β2-adrenoceptors. One hundred nM clenbuterol also stimulated glucose uptake in normal muscle when β2-adrenoceptors were blocked with ICI118551, and this was not prevented by antagonism of β1- or β3-adrenoceptors. Conclusions and implications: Ten nM BRL37344 and 100 nM clenbuterol have opposite effects on glucose uptake but both effects are mediated by the β2-adrenoceptor – apparently an example of agonist-directed signalling. Ten pM BRL37344, 10 pM clenbuterol and 100 nM clenbuterol in the presence of ICI118551 stimulate glucose uptake via β-adrenoceptor-independent mechanisms, demonstrating unknown properties for the agonists. PMID:19912225

  12. Characterization of rat cerebral cortical beta adrenoceptor subtypes using (-)-[125I]-iodocyanopindolol

    International Nuclear Information System (INIS)

    Tiong, A.H.; Richardson, J.S.

    1990-01-01

    (-)-[125I]-Iodocyanopindolol [-(ICYP)], used to characterize beta adrenoceptors on membrane preparations from rat cerebral cortex, was shown to have affinity for both beta adrenoceptors and serotonin receptors. Therefore, 10 microM serotonin was added to the assays to prevent (-)ICYP binding to serotonin receptors. Under these conditions, (-)ICYP binding to the cortical membrane preparation was reversible and saturable, and the association reaction was very slow. The dissociation reaction was also very slow, and revealed two affinity states corresponding to a high and a low affinity state. Scatchard analysis showed a single class of binding sites with an equilibrium dissociation constant (KD) of 20.7 pM, and a maximal density of binding sites (Bmax) of 95.1 fmol/mg membrane protein. Displacement binding analyses revealed a potency series of (-) isoproterenol greater than (-) epinephrine equal to (-) norepinephrine, suggesting a predominance of the beta 1 adrenoceptor subtype. Detailed competition ligand binding studies with the selective beta 1 adrenoceptor antagonist ICI-89406 and the selective beta 2 adrenoceptor antagonist ICI-118551, showed that about 70% of the beta adrenoceptor population in the rat cortex is of the beta 1 subtype with the remainder being of the beta 2 subtype. We conclude that since (-)ICYP binds to both beta adrenoceptors and serotonin receptors, it is important to prevent the binding of (-)ICYP to serotonin receptors by adding a suppressing ligand like excess cold serotonin when assaying beta adrenoceptors. We have presented the first such characterization of rat cerebral cortical beta adrenoceptors with (-)ICYP in this study

  13. The effects of dexamethasone and chlorpromazine on tumour necrosis factor-alpha, interleukin-1 beta, interleukin-1 receptor antagonist and interleukin-10 in human volunteers.

    Science.gov (United States)

    Bleeker, M W; Netea, M G; Kullberg, B J; Van der Ven-Jongekrijg, J; Van der Meer, J W

    1997-01-01

    Tumour necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) are pro-inflammatory cytokines that play an important role in severe infections, whereas IL-1 receptor antagonist (IL-1ra) and IL-10 are anti-inflammatory cytokines that counteract their effects. Chlorpromazine and dexamethasone protect mice against lethal endotoxaemia by decreasing circulating concentrations of TNF-alpha and IL-1 beta. We investigated whether administration of chlorpromazine or dexamethasone to human volunteers is able to modulate the lipopolysaccharide (LPS)-stimulated cytokine production capacity in whole blood. Blood samples were taken before and several time-points after medication. Circulating cytokine concentrations were low in all samples. LPS-induced TNF-alpha and IL-1 beta production in whole blood was inhibited by dexamethasone treatment, while chlorpromazine had no effect. When peripheral blood mononuclear cells were stimulated in vitro with LPS, the addition of chlorpromazine (1-100 ng/ml) had no modulatory action on TNF-alpha, IL-1 beta, IL-1ra or IL-10 synthesis. The chlorpromazine concentrations measured in circulation of volunteers were eight to 40 times lower than the concentrations shown to be effective in mice. In conclusion, chlorpromazine inhibits TNF-alpha and IL-1 beta production in mice at concentrations that cannot be reached in humans, thus precluding its usage in clinical anti-cytokine strategies. In contrast, dexamethasone is an effective inhibitor of pro-inflammatory cytokine production. PMID:9378493

  14. Contribution of α-adrenoceptors to depolarization and contraction evoked by continuous asynchronous sympathetic nerve activity in rat tail artery

    Science.gov (United States)

    Brock, J A; McLachlan, E M; Rayner, S E

    1997-01-01

    The effects of continuous but asynchronous nerve activity induced by ciguatoxin (CTX-1) on the membrane potential and contraction of smooth muscle cells have been investigated in rat proximal tail arteries isolated in vitro. These effects have been compared with those produced by the continuous application of phenylephrine (PE).CTX-1 (0.4 nM) and PE (10 μM) produced a maintained depolarization of the arterial smooth muscle that was almost completely blocked by α-adrenoceptor blockade. In both cases, the depolarization was more sensitive to the selective α2-adrenoceptor antagonist, idazoxan (0.1 μM), than to the selective α1-adrenoceptor antagonist, prazosin (0.01 μM).In contrast, the maintained contraction of the tail artery induced by CTX-1 (0.2 nM) and PE (2 and 10 μM) was more sensitive to prazosin (0.01) μM, than to idazoxan (0.01 μM). In combination, these antagonists almost completely inhibited contraction to both agents.Application of the calcium channel antagonist, nifedipine (1 μM), had no effect on the depolarization induced by either CTX-1 or PE but maximally reduced the force of the maintained contraction to both agents by about 50%.We conclude that the constriction of the tail artery induced by CTX-1, which mimics the natural discharge of postganglionic perivascular axons, is due almost entirely to α-adrenoceptor activation. The results indicate that neuronally released noradrenaline activates more than one α-adrenoceptor subtype. The depolarization is dependent primarily on α2-adrenoceptor activation whereas the contraction is dependent primarily on α1-adrenoceptor activation. The links between α-adrenoceptor activation and the voltage-dependent and voltage-independent mechanisms that deliver Ca2+ to the contractile apparatus appear to be complex. PMID:9113373

  15. Effects of chronic delta-9-THC treatment on cardiac beta-adrenoceptors in rats

    Energy Technology Data Exchange (ETDEWEB)

    Evans, E.B.; Seifen, E.; Kennedy, R.H.; Kafiluddi, R.; Paule, M.G.; Scallet, A.C.; Ali, S.F.; Slikker, W. Jr.

    1987-10-01

    This study was designed to determine if chronic treatment with delta-9-tetrahydrocannabinol (THC) alters cardiac beta-adrenoceptors in the rat. Following daily oral administration of 10 or 20 mg/kg THC or an equivalent volume of control solvent for 90 days, rats were sacrificed, and sarcolemmal membranes were prepared from ventricular myocardium. Beta-adrenoceptor density and binding affinity estimated with (-)(/sup 3/H)dihydroalprenolol; a beta-adrenergic antagonist, were not significantly affected by treatment with THC when compared to vehicle controls. These results suggest that the tolerance to cardiovascular effects of THC which develops during chronic exposure in the rat is not associated with alterations in cardiac beta-adrenoceptors as monitored by radiolabeled antagonist binding.

  16. Nutrition, anthropometry, gastrointestinal dysfunction, and circulating levels of tumour necrosis factor alpha receptor I and interleukin-1 receptor antagonist in children during stem cell transplantation

    DEFF Research Database (Denmark)

    Andreassen, B. U.; Pærregaard, Anders; Michaelsen, Kim F.

    2008-01-01

    To evaluate anthropometry, nutrition and gastrointestinal dysfunction, and to characterize the relation between these parameters and the inflammatory activity evaluated by plasma levels of soluble tumour necrosis factor alpha receptor I (sTNFRI) and interleukin-1 receptor antagonist (IL-1Ra) levels...... during stem cell transplantation (SCT) in children. Clinical assessments and blood sampling were performed on days -3, 0, +7, +15 and +31 in eight children undergoing SCT. Energy intake, anthropometry, gastrointestinal dysfunction (WHO toxicity score) and sTNFRI and IL-1Ra were evaluated. The energy...

  17. Polymorphisms of Adrenoceptors are Not Associated With an Increased Risk of Adverse Event in Heart Failure : A MERIT-HF Substudy

    NARCIS (Netherlands)

    Savva, Jacqueline; Maqbool, Azhar; White, Hazel L.; Galloway, Stacey L.; Yuldasheva, Nadira Y.; Ball, Stephen G.; West, Robert M.; De Boer, Rudolf A.; Van Veldhuisen, Dirk J.; Balmforth, Anthony J.

    Background: Enhanced sympathetic activation has a central role in the development of heart failure (HF). We assessed whether the alpha(2C)-adrenoceptor (Del322-325) polymorphism exclusively or in combination with a beta(1)-adrenoceptor (Arg389) polymorphism, each with known independent effects oil

  18. Xamoterol, a new selective beta-1-adrenoceptor partial agonist, in the treatment of postural hypotension

    DEFF Research Database (Denmark)

    Mehlsen, J; Trap-Jensen, J

    1986-01-01

    Three patients severely disabled from postural hypotension were treated with xamoterol, a selective beta-1-adrenoceptor antagonist with a high degree of partial agonist activity. Oral treatment (200 mg b.i.d.) was chosen on the basis of the effects of acute intravenous administration of xamoterol...

  19. Β-adrenoceptors in the hypothalamic paraventricular nucleus modulate the baroreflex in conscious rats.

    Science.gov (United States)

    Wang, Dan; Feng, Hao; Li, Ying-Shun; Qiu, De-Lai; Jin, Hua; Jin, Qing-Hua

    2013-09-13

    The role of β-adrenoceptors of the hypothalamic paraventricular nucleus (PVN) in modulation of the baroreflex was investigated in conscious rats. The baroreflex was induced by intravenous injection of phenylephrine, and then the extracellular concentration of norepinephrine in the PVN region determined using microdialysis and high-performance liquid chromatography. Next, the role of the β-adrenoceptor in modulation of the baroreflex was investigated by perfusion of its antagonist or agonist into the PVN using microdialysis. Intravenous injection of phenylephrine increased the norepinephrine concentration in the PVN by 35.83 ± 5.71%. Propranolol (an antagonist of the β-adrenoceptor) significantly decreased the gain of reflex bradycardia, but did not affect the magnitude of blood-pressure increases in the baroreflex, resulting in reduced baroreflex sensitivity. Isoprenaline (an agonist of the β-adrenoceptor) significantly increased the gain of reflex bradycardia without affecting blood-pressure increases, leading to increased baroreflex sensitivity. Our results suggest that norepinephrine in the PVN facilitates the phenylephrine-induced baroreflex via β-adrenoceptors. Copyright © 2013. Published by Elsevier Ireland Ltd.

  20. Sepsis causes presynaptic histamine H3 and alpha2-adrenergic dysfunction in canine myocardium.

    Science.gov (United States)

    Cheng, Zao-Qin; Bose, Deepak; Jacobs, Han; Light, R Bruce; Mink, Steven N

    2002-11-01

    Histamine H3 receptors and alpha2-adrenoceptors are presynaptic receptors that modulate norepinephrine (NE) release from sympathetic nerves innervating the cardiovascular system. We previously showed that cardiac H3 receptors are activated in sepsis, and that this activation leads to a decrease in the adrenergic response (AR) [J. Appl. Physiol. 85 (1998) 1693-1701] H3-receptors and alpha2-receptors appear to be coupled to GTP binding regulatory proteins (G) that modulate transmitter release by reducing calcium current into the nerve terminals through neuronal calcium channels. There may also be interaction between H3-receptors and alpha2-receptors on AR that may occur either at the receptor or a more downstream level. In the present study, we examined the effect of septic plasma on AR in a canine ventricular preparation in which field stimulation was used to produce AR. We determined whether there was interaction between H(3)-receptors and alpha2-adrenoceptors and tested whether H3 activation would attenuate the alpha2-agonist and alpha2-antagonist effects of clonidine and yohimbine, respectively. We also determined whether the mechanism by which septic plasma decreases the adrenergic response involves inactivation of an inhibitory G protein and used pertussis toxin (PTX) to assess this effect. We found that septic plasma attenuated AR produced by field stimulation, and that this decrease was mediated by a PTX sensitive inhibitory G protein. H3 activation also attenuated the alpha2-agonist and alpha2-antagonist effects on adrenergic activation as compared with nonseptic plasma. We conclude that presynaptic sympathetic dysfunction may contribute to cardiovascular collapse in sepsis.

  1. Altered contractile response due to increased beta3-adrenoceptor stimulation in diabetic cardiomyopathy: the role of nitric oxide synthase 1-derived nitric oxide.

    Science.gov (United States)

    Amour, Julien; Loyer, Xavier; Le Guen, Morgan; Mabrouk, Nejma; David, Jean-Stéphane; Camors, Emmanuel; Carusio, Nunzia; Vivien, Benoît; Andriantsitohaina, Ramaroson; Heymes, Christophe; Riou, Bruno

    2007-09-01

    In the diabetic heart, the positive inotropic response to beta-adrenoceptor stimulation is altered and beta1 and beta2 adrenoceptors are down-regulated, whereas beta3 adrenoceptor is up-regulated. In heart failure, beta3-adrenoceptor stimulation induces a negative inotropic effect that results from endothelial nitric oxide synthase (NOS3)-derived nitric oxide production. The objective of our study was to investigate the role of beta3-adrenoceptor in diabetic cardiomyopathy. beta-Adrenergic responses were investigated in vivo (dobutamine echocardiography) and in vitro (left ventricular papillary muscle) in healthy and streptozotocin-induced diabetic rats. The effect of beta3-adrenoceptor inhibition on the inotropic response was studied in vitro. Immunoblots and NOS activities were performed in heart homogenates (electron paramagnetic resonance) and isolated cardiomyocytes. Data are mean percentage of baseline +/- SD. The impaired positive inotropic effect was confirmed in diabetes both in vivo (121 +/- 15% vs. 160 +/- 16%; P < 0.05) and in vitro (112 +/- 5% vs. 179 +/- 15%; P < 0.05). In healthy rat, the positive inotropic effect was not significantly modified in presence of beta3-adrenoceptor antagonist (174 +/- 20%), nonselective NOS inhibitor (N -nitro-l-arginine methylester [l-NAME]; 183 +/- 19%), or selective NOS1 inhibitor (vinyl-l-N-5-(1-imino-3-butenyl)-l-ornithine [l-VNIO]; 172 +/- 13%). In diabetes, in parallel with the increase in beta3-adrenoceptor protein expression, the positive inotropic effect was partially restored by beta3-adrenoceptor antagonist (137 +/- 8%; P < 0.05), l-NAME (133 +/- 11%; P < 0.05), or l-VNIO (130 +/- 13%; P < 0.05). Nitric oxide was exclusively produced by NOS1 within diabetic cardiomyocytes. NOS2 and NOS3 proteins were undetectable. beta3-Adrenoceptor is involved in altered positive inotropic response to beta-adrenoceptor stimulation in diabetic cardiomyopathy. This effect is mediated by NOS1-derived nitric oxide in diabetic

  2. Low-dose methotrexate - a therapeutical kick in TNF-alpha antagonist treatment for recalcitrant psoriasis vulgaris.

    Science.gov (United States)

    Wilsmann-Theis, Dagmar; Fronhoffs, Kristina; Ehler, Lin-Kristin; Wenzel, Joerg; Bieber, Thomas; Klingmueller, Karin

    2014-01-01

    In contrast to the treatment of rheumatoid arthritis, there are few data in psoriasis vulgaris regarding the efficacy of combining tumor necrosis factor (TNF)-alpha inhibitors and methotrexate (MTX). Indeed, combination of MTX with different TNF-alpha inhibitors may enhance the therapeutic effects and reduce side effects because of less dosage of the single agent. The present authors present five cases in which low-dose MTX combined with TNF-alpha inhibitors led to impressive improvement in Psoriasis Area and Severity Index scores. Here, the present authors initiated very low-dose MTX treatment in addition to existing TNF-alpha inhibitor therapy to exhaust current therapy and prevent premature change of the biologic. These observations support the concept of combined treatment in recalcitrant cases of psoriasis, which need a systemically lifelong treatment when both first-line and second-line monotherapies fail to provide sufficient clinical response. © 2013 Wiley Periodicals, Inc.

  3. Role of beta adrenoceptors in the hypertrophic response to thyroxine

    International Nuclear Information System (INIS)

    Eliades, D.; Weiss, H.R.

    1989-01-01

    The ability of beta-adrenoceptor blockade to reduce the hypertrophic response to thyroxine (T4, 0.5 mg/kg per day, s.c.) was tested in New Zealand white rabbits. Two beta-adrenergic blocking agents, one a full antagonist (propranolol, 9.6 mg/kg per day) and the other a partial agonist (pindolol, 0.96 mg/kg per day) were administered in combination with T4 in an effort to reduce myocardial hypertrophy. A 3 and 16 day group were generated to test the time course of the hypertrophic and receptor responses. Coronary blood flow was measured using radioactive microspheres, and beta-adrenoceptor number and affinity were measured using 125I(-) pindolol as the radioligand. T4 increased coronary blood flow to 1.95 times control values in the 3 day group and 2.2 times control levels in the 16 day group; beta-adrenoceptor number was increased similarly in 3 and 16 day groups to 1.9 times control Bmax levels. Heart weight (HW) to body weight (BW) ratios were significantly increased in only the 16 day group to 1.22 and 1.61 times control, respectively. Treatment with propranolol + T4 blunted the coronary blood flow increase, but receptor upregulation occurred to the same extent as with either substance alone. The HW/BW was increased to 1.49 times control. Pindolol + T4 did not decrease coronary blood flow but blocked beta-adrenoceptor upregulation. The HW was reduced to control levels and the HW/BW ratio was 1.40 times control and significantly decreased from T4 alone. Thus, pindolol was effective in reducing the hypertrophic response to T4, whereas propranolol was only moderately effective in doing so

  4. Activation of Spinal α2-Adrenoceptors Using Diluted Bee Venom Stimulation Reduces Cold Allodynia in Neuropathic Pain Rats

    Directory of Open Access Journals (Sweden)

    Suk-Yun Kang

    2012-01-01

    Full Text Available Cold allodynia is an important distinctive feature of neuropathic pain. The present study examined whether single or repetitive treatment of diluted bee venom (DBV reduced cold allodynia in sciatic nerve chronic constriction injury (CCI rats and whether these effects were mediated by spinal adrenergic receptors. Single injection of DBV (0.25 or 2.5 mg/kg was performed into Zusanli acupoint 2 weeks post CCI, and repetitive DBV (0.25 mg/kg was injected for 2 weeks beginning on day 15 after CCI surgery. Single treatment of DBV at a low dose (0.25 mg/kg did not produce any anticold allodynic effect, while a high dose of DBV (2.5 mg/kg significantly reduced cold allodynia. Moreover, this effect of high-dose DBV was completely blocked by intrathecal pretreatment of idazoxan (α2-adrenoceptor antagonist, but not prazosin (α1-adrenoceptor antagonist or propranolol (nonselective β-adrenoceptor antagonist. In addition, coadministration of low-dose DBV (0.25 mg/kg and intrathecal clonidine (α2-adrenoceptor agonist synergically reduced cold allodynia. On the other hand, repetitive treatments of low-dose DBV showing no motor deficit remarkably suppressed cold allodynia from 7 days after DBV treatment. This effect was also reversed by intrathecal idazoxan injection. These findings demonstrated that single or repetitive stimulation of DBV could alleviate CCI-induced cold allodynia via activation of spinal α2-adrenoceptor.

  5. Characterising the mechanism of airway smooth muscle β2 adrenoceptor desensitization by rhinovirus infected bronchial epithelial cells.

    Directory of Open Access Journals (Sweden)

    David Van Ly

    Full Text Available Rhinovirus (RV infections account for approximately two thirds of all virus-induced asthma exacerbations and often result in an impaired response to β2 agonist therapy. Using an in vitro model of RV infection, we investigated the mechanisms underlying RV-induced β2 adrenoceptor desensitization in primary human airway smooth muscle cells (ASMC. RV infection of primary human bronchial epithelial cells (HBEC for 24 hours produced conditioned medium that caused β2 adrenoceptor desensitization on ASMCs without an effect on ASMCs viability. Less than 3 kDa size fractionation together with trypsin digestion of RV-induced conditioned medium did not prevent β2 adrenoceptor desensitization, suggesting it could potentially be mediated by a small peptide or lipid. RV infection of BECs, ASMCs and fibroblasts produced prostaglandins, of which PGE2, PGF2α and PGI2 had the ability to cause β2 adrenoceptor desensitization on ASMCs. RV-induced conditioned medium from HBECs depleted of PGE2 did not prevent ASMC β2 adrenoceptor desensitization; however this medium induced PGE2 from ASMCs, suggesting that autocrine prostaglandin production may be responsible. Using inhibitors of cyclooxygenase and prostaglandin receptor antagonists, we found that β2 adrenoceptor desensitization was mediated through ASMC derived COX-2 induced prostaglandins. Since ASMC prostaglandin production is unlikely to be caused by RV-induced epithelial derived proteins or lipids we next investigated activation of toll-like receptors (TLR by viral RNA. The combination of TLR agonists poly I:C and imiquimod induced PGE2 and β2 adrenoceptor desensitization on ASMC as did the RNA extracted from RV-induced conditioned medium. Viral RNA but not epithelial RNA caused β2 adrenoceptor desensitization confirming that viral RNA and not endogenous human RNA was responsible. It was deduced that the mechanism by which β2 adrenoceptor desensitization occurs was by pattern recognition receptor

  6. Apoptosis and the FLIP and NF-kappa B proteins as pharmacodynamic criteria for biosimilar TNF-alpha antagonists

    Directory of Open Access Journals (Sweden)

    Urbano PCM

    2014-07-01

    Full Text Available Paulo César Martins Urbano,1 Vanete Thomaz Soccol,1 Valderilio Feijó Azevedo2 1Biotechnology and Bioprocess Engineering Program, Federal University of Parana, Curitiba, Parana, Brazil; 2Hospital de Clínicas, Federal University of Parana, Curitiba, Parana, Brazil Abstract: Various criteria are necessary to assess the efficacy and safety of biological medications in order to grant companies the right to register these medications with the appropriate bodies that regulate their sale. The imminent expiration of the patents on reference biological products which block the cytokine TNF-α (tumor necrosis factor-α raises the possibility of bringing so-called biosimilars to the market (similar to the biologicals of reference products. This occurrence is inevitable, but criteria to adequately evaluate these medications are now needed. Even among controversy, there is a demand from publications correlating the pro-apoptotic mechanism of the original TNF-α antagonists (etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol in the treatment of rheumatoid arthritis and other diseases. In this article, the authors discuss the possibility of utilizing the pro-apoptotic effect correlated with the regulation of the anti-apoptotic proteins FLIP and NF-κB as new criteria for analyzing the pharmacodynamics of possible biosimilar TNF-α antagonists which should be submitted to regulatory agencies for evaluation. Keywords: anti-TNF drugs, rheumatoid arthritis, apoptosis, NF-κB, FLIP

  7. The beta 2-adrenoceptor agonists clenbuterol and salbutamol enhance the hypothermic action of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) in mice by a central mechanism.

    Science.gov (United States)

    Green, A R; Goodwin, G M; De Souza, R J; Heal, D J

    1986-01-01

    The hypothermic response of mice to injection of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) was enhanced by injection of the beta 2-adrenoceptor agonist clenbuterol with an ED50 of 0.4 mg/kg. This effect of clenbuterol is through a central mechanism since salbutamol, a beta 2-adrenoceptor agonist with poor penetration into the brain, had no effect at a dose of 2 mg/kg, whereas intracerebroventricular injection of clenbuterol (3 micrograms) or salbutamol (2 micrograms), produced a significant enhancement. The enhancing effect of clenbuterol was unaffected by pretreatment with the beta 1-adrenoceptor antagonist metoprolol but was totally antagonised by the beta 2-adrenoceptor antagonist ICI 118,551 and to a lesser extent by butoxamine. Clenbuterol therefore enhances the function of the presynaptic 5-HT1 receptor through a beta 2-adrenoceptor mechanism.

  8. Discovery, SAR, and Radiolabeling of Halogenated Benzimidazole Carboxamide Antagonists as Useful Tools for (alpha)4(beta)1 Integrin Expressed on T- and B-cell Lymphomas

    Energy Technology Data Exchange (ETDEWEB)

    Carpenter, R D; Natarajan, A; Lau, E Y; Andrei, M; Solano, D M; Lightstone, F C; DeNardo, S J; Lam, K S; Kurth, M J

    2010-02-08

    The cell surface receptor {alpha}{sub 4}{beta}{sub 1} integrin is an attractive yet poorly understood target for selective diagnosis and treatment of T- and B-cell lymphomas. This report focuses on the rapid microwave preparation of medicinally pertinent benzimidazole heterocycles, structure-activity relationships (SAR) of novel halobenzimidazole carboxamide antagonists 3-6, and preliminary biological evaluation of radioiodinated agents 7, 8, and 18. The I-125 derivative 18 had good tumor uptake (12 {+-} 1% ID/g at 24 h; 4.5 {+-} 1% ID/g at 48 h) and tumor:kidney ratio ({approx}4:1 at 24 h; 2.5:1 at 48 h) in xenograft murine models of B-cell lymphoma. Molecular homology models of {alpha}{sub 4}{beta}{sub 1} integrin have predicted that docked halobenzimidazole carboxamides have the halogen atom in a suitable orientation for halogen-hydrogen bonding. These high affinity ({approx} pM binding) halogenated ligands are attractive tools for medicinal and biological use; the fluoro and iodo derivatives are potential radiodiagnostic ({sup 18}F) or radiotherapeutic ({sup 131}I) agents, whereas the chloro and bromo analogues could provide structural insight into integrin-ligand interactions through photoaffinity cross-linking/mass spectroscopy experiments, as well as co-crystallization X-ray studies.

  9. Decrease in rat cardiac beta1- and beta2- adrenoceptors by training and endurance exercise

    International Nuclear Information System (INIS)

    Werle, E.O.; Strobel, G.; Weicker, H.

    1990-01-01

    The cardiac β-adrenoceptor adaptation to physical activity was investigated in rats which were subjected to a six-week endurance swimming training (ET; n=7) and a training of high intensity (MT; n=7). In addition, the effect of a single bout of endurance exercise without preceding training (EE; n=7) was evaluated. These groups were compared with a sedentary control group (C; n=9). Beta-adrenergic receptors in rat myocardial membranes were labelled using the high affinity antagonist radioligand (-) 125 iodocyanopindolol (ICYP). Computer modelling techniques provided estimates of the maximal binding capacity (B max ) and the dissociation constants (K D ). Tissue was constantly kept at temperatures of ≤4 degrees C and incubated at 4 degrees C for 18 h in buffer containing 100 μM GTP so as to prevent masking of β-adrenoceptors by endogenous norepinephrine. In comparison with the C group computerized coanalyses of saturation binding data of ET, MT, and EE revealed a 13.0%, 25.5%, and 16.6% decrease in B max , respectively, without significantly differing K D values. We provide the first evidence that acute exercise lowers the sarcolemmal β-adrenoceptor number in the rat heart. In the competition radioligand binding, CGP20712A and ICI118.551 were employed as subtype-selective antagonists of β 1 - and β 2 -adrenoceptors, respectively, to determine the relative proportions of the receptor subtypes

  10. Lymphocyte beta 2-adrenoceptors mirror precisely beta 2-adrenoceptor, but poorly beta 1-adrenoceptor changes in the human heart

    NARCIS (Netherlands)

    Michel, M. C.; Beckeringh, J. J.; Ikezono, K.; Kretsch, R.; Brodde, O. E.

    1986-01-01

    To study the relationship of changes in human lymphocyte beta-adrenoceptors to changes potentially occurring in solid tissues we studied 16 patients undergoing elective coronary artery bypass grafting and determined the density of lymphocyte beta 2-adrenoceptors [by (-)125I-iodocyanopindolol (ICYP)

  11. β2-adrenoceptor blockage induces G1/S phase arrest and apoptosis in pancreatic cancer cells via Ras/Akt/NFκB pathway

    Directory of Open Access Journals (Sweden)

    Zhang Dong

    2011-11-01

    Full Text Available Abstract Background Smoking and stress, pancreatic cancer (PanCa risk factors, stimulate nitrosamine 4-(methylnitrosamino-1-(3-pyridyl-1-butanone (NNK and catecholamines production respectively. NNK and catecholamine bind the β-adrenoceptors and induce PanCa cell proliferation; and we have previously suggested that β-adrenergic antagonists may suppress proliferation and invasion and stimulate apoptosis in PanCa. To clarify the mechanism of apoptosis induced by β2-adrenergic antagonist, we hypothesize that blockage of the β2-adrenoceptor could induce G1/S phase arrest and apoptosis and Ras may be a key player in PanCa cells. Results The β1 and β2-adrenoceptor proteins were detected on the cell surface of PanCa cells from pancreatic carcinoma specimen samples by immunohistochemistry. The β2-adrenergic antagonist ICI118,551 significantly induced G1/S phase arrest and apoptosis compared with the β1-adrenergic antagonist metoprolol, which was determined by the flow cytometry assay. β2-adrenergic antagonist therapy significantly suppressed the expression of extracellular signal-regulated kinase, Akt, Bcl-2, cyclin D1, and cyclin E and induced the activation of caspase-3, caspase-9 and Bax by Western blotting. Additionally, the β2-adrenergic antagonist reduced the activation of NFκB in vitro cultured PanCa cells. Conclusions The blockage of β2-adrenoceptor markedly induced PanCa cells to arrest at G1/S phase and consequently resulted in cell death, which is possibly due to that the blockage of β2-adrenoceptor inhibited NFκB, extracellular signal-regulated kinase, and Akt pathways. Therefore, their upstream molecule Ras may be a key factor in the β2-adrenoceptor antagonist induced G1/S phase arrest and apoptosis in PanCa cells. The new pathway discovered in this study may provide an effective therapeutic strategy for PanCa.

  12. Hemodynamic effects of arotinolol in anesthetized dogs and its affinities for adrenoceptors in vitro.

    Science.gov (United States)

    Hashimoto, H; Asano, M; Hayashi, T; Oguro, K; Takiguchi, Y; Nakashima, M

    1984-01-01

    Hemodynamic actions of arotinolol in anesthetized dogs and its effects on alpha- and beta-adrenoceptors were examined. Arotinolol produced dose-dependent decrease in mean blood pressure, heart rate, cardiac output, maximum rate of left ventricular pressure rise and coronary blood flow in a dose range of 1 microgram/kg-3 mg/kg. Total peripheral resistance (TPR) increased with arotinolol dose-dependently in a dose range of 1 microgram/kg-0.3 mg/kg, but at doses of 1 and 3 mg/kg the increase in TPR was less. Arotinolol at a dose of 10 micrograms/kg significantly inhibited the blood pressure and heart rate responses to isoproterenol. Propranolol at the same dose produced only a slight inhibition of these. Arotinolol at a dose of 3 mg/kg attenuated the pressor response to phenylephrine without any effect on the response to angiotensin-II in anesthetized dogs. Propranolol at the same dose produced only a slight inhibition of the response to phenylephrine. In the study of radioactive ligand binding assays, arotinolol showed high affinities for both beta 1- and beta 2-adrenoceptors. Arotinolol showed an affinity also for alpha 1-adrenoceptors which was comparable to the affinity of yohimbine. Thus, the present results support the idea that arotinolol possesses both alpha- and beta-adrenoceptors blocking effects.

  13. Postvagotomy acid secretion and mucosal blood flow during beta-adrenoceptor stimulation and universal chemical sympathectomy in dogs

    DEFF Research Database (Denmark)

    Hovendal, C P

    1983-01-01

    The aim of the present study was to examine the effect of beta-adrenoceptor stimulation, alpha blockade, and elimination of the adrenergic nerve function on mucosal blood flow and acid secretion in parietal-cell-vagotomized (PCV) gastric fistula dogs. Isoprenaline inhibited pentagastrin-stimulate......The aim of the present study was to examine the effect of beta-adrenoceptor stimulation, alpha blockade, and elimination of the adrenergic nerve function on mucosal blood flow and acid secretion in parietal-cell-vagotomized (PCV) gastric fistula dogs. Isoprenaline inhibited pentagastrin...

  14. Canadian Association of Gastroenterology Clinical Practice Guidelines: The use of tumour necrosis factor-alpha antagonist therapy in Crohn’s disease

    Science.gov (United States)

    Sadowski, Daniel C; Bernstein, Charles N; Bitton, Alain; Croitoru, Ken; Fedorak, Richard N; Griffiths, Anne

    2009-01-01

    BACKGROUND: Guidelines regarding the use of infliximab in Crohn’s disease were previously published by the Canadian Association of Gastroenterology in 2004. However, recent clinical findings and drug developments warrant a review and update of these guidelines. OBJECTIVE: To review and update Canadian guidelines regarding the use of tumour necrosis factor-alpha antibody therapy in both luminal and fistulizing Crohn’s disease. METHODS: A consensus group of 25 voting participants developed a series of recommendation statements that addressed pertinent clinical questions and gaps in existing knowledge. An iterative voting and feedback process was used in advance of the consensus meeting in conjunction with a systematic literature review to refine the voting statements. These statements were brought to a formal consensus meeting held in Montreal, Quebec (March 2008), wherein each statement underwent discussion, reformulation, voting and subsequent revision until group consensus was obtained (at least 80% agreement). OUTCOME: The 47 voting statements addressed three themes: induction therapy, maintenance therapy and safety issues. As a result of the iterative process, 23 statements achieved consensus and were submitted for publication. CONCLUSION: In the past five years, tumour necrosis factor-alpha antagonist therapy has become a cornerstone in the management of moderate-to-severe Crohn’s disease refractory to conventional treatment algorithms. The evidentiary base supporting the use of these drugs in Crohn’s disease is substantial and strengthened by results from long-term clinical and molecular studies. However, significant gaps in knowledge exist, particularly with regard to treatment failure. Confidence in the safety of these drugs is increasing, provided that therapy is administered in a clinical setting in which potential complications can be readily recognized and treated. PMID:19319383

  15. Prolonged Survival in a Case of Chemotherapy-Sensitive Gastric Cancer That Produced Alpha-Fetoprotein and Protein Induced by Vitamin K Antagonist-II

    Directory of Open Access Journals (Sweden)

    Naotaka Ogasawara

    2015-04-01

    Full Text Available The number of reported cases of alpha-fetoprotein (AFP-producing gastric cancer has gradually increased, with a reported prevalence of 1.3-1.5% of all gastric cancer cases. However, reports of gastric cancer accompanied by elevated serum levels of both AFP and protein induced by vitamin K antagonist-II (PIVKA-II are rare. The prognosis of AFP- and PIVKA-II-producing gastric cancer has been reported to be very poor because the tumor cells were considered to have a high malignant potential and the cancer progressed rapidly. We described a case of gastric cancer producing AFP and PIVKA-II in which chemotherapy was effective and resulted in prolonged survival, and these two tumor markers were useful for monitoring the treatment response. Routine health screening using upper abdominal ultrasonography revealed hepatic tumors in an apparently healthy 65-year-old man. Whole-body computed tomography (CT revealed multiple hepatic tumors, and an esophagogastroduodenoscopy (EGD revealed a Bormann type 3 tumor in the lower stomach. A biopsy specimen confirmed that the tumor was immunohistochemically positive for AFP, PIVKA-II, and human epidermal growth factor receptor 2. After chemotherapy, the gastric tumor appeared as a small elevated lesion on EGD, and CT revealed a remarkable reduction in the size of the metastatic liver tumors. The patient is still alive, 35 months after the initial chemotherapy.

  16. Alpha 2-adrenergic receptor turnover in adipose tissue and kidney: irreversible blockade of alpha 2-adrenergic receptors by benextramine

    Energy Technology Data Exchange (ETDEWEB)

    Taouis, M.; Berlan, M.; Lafontan, M.

    1987-01-01

    The recovery of post- and extrasynaptic alpha 2-adrenergic receptor-binding sites was studied in vivo in male golden hamsters after treatment with an irreversible alpha-adrenoceptor antagonist benextramine, a tetramine disulfide that possesses a high affinity for alpha 2-binding sites. The kidney alpha 2-adrenergic receptor number was measured with (/sup 3/H)yohimbine, whereas (/sup 3/H)clonidine was used for fat cell and brain membrane alpha 2-binding site identification. Benextramine treatment of fat cell, kidney, and brain membranes reduced or completely suppressed, in an irreversible manner, (/sup 3/H) clonidine and (/sup 3/H)yohimbine binding without modifying adenosine (A1-receptor) and beta-adrenergic receptor sites. This irreversible binding was also found 1 and 2 hr after intraperitoneal administration of benextramine to the hamsters. Although it bound irreversibly to peripheral and central alpha 2-adrenergic receptors on isolated membranes, benextramine was unable to cross the blood-brain barrier of the hamster at the concentrations used (10-20 mg/kg). After the irreversible blockade, alpha 2-binding sites reappeared in kidney and adipose tissue following a monoexponential time course. Recovery of binding sites was more rapid in kidney than in adipose tissue; the half-lives of the receptor were 31 and 46 hr, respectively in the tissues. The rates of receptor production were 1.5 and 1.8 fmol/mg of protein/hr in kidney and adipose tissue. Reappearance of alpha 2-binding sites was associated with a rapid recovery of function (antilipolytic potencies of alpha 2-agonists) in fat cells inasmuch as occupancy of 15% of (/sup 3/H)clonidine-binding sites was sufficient to promote 40% inhibition of lipolysis. Benextramine is a useful tool to estimate turnover of alpha 2-adrenergic receptors under normal and pathological situations.

  17. Investigations into factors determining the duration of action of the beta 2-adrenoceptor agonist, salmeterol.

    Science.gov (United States)

    Nials, A T; Sumner, M J; Johnson, M; Coleman, R A

    1993-02-01

    1. This study has explored the mechanism underlying the long duration of action of the beta 2-adrenoceptor agonist, salmeterol. 2. Salmeterol, salbutamol and isoprenaline caused a concentration-related inhibition of electrically-induced contractile responses of the guinea-pig superfused trachea preparation. The effects of both isoprenaline and salbutamol were rapid in onset and rapidly reversed upon removal of the agonist. In contrast, the effects of salmeterol were slower in onset and could not be reversed by superfusion of the tissue with agonist-free Krebs solution even for periods of up to 10 h. 3. The effects of salmeterol were, however, readily reversed by a number of beta-adrenoceptor blocking drugs, as was the effect of a continuous infusion of isoprenaline. Upon removal of the antagonist, however, the effects of salmeterol and of the isoprenaline infusion were reasserted at a rate which was inversely related to the lipophilicity of a beta-adrenoceptor blocking drugs. 4. Salmeterol inhibited the binding of [125I]-(-)-iodopindolol (100 pM) to rat lung membranes (pIC50 7.1), with isoprenaline (pIC50 6.2) and salbutamol (pIC50 5.1) having lower potencies. The inhibition of binding by salmeterol was apparently non-competitive, whereas that produced by salbutamol and isoprenaline was competitive in nature. 5. Isoprenaline and salbutamol rapidly dissociated from their binding sites, whereas in marked contrast, the binding of salmeterol showed no dissociation for periods of up to 1 h. 6. These data are consistent with the mechanism in which salmeterol binds adjacent to the active site of the beta 2-adrenoceptor, such that the drug cannot be washed out of the tissue, yet can interact with and activate the receptor. This latter property is susceptible to antagonism by beta-adrenoceptor blocking drugs but is reassured when the antagonists are removed.

  18. Evidence that the novel imidazoline compound FT005 is anα2-adrenoceptor agonist

    Science.gov (United States)

    Slough, Scott; Guillaumet, Gerald; Taberner, Peter V

    2002-01-01

    The aim of this study was to determine whether the hyperglycaemic action of the novel imidazoline compound FT005 could be mediated by activation of α2-adrenoceptors, using a variety of in vivo and in vitro methods including radioligand binding. FT005 produced a dose-dependent increase in blood glucose levels of CBA/Ca mice (0.125–25 mg kg−1, i.p.). The time course of this hyperglycaemic effect matched that of adrenaline (1 mg kg−1) more closely than glucagon (1 mg kg−1) or the KATP channel opener diazoxide (25 mg kg−1). The hyperglycaemic effect of FT005 (1 mg kg−1) was significantly reduced by the α2-adrenoceptor antagonist rauwolscine (0.5 mg kg−1). FT005 produced a significant reduction in plasma insulin levels of mice 30 min after administration. The hyperglycaemic effect of FT005 (25 mg kg−1), although still present, was significantly less in fasted mice in which insulin levels are lower, suggesting that a reduction of insulin secretion contributes to the action of FT005. When studied in the mouse isolated vas deferens preparation, FT005 produced a complete inhibition of neurogenic contractions, which was blocked by rauwolscine. This is consistent with activation of pre-synaptic α2-adrenoceptors. In radioligand binding studies FT005 completely displaced the α2-adrenoceptor antagonist [3H]-RX821002 from mouse whole brain homogenates. The displacement was best described by a two-site model of interaction comprising high and low affinity components. The results indicate that FT005 is an agonist at α2-adrenoceptors. A reduction in insulin secretion contributes to the hyperglycaemic action of FT005, although an additional mechanism can not be excluded. PMID:12145105

  19. The expression of functional postsynaptic α2-adrenoceptors in the corpus cavernosum smooth muscle

    Science.gov (United States)

    Gupta, Sandeep; Moreland, Robert B; Yang, Stone; Gallant, Cynthia M; Goldstein, Irwin; Traish, Abdulmaged

    1998-01-01

    The purpose of this study was to determine if corpus cavernosum smooth muscle expresses functional postsynaptic α2-adrenoceptors (AR).The α2-adrenoceptor agonist UK 14,304 elicited concentration-dependent contractions in rabbit corpus cavernosum smooth muscle (CCSM). The half-maximal response occurred at 0.32±0.03 μM and the maximum contraction at 10 μM UK 14,304.Pretreatment of CCSM strips with selective α2-adrenoceptor antagonists, rauwolscine and RS-15385, produced rightward shifts in the dose-response curves to UK 14,304 (pA2 values 7.1 and 8.5, respectively). In contrast, these antagonists did not alter contraction induced by the α1-adrenoceptor agonist phenylephrine (PE) or oxymetazoline. UK 14,304-induced contractions were also inhibited by prazosin (pA2=9.08).UK 14,304-induced contractions, unlike those to PE, were highly dependent on the presence of extracellular Ca2+.[3H]-rauwolscine bound to CCSM membranes with high affinity (Kd=1.5 nM). [3H]-rauwolscine binding was displaced by unlabelled rauwolscine, RS-15385, UK 14,304 and prazosin, but not by PE.UK 14,304 inhibited forskolin and prostaglandin E1 (PGE1)-induced increases in intracellular cyclic AMP concentration in primary cultures of rabbit CCSM cells.These results demonstrate that CCSM expresses Gi-coupled postsynaptic α2-adrenoceptors, and activation of these receptors causes contraction of trabecular smooth muscle. PMID:9559910

  20. Mapping a2 Adrenoceptors of the Human Brain with 11C-Yohimbine

    DEFF Research Database (Denmark)

    Nahimi, Adjmal; Jakobsen, Steen; Munk, Ole

    2015-01-01

    adrenoceptors in human brain had the highest values in cortical areas and hippocampus, with moderate values in subcortical structures, as found also in vitro. The results confirm the usefulness of the tracer 11C-yohimbine for mapping α2 adrenoceptors in human brain in vivo.......A previous study from this laboratory suggested that 11C-yohimbine, a selective α2-adrenoceptor antagonist, is an appropriate ligand for PET of α2 adrenoceptors that passes readily from blood to brain tissue in pigs but not in rodents. To test usefulness in humans, we determined blood–brain...... values of VT ranged from 0.82 mL cm−3 in the right frontal cortex to 0.46 mL cm−3 in the corpus callosum, with intermediate VT values in subcortical structures. Binding potentials averaged 0.6–0.8 in the cortex and 0.2–0.5 in subcortical regions. Conclusion: The maps of 11C-yohimbine binding to α2...

  1. Why are long-acting beta-adrenoceptor agonists long-acting?

    Science.gov (United States)

    Anderson, G P; Lindén, A; Rabe, K F

    1994-03-01

    The extended duration of bronchodilation due to formoterol and salmeterol greatly exceeds that of short acting beta 2-adrenoceptor agonists, such as salbutamol or terbutaline. This extended duration and their capacity to "reassert" airway smooth muscle relaxation in vitro despite repeated washing has prompted considerable debate on the underlying mechanism(s). The comparative pharmacology, and molecular modelling of these drugs and of the beta 2-adrenoceptor and its ligand binding core have cast doubt on the exosite/exoceptor model previously proposed to explain the behaviour of salmeterol. We present evidence supporting a unifying hypothesis that the duration of action both of formoterol and salmeterol is determined principally by their physicochemical interactions with membrane lipid bilayers (plasmalemma diffusion microkinetic model), rather than putative distinct exosite/exoceptor binding sites in or near the beta 2-adrenoceptor. This model provides a clearer understanding of the pharmacological profile of these drugs (rate of onset, duration, "reassertion", interaction with hydrophilic and hydrophobic beta 2-adrenoceptor antagonists), and explains why in human airway smooth muscle in vitro a true relaxation-concentration response may not exist for salmeterol.

  2. Synthesis and development of new 2-substituted 1-[3-(4-arylpiperazin-1-yl)propyl]-pyrrolidin-2-one derivatives with antiarrhythmic, hypotensive, and alpha-adrenolytic activity.

    Science.gov (United States)

    Malawska, Barbara; Kulig, Katarzyna; Gippert, Annika; Filipek, Barbara; Sapa, Jacek; Maciag, Dorota

    2005-10-01

    A series of new 1-[3-(4-arylpiperazinyl-1-yl)-2-(N-alkylcarbamoyloxy)propyl]-pyrrolidin-2-one derivatives (4a-12a) were synthesised and tested for their electrocardiographic, antiarrhythmic and antihypertensive activity, as well as for the alpha1- and alpha2-adrenoceptor binding affinities. Of the newly synthesised derivatives, 1-{2-(N-2-methylethylcarbamoiloxy)-3-[4-(2-methoxyphenyl)piperazin-1-yl)]propyl}pyrrolidin-2-one dihydrochloride (10a) was the most active in prophylactic antiarrhythmic tests, its ED50 value equalling 2.7 mg kg(-1), and the therapeutic index being 75.2; moreover, compound 10a was also found to possess hypotensive activity. A preliminary molecular modelling study suggested that the selected alpha1-AR antagonist distances and angles between pharmacophoric features, estimated for the tested compounds, were in good agreement with the parameters evaluated for ligands.

  3. Central α-adrenoceptors contribute to mustard oil-induced central sensitization in the rat medullary dorsal horn.

    Science.gov (United States)

    Wang, H; Xie, Y F; Chiang, C Y; Dostrovsky, J O; Sessle, B J

    2013-04-16

    Our previous studies have demonstrated that application of the inflammatory irritant mustard oil (MO) to the tooth pulp produces trigeminal central sensitization that includes increases in mechanoreceptive field size and responses to noxious stimuli and decrease in activation threshold in brainstem nociceptive neurons of trigeminal subnucleus caudalis (the medullary dorsal horn, MDH). The aim of the present study was to test if central noradrenergic processes are involved in the central sensitization of MDH neurons and if α1-adrenoceptors or α2-adrenoceptors or both are involved. In urethane/α-chloralose-anesthetized rats, the activity of extracellularly recorded and functionally identified single nociceptive neurons in the MDH was studied. Continuous intrathecal (i.t.) superfusion of the adrenergic modulator guanethidine and α-adrenoceptor blocker phentolamine or selective α1-adrenoceptor antagonist prazosin over the medulla strongly attenuated all three MO-induced parameters of central sensitization in the MDH nociceptive neurons, compared to phosphate-buffered saline (as vehicle control). In contrast, i.t. superfusion of the selective α2-adrenoceptor antagonist yohimbine had little effect on the mechanoreceptive field expansion and the decreased mechanical activation threshold, and indeed facilitated responses to noxious stimuli of sensitized nociceptive neurons. Superfusion of each of the four chemicals alone did not affect baseline nociceptive neuronal properties. These findings provide the first documentation of the involvement of central noradrenergic processes in MDH in the development of the central sensitization, and that α1- and α2-adrenoceptors may be differentially involved. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

  4. Alpha-1 adrenergic antagonists, 5-alpha reductase inhibitors, phosphodiesterase type 5 inhibitors, and phytotherapic compounds in men with lower urinary tract symptoms suggestive of benign prostatic obstruction: A systematic review and meta-analysis of urodynamic studies.

    Science.gov (United States)

    Fusco, Ferdinando; Creta, Massimiliano; De Nunzio, Cosimo; Gacci, Mauro; Li Marzi, Vincenzo; Finazzi Agrò, Enrico

    2018-03-31

    To perform a systematic review and meta-analysis of studies evaluating the urodynamic outcomes of alpha-1 adrenergic antagonists (ABs), 5-alpha reductase inhibitors (5-ARIs), phosphodiesterase type 5 inhibitors (PDE5is), and phytotherapic compounds in patients with lower urinary tract symptoms related to benign prostatic obstruction (LUTS/BPO). A systematic review of PubMed/Medline, ISI Web of Knowledge, and Scopus databases was performed in June 2017. We included full papers that met the following criteria: original research; English language; human studies; enrolling LUTS/BPO patients; reporting maximum urinary flow (Qmax), and detrusor pressure at maximum urinary flow (PdetQmax). The primary endpoint was variation in bladder outlet obstruction index (BOOI). Secondary endpoints were variations in Qmax and PdetQmax. Twenty-three studies involving 1044 patients were included in the final analysis. Eighteen, three, two, and one study evaluated the urodynamic outcomes of ABs, 5-ARIs, PDE5is, and phytotherapic compounds, respectively. BOOI, PdetQmax, and Qmax improved in a statistically significant manner in patients receiving ABs and in those receiving 5-ARIs. The overall pooled data showed a mean BOOI change of -15.40 (P < 0.00001) and of -10.55 (P = 0,004) for ABs and 5-ARIs, respectively. Mean PdetQmax and Qmax changes were:12.30 cm H 2 O (P < 0.00001) and +2.27 ml/s (P < 0.00001) for ABs and -9.63 cm H 2 O (P = 0.05), and +1.18 mL/s (P = 0.04) for 5-ARIs. PDE5is and phytotherapic compounds had no significant effects on urodynamic parameters. ABs and 5-ARIs efficiently improve BOOI in men with LUTS/BPO. Both treatments are associated with a clinically significant decrease in PdetQmax but only marginal improvements in Qmax. © 2018 Wiley Periodicals, Inc.

  5. Alopecia induced by tumour necrosis factor-alpha antagonists: description of 52 cases and disproportionality analysis in a nationwide pharmacovigilance database.

    Science.gov (United States)

    Béné, Johana; Moulis, Guillaume; Auffret, Marine; Lefevre, Guillaume; Coquerelle, Pascal; Coupe, Patrick; Péré, Patrice; Gautier, Sophie

    2014-08-01

    The aim of this research was to describe the cases of TNF-α antagonist-related alopecia reported in the French Pharmacovigilance Database (FPVD) and to investigate the association between exposure to TNF-α antagonists and occurrence of alopecia. All spontaneous reports of TNF-α antagonist-related alopecia recorded in the FPVD between January 2000 and April 2012 were colligated and described. We conducted disproportionality analyses (case/non-case method) to assess the link between the occurrence of alopecia and exposure to TNF-α antagonists. Cases were all reports of alopecia and non-cases were all other reports recorded during the study period. Exposure to TNF-α antagonists was sought in cases and in non-cases. Reporting odds ratios (RORs) were calculated to assess the association. Docetaxel was used as positive control and acetaminophen as negative control. We performed sensitivity analyses excluding cases of androgenic alopecia and those occurring in psoriatic patients. Among 282 590 spontaneous reports of adverse drug reactions (ADRs) collated in the FPVD, 1068 cases (alopecia reports) were identified. Of these cases, 52 (4.9%) occurred during exposure to TNF-α antagonists (18 involved infliximab, 17 adalimumab, 15 etanercept and 2 certolizumab). Exposure to TNF-α antagonists was more frequent among alopecia reports than among other ADR reports for all TNF-α antagonists pooled (ROR 3.0, 95% CI 2.3, 4.0) as well as for each antagonist separately, with similar values. Sensitivity analyses yielded similar results. The RORs were 29.9 (95% CI 25.3, 35.5) with docetaxel and 0.3 (95% CI 0.2, 0.4) with acetaminophen. The present study confirms a strong link between TNF-α antagonist exposure (class effect) and the occurrence of alopecia. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  6. Adenosine receptor antagonist and augmented vasodilation during hypoxic exercise.

    Science.gov (United States)

    Casey, Darren P; Madery, Brandon D; Pike, Tasha L; Eisenach, John H; Dietz, Niki M; Joyner, Michael J; Wilkins, Brad W

    2009-10-01

    We tested the hypothesis that adenosine contributes to augmented skeletal muscle vasodilation during hypoxic exercise. In separate protocols, subjects performed incremental rhythmic forearm exercise (10% and 20% of maximum) during normoxia and normocapnic hypoxia (80% arterial O2 saturation). In protocol 1 (n = 8), subjects received an intra-arterial administration of saline (control) and aminophylline (adenosine receptor antagonist). In protocol 2 (n = 10), subjects received intra-arterial phentolamine (alpha-adrenoceptor antagonist) and combined phentolamine and aminophylline administration. Forearm vascular conductance (FVC; in ml x min(-1).100 mmHg(-1)) was calculated from forearm blood flow (in ml/min) and blood pressure (in mmHg). In protocol 1, the change in FVC (DeltaFVC; change from normoxic baseline) during hypoxic exercise with saline was 172 +/- 29 and 314 +/- 34 ml x min(-1) x 100 mmHg(-1) (10% and 20%, respectively). Aminophylline administration did not affect DeltaFVC during hypoxic exercise at 10% (190 +/- 29 ml x min(-1)x100 mmHg(-1), P = 0.4) or 20% (287 +/- 48 ml x min(-1) x 100 mmHg(-1), P = 0.3). In protocol 2, DeltaFVC due to hypoxic exercise with phentolamine infusion was 313 +/- 30 and 453 +/- 41 ml x min(-1) x 100 mmHg(-1) (10% and 20% respectively). DeltaFVC was similar at 10% (352 +/- 39 ml min(-1) x 100 mmHg(-1), P = 0.8) and 20% (528 +/- 45 ml x min(-1) x 100 mmHg(-1), P = 0.2) hypoxic exercise with combined phentolamine and aminophylline. In contrast, DeltaFVC to exogenous adenosine was reduced by aminophylline administration in both protocols (P < 0.05 for both). These observations suggest that adenosine receptor activation is not obligatory for the augmented hyperemia during hypoxic exercise in humans.

  7. Alpha-adrenergic stimulation of corticotropin secretion by a specific central mechanism in man.

    Science.gov (United States)

    Al-Damluji, S; Perry, L; Tomlin, S; Bouloux, P; Grossman, A; Rees, L H; Besser, G M

    1987-01-01

    In a double-blind study in normal subjects, methoxamine, a highly selective agonist at alpha-1-adrenoceptors, significantly increased circulating ACTH and cortisol. The stimulant effect of methoxamine on cortisol secretion was dose dependent in the range 3.5-7 micrograms/kg/min, was abolished by concomitant administration of the strong alpha-1-adrenergic (and weak H1) antagonist thymoxamine but unaffected by the antihistamine, chlorpheniramine. In order to test whether the action of methoxamine on ACTH secretion was exerted centrally or peripherally, the effects of norepinephrine (NE), an alpha-1-agonist that does not cross the blood-brain barrier, were studied. Doses of NE (1-12 micrograms/min) that increased systolic blood pressure by amounts similar to the changes produced by methoxamine, did not result in any rise in plasma cortisol in normal subjects. The effect of methoxamine, which is more lipid soluble than NE, on plasma ACTH and cortisol, appears to be exerted on the CNS and not at the pituitary or via nonspecific peripheral mechanisms. In addition to its water solubility, NE differs from methoxamine in its beta-1-, beta-2- and alpha-2-agonist actions. However, prenalterol (2 mg) and salbutamol (250 micrograms), respectively beta-1- and beta-2-adrenergic agonist drugs, had no effect on the secretion of ACTH or cortisol and the alpha-2-antagonist yohimbine in an effective dose did not unmask a stimulant effect of intravenous NE on plasma cortisol. At high infusion rates, NE significantly inhibited cortisol secretion. Stimulation of central alpha-1-adrenergic mechanisms results in secretion of ACTH in man, presumably by increased release of a corticotropin-releasing factor.

  8. The effects of the alpha2-adrenergic receptor agonists clonidine and rilmenidine, and antagonists yohimbine and efaroxan, on the spinal cholinergic receptor system in the rat

    DEFF Research Database (Denmark)

    Abelson, Klas S P; Höglund, A Urban

    2004-01-01

    Cholinergic agonists produce spinal antinociception via mechanisms involving an increased release of intraspinal acetylcholine. The cholinergic receptor system interacts with several other receptor types, such as alpha2-adrenergic receptors. To fully understand these interactions, the effects of ...

  9. Energy-sensing Factors Coactivator Peroxisome Proliferator-activated Receptor gamma Coactivator 1-alpha (PGC-1 alpha) and AMP-activated Protein Kinase Control Expression of Inflammatory Mediators in Liver INDUCTION OF INTERLEUKIN 1 RECEPTOR ANTAGONIST

    NARCIS (Netherlands)

    Buler, M.; Aatsinki, S.M.; Skoumal, R.; Komka, Z.; Toth, M.; Kerkela, R.; Georgiadi, A.; Kersten, A.H.; Hakkola, J.

    2012-01-01

    Obesity and insulin resistance are associated with chronic, low grade inflammation. Moreover, regulation of energy metabolism and immunity are highly integrated. We hypothesized that energy-sensitive coactivator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1 alpha) and

  10. The MAPKERK-1,2 pathway integrates distinct and antagonistic signals from TGF alpha and FGF7 in morphogenesis of mouse mammary epithelium

    Energy Technology Data Exchange (ETDEWEB)

    Fata, Jimmie E; Mori, Hidetoshi; Ewald, Andrew J; Zhang, Hui; Yao, Evelyn; Werb, Zena; Bissell, Mina J

    2006-10-03

    Transforming growth factor-{alpha} (TGF{alpha}) and fibroblast growth factor-7 (FGF7) exhibit distinct expression patterns in the mammary gland. Both factors signal through mitogen-activated kinase/extracellular regulated kinase-1,2 (MAPK{sup ERK1,2}); however, their unique and/or combined contributions to mammary morphogenesis have not been examined. In ex vivo mammary explants, we show that a sustained activation of MAPK{sup ERK1,2} for 1 h, induced by TGF{alpha}, was necessary and sufficient to initiate branching morphogenesis, whereas a transient activation (15 min) of MAPK{sup ERK1,2}, induced by FGF7, led to growth without branching. Unlike TGF{alpha}, FGF7 promoted sustained proliferation as well as ectopic localization of, and increase in, keratin-6 expressing cells. The response of the explants to FGF10 was similar to that to FGF7. Simultaneous stimulation by FGF7 and TGF{alpha} indicated that the FGF7-induced MAPK{sup ERK1,2} signaling and associated phenotypes were dominant: FGF7 may prevent branching by suppression of two necessary TGF{alpha}-induced morphogenetic effectors, matrix metalloproteinase-3 (MMP-3/stromelysin-1), and fibronectin. Our findings indicate that expression of morphogenetic effectors, proliferation, and cell-type decisions during mammary organoid morphogenesis are intimately dependent on the duration of activation of MAPK{sup ERK1,2} activation.

  11. 3 alpha 5 beta-Pregnanolone glutamate, a use-dependent NMDA antagonist, reversed spatial learning deficit in an animal model of schizophrenia

    Czech Academy of Sciences Publication Activity Database

    Valeš, Karel; Rambousek, Lukáš; Holubová, Kristína; Svoboda, Jan; Bubeníková-Valešová, V.; Chodounská, Hana; Vyklický ml., Ladislav; Stuchlík, Aleš

    2012-01-01

    Roč. 235, č. 1 (2012), s. 82-88 ISSN 0166-4328 R&D Projects: GA MZd(CZ) NS10365 Institutional research plan: CEZ:AV0Z50110509 Institutional support: RVO:67985823 ; RVO:61388963 Keywords : schizophrenia -like behavior * MK-801 * use-dependent * NMDA antagonist * anxiety * pregnanolone glutamate * Carousel maze Subject RIV: FH - Neurology Impact factor: 3.327, year: 2012

  12. Preferential reduction of binding of 125I-iodopindolol to beta-1 adrenoceptors in the amygdala of rat after antidepressant treatments

    International Nuclear Information System (INIS)

    Ordway, G.A.; Gambarana, C.; Tejani-Butt, S.M.; Areso, P.; Hauptmann, M.; Frazer, A.

    1991-01-01

    This study utilized quantitative receptor autoradiography to examine the effects of repeated administration of antidepressants to rats on the binding of the beta adrenoceptor antagonist, 125 I-iodopindolol ( 125 I-IPIN) to either beta-1 or beta-2 adrenoceptors in various regions of brain. Antidepressants were selected to represent various chemical and pharmacological classes including tricyclic compounds (desipramine and protriptyline), monoamine oxidase inhibitors (clorgyline, phenelzine and tranylcypromine), atypical antidepressants (mianserin and trazodone) and selective inhibitors of the uptake of serotonin (citalopram and sertraline). Additionally, rats were treated with various psychotropic drugs that lack antidepressant efficacy (cocaine, deprenyl, diazepam and haloperidol). Repeated treatment of rats with desipramine, protriptyline, clorgyline, phenelzine, tranylcypromine or mianserin reduced the binding of 125 I-IPIN to beta-1 adrenoceptors in many brain areas. Only in the basolateral and lateral nuclei of the amygdala did all six of these antidepressants significantly reduce 125 I-IPIN binding to beta-1 adrenoceptors. In these amygdaloid nuclei, the magnitude of the reduction in the binding of 125 I-IPIN caused by each of these drugs was comparable to or greater than the reduction in binding produced in any other region of brain. Reductions of binding of 125 I-IPIN after antidepressant treatments were not consistently observed in the cortex, the area of brain examined most often in homogenate binding studies. Only the monoamine oxidase inhibitors caused reductions in the binding of 125 I-IPIN to beta-2 adrenoceptors, and this effect was generally localized to the amygdala and hypothalamus

  13. Presynaptic beta-adrenoceptors in guinea pig papillary muscle: evidence for adrenaline-mediated positive feedback on noradrenergic transmission

    International Nuclear Information System (INIS)

    Valenta, B.; Singer, E.A.

    1991-01-01

    Guinea pig papillary muscles were preincubated in the presence of 5 x 10 - 9 mol/L unlabeled noradrenaline or adrenaline then incubated with ( 3 H)-noradrenaline and superfused. Electrical field stimulation with 180 pulses delivered at 1 or 3 Hz was used to induce overflow of radioactivity. Comparison of the effects of preexposure of the tissue to adrenaline or noradrenaline revealed that adrenaline incubation caused an enhancement of stimulation-evoked overflow of ( 3 H)noradrenaline and a reduction of the effect of exogenously added isoprenaline. Furthermore, the selective beta 2-adrenoceptor antagonist ICI 118,551 (10 - 7 mol/L), but not the selective beta 1-adrenoceptor antagonist ICI 89,406 (10 - 7 mol/L), reduced electrically evoked overflow of ( 3 H)noradrenaline in tissue preincubated with adrenaline but not in tissue preincubated with noradrenaline. The overflow-reducing effect of ICI 118.551 occurred at stimulation with 3 Hz but not at stimulation with 1 Hz. The present results support the hypothesis that noradrenergic transmission in guinea pig papillary muscle is facilitated via beta 2-adrenoceptors, and that adrenaline may serve as transmitter in this positive feedback mechanism after its incorporation into sympathetic nerves

  14. Agonist pharmacology at recombinant α1A - and α1L -adrenoceptors and in lower urinary tract α1 -adrenoceptors.

    Science.gov (United States)

    Yoshiki, Hatsumi; Uwada, Junsuke; Umada, Hidenori; Kobayashi, Tadashi; Takahashi, Toshihiro; Yamakawa, Tomio; Yamaguchi, Akio; Yokoyama, Osamu; Muramatsu, Ikunobu

    2013-11-01

    Two distinct α1 -adrenoceptor phenotypes (α1A and α1L ) have recently been demonstrated to originate from a single α1A -adrenoceptor gene. Here, we examined the agonist profiles of recombinant α1A and α1L phenotypes and of lower urinary tract (LUT) α1 -adrenoceptors. A series of drugs (A61603, Ro 115-1240, NS-49 , MK017 and ESR1150) originally developed for stress urinary incontinence (SUI) therapy were used to stimulate recombinant α1A - and α1L -adrenoceptor phenotypes, and their potencies and intrinsic activity estimated from Ca(2+) responses. Agonist-induced contractions were also examined in LUT tissues of rats and humans and in human mesenteric artery and rat tail artery. All the drugs were potent agonists of the α1A -adrenoceptor compared with the α1L -adrenoceptor phenotype. Among them, Ro 115-1240 was shown to be an α1A -specific partial agonist that produced partial contractions through α1A -adrenoceptors in rat prostate and tail artery, but not in the other LUT tissues and human mesenteric artery. In contrast, P-come 102 showed full agonist activity at α1A - and α1L -adrenoceptors, but was less selective than noradrenaline for α1A -adrenoceptors. Like noradrenaline, P-come 102 was highly potent at inducing contractions in all of the LUT tissues tested. However, the potency and intrinsic activity of P-come 102 were significantly lower than those of noradrenaline in human mesenteric artery. The α1A - and α1L -adrenoceptor phenotypes and LUT α1 -adrenoceptors were demonstrated to have distinct agonist profiles. As adrenergic contractions in LUT are predominantly mediated through α1L -adrenoceptors, the development of α1L -selective agonists may provide clinically useful drugs for SUI therapy. © 2013 The British Pharmacological Society.

  15. β-Adrenergic receptor antagonists inhibit vasculogenesis of embryonic stem cells by downregulation of nitric oxide generation and interference with VEGF signalling.

    Science.gov (United States)

    Sharifpanah, Fatemeh; Saliu, Fatjon; Bekhite, Mohamed M; Wartenberg, Maria; Sauer, Heinrich

    2014-11-01

    The β-adrenoceptor antagonist Propranolol has been successfully used to treat infantile hemangioma. However, its mechanism of action is so far unknown. The hypothesis of this research was that β-adrenoceptor antagonists may interfere with endothelial cell differentiation of stem cells. Specifically, the effects of the non-specific β-adrenergic receptor (β-adrenoceptor) antagonist Propranolol, the β1-adrenoceptor-specific antagonist Atenolol and the β2-adrenoceptor-specific antagonist ICI118,551 on vasculogenesis of mouse embryonic stem (ES) cells were investigated. All three β-blockers dose-dependently downregulated formation of capillary structures in ES cell-derived embryoid bodies and decreased the expression of the vascular cell markers CD31 and VE-cadherin. Furthermore, β-blockers downregulated the expression of fibroblast growth factor-2 (FGF-2), hypoxia inducible factor-1α (HIF-1α), vascular endothelial growth factor 165 (VEGF165), VEGF receptor 2 (VEGF-R2) and phospho VEGF-R2, as well as neuropilin 1 (NRP1) and plexin-B1 which are essential modulators of embryonic angiogenesis with additional roles in vessel remodelling and arteriogenesis. Under conditions of β-adrenoceptor inhibition, the endogenous generation of nitric oxide (NO) as well as the phosphorylation of endothelial nitric oxide synthase (eNOS) was decreased in embryoid bodies, whereas an increase in NO generation was observed with the NO donor S-nitroso-N-acetyl-D,L-penicillamine (SNAP). Consequently, vasculogenesis of ES cells was restored upon treatment of differentiating ES cells with β-adrenoceptor antagonists in the presence of NO donor. In summary, our data suggest that β-blockers impair vasculogenesis of ES cells by interfering with NO generation which could be the explanation for their anti-angiogenic effects in infantile hemangioma.

  16. Action of Specific Thyroid Hormone Receptor alpha(1) and beta(1) Antagonists in the Central and Peripheral Regulation of Thyroid Hormone Metabolism in the Rat

    NARCIS (Netherlands)

    van Beeren, Hermina C.; Kwakkel, Joan; Ackermans, Mariëtte T.; Wiersinga, Wilmar M.; Fliers, Eric; Boelen, Anita

    2012-01-01

    Background: The iodine-containing drug amiodarone (Amio) and its noniodine containing analogue dronedarone (Dron) are potent antiarrhythmic drugs. Previous in vivo and in vitro studies have shown that the major metabolite of Amio, desethylamiodarone, acts as a thyroid hormone receptor (TR) alpha(1)

  17. Role of α{sub 2}-adrenoceptors in the lateral parabrachial nucleus in the control of body fluid homeostasis

    Energy Technology Data Exchange (ETDEWEB)

    Andrade, C.A.F.; Andrade-Franzé, G.M.F.; De Paula, P.M.; De Luca, L.A. Jr.; Menani, J.V. [Departamento de Fisiologia e Patologia, Faculdade de Odontologia, Universidade Estadual Paulista, Araraquara, SP (Brazil)

    2014-01-10

    Central α{sub 2}-adrenoceptors and the pontine lateral parabrachial nucleus (LPBN) are involved in the control of sodium and water intake. Bilateral injections of moxonidine (α{sub 2}-adrenergic/imidazoline receptor agonist) or noradrenaline into the LPBN strongly increases 0.3 M NaCl intake induced by a combined treatment of furosemide plus captopril. Injection of moxonidine into the LPBN also increases hypertonic NaCl and water intake and reduces oxytocin secretion, urinary sodium, and water excreted by cell-dehydrated rats, causing a positive sodium and water balance, which suggests that moxonidine injected into the LPBN deactivates mechanisms that restrain body fluid volume expansion. Pretreatment with specific α{sub 2}-adrenoceptor antagonists injected into the LPBN abolishes the behavioral and renal effects of moxonidine or noradrenaline injected into the same area, suggesting that these effects depend on activation of LPBN α{sub 2}-adrenoceptors. In fluid-depleted rats, the palatability of sodium is reduced by ingestion of hypertonic NaCl, limiting intake. However, in rats treated with moxonidine injected into the LPBN, the NaCl palatability remains high, even after ingestion of significant amounts of 0.3 M NaCl. The changes in behavioral and renal responses produced by activation of α{sub 2}-adrenoceptors in the LPBN are probably a consequence of reduction of oxytocin secretion and blockade of inhibitory signals that affect sodium palatability. In this review, a model is proposed to show how activation of α{sub 2}-adrenoceptors in the LPBN may affect palatability and, consequently, ingestion of sodium as well as renal sodium excretion.

  18. Role of α2-adrenoceptors in the lateral parabrachial nucleus in the control of body fluid homeostasis

    International Nuclear Information System (INIS)

    Andrade, C.A.F.; Andrade-Franzé, G.M.F.; De Paula, P.M.; De Luca, L.A. Jr.; Menani, J.V.

    2014-01-01

    Central α 2 -adrenoceptors and the pontine lateral parabrachial nucleus (LPBN) are involved in the control of sodium and water intake. Bilateral injections of moxonidine (α 2 -adrenergic/imidazoline receptor agonist) or noradrenaline into the LPBN strongly increases 0.3 M NaCl intake induced by a combined treatment of furosemide plus captopril. Injection of moxonidine into the LPBN also increases hypertonic NaCl and water intake and reduces oxytocin secretion, urinary sodium, and water excreted by cell-dehydrated rats, causing a positive sodium and water balance, which suggests that moxonidine injected into the LPBN deactivates mechanisms that restrain body fluid volume expansion. Pretreatment with specific α 2 -adrenoceptor antagonists injected into the LPBN abolishes the behavioral and renal effects of moxonidine or noradrenaline injected into the same area, suggesting that these effects depend on activation of LPBN α 2 -adrenoceptors. In fluid-depleted rats, the palatability of sodium is reduced by ingestion of hypertonic NaCl, limiting intake. However, in rats treated with moxonidine injected into the LPBN, the NaCl palatability remains high, even after ingestion of significant amounts of 0.3 M NaCl. The changes in behavioral and renal responses produced by activation of α 2 -adrenoceptors in the LPBN are probably a consequence of reduction of oxytocin secretion and blockade of inhibitory signals that affect sodium palatability. In this review, a model is proposed to show how activation of α 2 -adrenoceptors in the LPBN may affect palatability and, consequently, ingestion of sodium as well as renal sodium excretion

  19. β2-adrenoceptor agonist clenbuterol reduces infarct size and myocardial apoptosis after myocardial ischaemia/reperfusion in anaesthetized rats

    Science.gov (United States)

    Zhang, Qiufang; Xiang, Jizhou; Wang, Xuanbin; Liu, Hui; Hu, Benrong; Feng, Mei; Fu, Qin

    2010-01-01

    Background and purpose: Considerable evidence indicates that the β2-adrenoceptor agonist clenbuterol decreases apoptosis in a rodent model of ischaemic cardiomyopathy. In this study, we investigated the effects of clenbuterol on infarct size caused by myocardial ischaemia/reperfusion (I/R) in anaesthetized rats. Experimental approach: Rats were randomly assigned to the following groups: (i) sham (ii) I/R (iii) clenbuterol + I/R (iv) ICI 118551 + clenbuterol + I/R (v) metoprolol + clenbuterol + I/R (vi) metoprolol + I/R (vii) pertussis toxin + clenbuterol + I/R. Under anaesthesia, left anterior descending coronary artery was occluded for 30 min followed by reperfusion for 2 h. Key results: Compared with the control I/R group,the clenbuterol (0.5 mg·kg−1, i.p.) group had reduced infarct size, improved diastolic function and sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) activity, increased superoxide dismutase activity, and decreased malondialdehyde (MDA) level and LDH, CK release. Clenbuterol increased the phosphorylation of ERK1/2, which resulted in inhibition of myocardial apoptosis as indicated by the reduction of terminal deoxynucleotidyltransferase end labelling-positive staining, Bax/Bcl-2 mRNA and caspase-3 protein expression. The Gi-protein inhibitor pertussis toxin blocked the clenbuterol-induced improvement in cardiac function and infarct size. Pretreatment with ICI 118551(a selective β2-adrenoceptor antagonist) inhibited the effects of clenbuterol mentioned above. The β1-adrenoceptor agonist metoprolol had similar effects to clenbuterol but failed to reduce MDA and improve SERCA activity. When administered together, metoprolol and clenbuterol did not induce synergistic effects. Conclusions and implications: Clenbuterol pretreatment provides significant cardioprotection against ischaemia/reperfusion injury and this is mediated by the β2-adrenoceptor–Gi-protein signalling. A combination of the β2-adrenoceptor agonist clenbuterol and the

  20. High isoproterenol doses are required to activate beta3-adrenoceptor-mediated functions in dogs.

    Science.gov (United States)

    Pelat, Michel; Verwaerde, Patrick; Galitzky, Jean; Lafontan, Max; Berlan, Michel; Senard, Jean-Michel; Montastruc, Jean-Louis

    2003-01-01

    The "in vivo" conditions for beta3-adrenoceptors (beta-AR) activation by isoproterenol were investigated in dog. Experiments were carried out in anesthetized dogs using isoproterenol as a nonselective beta-AR agonist. Intravenous infusion of isoproterenol (0.4 nmol/kg/min) induced arterial hypotension and tachycardia with a slight decrease in cutaneous blood flow. At this dose, isoproterenol increased glucose, glycerol, and nonesterified fatty acid plasma levels. The changes in cardiovascular and endocrine-metabolic parameters, induced by the low dose of isoproterenol, were suppressed by pretreatment with nadolol (1 mg/kg, i.v.). After nadolol administration, however, a 10-fold higher dose (4 nmol/kg/min) of isoproterenol was able to induce a decrease in arterial blood pressure with a slight tachycardia and an increase in cutaneous blood flow. This high dose of isoproterenol increased nonesterified fatty acid and glycerol plasma levels but failed to change glucose plasma levels. All these effects were abolished by a pretreatment with nadolol (1 mg/kg, i.v.) plus SR59230A [a selective beta3-adrenoceptor antagonist; (3-(2-ethylphenoxy)-1(1S)-1,2,3,4-tetrahydronaphth-1-ylaminol-(2S)2-propanol oxalate); 1 mg/kg, i.v.]. Moreover, as observed with the high dose of isoproterenol under nadolol pretreatment, an infusion of SR58611A [a selective beta3-adrenoceptor agonist; ((N2S)-7-carbethoxymethoxy-1,2,3,4-tetrahydronaphth-2-yl-(2R)-2-hydroxy-2-chlorophenyl) ethanamine hydrochloride] induces a decrease in mean arterial blood pressure associated with an increase in heart rate, cutaneous blood flow, and nonesterified fatty acid and glycerol plasma levels. These results demonstrate that the in vivo activation of beta3-adrenoceptors requires higher doses of catecholamine than those necessary for beta1- and/or beta2-adrenoceptor stimulation. These results also argue for the lack of a beta3-AR involvement in the control of heart rate and glycogenolysis in dogs.

  1. Orthosteric Binding of ρ-Da1a, a Natural Peptide of Snake Venom Interacting Selectively with the α1A-Adrenoceptor

    Science.gov (United States)

    Maïga, Arhamatoulaye; Merlin, Jon; Marcon, Elodie; Rouget, Céline; Larregola, Maud; Gilquin, Bernard; Fruchart-Gaillard, Carole; Lajeunesse, Evelyne; Marchetti, Charles; Lorphelin, Alain; Bellanger, Laurent; Summers, Roger J.; Hutchinson, Dana S.; Evans, Bronwyn A.; Servent, Denis; Gilles, Nicolas

    2013-01-01

    ρ-Da1a is a three-finger fold toxin from green mamba venom that is highly selective for the α1A-adrenoceptor. This toxin has atypical pharmacological properties, including incomplete inhibition of 3H-prazosin or 125I-HEAT binding and insurmountable antagonist action. We aimed to clarify its mode of action at the α1A-adrenoceptor. The affinity (pKi 9.26) and selectivity of ρ-Da1a for the α1A-adrenoceptor were confirmed by comparing binding to human adrenoceptors expressed in eukaryotic cells. Equilibrium and kinetic binding experiments were used to demonstrate that ρ-Da1a, prazosin and HEAT compete at the α1A-adrenoceptor. ρ-Da1a did not affect the dissociation kinetics of 3H-prazosin or 125I-HEAT, and the IC50 of ρ-Da1a, determined by competition experiments, increased linearly with the concentration of radioligands used, while the residual binding by ρ-Da1a remained stable. The effect of ρ-Da1a on agonist-stimulated Ca2+ release was insurmountable in the presence of phenethylamine- or imidazoline-type agonists. Ten mutations in the orthosteric binding pocket of the α1A-adrenoceptor were evaluated for alterations in ρ-Da1a affinity. The D1063.32A and the S1885.42A/S1925.46A receptor mutations reduced toxin affinity moderately (6 and 7.6 times, respectively), while the F862.64A, F2886.51A and F3127.39A mutations diminished it dramatically by 18- to 93-fold. In addition, residue F862.64 was identified as a key interaction point for 125I-HEAT, as the variant F862.64A induced a 23-fold reduction in HEAT affinity. Unlike the M1 muscarinic acetylcholine receptor toxin MT7, ρ-Da1a interacts with the human α1A-adrenoceptor orthosteric pocket and shares receptor interaction points with antagonist (F862.64, F2886.51 and F3127.39) and agonist (F2886.51 and F3127.39) ligands. Its selectivity for the α1A-adrenoceptor may result, at least partly, from its interaction with the residue F862.64, which appears to be important also for HEAT binding. PMID:23935897

  2. Central beta adrenoceptor mediation of the antinatriuretic response to behavioral stress in conscious dogs.

    Science.gov (United States)

    Koepke, J P; Grignolo, A; Light, K C; Obrist, P A

    1983-10-01

    This study examined the renal excretory response to behavioral stress (aversive conditioning) in conscious dogs during infusion of beta adrenoceptor antagonists that either readily cross, or that do not readily cross the blood-brain barrier. With saline infusion alone (n = 7), behavioral stress decreased sodium excretion (-47 +/- 7% from 345 microEq/min) and urine flow rate (-48 +/- 5% from 2.1 ml/min). In the same dogs, infusion of propranolol, which readily crosses the blood-brain barrier, abolished the sodium excretion and urine flow rate responses to behavioral stress (-2 +/- 6% from 527 microEq/min and -5 +/- 3% from 3.0 ml/min, respectively). In a different group of dogs (n = 5), infusion of timolol or oxprenolol, antagonists that cross the blood-brain barrier less readily than propranolol, did not abolish the excretory response to behavioral stress. Behavioral stress decreased sodium excretion and urine flow rate during timolol infusion (-38 +/- 6% from 452 microEq/min and -36 +/- 6% from 2.4 ml/min, respectively) and oxprenolol infusion (-25 +/- 9% from 328 microEq/min and -19 +/- 8% from 1.8 ml/min, respectively). With saline infusion alone in these same dogs, behavioral stress decreased sodium excretion (-48 +/- 7% from 316 microEq/min) and urine flow rate (-40 +/- 7% from 1.7 ml/min). Mean arterial pressure increased similarly among all conditions in this study. Since the three antagonists accumulate to a high degree in the kidney, but only propranolol abolished the excretory response to behavioral stress, renal beta adrenoceptors did not appear to mediate the excretory response.(ABSTRACT TRUNCATED AT 250 WORDS)

  3. The effects of the alpha2-adrenergic receptor agonists clonidine and rilmenidine, and antagonists yohimbine and efaroxan, on the spinal cholinergic receptor system in the rat

    DEFF Research Database (Denmark)

    Abelson, Klas S P; Höglund, A Urban

    2004-01-01

    in the rat. Spinal microdialysis was used to measure in vivo changes of acetylcholine after administration of the ligands, with or without nicotinic receptor blockade. In addition, in vitro binding properties of the ligands on muscarinic and nicotinic receptors were investigated. It was found that clonidine...... and rilmenidine increased, while yohimbine decreased spinal acetylcholine release. Efaroxan affected acetylcholine release differently depending on concentration. Nicotinic receptor blockade attenuated the effect of all ligands. All ligands showed poor binding affinity for muscarinic receptors. On the other hand......, all ligands possessed affinity for nicotinic receptors. Clonidine and yohimbine binding was best fit to a one site binding curve and rilmenidine and efaroxan to a two site binding curve. The present study demonstrates that the tested alpha2-adrenergic receptor ligands affect intraspinal acetylcholine...

  4. Effect of. cap alpha. -,. beta. -adrenergic receptor agonists and antagonists of the efflux of /sup 22/Na and uptake of /sup 42/K by rat brain cortical slices

    Energy Technology Data Exchange (ETDEWEB)

    Phillis, J.W.; Wu, P.H.; Thierry, D.L.

    1982-03-18

    The effects of norepinephrine on ion fluxes in rat brain cortical slices have now been ascertained. /sup 22/Na efflux and /sup 42/K influx are enhanced by norepinephrine. The increase in ion fluxes can be blocked by ouabain, phentolamine and propranolol, suggesting that the catecholamine activates a membrane sodium pump by a receptor-mediated step. The facilitation of /sup 22/Na efflux is stereospecific as demonstrated by the very weak action of D-norepinephrine at 10/sup -5/ M concentration. Various ..cap alpha..-adrenergic and ..beta..-adrenergic receptor agonists, including oxymetazoline, naphazoline, clonidine, tramazoline, methoxamine, phenylephrine, L-isoproterenol and methoxyphenamine are potent stimulants of the sodium pump as demonstrated by their enhancement of ion fluxes in rat brain cortical slices. The results are consistent with the hypothesis that norepinephrine hyperpolarizes central neurons by activating an ouabain-sensitive, receptor-mediated sodium pump.

  5. A discrepancy between platelet alpha 2-receptor density and functional circulatory changes in hypertensives

    International Nuclear Information System (INIS)

    Mores, N.; Martire, M.; Pistritto, G.; Cardillo, C.; Folli, G.

    1990-01-01

    To investigate whether differences exist in peripheral alpha 2-adrenoceptors between normotensive and hypertensive subjects, we determined platelet alpha 2-adrenoceptor density in 10 (7 males) untreated essential hypertensives (mean age of 51.1 years, range of 44-59 years) and in 10 age- and sex-matched normotensive controls. Moreover, in hypertensive patients, we examined the relationship between receptor density and cardiovascular reactivity to mental arithmetic, static handgrip, and bicycle exercise, to verify the hypothesis that alpha 2-adrenoceptors might play a role in modulation of hemodynamic response to sympathetic stimuli. alpha 2-Adrenoceptor density, as calculated by binding of [3H]yohimbine to platelets, was significantly higher in essential hypertensives (314.8 +/- 38.7 fmol/mg) than in normotensive subjects (213.6 +/- 34.7 fmol/mg) (p less than 0.05), whereas receptor affinity was similar in both groups (4.0 +/- 0.5 nM hypertensives, 4.3 +/- 0.5 nM normotensives; p greater than 0.05). Mental arithmetic increased mean arterial pressure (MAP) by 21.5% from basal values and heart rate (HR) by 13.2%. During isometric exercise, MAP increased by 38.1% and HR by 24.7%, while during bicycle ergometry, mean increases in MAP and HR from baseline were of 27.2 and 54.3%, respectively. No correlation was found between platelet alpha 2-adrenoceptor density and percent changes in MAP induced by all tests, or between adrenoceptors and absolute basal and peak MAP values. Our findings suggest that in hypertensive patients, peripheral alpha 2-adrenoceptors are increased with respect to matched normotensives, but these receptors seem not to be involved in the modulation of cardiovascular adaptation to enhanced sympathetic activity

  6. Effects of chronic treatment with the new ultra-long-acting β2 -adrenoceptor agonist indacaterol alone or in combination with the β1 -adrenoceptor blocker metoprolol on cardiac remodelling.

    Science.gov (United States)

    Rinaldi, Barbara; Donniacuo, Maria; Sodano, Loredana; Gritti, Giulia; Martuscelli, Eugenio; Orlandi, Augusto; Rafaniello, Concetta; Rossi, Francesco; Calzetta, Luigino; Capuano, Annalisa; Matera, Maria Gabriella

    2015-07-01

    The ability of a chronic treatment with indacaterol, a new ultra-long-acting β2 -adrenoceptor agonist, to reverse cardiac remodelling and its effects in combination with metoprolol, a selective β1 -adrenoceptor antagonist, were investigated on myocardial infarction in a rat model of heart failure (HF). We investigated the effects of indacaterol and metoprolol, administered alone or in combination, on myocardial histology, β-adrenoceptor-mediated pathways, markers of remodelling and haemodynamic parameters in a rat model of HF. Five groups of rats were assessed: sham-operated rats; HF rats; HF + indacaterol 0.3 mg·kg(-1) ·day(-1) ; HF + metoprolol 100 mg·kg(-1) ·day(-1) ; HF + metoprolol + indacaterol. All pharmacological treatments continued for 15 weeks. Treatment with either indacaterol or metoprolol significantly reduced the infarct size in HF rats. However, the combination of indacaterol and metoprolol reduced the infarct size even further, reduced both BP and heart rate, reversed the decrease in ejection fraction, normalized left ventricular systolic and diastolic internal diameters, normalized the decreased β1 adrenoceptor mRNA expression as well as cardiac cAMP levels and reduced cardiac GPCR kinase 2 expression, compared with the untreated HF group. The results of our study demonstrated an additive interaction between indacaterol and metoprolol in normalizing and reversing cardiac remodelling in our experimental model of HF. The translation of these findings to clinical practice might be of interest, as this combination of drugs could be safer and more effective in patients suffering from HF and COPD. © 2015 The British Pharmacological Society.

  7. Metabolic responses to BRL37344 and clenbuterol in soleus muscle and C2C12 cells via different atypical pharmacologies and β2-adrenoceptor mechanisms

    Science.gov (United States)

    Ngala, R A; O'Dowd, J; Wang, S J; Agarwal, A; Stocker, C; Cawthorne, M A; Arch, J R S

    2008-01-01

    Background and purpose: Picomolar concentrations of the β3-adrenoceptor agonist BRL37344 stimulate 2-deoxyglucose uptake in soleus muscle via undefined receptors. Higher concentrations alter uptake, apparently via β2-adrenoceptors. Effects of BRL37344 and β2-adrenoceptor agonists are compared. Experimental approach: Mouse soleus muscles were incubated with 2-deoxy[1-14C]-glucose, [1-14C]-palmitate or [2-14C]-pyruvate, and BRL37344, β2-adrenoceptor agonists and selective β-adrenoceptor antagonists. Formation of 2-deoxy[1-14C]-glucose-6-phosphate or 14CO2 was measured. 2-Deoxy[1-14C]-glucose uptake and β-adrenoceptor mRNA were measured in C2C12 cells. Key results: 10 pM BRL37344, 10 pM clenbuterol and 100 pM salbutamol stimulated 2-deoxyglucose uptake in soleus muscle by 33–54%. The effect of BRL37344 was prevented by 1 μM atenolol but not by 300 nM CGP20712A or IC3118551, or 1 μM SR59230A; that of clenbuterol was prevented by ICI118551 but not atenolol. 10 nM BRL37344 st4mulated 2-deoxyglucose uptake, whereas 100 nM clenbuterol and salbutamol inhibited uptake. These effects were blocked by ICI118551. Similar results were obtained in C2C12 cells, in which only β2-adrenoceptor mRNA could be detected by RT-PCR. 10 nM BRL37344 and 10 pM clenbuterol stimulated muscle palmitate oxidation. In the presence of palmitate, BRL37344 no longer stimulated 2-deoxyglucose uptake and the effect of clenbuterol was not significant. Conclusions and implications: Stimulation of glucose uptake by 10 pM BRL37344 and clenbuterol involves different atypical pharmacologies. Nanomolar concentrations of BRL37344 and clenbuterol, probably acting via β2-adrenoceptors, have opposite effects on glucose uptake. The agonists preferentially stimulate fat rather than carbohydrate oxidation, but stimulation of endogenous fat oxidation cannot explain why 100 nM clenbuterol inhibited 2-deoxyglucose uptake. PMID:18552870

  8. Tumour necrosis factor-alpha antagonists in the management of rheumatoid arthritis in the elderly: a review of their efficacy and safety.

    Science.gov (United States)

    Radovits, Beáta J; Kievit, Wietske; Laan, Roland F J M

    2009-01-01

    Rheumatoid arthritis (RA) is a chronic inflammatory disease that frequently affects people aged >or=65 years, causing significant impairment with pain and functional disability. Elderly RA patients have specific problems, including co-morbid diseases, numerous concomitant medications, greater number of damaged joints as a result of longer disease duration and often a more severe disease presentation in elderly-onset RA. These factors, together with an age-related decline in the immune defence mechanisms, make elderly patients more vulnerable. The new era of biologic medications has made intensive treatment of RA patients possible. Anti-tumour necrosis factor-alpha (anti-TNFalpha) agents can cause a dramatic improvement in disease activity and functional capacity, making complete remission of RA a possible target. TNFalpha has been shown to play an important role in both the healthy aging process and age-related diseases such as RA. Targeting this cytokine in elderly patients is therefore reasonable. However, it is not clear whether treatment effects can be reached to the same extent in both elderly and younger patients and whether anti-TNFalpha treatment specifically increases the risk of certain adverse events in elderly RA patients. This review discusses the currently available evidence relating to the efficacy and safety of anti-TNFalpha medication in RA patients aged >or=65 years treated in clinical trials and observational studies. Despite a slightly less robust effect in elderly patients, anti-TNFalpha treatment has a similar long-term efficacy in patients aged >or=65 years and patients aged relatively safe in the treatment of elderly RA patients, treatment with corticosteroids significantly elevated the risk of serious infections. Corticosteroids are frequently used in elderly patients, but the evidence suggests that preference should increasingly be given to anti-TNFalpha agents, for which the expected benefits will mostly outweigh the modestly increased

  9. GABAB antagonists

    DEFF Research Database (Denmark)

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

    1994-01-01

    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......)-baclofen and the antagonist (-)-(R)-phaclofen suggests that these ligands interact with the GABAB receptor sites in a similar manner. Thus, it may be concluded that the different pharmacological effects of these compounds essentially result from the different spatial and proteolytic properties of their acid groups....

  10. Preferential reduction of binding of sup 125 I-iodopindolol to beta-1 adrenoceptors in the amygdala of rat after antidepressant treatments

    Energy Technology Data Exchange (ETDEWEB)

    Ordway, G.A.; Gambarana, C.; Tejani-Butt, S.M.; Areso, P.; Hauptmann, M.; Frazer, A. (Veterans Affairs Medical Center, Philadelphia, PA (USA))

    1991-05-01

    This study utilized quantitative receptor autoradiography to examine the effects of repeated administration of antidepressants to rats on the binding of the beta adrenoceptor antagonist, {sup 125}I-iodopindolol ({sup 125}I-IPIN) to either beta-1 or beta-2 adrenoceptors in various regions of brain. Antidepressants were selected to represent various chemical and pharmacological classes including tricyclic compounds (desipramine and protriptyline), monoamine oxidase inhibitors (clorgyline, phenelzine and tranylcypromine), atypical antidepressants (mianserin and trazodone) and selective inhibitors of the uptake of serotonin (citalopram and sertraline). Additionally, rats were treated with various psychotropic drugs that lack antidepressant efficacy (cocaine, deprenyl, diazepam and haloperidol). Repeated treatment of rats with desipramine, protriptyline, clorgyline, phenelzine, tranylcypromine or mianserin reduced the binding of {sup 125}I-IPIN to beta-1 adrenoceptors in many brain areas. Only in the basolateral and lateral nuclei of the amygdala did all six of these antidepressants significantly reduce {sup 125}I-IPIN binding to beta-1 adrenoceptors. In these amygdaloid nuclei, the magnitude of the reduction in the binding of {sup 125}I-IPIN caused by each of these drugs was comparable to or greater than the reduction in binding produced in any other region of brain. Reductions of binding of {sup 125}I-IPIN after antidepressant treatments were not consistently observed in the cortex, the area of brain examined most often in homogenate binding studies. Only the monoamine oxidase inhibitors caused reductions in the binding of {sup 125}I-IPIN to beta-2 adrenoceptors, and this effect was generally localized to the amygdala and hypothalamus.

  11. Test-retest reliability of {sup 11}C-ORM-13070 in PET imaging of α{sub 2C}-adrenoceptors in vivo in the human brain

    Energy Technology Data Exchange (ETDEWEB)

    Lehto, Jussi; Peltonen, Juha M.; Volanen, Iina; Scheinin, Mika [University of Turku, Clinical Research Services Turku CRST, Turku (Finland); TYKSLAB, Unit of Clinical Pharmacology, Turku (Finland); Virta, Jere R. [University of Turku and Turku University Hospital, Turku PET Centre, Turku (Finland); Turku University Hospital, Division of Clinical Neurosciences, Turku (Finland); Oikonen, Vesa; Roivainen, Anne; Luoto, Pauliina; Arponen, Eveliina; Helin, Semi; Virtanen, Kirsi [University of Turku and Turku University Hospital, Turku PET Centre, Turku (Finland); Hietamaeki, Johanna; Holopainen, Aila; Rouru, Juha; Sallinen, Jukka [Orion Pharma, Turku (Finland); Kailajaervi, Marita [Turku Imanet, GE Healthcare, Turku (Finland); Rinne, Juha O. [University of Turku and Turku University Hospital, Turku PET Centre, Turku (Finland); Turku University Hospital, Division of Clinical Neurosciences, Turku (Finland); University of Turku, Clinical Research Services Turku CRST, Turku (Finland)

    2015-01-15

    α{sub 2C}-Adrenoceptors share inhibitory presynaptic functions with the more abundant α{sub 2A}-adrenoceptor subtype, but they also have widespread postsynaptic modulatory functions in the brain. Research on the noradrenergic system of the human brain has been hampered by the lack of suitable PET tracers targeted to the α{sub 2}-adrenoceptor subtypes. PET imaging with the specific α{sub 2C}-adrenoceptor antagonist tracer [{sup 11}C]ORM-13070 was performed twice in six healthy male subjects to investigate the test-retest reliability of tracer binding. The bound/free ratio of tracer uptake relative to nonspecific uptake into the cerebellum during the time interval of 5 - 30 min was most prominent in the dorsal striatum: 0.77 in the putamen and 0.58 in the caudate nucleus. Absolute test-retest variability in bound/free ratios of tracer ranged from 4.3 % in the putamen to 29 % in the hippocampus. Variability was also <10 % in the caudate nucleus and thalamus. Intraclass correlation coefficients (ICC) ranged from 0.50 in the hippocampus to 0.89 in the thalamus (ICC >0.70 was also reached in the caudate nucleus, putamen, lateral frontal cortex and parietal cortex). The pattern of [{sup 11}C]ORM-13070 binding, as determined by PET, was in good agreement with receptor density results previously derived from post-mortem autoradiography. PET data analysis results obtained with a compartmental model fit, the simplified reference tissue model and a graphical reference tissue analysis method were convergent with the tissue ratio method. The results of this study support the use of [{sup 11}C]ORM-13070 PET in the quantitative assessment of α{sub 2C}-adrenoceptors in the human brain in vivo. Reliable assessment of specific tracer binding in the dorsal striatum is possible with the help of reference tissue ratios. (orig.)

  12. Quetiapine reverse paclitaxel-induced neuropathic pain in mice: Role of Alpha2- adrenergic receptors

    Directory of Open Access Journals (Sweden)

    Alireza Abed

    2017-11-01

    Full Text Available Objective(s: Paclitaxel-induced peripheral neuropathy is a common adverse effect of cancer chemo -therapy. This neuropathy has a profound impact on quality of life and patient’s survival. Preventing and treating paclitaxel-induced peripheral neuropathy is a major concern. First- and second-generation antipsychotics have shown analgesic effects both in humans and animals. Quetiapine is a novel atypical antipsychotic with low propensity to induce extrapyramidal or hyperprolactinemia side effects. The present study was designed to investigate the effects of quetiapine on the development and expression of neuropathic pain induced by paclitaxel in mice and the role of α2-adrenoceptors on its antinociception. Materials and Methods: Paclitaxel (2 mg/kg IP was injected for five consecutive days which resulted in thermal hyperalgesia and mechanical and cold allodynia. Results: Early administration of quetiapine from the 1st day until the 5th day (5, 10, and 15 mg/kg PO did not affect thermal, mechanical, and cold stimuli and could not prevent the development of neuropathic pain. In contrast, when quetiapine (10 and 15 mg/kg PO administration was started on the 6th day after the first paclitaxel injections, once the model had been established, and given daily until the 10th day, heat hyperalgesia and mechanical and cold allodynia were significantly attenuated. Also, the effect of quetiapine on heat hyperalgesia was reversed by pretreatment with yohimbine, as an alpha-2 adrenergic receptor antagonist. Conclusion: These results indicate that quetiapine, when administered after nerve injury can reverse the expression of neuropathic pain. Also, we conclude that α2-adrenoceptors participate in the antinociceptive effects of quetiapine.

  13. Analgesic synergy between opioid and α2 -adrenoceptors.

    Science.gov (United States)

    Chabot-Doré, A-J; Schuster, D J; Stone, L S; Wilcox, G L

    2015-01-01

    Opioid and α2 -adrenoceptor agonists are potent analgesic drugs and their analgesic effects can synergize when co-administered. These supra-additive interactions are potentially beneficial clinically; by increasing efficacy and/or reducing the total drug required to produce sufficient pain relief, undesired side effects can be minimized. However, combination therapies of opioids and α2 -adrenoceptor agonists remain underutilized clinically, in spite of a large body of preclinical evidence describing their synergistic interaction. One possible obstacle to the translation of preclinical findings to clinical applications is a lack of understanding of the mechanisms underlying the synergistic interactions between these two drug classes. In this review, we provide a detailed overview of the interactions between different opioid and α2 -adrenoceptor agonist combinations in preclinical studies. These studies have identified the spinal cord as an important site of action of synergistic interactions, provided insights into which receptors mediate these interactions and explored downstream signalling events enabling synergy. It is now well documented that the activation of both μ and δ opioid receptors can produce synergy with α2 -adrenoceptor agonists and that α2 -adrenoceptor agonists can mediate synergy through either the α2A or the α2C adrenoceptor subtypes. Current hypotheses surrounding the cellular mechanisms mediating opioid-adrenoceptor synergy, including PKC signalling and receptor oligomerization, and the evidence supporting them are presented. Finally, the implications of these findings for clinical applications and drug discovery are discussed. This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2. © 2014 The British Pharmacological Society.

  14. Terbutaline-induced desensitization of beta 2-adrenoceptor in vivo function in humans: attenuation by ketotifen

    NARCIS (Netherlands)

    Brodde, O. E.; Petrasch, S.; Bauch, H. J.; Daul, A.; Gnadt, M.; Oefler, D.; Michel, M. C.

    1992-01-01

    Use of beta-adrenoceptor agonists in long-term treatment of patients with chronic asthma bronchiale or heart failure is of limited value because beta-adrenoceptor desensitization develops. The antiallergic drug ketotifen prevents beta-adrenoceptor agonist-induced desensitization of rat and human

  15. Drug- and disease-induced changes of human cardiac beta 1- and beta 2-adrenoceptors

    NARCIS (Netherlands)

    Brodde, O. E.; Zerkowski, H. R.; Borst, H. G.; Maier, W.; Michel, M. C.

    1989-01-01

    Cardiac beta-adrenoceptor density and subtype distribution has been determined in different kinds of heart failure. A decrease in cardiac beta-adrenoceptor function appears to be a general phenomenon in all kinds of heart failure. However, cardiac beta 1- and beta 2-adrenoceptors seem to be

  16. 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.

    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

  17. The adrenergic alpha2 receptor and sexual incentive motivation in male rats.

    Science.gov (United States)

    Viitamaa, Timo; Haapalinna, Antti; Agmo, Anders

    2006-03-01

    The purpose of the present series of experiments was to determine whether drugs acting at the alpha2-adrenoceptor modify unconditioned sexual incentive motivation in the male rat. To that end a highly specific agonist, dexmedetomidine, a corresponding antagonist, atipamezole, and a less specific antagonist, yohimbine, were administered to groups of sexually inexperienced male rats. The subjects were tested in a large rectangular arena, where a sexually receptive female and an intact male were employed as incentives. The incentive animals were confined behind a wire mesh in opposite corners of the arena. The animals could see, hear and smell each other, but no sexual interaction was possible. Approach to the incentives constituted the measure of incentive motivation. In addition, the test provided data on ambulatory activity and general arousal. Dexmedetomidine, at a dose of 8 microg/kg, produced a slight reduction of sexual incentive motivation. Ambulatory activity and general arousal were also inhibited. Atipamezole, in doses of 0.1 and 0.3mg/kg enhanced the positive incentive properties of the receptive female. A high dose of 1mg/kg did not have any significant effect. Ambulatory activity was slightly reduced by the two larger doses of atipamezole. Yohimbine had a slight stimulatory effect on sexual incentive motivation at a dose (4 mg/kg) that also reduced ambulatory activity and general arousal. It is concluded that blockade of the adrenergic alpha2 receptor stimulates sexual incentive motivation in the male rat whereas stimulation of it has the opposite effect. At present it is not clear if these drug effects are caused by pre- or postsynaptic actions of the drugs, and the importance of secondary changes in other neurotransmitter systems remains unknown.

  18. Oral beta-stimulants can inhibit passive cutaneous anaphylaxis in rats through an indirect inhibitory mechanism: possible involvement of afferent and efferent nervous system via gastric beta2-adrenoceptor stimulation.

    Science.gov (United States)

    Shibata, H; Minami, E; Hirata, R; Nabe, T; Kohno, S

    2000-12-01

    We previously demonstrated that oral l-ephedrine exerts an extremely rapid (within 20 s) inhibition of 48-h passive cutaneous anaphylaxis reaction (PCA) in rats by a possibly unidentified mode of action. In the present experiments, we elucidated the mechanism of the PCA inhibition by l-ephedrine using adrenoceptor agonists and antagonists. Rat antiserum was prepared with dinitrophenylated Ascaris suum extract + Bordetella pertussis. Passively skin-sensitised Wistar rats were mainly used. l-Ephedrine, and adrenoceptor agonists and antagonists were orally administered immediately before PCA provocation. Catecholamine depleting (6-hydroxydopamine, 6-OHDA), amine depleting (reserpine) or ganglion blocking (hexamethonium) agent was intraperitoneally or intravenously administered before the provocation. The effects of the drugs on PCA were assessed by inhibition of the dye leakage. beta-(propranolol) and beta2-(butoxamine) blocking agents reduced the inhibition of PCA by l-ephedrine, while the inhibition was not altered by either an a-blocking agent (phentolamine) or a beta1-(atenolol) selective antagonist. On the other hand, beta-(isoproterenol) and beta2-selective (salbutamol) agonists showed extremely rapid inhibition of PCA. However, the beta-selective agonist (dobutamine) had no effect on the reaction. The pretreatment with hexamethonium, reserpine or 6-OH-DA substantially attenuated the inhibitory effect of l-ephedrine on PCA. The results strongly suggest that beta2-adrenoceptors locate in the stomach and that their receptor excitement finally may lead to the inhibition of PCA via the stimulation of the central and peripheral nervous systems.

  19. β1-Adrenoceptor blocker aggravated ventricular arrhythmia.

    Science.gov (United States)

    Wang, Yan; Patel, Dimpi; Wang, Dao Wu; Yan, Jiang Tao; Hsia, Henry H; Liu, Hao; Zhao, Chun Xia; Zuo, Hou Juan; Wang, Dao Wen

    2013-11-01

    To assess the impact of β1 -adrenoceptor blockers (β1 -blocker) and isoprenaline on the incidence of idiopathic repetitive ventricular arrhythmia that apparently decreases with preprocedural anxiety. From January 2010 to July 2012, six patients were identified who had idiopathic ventricular arrhythmias that apparently decreased (by greater than 90%) with preprocedural anxiety. The number of ectopic ventricular beats per hour (VPH) was calculated from Holter or telemetry monitoring to assess the ectopic burden. The mean VPH of 24 hours from Holter before admission (VPH-m) was used as baseline (100%) for normalization. β1 -Blockers, isoprenaline, and/or aminophylline were administrated successively on the ward and catheter lab to evaluate their effects on the ventricular arrhythmias. Among 97 consecutive patients with idiopathic ventricular arrhythmias, six had reduction in normalized VPHs in the hour before the scheduled procedure time from (104.6 ± 4.6%) to (2.8 ± 1.6%) possibly due to preprocedural anxiety (P < 0.05), then increased to (97.9 ± 9.7%) during β1 -blocker administration (P < 0.05), then quickly reduced to (1.6 ± 1.0%) during subsequent isoprenaline infusion. Repeated β1 -blocker quickly counteracted the inhibitory effect of isoprenaline, and VPHs increased to (120.9 ± 2.4%) from (1.6 ± 1.0%; P < 0.05). Isoprenaline and β1 -blocker showed similar effects on the arrhythmias in catheter lab. In some patients with structurally normal heart and ventricular arrhythmias there is a marked reduction of arrhythmias associated with preprocedural anxiety. These patients exhibit a reproducible sequence of β1 -blocker aggravation and catecholamine inhibition of ventricular arrhythmias, including both repetitive ventricular premature beats and monomorphic ventricular tachycardia. ©2013, The Authors. Journal compilation ©2013 Wiley Periodicals, Inc.

  20. Altered β1-3-adrenoceptor influence on α2-adrenoceptor-mediated control of catecholamine release and vascular tension in hypertensive rats.

    Science.gov (United States)

    Berg, Torill

    2015-01-01

    α2- and β-adrenoceptors (AR) reciprocally control catecholamine release and vascular tension. Disorders in these functions are present in spontaneously hypertensive rats (SHR). The present study tested if α2AR dysfunctions resulted from altered α2AR/βAR interaction. Blood pressure (BP) was recorded through a femoral artery catheter and cardiac output by an ascending aorta flow probe. Total peripheral vascular resistance (TPR) was calculated. Norepinephrine release was stimulated by a 15-min tyramine-infusion, which allows presynaptic release-control to be reflected as differences in overflow to plasma. Surgical stress activated some secretion of epinephrine. L-659,066 (α2AR-antagonist) enhanced norepinephrine overflow in normotensive controls (WKY) but not SHR. Nadolol (β1+2) and ICI-118551 (β2), but not atenolol (β1) or SR59230A [β(3)/1L ] prevented this increase. All βAR antagonists allowed L-659,066 to augment tyramine-induced norepinephrine overflow in SHR and epinephrine secretion in both strains. Inhibition of cAMP-degradation with milrinone and β3AR agonist (BRL37344) enhanced the effect of L-659,066 on release of both catecholamines in SHR and epinephrine in WKY. β1/2AR antagonists and BRL37344 opposed the L-659,066-dependent elimination of the TPR-response to tyramine in WKY. α2AR/βAR antagonists had little influence on the TPR-response in SHR. Milrinone potentiated the L-659,066-dependent reduction of the TPR-response to tyramine. β2AR activity was a required substrate for α2AR auto inhibition of norepinephrine release in WKY. β1+2AR opposed α2AR inhibition of norepinephrine release in SHR and epinephrine secretion in both strains. βAR-α2AR reciprocal control of vascular tension was absent in SHR. Selective agonist provoked β3AR-Gi signaling and influenced the tyramine-induced TPR-response in WKY and catecholamine release in SHR.

  1. Altered β1-3-adrenoceptor influence on α2-adrenoceptor-mediated control of catecholamine release and vascular tension in hypertensive rats

    Directory of Open Access Journals (Sweden)

    Torill eBerg

    2015-04-01

    Full Text Available α2- and β-adrenoceptors (AR reciprocally control catecholamine release and vascular tension. Disorders in these functions are present in spontaneously hypertensive rats (SHR. The present study tested if α2AR dysfunctions resulted from altered α2AR/βAR interaction. Blood pressure was recorded through a femoral artery catheter and cardiac output by an ascending aorta flow probe. Total peripheral vascular resistance (TPR was calculated. Norepinephrine release was stimulated by a 15-min tyramine-infusion, which allows presynaptic release-control to be reflected as differences in overflow to plasma. Surgical stress activated some secretion of epinephrine. L-659,066 (α2AR-antagonist enhanced norepinephrine overflow in normotensive controls (WKY but not SHR. Nadolol (β1+2 and ICI-118551 (β2, but not atenolol (β1 or SR59230A (β(3/1L prevented this increase. All βAR antagonists allowed L-659,066 to augment tyramine-induced norepinephrine overflow in SHR and epinephrine secretion in both strains. Inhibition of cAMP-degradation with milrinone and β3AR agonist (BRL37344 enhanced the effect of L-659,066 on release of both catecholamines in SHR and epinephrine in WKY. β1/2AR antagonists and BRL37344 opposed the L-659,066-dependent elimination of the TPR-response to tyramine in WKY. α2AR/βAR antagonists had little influence on the TPR-response in SHR. Milrinone potentiated the L-659,066-dependent reduction of the TPR-response to tyramine. Conclusions: β2AR activity was a required substrate for α2AR auto inhibition of norepinephrine release in WKY. β1+2AR opposed α2AR inhibition of norepinephrine release in SHR and epinephrine secretion in both strains. βAR-α2AR reciprocal control of vascular tension was absent in SHR. Selective agonist provoked β3AR-Gi signaling and influenced the tyramine-induced TPR-response in WKY and catecholamine release in SHR.

  2. Effects of a new beta-adrenoceptor blocking agent, S-596 (arotinolol), on isolated dog coronary arteries.

    Science.gov (United States)

    Sakanashi, M; Miyamoto, Y; Takeo, S; Noguchi, K

    1983-06-01

    Effects of S-596 on dog coronary arteries were investigated in vitro. S-596 produced concentration-dependent relaxations of coronary arterial strips under potassium-, prostaglandin (PG) F2 alpha- or PGE2-contracture. S-596-induced relaxations of the strips were not influenced by tetraethylammonium or tranylcypromine, but restored by additional Ca++ or prevented by prior administration of Ca++. In distal portions of coronary arteries, S-596 significantly inhibited concentration-dependent relaxations of the strips induced by norepinephrine and reversed to weak contractions. In proximal portions, S-596 significantly inhibited concentration-dependent contractions induced by norepinephrine. Results indicate that S-596 has a nonspecific relaxant effect on isolated dog coronary arteries maybe through impairment of Ca++ availability and simultaneously has an alpha-adrenoceptor blocking effect, particularly on large coronary arteries.

  3. Hippocampal α-adrenoceptors involve in the effect of histamine on spatial learning.

    Science.gov (United States)

    Torkaman-Boutorabi, Anahita; Danyali, Fatemeh; Oryan, Shahrbanoo; Ebrahimi-Ghiri, Mohaddeseh; Zarrindast, Mohammad-Reza

    2014-04-22

    Spatial learning is a model of higher human cognitive functions which is used for studying animal behavior. Histaminergic and noradrenergic systems play a modulatory role in learning and memory. The present study aimed to test the effects of α-adrenoceptor agonist/antagonist microinjection into the CA1 region of dorsal hippocampus on histamine-induced spatial learning facilitation in the water maze task. Pre-training intra-CA1 microinjection of α1- or α2-adrenergic agonist, phenylephrine (0.0025μg/rat) or clonidine (0.05μg/rat) decreased traveled distance and escape latency at the start of the training phase, suggesting a spatial learning facilitation; while the higher dose of the drugs (phenylephrine 0.005μg/rat, clonidine 0.2 and 0.5μg/rat) increased the performance level at the end of the training phase, indicating a water maze spatial acquisition impairment. However, α1-receptor antagonist, prazosin (1μg/rat) impaired spatial learning; α2-receptor antagonist, yohimbine (0.25μg/rat) facilitated spatial acquisition. Moreover, pre-training intra-CA1 microinjection of a subthreshold dose of phenylephrine (0.001μg/rat) reversed histamine response, while ineffective dose co-administration of clonidine (0.1μg/rat) potentiated histamine (0.01μg/rat) response. Subthreshold dose of prazosin or yohimbine did not alter histamine response. Bilateral infusion of histamine (0.05μg/rat) facilitated spatial learning by itself. Furthermore, the drug's injections had no effect on swimming speed on the training days of MWM. These results suggest that α-adrenergic receptors of the dorsal hippocampal CA1 regions may play an important role in histamine-induced facilitation of spatial acquisition. Copyright © 2014 Elsevier Inc. All rights reserved.

  4. Pharmacological identification of β-adrenoceptor subtypes mediating isoprenaline-induced relaxation of guinea pig colonic longitudinal smooth muscle

    Science.gov (United States)

    Chino, Daisuke; Sone, Tomoyo; Yamazaki, Kumi; Tsuruoka, Yuri; Yamagishi, Risa; Shiina, Shunsuke; Obara, Keisuke; Yamaki, Fumiko; Higai, Koji; Tanaka, Yoshio

    2018-01-01

    Object We aimed to identify the β-adrenoceptor (β-AR) subtypes involved in isoprenaline-induced relaxation of guinea pig colonic longitudinal smooth muscle using pharmacological and biochemical approaches. Methods Longitudinal smooth muscle was prepared from the male guinea pig ascending colon and contracted with histamine prior to comparing the relaxant responses to three catecholamines (isoprenaline, adrenaline, and noradrenaline). The inhibitory effects of subtype-selective β-AR antagonists on isoprenaline-induced relaxation were then investigated. Results The relaxant potencies of the catecholamines were ranked as: isoprenaline > noradrenaline ≈ adrenaline, whereas the rank order was isoprenaline > noradrenaline > adrenaline in the presence of propranolol (a non-selective β-AR antagonist; 3 × 10−7 M). Atenolol (a selective β1-AR antagonist; 3 × 10−7–10−6 M) acted as a competitive antagonist of isoprenaline-induced relaxation, and the pA2 value was calculated to be 6.49 (95% confidence interval: 6.34–6.83). The relaxation to isoprenaline was not affected by ICI-118,551 (a selective β2-AR antagonist) at 10−9–10−8 M, but was competitively antagonized by 10−7–3 × 10−7 M, with a pA2 value of 7.41 (95% confidence interval: 7.18–8.02). In the presence of propranolol (3 × 10−7 M), the relaxant effect of isoprenaline was competitively antagonized by bupranolol (a non-selective β-AR antagonist), with a pA2 value of 5.90 (95% confidence interval: 5.73–6.35). Conclusion These findings indicated that the β-AR subtypes involved in isoprenaline-induced relaxation of colonic longitudinal guinea pig muscles are β1-AR and β3-AR. PMID:29540623

  5. BETA(2)-ADRENOCEPTORS BUT NOT BETA(3)-ADRENOCEPTORS MEDIATE PREJUNCTIONAL INHIBITION OF NONADRENERGIC NONCHOLINERGIC CONTRACTION OF GUINEA-PIG MAIN BRONCHI

    NARCIS (Netherlands)

    TENBERGE, REJ; WEENING, EC; ROFFEL, AF; ZAAGSMA, J

    1995-01-01

    We studied the effects of selective beta-adrenoceptor agonists on the cholinergic and non-adrenergic non-cholinergic (excitatory NANC) contractions elicited by electrical field stimulation of guinea pig main bronchi in vitro. Addition of the selective beta(2)-adrenoceptor agonists, fenoterol and

  6. Efficacy and safety of tamsulosin in the treatment of urological diseases

    NARCIS (Netherlands)

    Michel, Martin C.; de La Rosette, Jean J. M. C. H.

    2004-01-01

    The alpha(1)-adrenoceptor antagonist tamsulosin, is selective for alpha(1A)- and alpha(1D)-over alpha(1B)-adrenoceptors. Both placebo-controlled and comparative studies with other agents have demonstrated tamsulosin to be an effective treatment for patients with lower urinary symptoms suggestive of

  7. Modulatory role of endogenous androgens on airway smooth muscle tone in isolated guinea-pig and bovine trachea; involvement of beta2-adrenoceptors, the polyamine system and external calcium.

    Science.gov (United States)

    Bordallo, Javier; de Boto, María José García; Meana, Clara; Velasco, Lucía; Bordallo, Carmen; Suárez, Lorena; Cantabrana, Begoña; Sánchez, Manuel

    2008-12-28

    Androgens relax several smooth muscles, including the airways. They also contract ileum and myocardium via nongenomic mechanisms. To find out whether androgens modulate airway smooth muscles in different species and further assess their mechanism of action, regarding the role of beta-adrenoceptors, polyamines and extracellular Ca(2+), and the modulation of contraction, 5 alpha-dihydrotestosterone, testosterone and 5 beta-dihydrotestosterone were used. A preliminary study was performed to evaluate the effect of 5 alpha-dihydrotestosterone, a non-aromatisable derivate of testosterone, in isolated guinea-pig trachea and a more exhaustive characterisation was followed in bovine trachea, to also characterise the effect of testosterone and 5 beta-dihydrotestosterone. The androgens elicited a nongenomic epithelium-independent relaxation of the trachea which had been precontracted. In the bovine trachea, the order of potency was: testosterone>5 alpha-dihydrotestosterone=5 beta-dihydrotestosterone. This effect was inversely proportional to the magnitude of carbachol-raised tone and was independent of beta(2)-adrenoceptors, since the beta-blockers, propranolol and ICI-118,551, and beta(2)-adrenoceptor desensitisation did not modify 5 alpha-dihydrotestosterone-elicited relaxation. 5 alpha-Dihydrotestosterone was unable to displace the radiolabel, [(3)H]dihydroalprenolol, from these receptors in the binding assay. Polyamine synthesis was not involved in this androgen effect, since an ornithine decarboxylase inhibitor, alpha-difluoromethylornithine, was ineffective. The androgens were more effective relaxing bovine trachea precontracted by KCl (80 mM), suggesting a calcium entry blockade, as reported for several smooth muscles. This mechanism might be involved in the observed 5 alpha-dihydrotestosterone facilitation of salbutamol-relaxation. Androgens facilitated carbachol-elicited contraction independently of polyamine synthesis, contrary to what has been reported in the ileum

  8. Beta2-adrenoceptors: mechanisms of action of beta2-agonists.

    Science.gov (United States)

    Johnson, M

    2001-03-01

    The human beta2-adrenoceptor is a member of the 7 transmembrane family of receptors. It is encoded by a gene on chromosome 5 and is widely distributed in the respiratory tract. Following beta2-adrenoceptor activation, intracellular signalling is mainly produced by inducing cyclic AMP. This produces airway relaxation through phosphorylation of muscle regulatory proteins and modification of cellular Ca2+concentrations. Beta2-agonists have been characterised into those which directly activate the receptor (salbutamol/terbutaline), those which are taken up into a membrane depot (formoterol) and those which interact with a receptor-specific, auxiliary binding site (salmeterol). These differences in mechanism of action are reflected in the kinetics of airway smooth muscle relaxation and bronchodilation in asthmatic patients. Beta-adrenoceptor desensitisation is associated with beta2-agonist activation and differs depending on the cell type. It is reflected in the different profiles of clinical tolerance to chronic beta2-agonist therapy. A number of polymorphisms of the beta2-receptor have been described which appear to alter the behaviour of the receptor, including the degree of downregulation and response to beta2-agonists.

  9. Myocardial beta-adrenoceptor changes in heart failure: concomitant reduction in beta 1- and beta 2-adrenoceptor function related to the degree of heart failure in patients with mitral valve disease

    NARCIS (Netherlands)

    Brodde, O. E.; Zerkowski, H. R.; Doetsch, N.; Motomura, S.; Khamssi, M.; Michel, M. C.

    1989-01-01

    In patients suffering from end-stage congestive cardiomyopathy, cardiac beta 1-adrenoceptor function is markedly reduced, whereas cardiac beta 2-adrenoceptor function is nearly normal. To determine whether beta 1-adrenoceptor function is impaired in heart failure selectively, beta 1- and beta

  10. Agonist-induced desensitization of beta-adrenoceptor function in humans. Subtype-selective reduction in beta 1- or beta 2-adrenoceptor-mediated physiological effects by xamoterol or procaterol

    NARCIS (Netherlands)

    Brodde, O. E.; Daul, A.; Michel-Reher, M.; Boomsma, F.; Man in 't Veld, A. J.; Schlieper, P.; Michel, M. C.

    1990-01-01

    We investigated the effects of beta 2- (procaterol 2 x 50 micrograms/day for 9 days) and beta 1- (xamoterol 2 x 200 mg/day for 14 days) adrenoceptor agonists on lymphocyte beta 2-adrenoceptor density and beta 1- and beta 2-adrenoceptor in vivo function (assessed as isoprenaline-infusion-evoked

  11. Thyroid status affects the rat cardiac beta-adrenoceptor system transiently and time-dependently

    NARCIS (Netherlands)

    Zwaveling, J.; Batink, H. D.; Taguchi, K.; de Jong, J.; Michel, M. C.; Pfaffendorf, M.; van Zwieten, A.

    1998-01-01

    1. The aim of this study was to investigate the time-dependency of the influence of dysthyroid states on the beta-adrenoceptor system in rat heart left ventricle. Therefore, the influence of acute and chronic hyper- and hypothyroidism on beta-adrenoceptor-induced left ventricular responses,

  12. Beta-adrenoceptor regulation in the human heart: can it be monitored in circulating lymphocytes?

    NARCIS (Netherlands)

    Brodde, O. E.; Michel, M. C.; Gordon, E. P.; Sandoval, A.; Gilbert, E. M.; Bristow, M. R.

    1989-01-01

    In heart failure a decrease in cardiac beta-adrenoceptors presumably due to endogenous down-regulation by the elevated catecholamines is a general phenomenon. Thus, attempts have been made to assess beta-adrenoceptor function in patients with chronic heart failure in order to monitor the functional

  13. The selective action of beta-adrenoceptor blocking drugs and the nature of beta1 and beta2 adrenoceptors.

    Science.gov (United States)

    Coleman, A J; Somerville, A R

    1977-01-01

    1 Purified membranes retaining a catecholamine responsive adenylate cyclase have prepared from rabbit heart, lung and (pseudo-pregnant) uterus. 2 These preparations have the characteristics of plasma membranes and both heart and lung respond to beta-adrenoceptor agonists in the order: (+/-)-isoprenaline greater than (-)-noradrenaline greater than (-)-adrenaline greater than (+)-isoprenaline greater than salbutamol. The sensitivity of the adenylate cyclase to beta-adrenoceptor stimulation is improved by pre-treatment of the animals with reserpine and syrosingopine. 3 Dose-ratios for several concentrations of propranolol (non-selective beta-adrenoceptor blocker), practolol and atenolol (cardio-selective beta-adrenoceptor blockers) have been measured on all three membrane preparations. Schild plots of log (dose ratio -1) vs. log dose were virtually coincident for heart and lung with a dissociation constant (Kb) for propranolol very close to the pharmacological value. The ratio of Kb values was 0.65 for practolol and 1.23 for atenolol compared with pharmacological cardio-selectivity ratios (measured on isolated atria and tracheal chain) of 67.6 and 110 respectively. The uterus/heart Kb ratio was 51.5 for atenolol. Inhibition of the uterus by practolol gave a Schild plot with slope significantly less than 1, indicating a different mechanism of action from the heart. 4 Kb values obtained by measuring adenylate cyclase stimulation in chopped tissue (including preparations of bronchial tree and alveolar tissue as well as whole lung) resembled the membrane values rather than those found in whole organs. 5 The results show that the pharmacological selectivity of practolol and atenolol is maintained at the receptor-adenylate cyclase level, at least as far as heart and uterus are concerned, though the smaller selectivity ratios in the biochemical system suggest that receptor differences is not the only factor and that phase distribution of the drug may also be important

  14. Enhanced Noradrenergic Activity Potentiates Fear Memory Consolidation and Reconsolidation by Differentially Recruiting alpha1- and beta-Adrenergic Receptors

    Science.gov (United States)

    Gazarini, Lucas; Stern, Cristina A. Jark; Carobrez, Antonio P.; Bertoglio, Leandro J.

    2013-01-01

    Consolidation and reconsolidation are phases of memory stabilization that diverge slightly. Noradrenaline is known to influence both processes, but the relative contribution of alpha1- and beta-adrenoceptors is unclear. The present study sought to investigate this matter by comparing their recruitment to consolidate and/or reconsolidate a…

  15. Modification of the β-Adrenoceptor Stimulation Pathway in Zucker Obese and Obese Diabetic Rat Myocardium.

    Science.gov (United States)

    Jiang, Cheng; Carillion, Aude; Na, Na; De Jong, Audrey; Feldman, Sarah; Lacorte, Jean-Marc; Bonnefont-Rousselot, Dominique; Riou, Bruno; Amour, Julien

    2015-07-01

    Although metabolic syndrome is associated with increased sympathetic activity that chronically stimulates β-adrenoceptors, the β-adrenoceptor signaling pathway has been poorly studied in this situation. We studied the β-adrenoceptor signaling pathway in Zucker lean, obese, and obese diabetic rats. Experimental, prospective study. University medical research laboratory. Adult male Zucker lean (control), obese, and obese diabetic rats. The effects of β-adrenoceptor stimulation were investigated in vitro in isolated left ventricular papillary muscles in control, obese, and obese diabetic rats. β1-, β2-, and β3-adrenoceptors and multidrug resistance-associated protein 4 were quantified by Western Blotting. Triglyceride, cholesterol, leptin, adiponectin, and C-peptide plasma concentrations were measured. Data are mean ± SD. Hyperlipidemia, high leptin, and C-peptide concentrations were observed in obese and obese diabetic strains, whereas hyperglycemia occurred only in the diabetic strain. The positive inotropic effect of isoproterenol was slightly reduced in obese rats (183% ± 11% of baseline; p = 0.003; n = 7) and markedly reduced in obese diabetic rats (137% ± 18% of baseline; p < 0.001; n = 10) when compared with control rats (210% ± 17% of baseline; n = 9). β1-adrenoceptors were down-regulated in obese (-41%; p = 0.02) and diabetic (-54%; p = 0.003) when compared with control rats, whereas β3-adrenoceptors and multidrug resistance-associated protein expression remained unchanged. Direct stimulation of adenylate cyclase with forskolin or administration of 3',5'-cyclic adenosine monophosphate suggests that subtle impairments also occurred beside the down-regulation of β1-adrenoceptor. The positive inotropic effect of β-adrenoceptor stimulation is slightly decreased in Zucker obese rats and was more markedly decreased in Zucker diabetic rats. These decreases are mainly related to β1-adrenoceptor down-regulation.

  16. Perspectives on mirabegron in the treatment of overactive bladder syndrome: A new beta-3 adrenoceptor agonist

    Directory of Open Access Journals (Sweden)

    Chia-Hao Kuei

    2015-03-01

    Full Text Available Mirabegron, the first β3-adrenoceptor agonist introduced for use in clinical practice, differs from antimuscarinic agents in terms of mechanism of action. This review discusses various perspectives on mirabegron in terms of efficacy, mechanism of action, pharmacokinetics, safety, and tolerability for overactive bladder syndrome in studies conducted thus far. Mirabegron administered at daily doses of 25 mg, 50 mg, and 100 mg demonstrated significant improvements in micturition frequency, urgency incontinence, and mean volume voided/micturition as early as the first assessment, and these were maintained throughout the treatment course. Mirabegron seemed well tolerated. The most common adverse events observed with mirabegron in clinical trials were hypertension, nasopharyngitis, and urinary tract infection. The incidence of dry mouth was similar to that with placebo, between 3- and 5-fold lower than with 4 mg tolterodine extended release. Considering that dry mouth is the most bothersome adverse event associated with antimuscarinic drugs and often a reason for treatment discontinuation, mirabegron may be a valuable treatment option for these patients. The benefit of mirabegron (at doses of 50 mg and 100 mg was also evident in elderly patients and in both treatment-naive patients and those who previously discontinued antimuscarinic therapy. Mirabegron can also be used in combination with antimuscarinics or in addition to alpha blockers. Mirabegron may quickly become a standard treatment of overactive bladder syndrome.

  17. Stress Alone or associated with Ethanol Induces Prostanoid Release in Rat Aorta via α2-Adrenoceptor

    International Nuclear Information System (INIS)

    Baptista, Rafaela de Fátima Ferreira; Taipeiro, Elane de Fátima; Queiroz, Regina Helena Costa; Chies, Agnaldo Bruno; Cordellini, Sandra

    2014-01-01

    Stress and ethanol are both, independently, important cardiovascular risk factors. To evaluate the cardiovascular risk of ethanol consumption and stress exposure, isolated and in association, in male adult rats. Rats were separated into 4 groups: Control, ethanol (20% in drinking water for 6 weeks), stress (immobilization 1h day/5 days a week for 6 weeks) and stress/ethanol. Concentration-responses curves to noradrenaline - in the absence and presence of yohimbine, L-NAME or indomethacin - or to phenylephrine were determined in thoracic aortas with and without endothelium. EC50 and maximum response (n=8-12) were compared using two-way ANOVA/Bonferroni method. Either stress or stress in association with ethanol consumption increased the noradrenaline maximum responses in intact aortas. This hyper-reactivity was eliminated by endothelium removal or by the presence of either indomethacin or yohimbine, but was not altered by the presence of L-NAME. Meanwhile, ethanol consumption did not alter the reactivity to noradrenaline. The phenylephrine responses in aortas both with and without endothelium also remained unaffected regardless of protocol. Chronic stress increased rat aortic responses to noradrenaline. This effect is dependent upon the vascular endothelium and involves the release of vasoconstrictor prostanoids via stimulation of endothelial alpha-2 adrenoceptors. Moreover, chronic ethanol consumption appeared to neither influence noradrenaline responses in rat thoracic aorta, nor did it modify the increase of such responses observed as a consequence of stress exposure

  18. Stress Alone or associated with Ethanol Induces Prostanoid Release in Rat Aorta via α2-Adrenoceptor

    Science.gov (United States)

    Baptista, Rafaela de Fátima Ferreira; Taipeiro, Elane de Fátima; Queiroz, Regina Helena Costa; Chies, Agnaldo Bruno; Cordellini, Sandra

    2014-01-01

    Background Stress and ethanol are both, independently, important cardiovascular risk factors. Objective To evaluate the cardiovascular risk of ethanol consumption and stress exposure, isolated and in association, in male adult rats. Methods Rats were separated into 4 groups: Control, ethanol (20% in drinking water for 6 weeks), stress (immobilization 1h day/5 days a week for 6 weeks) and stress/ethanol. Concentration-responses curves to noradrenaline - in the absence and presence of yohimbine, L-NAME or indomethacin - or to phenylephrine were determined in thoracic aortas with and without endothelium. EC50 and maximum response (n=8-12) were compared using two-way ANOVA/Bonferroni method. Results Either stress or stress in association with ethanol consumption increased the noradrenaline maximum responses in intact aortas. This hyper-reactivity was eliminated by endothelium removal or by the presence of either indomethacin or yohimbine, but was not altered by the presence of L-NAME. Meanwhile, ethanol consumption did not alter the reactivity to noradrenaline. The phenylephrine responses in aortas both with and without endothelium also remained unaffected regardless of protocol. Conclusion Chronic stress increased rat aortic responses to noradrenaline. This effect is dependent upon the vascular endothelium and involves the release of vasoconstrictor prostanoids via stimulation of endothelial alpha-2 adrenoceptors. Moreover, chronic ethanol consumption appeared to neither influence noradrenaline responses in rat thoracic aorta, nor did it modify the increase of such responses observed as a consequence of stress exposure. PMID:24676223

  19. Stress Alone or associated with Ethanol Induces Prostanoid Release in Rat Aorta via α2-Adrenoceptor

    Energy Technology Data Exchange (ETDEWEB)

    Baptista, Rafaela de Fátima Ferreira [Departamento de Farmacologia - Instituto de Biociências - Universidade Estadual Paulista - UNESP - São Paulo, SP (Brazil); Laboratório de Farmacologia - Faculdade de Medicina de Marília - FAMEMA, SP (Brazil); Taipeiro, Elane de Fátima [Laboratório de Farmacologia - Faculdade de Medicina de Marília - FAMEMA, SP (Brazil); Queiroz, Regina Helena Costa [Departamento de Análise Clínica - Toxicológica e Ciência de Alimentos - Faculdade de Ciências Farmacêuticas - USP, São Paulo, SP (Brazil); Chies, Agnaldo Bruno [Departamento de Farmacologia - Instituto de Biociências - Universidade Estadual Paulista - UNESP - São Paulo, SP (Brazil); Laboratório de Farmacologia - Faculdade de Medicina de Marília - FAMEMA, SP (Brazil); Cordellini, Sandra, E-mail: cordelli@ibb.unesp.br [Departamento de Farmacologia - Instituto de Biociências - Universidade Estadual Paulista - UNESP - São Paulo, SP (Brazil)

    2014-03-15

    Stress and ethanol are both, independently, important cardiovascular risk factors. To evaluate the cardiovascular risk of ethanol consumption and stress exposure, isolated and in association, in male adult rats. Rats were separated into 4 groups: Control, ethanol (20% in drinking water for 6 weeks), stress (immobilization 1h day/5 days a week for 6 weeks) and stress/ethanol. Concentration-responses curves to noradrenaline - in the absence and presence of yohimbine, L-NAME or indomethacin - or to phenylephrine were determined in thoracic aortas with and without endothelium. EC50 and maximum response (n=8-12) were compared using two-way ANOVA/Bonferroni method. Either stress or stress in association with ethanol consumption increased the noradrenaline maximum responses in intact aortas. This hyper-reactivity was eliminated by endothelium removal or by the presence of either indomethacin or yohimbine, but was not altered by the presence of L-NAME. Meanwhile, ethanol consumption did not alter the reactivity to noradrenaline. The phenylephrine responses in aortas both with and without endothelium also remained unaffected regardless of protocol. Chronic stress increased rat aortic responses to noradrenaline. This effect is dependent upon the vascular endothelium and involves the release of vasoconstrictor prostanoids via stimulation of endothelial alpha-2 adrenoceptors. Moreover, chronic ethanol consumption appeared to neither influence noradrenaline responses in rat thoracic aorta, nor did it modify the increase of such responses observed as a consequence of stress exposure.

  20. Complementary anti-inflammatory actions of the β₂-adrenoceptor agonist clenbuterol and the glucocorticoid dexamethasone in rat brain.

    Science.gov (United States)

    Ryan, Katie J; Griffin, Eadaoin W; Connor, Thomas J

    2011-03-01

    Systemic administration of the β(2)-adrenoceptor agonist clenbuterol induces expression of IL-1β and its negative regulators, interleukin-1 receptor antagonist (IL-1ra) and the interleukin-1 type II decoy receptor (IL-1RII) in rat brain. Clenbuterol also increases central expression of the broad spectrum anti-inflammatory cytokine interleukin-10 (IL-10) and its downstream signalling molecule, suppressor of cytokine signalling-3 (SOCS-3). Here we examine the impact of combined treatment with clenbuterol (0.5mg/kg) and the glucocorticoid dexamethasone (1mg/kg) on mRNA expression of IL-1β and the IL-1β-inducible gene iNOS, on IκBα mRNA expression and NFκB activation, and on mRNA expression of the anti-inflammatory molecules IL-1ra, IL-1RII, IL-10 and SOCS-3 in rat cortex, striatum and hippocampus. Dexamethasone inhibited induction of IL-1β and iNOS mRNA expression by clenbuterol in all three brain regions, without altering its ability to induce IL-1ra mRNA expression. In the case of IL-1RII, dexamethasone further augmented clenbuterol-induced IL-1RII mRNA expression in hippocampus and striatum. These data highlight a mechanistic dissociation between the ability of β(2)-adrenoceptor activation to induce expression of IL-1β, and its negative regulators IL-1ra and IL-1RII in the brain. Treatment with either dexamethasone or clenbuterol alone independently induced IκBα mRNA expression, and elicited a concomitant decrease in the DNA binding of NFκB in all three brain regions. In the hippocampus and striatum dexamethasone treatment did not influence the ability of clenbuterol to induce IL-10 mRNA expression. In contrast in the cortex, induction of IL-10 and SOCS-3 mRNA expression by clenbuterol administered in combination with dexamethasone was less than induced by clenbuterol alone. Overall these data indicate that combined treatment with dexamethasone and the β(2)-adrenoceptor agonist clenbuterol elicit complementary anti-inflammatory actions in the CNS

  1. Roles of Beta2- and Beta3-Adrenoceptor Polymorphisms in Hypertension and Metabolic Syndrome

    Directory of Open Access Journals (Sweden)

    Kazuko Masuo

    2010-01-01

    gain, and the sympathetic nervous system participates in regulating energy balance through thermogenesis. The thermogenic effects of catecholamines in obesity have been mainly mediated via the 2- and 3-adrenergic receptors in humans. Further, 2-adrenoceptors importantly influence vascular reactivity and may regulate blood pressure. Genetic polymorphistns of the -adrenoceptor gene have been shown to alter the function of several adrenoceptor subtypes and thus to modify the response to catecholamine. 2-adrenoceptor polymorphisms (Arg16Gly, Gln27Glu, and Thr164Ile have been studied in relation to hypertension. Genetic variations in the 3-adrenoceptor (i.e. Try64Arg variant are also associated with both obesity and hypertension. However, the precise relationships of the polymorphisms of 2- and 3-adrenoceptor genes with sympathetic nervous system activity, hypertension, and metabolic syndrome have not been fully clarified. This paper will discuss the current topics involving the influence of the sympathetic nervous system and 2- and 3- adrenoceptor polymorphisms in hypertension and metabolic syndrome.

  2. Changes in cardiovascular beta-adrenoceptor responses during hypothermia.

    Science.gov (United States)

    Han, Young-Soo; Tveita, Torkjel; Kondratiev, Timofei V; Prakash, Y S; Sieck, Gary C

    2008-12-01

    The purpose of this study was to determine cardiovascular beta-adrenergic responses during hypothermia. In the present study, we used isoproterenol (Iso), a nonselective, potent beta-adrenoceptor agonist, well known for its positive chronotropic and inotropic pharmacologic actions at normothermia. Rats were instrumented to measure mean arterial pressure (MAP) and left ventricular (LV) pressure-volume changes using a Millar pressure-volume conductance catheter. Core temperature was manipulated from 37 (normothermia) to 24 degrees C (hypothermia) and back to 37 degrees C (rewarming) using both internal and external heat exchangers. During cooling at each temperature (33, 30, 27, and 24 degrees C), central hemodynamic variables and MAP were measured while intravenously infusing Iso (doses of 1.7, 5, 10, and 20 ng/min). Seven animals underwent all phases of the protocol. At normothermia Iso infusion resulted in a significant, dose-dependent increase in heart rate (HR), stroke volume (SV), cardiac output (CO), LV dP/dt(max) (left ventricular maximum derivative of systolic pressure over time) but no change in MAP. During cooling Iso infusion caused no dose-dependent change in any of the hemodynamic variables. After rewarming, baseline HR and LV dP/dt(max) were increased, whereas SV was significantly reduced when compared with their pre-hypothermic baseline values. This study shows that physiological cardiovascular responses mediated by the beta-adrenoceptor are significantly diminished during core hypothermia.

  3. Preclinical evaluation of an 18F-labelled beta1-adrenoceptor selective radioligand based on ICI 89,406.

    Science.gov (United States)

    Law, Marilyn P; Wagner, Stefan; Kopka, Klaus; Renner, Christiane; Pike, Victor W; Schober, Otmar; Schäfers, Michael

    2010-05-01

    Radioligand binding studies indicate a down-regulation of myocardial beta(1)-adrenoceptors (beta(1)-AR) in cardiac disease which may or may not be associated with a decrease in beta(2)-ARs. We have chosen ICI 89,406, a beta(1)-selective AR antagonist, as the lead structure to develop new beta(1)-AR radioligands for PET and have synthesised a fluoro-ethoxy derivative (F-ICI). (S)-N-[2-[3-(2-Cyano-phenoxy)-2-hydroxy-propylamino]-ethyl]-N'-[4-(2-[(18)F]fluoro-ethoxy)-phenyl]-urea ((S)-[(18)F]F-ICI) was synthesised. Myocardial uptake of radioactivity after intravenous injection of (S)-[(18)F]F-ICI into adult CD(1) mice or Wistar rats was assessed with positron emission tomography (PET) and postmortem dissection. Metabolism was assessed by high-performance liquid chromatography analysis of plasma and urine. The heart was visualised with PET after injection of (S)-[(18)F]F-ICI but neither unlabelled F-ICI nor propranolol (non-selective beta-AR antagonist) injected 15 min after (S)-[(18)F]F-ICI affected myocardial radioactivity. Ex vivo dissection demonstrated that predosing with propranolol or CGP 20712 (beta(1)-selective AR-antagonist) did not affect myocardial radioactivity. Radiometabolites rapidly appeared in plasma and both (S)-[(18)F]F-ICI and radiometabolites accumulated in urine. Myocardial uptake of (S)-[(18)F]F-ICI after intravenous injection was mainly at sites unrelated to beta(1)-ARs. (S)-[(18)F]F-ICI is not a suitable beta(1)-selective-AR radioligand for PET. (c) 2010 Elsevier Inc. All rights reserved.

  4. Plasma norepinephrine in hypertensive rats reflects α2-adrenoceptor release control only when re-uptake is inhibited

    Directory of Open Access Journals (Sweden)

    Torill eBerg

    2012-11-01

    Full Text Available α2 adrenoceptors (AR lower central sympathetic output and peripheral catecholamine release, thereby protecting against sympathetic hyperactivity and hypertension. Norepinephrine re-uptake transporter effectively (NET removes norepinephrine from the synapse. Overflow to plasma will therefore not reflect release. Here we tested if inhibition of re-uptake allowed presynaptic α2AR release-control to be reflected as differences in norepinephrine overflow in anesthetized hypertensive (SHR and normotensive (WKY rats. We also tested if α2AR modulated the experiment-induced epinephrine secretion, and a phenylephrine-induced, α1-adrenergic vasoconstriction. Blood pressure was recorded through a femoral artery catheter, and cardiac output by ascending aorta flow. After pre-treatment with NET inhibitor (desipramine, and/or α2AR antagonist (yohimbine, L-659,066 or agonist (clonidine, ST-91, we injected phenylephrine. Arterial blood was sampled 15 min later. Plasma catecholamine concentrations were not influenced by phenylephrine, and therefore reflected effects of pre-treatment. Desipramine and α2AR antagonist separately had little effect on norepinephrine overflow. Combined, they increased norepinephrine overflow, particularly in SHR. Clonidine, but not ST-91, reduced, and pertussis toxin increased norepinephrine overflow in SHR and epinephrine secretion in both strains. L-659,066+clonidine (central α2AR-stimulation normalized the high blood pressure, heart rate and vascular tension in SHR. α2AR antagonists reduced phenylephrine induced vasoconstriction equally in WKY and SHR. Conclusions: α2AAR inhibition increased norepinephrine overflow only when re-uptake was blocked, and then with particular efficacy in SHR, possibly due to their high sympathetic tone. α2AAR inhibited epinephrine secretion, particularly in SHR. α2AAR supported α1AR-induced vasoconstriction equally in the two strains. α2AR malfunctions were therefore not detected in SHR

  5. Blockade of Adrenal Medulla-Derived Epinephrine Potentiates Bee Venom-Induced Antinociception in the Mouse Formalin Test: Involvement of Peripheral β-Adrenoceptors

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    Suk-Yun Kang

    2013-01-01

    Full Text Available The injection of diluted bee venom (DBV into an acupoint has been used traditionally in eastern medicine to treat a variety of inflammatory chronic pain conditions. We have previously shown that DBV had a potent antinociceptive efficacy in several rodent pain models. However, the peripheral mechanisms underlying DBV-induced antinociception remain unclear. The present study was designed to investigate the role of peripheral epinephrine on the DBV-induced antinociceptive effect in the mouse formalin assay. Adrenalectomy significantly enhanced the antinociceptive effect of DBV during the late phase of the formalin test, while chemical sympathectomy had no effect. Intraperitoneal injection of epinephrine blocked this adrenalectomy-induced enhancement of the DBV-induced antinociceptive effect. Moreover, injection of a phenylethanolamine N-methyltransferase (PNMT inhibitor enhanced the DBV-induced antinociceptive effect. Administration of nonselective β-adrenergic antagonists also significantly potentiated this DBV-induced antinociception, in a manner similar to adrenalectomy. These results demonstrate that the antinociceptive effect of DBV treatment can be significantly enhanced by modulation of adrenal medulla-derived epinephrine and this effect is mediated by peripheral β-adrenoceptors. Thus, DBV acupoint stimulation in combination with inhibition of peripheral β-adrenoceptors could be a potentially novel strategy for the management of inflammatory pain.

  6. PET imaging of beta-adrenoceptors in human brain: A realistic goal or a mirage?

    NARCIS (Netherlands)

    van Waarde, Aaren; Vaalburg, W.; Doze, Petra; Bosker, Fokko; Elsinga, P.H

    2004-01-01

    Beta-adrenoceptors are predominantly located in the cerebral cortex, nucleus accumbens and striatum. At lower densities, they are also present in amygdala, hippocampus and cerebellum. Beta-2 sites regulate glial proliferation during ontogenic development, after trauma and in neurodegenerative

  7. Effect of glucose infusion on endurance performance after beta-adrenoceptor blocker administration

    NARCIS (Netherlands)

    van Baak, M.A.; Mooij, J.M.

    1994-01-01

    Effect of glucose infusion on endurance performance after beta-adrenoceptor blocker administration. Van Baak MA, Mooij JM. Department of Human Biology, University of Limburg, Maastricht, The Netherlands. To investigate the effect of glucose (Glc) infusion on endurance performance after

  8. β- and α2-Adrenoceptor Control of Vascular Tension and Catecholamine Release in Female Normotensive and Spontaneously Hypertensive Rats.

    Science.gov (United States)

    Berg, Torill

    2017-01-01

    As in humans, young, female, spontaneously hypertensive rats (SHR) have a lower blood pressure than male SHR. In male, normotensive rats (WKY), α 2 - and β 1+2 -adrenoceptors (AR) reciprocally controlled catecholamine release and vascular smooth muscle tension. This interaction was malfunctioning in male SHR. The present study analyzed if a favorable shift in the α 2 /β 1+2 AR interaction may represent an antihypertensive protection in females. Female SHR (early hypertension, 12-14 weeks) and age-matched WKY were infused with tyramine (15 min) to stimulate norepinephrine (NE) release through the reuptake transporter, consequently preventing reuptake. Presynaptic control of vesicular release was therefore reflected as differences in overflow to plasma. The released NE increased total peripheral vascular resistance (TPR). The results showed that β 1>2 AR facilitated tyramine-stimulated NE release in both strains, also in the presence of α 2 AR-antagonist (L-659,066). βAR-antagonist (atenolol-β 1 , ICI-118551-β 2 , nadolol-β 1+2 ) had no effect on the increased secretion of epinephrine after L-659,066 in WKY, but β 1>2 AR-antagonist augmented the L-659,066-induced increase in the secretion of epinephrine in SHR. Nadolol increased the TPR response to tyramine with a greater effect in WKY than SHR, whereas β 1or2 -selective antagonists did not. One βAR-subtype may therefore substitute for the other. When both β 1+2 AR were blocked, α 2 AR-antagonist still reduced the TPR response in WKY but not SHR. Thus, α 2 /β 1+2 AR reciprocally controlled catecholamine release, with a particular negative β 1 AR-influence on α 2 AR-auto-inhibition of epinephrine secretion in SHR. Moreover, in these female rats, β 1/2 AR-independent α 2 AR-mediated vasoconstriction was seen in WKY but not SHR, but β 1/2 AR-mediated vasodilation downregulated adrenergic vasoconstriction, not only in WKY but also in SHR.

  9. Expression of adrenoceptor subtypes in preterm piglet heart is different to term heart.

    Directory of Open Access Journals (Sweden)

    Min Young Kim

    Full Text Available Preterm delivery increases the risk of inadequate systemic blood flow and hypotension, and many preterm infants fail to respond to conventional inotrope treatments. If the profile of cardiac adrenoceptor subtypes in the preterm neonate is different to that at term this may contribute to these clinical problems. This study measured mRNA expression of β1, β2, α1A, α2A and α2B-adrenoceptor subtypes by real time PCR in term (113d, preterm (91d and preterm piglets (91d exposed to maternal glucocorticoid treatment. Abundance of β-adrenoceptor binding sites in the left ventricle was measured using saturation binding assays. Relative abundance of β1-adrenoceptor mRNA in untreated preterm hearts was ∼50% of term abundance in both left and right ventricles (P0.1. Relative abundance of α1A-adrenoceptor mRNA was the same in preterm and term piglet hearts (P = >0.1 but was reduced by maternal glucocorticoid treatment (P<0.01; α2A-adrenoceptor mRNA abundance was higher in untreated and glucocorticoid exposed preterm piglet hearts than in term piglets (P<0.001. There was no difference between male and female piglets in mRNA abundance of any of the genes studied. In conclusion, there is reduced mRNA abundance of β1-adrenoceptors in the preterm pig heart. If this lower expression of β-adrenoceptors occurs in human preterm infants, it could explain their poor cardiovascular function and their frequent failure to respond to commonly used inotropes.

  10. α2A- and α2C-Adrenoceptors as Potential Targets for Dopamine and Dopamine Receptor Ligands.

    Science.gov (United States)

    Sánchez-Soto, Marta; Casadó-Anguera, Verònica; Yano, Hideaki; Bender, Brian Joseph; Cai, Ning-Sheng; Moreno, Estefanía; Canela, Enric I; Cortés, Antoni; Meiler, Jens; Casadó, Vicent; Ferré, Sergi

    2018-03-18

    The poor norepinephrine innervation and high density of Gi/o-coupled α 2A - and α 2C -adrenoceptors in the striatum and the dense striatal dopamine innervation have prompted the possibility that dopamine could be an effective adrenoceptor ligand. Nevertheless, the reported adrenoceptor agonistic properties of dopamine are still inconclusive. In this study, we analyzed the binding of norepinephrine, dopamine, and several compounds reported as selective dopamine D 2 -like receptor ligands, such as the D 3 receptor agonist 7-OH-PIPAT and the D 4 receptor agonist RO-105824, to α 2 -adrenoceptors in cortical and striatal tissue, which express α 2A -adrenoceptors and both α 2A - and α 2C -adrenoceptors, respectively. The affinity of dopamine for α 2 -adrenoceptors was found to be similar to that for D 1 -like and D 2 -like receptors. Moreover, the exogenous dopamine receptor ligands also showed high affinity for α 2A - and α 2C -adrenoceptors. Their ability to activate Gi/o proteins through α 2A - and α 2C -adrenoceptors was also analyzed in transfected cells with bioluminescent resonance energy transfer techniques. The relative ligand potencies and efficacies were dependent on the Gi/o protein subtype. Furthermore, dopamine binding to α 2 -adrenoceptors was functional, inducing changes in dynamic mass redistribution, adenylyl cyclase activity, and ERK1/2 phosphorylation. Binding events were further studied with computer modeling of ligand docking. Docking of dopamine at α 2A - and α 2C -adrenoceptors was nearly identical to its binding to the crystallized D 3 receptor. Therefore, we provide conclusive evidence that α 2A - and α 2C -adrenoceptors are functional receptors for norepinephrine, dopamine, and other previously assumed selective D 2 -like receptor ligands, which calls for revisiting previous studies with those ligands.

  11. Effects of ionotropic glutamate receptor antagonists on rat dural artery diameter in an intravital microscopy model

    DEFF Research Database (Denmark)

    Chan, K Y; Gupta, S; de Vries, R

    2010-01-01

    studies have shown that glutamate receptor antagonists affect the pathophysiology of migraine. This study investigated whether antagonists of NMDA (ketamine and MK801), AMPA (GYKI52466) and kainate (LY466195) glutamate receptors affected dural vasodilatation induced by alpha-CGRP, capsaicin...

  12. Amygdala, Anxiety and Alpha(1) Adrenoceptors: Investigations Utilizing a Rodent Model of Traumatic Stress

    Science.gov (United States)

    2006-08-23

    stress response. Its synthesis , storage, release, reuptake, and receptor binding are each areas where short and long-term changes can occur...Novas ML, De Robertis E (1983): Changes in benzodiazepine receptors by acute stress: different effect of chronic diazepam or RO 15-1788 treatment...Leonardi,A, Marucci,G, Rosini,M, Tarozzi,A, Tumiatti,V, Melchiorre,C. Design, synthesis , and biological evaluation of prazosin-related derivatives as

  13. Pharmacology of AH 5158; a drug which blocks both α- and β-adrenoceptors

    Science.gov (United States)

    Farmer, J. B.; Kennedy, I.; Levy, G. P.; Marshall, R. J.

    1972-01-01

    1. AH 5158 differs from conventional adrenoceptor blocking drugs in producing competitive blockade of both α- and β-adrenoceptors. 2. AH 5158 is 5-18 times less potent than propranolol in blocking β-adrenoceptors. It resembles propranolol in its non-selective blockade of β1-cardiac and β2-vascular and tracheal adrenoceptors and in its lack of intrinsic sympathomimetic activity. 3. AH 5158 is 2-7 times less potent than phentolamine in blocking α-adrenoceptors. AH 5158 itself is more active on β- than α-adrenoceptors. 4. Blockade of noradrenaline vasopressor responses by AH 5158 in anaesthetized dogs was dose-dependent up to 1 mg/kg but no further blockade was obtained with larger doses of AH 5158. `Self-limiting' blockade was not observed in dogs pretreated with cocaine, or in untreated dogs if the vasopressor agent was oxymetazoline instead of noradrenaline. A possible cause of `self-limiting' blockade is discussed. 5. In doses higher than those required for either α- or β-adrenoceptor blockade, AH 5158 produced effects on cardiac muscle that are attributable to membrane-stabilizing activity. This was manifested as a negative inotropic action in spinal dogs and in guinea-pig left atrial strips, as a negative chronotropic action in syrosingopine pre-treated dogs, and as an increase in the effective refractory period of guinea-pig left atrial strips. AH 5158 was 3-11 times less potent than propranolol in these tests. 6. In open chest dogs AH 5158 resembled propranolol in reducing cardiac output, rate and contractility, effects which are attributable to β-adrenoceptor blockade. The drug differed from propranolol in decreasing rather than increasing total peripheral resistance and in causing larger decreases in arterial blood pressure at equipotent β-adrenoceptor blocking doses. These differences are attributable to the α-adrenoceptor blocking actions of AH 5158. 7. In anaesthetized dogs, intravenously administered AH 5158 antagonized both catecholamine

  14. Neonatal domoic acid decreases in vivo binding of [11C]yohimbine to α2 adrenoceptors in adult rat brain

    DEFF Research Database (Denmark)

    Thomsen, Majken; Lillethorup, Thea Pinholt; Jakobsen, Steen

    -quantitative analysis. MicroPET images were analyzed using PMOD software and registered to an average Sprague-Dawley rat MRI brain atlas to acquire data in limbic and cortical regions of interest. Results: In behavioural testing DOM60, and to a lesser extent DOM20 rats, spent more time in the periphery during the open......-Dawley rats (n=6-7 per group) were injected (s.c.) daily from postnatal day 8-14 with saline or one of two low sub-convulsive doses, 20µg/kg [DOM20] or 60µg/kg [DOM60] of DOM, an AMPA/kainate receptor agonist. The behaviour of the rats was observed in an open field test, a social interaction test...... and the forced swim test at day 50, 75 and 98, respectively. At ~120 days of age 3-4 rats per group were injected with [11C]yohimbine, an α2 adrenergic receptor antagonist, and scanned in a Mediso micro positron emission tomography (PET) scanner, to measure α2 adrenoceptor binding. The volume of distribution (VT...

  15. α2-ADRENOCEPTOR CONSTRAINT OF CATECHOLAMINE RELEASE AND BLOOD PRESSURE IS ENHANCED IN FEMALE SPONTANEOUSLY HYPERTENSIVE RATS

    Directory of Open Access Journals (Sweden)

    Torill eBerg

    2016-03-01

    Full Text Available α2-adrenoceptors (α2AR lower central sympathetic output and peripheral catecholamine release, and may therefore prevent sympathetic hyperactivity and hypertension. The α2AR are dysfunctional in male spontaneously hypertensive rats (SHR. Premenopausal females are less hypertensive than males. The purpose of this study was to test if this difference could be explained by functional α2AR in the female SHR. A 15-min tyramine-infusion was used to stimulate norepinephrine release through the re-uptake transporter, consequently preventing re-uptake. Presynaptic control of vesicular release will therefore be reflected as differences in overflow to plasma. The surgical trauma activates secretion of epinephrine, also subjected to α2AR auto-inhibition. Blood pressure was monitored through a femoral artery catheter and cardiac output by ascending aorta flow in 12-14 weeks-old (early hypertension SHR and normotensive rats (WKY. Total peripheral vascular resistance (TPR was calculated. Female SHR, unlike male, were close to normotensive. Pre-treatment with none-selective (clonidine or non-A-selective (ST-91 α2AR agonist reduced, and none-selective α2AR antagonist (L-659,066 increased tyramine-induced norepinephrine overflow in female and WKY and SHR. L-659,066 also increased secretion of epinephrine. The L-659,066-induced increase in catecholamine release was further enhanced by additional pre-treatment with ST-91 or angiotensin AT1 receptor antagonist (losartan in SHR only. L-659,066 eliminated the tyramine-induced rise in TPR in both strains in female rats. Conclusion: α2AR-mediated control of catecholamine release and vascular tension was therefore functional in female SHR, unlike that previously observed in male SHR. Functional α2AR is likely to have a protective function and may explain the lack of hypertension in the young female SHR.

  16. Design and synthesis of novel potent and selective integrin alphanubeta3 antagonists--novel synthetic routes to isoquinolinone, benzoxazinone, and quinazolinone acetates.

    Science.gov (United States)

    Seitz, Werner; Geneste, Hervé; Backfisch, Gisela; Delzer, Jürgen; Graef, Claudia; Hornberger, Wilfried; Kling, Andreas; Subkowski, Thomas; Zimmermann, Norbert

    2008-01-15

    An unexpected ring contraction of benzazepinone based alpha(nu)beta(3) antagonists led to the design of quinolinone-type derivatives. Novel and efficient synthetic routes to isoquinolinone, benzoxazinone, and quinazolinone acetates were established. Nanomolar alpha(nu)beta(3) antagonists based on these new scaffolds were prepared. Moreover, benzoxazinones 15a and 15b exhibited high microsomal stability and good permeability.

  17. ß2-adrenoceptor agonist-induced upregulation of tachykinin NK2 receptor expression and function in airway smooth muscle

    NARCIS (Netherlands)

    Katsunuma, T; Roffel, A.F; Elzinga, C.R S; Zaagsma, Hans; Barnes, P.J; Mak, J.CW

    Neurokinin A (NKA) induces bronchoconstriction mediated by tachykinin NK2 receptors in animals and humans, and may be increased in asthma. Because beta(2)-adrenoceptor agonists are the most widely used bronchodilators in asthma, we investigated the effects of the beta(2)-adrenoceptor agonist

  18. Calcineurin mediates alpha-adrenergic stimulation of Na+,K(+)-ATPase activity in renal tubule cells.

    OpenAIRE

    Aperia, A; Ibarra, F; Svensson, L B; Klee, C; Greengard, P

    1992-01-01

    The alpha-adrenergic agonist oxymetazoline increased Na+,K(+)-ATPase activity of single proximal convoluted tubules dissected from rat kidney. Activation of the enzyme by oxymetazoline was prevented by either the alpha 1-adrenergic antagonist prazosin or the alpha 2-adrenergic antagonist yohimbine and was mimicked by the calcium ionophore A23187. The effect of oxymetazoline on Na+,K(+)-ATPase activity was prevented by a specific peptide inhibitor of calcineurin, as well as by FK 506, an immun...

  19. Beta-adrenoceptors in kidney tubules of spontaneously hypertensive and normotensive rats

    International Nuclear Information System (INIS)

    Struyker-Boudier, H.A.J.; Vervoort-Peters, L.H.T.M.; Rousch, M.J.M.; Smits, J.F.M.; Thijssen, H.H.W.

    1986-01-01

    Beta-adrenoceptor binding characteristics were determined in different fractions of rat kidney tubules using a ( 125 Iodo)-(-)-cyanopindolol (ICYP) binding assay. The highest amount of binding sites was found in a fraction containing predominantly distal tubular fragments. In a separate series of experiments the ICYP binding characteristics were compared in whole tubular fractions from spontaneously hypertensive (SHR) and normotensive Wistar Kyoto rats (WKY) of different ages. The maximum number of binding sites was significantly higher both in young (3 weeks) and adult (14 weeks) SHR when compared to age-matched WKY. These studies showed the presence of beta-adrenoceptor binding sites in rat kidney tubules and support the potential importance of tubular beta-adrenoceptors in the development of spontaneous hypertension and in the mechanism of antihypertensive action of beta-blockers. 35 references, 1 figure, 3 tables

  20. Do β-adrenoceptor agonists induce homologous or heterologous desensitization in rat urinary bladder?

    Science.gov (United States)

    Michel, Martin C

    2014-03-01

    β3-Adrenoceptor agonists have recently been introduced for the symptomatic treatment of the overactive bladder syndrome. As such treatment is not curative, long-term treatment is anticipated to be required. As the susceptibility of β3-adrenoceptors to undergo agonist-induced desensitization is cell type- and tissue-dependent, we have explored whether pre-treatment with a β-adrenoceptor agonist will attenuate subsequent relaxation responses to freshly added agonist using rat urinary bladder as a model. We have used the prototypical β-adrenoceptor agonist isoprenaline, the β2-selective fenoterol and the β3-selective CL 316,243 and mirabegron as well as the receptor-independent bladder relaxant forskolin. We show that a 6-h pre-treatment with agonist can significantly reduce subsequent relaxation against KCl-induced smooth muscle tone, but agonist-induced desensitization was also observed with longer pre-treatments or against passive tension. The agonist-induced desensitization was prominent for the β2 component of rat bladder relaxation but much weaker or even absent for the β3 component. Moreover, β-adrenoceptor agonist pre-treatment reduced contractile responses to the muscarinic agonist carbachol and the receptor-independent stimulus KCl. Taken together these data do not support the hypothesis that the long-term clinical efficacy of β3-adrenoceptor agonists in the treatment of the overactive bladder syndrome will be limited by receptor desensitization. Rather they raise the possibility that such treatment may not only cause smooth muscle relaxation but also may attenuate hyper-contractility of the bladder.

  1. Reversal of high pancreatic islet and white adipose tissue blood flow in type 2 diabetic GK rats by administration of the beta3-adrenoceptor inhibitor SR-59230A.

    Science.gov (United States)

    Pettersson, U S; Henriksnäs, J; Jansson, L

    2009-08-01

    Previous studies have shown that the Goto-Kakizaki (GK) rat, a nonobese type 2 diabetes model, has an increased white adipose tissue (WAT) and islet blood flow when compared with control rats. The aim of the study was to examine if these increased blood flow values in GK rats could be affected by the beta(3)-adrenoceptor antagonist SR-59230A. We measured organ blood flow with a microsphere technique 10 min after administration of SR-59230A (1 mg/kg body wt), or the corresponding volume of 0.9% NaCl solution (1 ml/kg body wt) in rats anaesthetized with thiobutabarbital. The GK rat had an increased blood flow in all intra-abdominal adipose tissue depots except for the sternal fat pad compared with Wistar-Furth (WF) rats. However, no differences were seen in the blood perfusion of subcutaneous white or brown adipose tissue. The blood flow was also increased in both the pancreas and in the islets in the GK rat compared with WF rats. SR-59230A treatment affected neither WAT nor pancreatic blood flow in WF rats. In GK rats, on the other hand, SR-59230A decreased both WAT and islet blood flow values to values similar to those seen in control WF rats. The whole pancreatic blood flow was not affected by SR-59230A administration in GK rats. Interestingly, the brown adipose tissue blood flow in GK rats increased after SR-59230A administration. These results suggest that beta(3)-adrenoceptors are involved in regulation of blood flow both in islet and in adipose tissue.

  2. Neurotensin agonists block the prepulse inhibition deficits produced by a 5-HT2A and an alpha1 agonist.

    Science.gov (United States)

    Shilling, P D; Melendez, G; Priebe, K; Richelson, E; Feifel, D

    2004-09-01

    Neurotensin (NT) agonists have been proposed as potential antipsychotics based exclusively upon their ability to inhibit dopamine-2 (D2) receptor transmission. Several other pharmacological mechanisms have been implicated in enhancing the antipsychotic profile produced by D2 inhibition alone. These include inhibition of 5-HT2A and alpha1-adrenoceptors. Recently, we reported that systemic administration of the neurotensin agonist PD149163 blocks deficits in prepulse inhibition (PPI) of the startle reflex produced by the 5-HT2A receptor agonist DOI. This suggested that NT agonists could inhibit 5-HT2A modulation of neurotransmission. To determine if other peripherally administered NT agonists shared this effect, we examined the effects of NT69L, another NT agonist, on DOI-induced PPI deficits. In addition, to determine if NT agonists also inhibit alpha1-adrenoceptor neurotransmission, we examined the effects of PD149163 and NT69L on PPI deficits induced by the alpha1-adrenoceptor agonist, cirazoline. In the NT69L/DOI study, rats received subcutaneous (SC) injections of NT69L (0, 0.1, 1, or 2 mg/kg) followed 30 min later by SC saline or DOI (0.5 mg/kg). In the NT agonist/cirazoline studies, animals received SC injections of either PD149163 (0, 0.01, 0.1, or 1 mg/kg) or NT69L (0, 0.01, 0.1, or 1 mg/kg) followed 30 min later by SC saline or cirazoline (0.7 mg/kg). Animals were tested in startle chambers 20 min later. In all three experiments the PPI disruption produced by DOI and cirazoline was blocked by the NT agonists. These findings provide strong evidence that NT agonists inhibit 5-HT2A and alpha1-adrenoceptor modulation of neurotransmission, pharmacological effects that, in conjunction with their known inhibition of dopamine transmission, strengthen the antipsychotic potential of NT agonists.

  3. Subclassification of release-regulating alpha 2-autoreceptors in human brain cortex.

    Science.gov (United States)

    Raiteri, M.; Bonanno, G.; Maura, G.; Pende, M.; Andrioli, G. C.; Ruelle, A.

    1992-01-01

    1. Release-regulating alpha 2-autoreceptors in human brain were characterized pharmacologically in cortical slices from patients undergoing neurosurgery to remove subcortical tumours; the slices were prelabelled with [3H]-noradrenaline ([3H]-NA) and stimulated electrically (3 Hz, 2 ms, 24 mA) under superfusion conditions. 2. The stimulus-evoked tritium overflow was almost totally Ca(2+)-dependent and tetrodotoxin-sensitive. 3. Clonidine and oxymetazoline 0.01 to 1 microM inhibited in a concentration-dependent manner the evoked overflow of tritium. The two drugs were equipotent (EC50 = 0.03 microM) and their maximal effect was approx. 45%. Phenylephrine and methoxamine, up to 1 microM, did not affect tritium overflow. 4. Yohimbine (0.01-0.1 microM) shifted the concentration-response curve of clonidine to the right. The calculated pA2 value was 8.29. 5. Prazosin and 2-[2-[4-(o-methoxyphenyl)piperazine-1-yl]ethyl]-4,4- dimethyl-1,3(2H,4H)-isoquinolinedione (AR-C 239), tested at 0.3 microM, did not modify the concentration-response curve of clonidine. 6. The effect of clonidine was antagonized by (+)-mianserin (pA2 = 7.74), but not by up to 0.3 microM of the (-)-enantiomer. The concentration-response curve of clonidine was shifted to the right by the novel alpha 2-adrenoceptor antagonist, 5-chloro-4-(1-butyl-1,2,5,6-tetrahydropyridin-3-yl)-thiazole-2-ami ne (Z)-2-butenedioate (1:1) salt (ORG 20350) (pA2 = 7.55). 7. Yohimbine, (+)-mianserin and ORG 20350, but not prazosin and (-)-mianserin, increased the electrically-evoked tritium overflow, suggesting that autoreceptors may be tonically activated by endogenous NA. 8. Desipramine (1 microM) increased evoked tritium overflow from human cortex slices.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1361400

  4. Effect of alpha1-blockers on stentless ureteroscopic lithotripsy

    Directory of Open Access Journals (Sweden)

    Jianguo Zhu

    2016-02-01

    Full Text Available ABSTRACT Objective To evaluate the clinical efficiency of alpha1-adrenergic antagonists on stentless ureteroscopic lithotripsy treating uncomplicated lower ureteral stones. Materials and Methods From January 2007 to January 2013, 84 patients who have uncomplicated lower ureteral stones treated by ureteroscopic intracorporeal lithotripsy with the holmium laser were analyzed. The patients were divided into two groups, group A (44 patients received indwelled double-J stents and group B (40 patients were treated by alpha1-adrenergic antagonists without stents. All cases of group B were treated with alpha1 blocker for 1 week. Results The mean operative time of group A was significantly longer than group B. The incidences of hematuria, flank/abdominal pain, frequency/urgency after surgery were statistically different between both groups. The stone-free rate of each group was 100%. Conclusions The effect of alpha1-adrenergic antagonists is more significant than indwelling stent after ureteroscopic lithotripsy in treating uncomplicated lower ureteral stones.

  5. Effects of D2-dopamine and alfa-adrenoceptor antagonists in stress induced changes on immune reponsiveness of mice

    Czech Academy of Sciences Publication Activity Database

    Fišerová, Anna; Starec, M.; Kuldová, M.; Kovářů, H.; Páv, M.; Vannucci, Luca; Pospíšil, Miloslav

    2002-01-01

    Roč. 130, - (2002), s. 55-65 ISSN 0165-5728 R&D Projects: GA ČR GA310/98/0347; GA ČR GV312/98/K034; GA ČR GA304/01/0850 Institutional research plan: CEZ:AV0Z5020903 Keywords : restraint stress * cytokine * nk cell Subject RIV: EE - Microbiology, Virology Impact factor: 3.577, year: 2002

  6. Negative inotropic effects of epinephrine in the presence of increased β-adrenoceptor sensitivity during hypothermia in a rat model.

    Science.gov (United States)

    Dietrichs, Erik Sveberg; Schanche, Torstein; Kondratiev, Timofei; Gaustad, Svein Erik; Sager, Georg; Tveita, Torkjel

    2015-02-01

    Animal studies show reduced inotropic effects of cardiac β-adrenoceptor agonists like epinephrine (Epi) during hypothermia and rewarming, while drugs targeting other pharmacological mechanisms have positive effects. This study therefore aimed to determine β-adrenoceptor sensitivity in isolated cardiomyocytes and investigate hemodynamic effects of Epi and its ability to stimulate cardiac β-adrenoceptors at different temperatures in vivo. Isolated rat myocardial cells were incubated with the radioactive β-adrenoceptor ligand [(3)H]-CGP12177 and propranolol, used as a displacer. Cells were subjected to normothermia (37 °C) or hypothermia (15 °C). After incubation, radioactivity was measured to estimate β-adrenoceptor affinity for propranolol (IC50), as a measure of β-adrenoceptor sensitivity. In separate in vivo experiments, Epi (1.25 μg/min) was administered the last 5min of experiments in normothermic (37 °C, 5h), hypothermic (4h at 15 °C) and rewarmed rats (4h at 15 °C, and subsequently rewarmed to 37 °C). Hemodynamic parameters were monitored during infusion. Hearts were thereafter freeze-clamped and tissue cAMP was measured. In vitro measurements of IC50 for propranolol showed a hypothermia-induced increase in β-adrenoceptor sensitivity at 15 °C. Corresponding in vivo experiments at 15 °C showed decreased cardiac output and stroke volume, whereas total peripheral resistance (TPR) increased during Epi infusion, simultaneous with a 4-fold cAMP increase. This experiment shows a hypothermia-induced in vivo and in vitro increase of cardiac β-adrenoceptor sensitivity, and simultaneous lack of inotropic effects of Epi in the presence of increased TPR. Our findings therefore indicate that hypothermia-induced reduction in inotropic effects of Epi is due to substantial elevation of TPR, rather than β-adrenoceptor dysfunction. Copyright © 2014 Elsevier Inc. All rights reserved.

  7. Buffett's Alpha

    DEFF Research Database (Denmark)

    Frazzini, Andrea; Kabiller, David; Heje Pedersen, Lasse

    Berkshire Hathaway has realized a Sharpe ratio of 0.76, higher than any other stock or mutual fund with a history of more than 30 years, and Berkshire has a significant alpha to traditional risk factors. However, we find that the alpha becomes insignificant when controlling for exposures to Betting-Against-Beta...... in publicly traded stocks versus wholly-owned private companies, we find that the former performs the best, suggesting that Buffett's returns are more due to stock selection than to his effect on management. These results have broad implications for market efficiency and the implementability of academic...

  8. Involvement of the beta(3) adrenoceptor in nebivolol-induced vasorelaxation in the rat aorta

    NARCIS (Netherlands)

    de Groot, Annemieke A.; Mathy, Marie-Jeanne; van Zwieten, Pieter A.; Peters, Stephan L. M.

    2003-01-01

    Nebivolol is a highly selective beta(1) adrenoceptor blocker with additional vasodilating properties. Although it has been shown that the nebivolol-induced vasorelaxation is nitric oxide (NO) and cGMP dependent, the receptor that mediates these actions remains controversial, and scrotonergic as well

  9. Desirable properties of β(3)-adrenoceptor agonists: Implications for the selection of drug development candidates

    NARCIS (Netherlands)

    Michel, Martin C.; Cernecka, Hana; Ochodnicky, Peter

    2011-01-01

    β(3)-adrenoceptor agonists are currently in clinical development for the treatment of overactive bladder and considered for several other indications. This Perspective discusses desirable properties of such drugs mainly based on the example of overactive bladder, but at least partly they should also

  10. Desirable properties of β3-adrenoceptor agonists : implications for the selection of drug development candidates

    NARCIS (Netherlands)

    Michel, Martin C; Cernecka, Hana; Ochodnicky, Peter

    2011-01-01

    β3-adrenoceptor agonists are currently in clinical development for the treatment of overactive bladder and considered for several other indications. This Perspective discusses desirable properties of such drugs mainly based on the example of overactive bladder, but at least partly they should also

  11. Effects of energy restriction on acute adrenoceptor and metabolic responses to exercise in obese subjects

    NARCIS (Netherlands)

    Kempen, K.P.G.; Saris, W.H.M.; Senden, J.M.G.; Menheere, P.P.C.A.; Blaak, E.E.; van Baak, M.A.

    1994-01-01

    Effects of energy restriction on acute adrenoceptor and metabolic responses to exercise in obese subjects. Kempen KP, Saris WH, Senden JM, Menheere PP, Blaak EE, van Baak MA. Department of Human Biology, University of Limburg, Maastricht, The Netherlands. This study was intended to investigate the

  12. Beta-adrenoceptor changes in hypertension: cause or consequence of the elevation in blood pressure?

    NARCIS (Netherlands)

    Kanczik, R.; Khamssi, M.; Michel, M. C.; Brodde, O. E.

    1988-01-01

    Cardiac, pulmonary and renal beta-adrenoceptor density and subtype distribution were measured by radioligand binding in three rat models of acquired hypertension. Dahl salt-sensitive (DS) rats on a high-sodium diet, renal hypertensive rats and DOCA-salt rats. The results were compared with

  13. Norepinephrine drives persistent activity in prefrontal cortex via synergistic α1 and α2 adrenoceptors.

    Directory of Open Access Journals (Sweden)

    Zizhen Zhang

    Full Text Available Optimal norepinephrine levels in the prefrontal cortex (PFC increase delay-related firing and enhance working memory, whereas stress-related or pathologically high levels of norepinephrine are believed to inhibit working memory via α1 adrenoceptors. However, it has been shown that activation of Gq-coupled and phospholipase C-linked receptors can induce persistent firing, a cellular correlate of working memory, in cortical pyramidal neurons. Therefore, despite its importance in stress and cognition, the exact role of norepinephrine in modulating PFC activity remains elusive. Using electrophysiology and optogenetics, we report here that norepinephrine induces persistent firing in pyramidal neurons of the PFC independent of recurrent fast synaptic excitation. This persistent excitatory effect involves presynaptic α1 adrenoceptors facilitating glutamate release and subsequent activation of postsynaptic mGluR5 receptors, and is enhanced by postsynaptic α2 adrenoceptors inhibiting HCN channel activity. Activation of α2 adrenoceptors or inhibition of HCN channels also enhances cholinergic persistent responses in pyramidal neurons, providing a mechanism of crosstalk between noradrenergic and cholinergic inputs. The present study describes a novel cellular basis for the noradrenergic control of cortical information processing and supports a synergistic combination of intrinsic and network mechanisms for the expression of mnemonic properties in pyramidal neurons.

  14. Dual aminergic regulation of central beta adrenoceptors. Effect of atypical antidepressants and 5-hydroxytryptophan

    Energy Technology Data Exchange (ETDEWEB)

    Manier, D.H.; Gillespie, D.D.; Sulser, F.

    1989-06-01

    Nonlinear regression analysis of agonist competition binding curves reveals that the (/sup 3/H)-dihydroalprenolol-labeled receptor population with low affinity for isoproterenol is increased by p-chlorophenylalanine (PCPA) and this increase is abolished by 5-hydroxytryptophan (5-HTP) in vivo. Desipramine (DMI) decreased the beta adrenoceptor population with high agonist affinity to the same degree in PCPA-treated animals as in control animals, thus explaining the reported discrepancy between beta adrenoceptor number and responsiveness of the beta adrenoceptor-coupled adenylate cyclase system. Mianserin also selectively reduced the beta adrenoceptor population with high agonist affinity in membrane preparations of normal animals, whereas fluoxetine selectively abolished the upregulation of the low affinity sites in reserpinized animals and had no effect on either receptor population from brain of normal animals. The results emphasize the importance of nonlinear regression analysis of agonist competition binding for the interpretation of drug action and encourage the pursuit of the molecular neurobiology of the serotonin (5-HT)/norepinephrine (NE) link in brain.

  15. Endotoxin-induced liver damage in rats is minimized by beta 2-adrenoceptor stimulation.

    NARCIS (Netherlands)

    Izeboud, C.A.; Hoebe, K.H.; Grootendorst, A.F.; Nijmeijer, S.M.; Miert, A.S. van; Witkamp, R.R.; Rodenburg, R.J.T.

    2004-01-01

    OBJECTIVE AND DESIGN: To investigate the effects of beta(2)-adrenoceptor (beta(2)-AR) stimulation on endotoxin-induced liver damage and systemic cytokine levels in rats. SUBJECTS: Standard male Wistar rats. TREATMENT: A disease-model of lipopolysaccharide (LPS)-induced acute systemic inflammation

  16. Endotoxin-induced liver damage in rats is minimized by β2- adrenoceptor stimulation

    NARCIS (Netherlands)

    Izeboud, C.A.; Hoebe, K.H.N.; Grootendorst, A.F.; Nijmeijer, S.M.; Miert, A.S. van; Witkamp, R.F.; Rodenburg, R.J.T.

    2004-01-01

    Objective and Design: To investigate the effects of β2- adrenoceptor (β2-AR) stimulation on endotoxin-induced liver damage and systemic cytokine levels in rats. Subjects: Standard male Wistar rats. Treatment: A disease-model of lipolysaccharide (LPS)-induced acute systemic inflammation was used. The

  17. Spare receptors for beta-adrenoceptor-mediated positive inotropic effects of catecholamines in the human heart

    NARCIS (Netherlands)

    Brown, L.; Deighton, N. M.; Bals, S.; Söhlmann, W.; Zerkowski, H. R.; Michel, M. C.; Brodde, O. E.

    1992-01-01

    We studied whether the human heart has spare receptors for beta-adrenoceptor-mediated positive inotropic effects. Thus, we assessed in right atria and left papillary muscles of patients with different degrees of heart failure under identical experimental conditions affinity (pKI values from

  18. Dual aminergic regulation of central beta adrenoceptors. Effect of atypical antidepressants and 5-hydroxytryptophan

    International Nuclear Information System (INIS)

    Manier, D.H.; Gillespie, D.D.; Sulser, F.

    1989-01-01

    Nonlinear regression analysis of agonist competition binding curves reveals that the [ 3 H]-dihydroalprenolol-labeled receptor population with low affinity for isoproterenol is increased by p-chlorophenylalanine (PCPA) and this increase is abolished by 5-hydroxytryptophan (5-HTP) in vivo. Desipramine (DMI) decreased the beta adrenoceptor population with high agonist affinity to the same degree in PCPA-treated animals as in control animals, thus explaining the reported discrepancy between beta adrenoceptor number and responsiveness of the beta adrenoceptor-coupled adenylate cyclase system. Mianserin also selectively reduced the beta adrenoceptor population with high agonist affinity in membrane preparations of normal animals, whereas fluoxetine selectively abolished the upregulation of the low affinity sites in reserpinized animals and had no effect on either receptor population from brain of normal animals. The results emphasize the importance of nonlinear regression analysis of agonist competition binding for the interpretation of drug action and encourage the pursuit of the molecular neurobiology of the serotonin (5-HT)/norepinephrine (NE) link in brain

  19. Adrenoceptors of the medial septal area modulate water intake and renal excretory function induced by central administration of angiotensin II

    Directory of Open Access Journals (Sweden)

    Saad W.A.

    2002-01-01

    Full Text Available We investigated the role of alpha-adrenergic antagonists and clonidine injected into the medial septal area (MSA on water intake and the decrease in Na+, K+ and urine elicited by ANGII injection into the third ventricle (3rdV. Male Holtzman rats with stainless steel cannulas implanted into the 3rdV and MSA were used. ANGII (12 nmol/µl increased water intake (12.5 ± 1.7 ml/120 min. Clonidine (20 nmol/µl injected into the MSA reduced the ANGII-induced water intake (2.9 ± 0.5 ml/120 min. Pretreatment with 80 nmol/µl yohimbine or prazosin into the MSA also reduced the ANGII-induced water intake (3.0 ± 0.4 and 3.1 ± 0.2 ml/120 min, respectively. Yohimbine + prazosin + clonidine injected into the MSA abolished the ANGII-induced water intake (0.2 ± 0.1 and 0.2 ± 0.1 ml/120 min, respectively. ANGII reduced Na+ (23 ± 7 µEq/120 min, K+ (27 ± 3 µEq/120 min and urine volume (4.3 ± 0.9 ml/120 min. Clonidine increased the parameters above. Clonidine injected into the MSA abolished the inhibitory effect of ANGII on urinary sodium. Yohimbine injected into the MSA also abolished the inhibitory effects of ANGII. Yohimbine + clonidine attenuated the inhibitory effects of ANGII. Prazosin injected into the MSA did not cause changes in ANGII responses. Prazosin + clonidine attenuated the inhibitory effects of ANGII. The results showed that MSA injections of alpha1- and alpha2-antagonists decreased ANGII-induced water intake, and abolished the Na+, K+ and urine decrease induced by ANGII into the 3rdV. These findings suggest the involvement of septal alpha1- and alpha2-adrenergic receptors in water intake and electrolyte and urine excretion induced by central ANGII.

  20. Carvedilol, a nonselective beta-blocker, suppresses the production of tumor necrosis factor and tissue factor by inhibiting early growth response factor-1 expression in human monocytes in vitro.

    Science.gov (United States)

    Mizuochi, Yuichiro; Okajima, Kenji; Harada, Naoaki; Molor-Erdene, Perenlei; Uchiba, Mitsuhiro; Komura, Hidefumi; Tsuda, Takako; Katsuya, Hirotada

    2007-04-01

    Tumor necrosis factor (TNF) and tissue factor (TF) produced by monocytes and macrophages have been shown to be among the aggravating factors for chronic heart failure (CHF), because they induce cardiac dysfunction and thrombotic complications, respectively. Carvedilol, a nonselective beta-adrenoceptor antagonist with alpha(1)- adrenoceptor blockade action, has been demonstrated to improve the outcome of patients with severe CHF, suggesting that carvedilol might inhibit the production of TNF and TF. In this study, this possibility is examined using isolated human monocytes stimulated with lipopolysaccharide (LPS) in vitro. Carvedilol (10 muM) significantly inhibited LPS-induced production of TNF and TF by monocytes, whereas prazosin (a selective alpha(1)-adrenoceptor antagonist), bisoprolol (a selective beta(1)-adrenoceptor antagonist), ICI-118,551 (a selective beta(2)-adrenoceptor antagonist), and arotinolol (a nonselective beta-adrenoceptor antagonist with alpha(1)-adrenoceptor blockade action) did not. Carvedilol inhibited both expression of early growth response factor-1 (Egr-1) and phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, but it did not inhibit activation of either nuclear factor-kappaB or activator protein-1 in monocytes stimulated with LPS. These results suggest that carvedilol inhibits LPS-induced production of TNF and TF by inhibiting activation of the ERK1/2-Egr-1 pathway independent of its adrenoceptor inhibitory activities in monocytes.

  1. The three α1-adrenoceptor subtypes show different spatio-temporal mechanisms of internalization and ERK1/2 phosphorylation.

    Science.gov (United States)

    Perez-Aso, M; Segura, V; Montó, F; Barettino, D; Noguera, M A; Milligan, G; D'Ocon, P

    2013-10-01

    We analyzed the kinetic and spatial patterns characterizing activation of the MAP kinases ERK 1 and 2 (ERK1/2) by the three α1-adrenoceptor (α1-AR) subtypes in HEK293 cells and the contribution of two different pathways to ERK1/2 phosphorylation: protein kinase C (PKC)-dependent ERK1/2 activation and internalization-dependent ERK1/2 activation. The different pathways of phenylephrine induced ERK phosphorylation were determined by western blot, using the PKC inhibitor Ro 31-8425, the receptor internalization inhibitor concanavalin A and the siRNA targeting β-arrestin 2. Receptor internalization properties were studied using CypHer5 technology and VSV-G epitope-tagged receptors. Activation of α1A- and α1B-ARs by phenylephrine elicited rapid ERK1/2 phosphorylation that was directed to the nucleus and inhibited by Ro 31-8425. Concomitant with phenylephrine induced receptor internalization α1A-AR, but not α1B-AR, produced a maintained and PKC-independent ERK phosphorylation, which was restricted to the cytosol and inhibited by β-arrestin 2 knockdown or concanavalin A treatment. α1D-AR displayed constitutive ERK phosphorylation, which was reduced by incubation with prazosin or the selective α1D antagonist BMY7378. Following activation by phenylephrine, α1D-AR elicited rapid, transient ERK1/2 phosphorylation that was restricted to the cytosol and not inhibited by Ro 31-8425. Internalization of the α1D-AR subtype was not observed via CypHer5 technology. The three α1-AR subtypes present different spatio-temporal patterns of receptor internalization, and only α1A-AR stimulation translates to a late, sustained ERK1/2 phosphorylation that is restricted to the cytosol and dependent on β-arrestin 2 mediated internalization. Copyright © 2013 Elsevier B.V. All rights reserved.

  2. Muscle cramps and elevated serum creatine phosphokinase levels induced by beta-adrenoceptor blockers.

    Science.gov (United States)

    Imai, Y; Watanabe, N; Hashimoto, J; Nishiyama, A; Sakuma, H; Sekino, H; Omata, K; Abe, K

    1995-01-01

    We have assessed the propensity of beta-adrenoceptor blockers to cause muscle cramps and to raise the serum creatine phosphokinase (CPK) level in 78 patients with essential hypertension. After a control period, a beta-adrenoceptor blocker without intrinsic sympathomimetic activity (ISA; propranolol, metoprolol or arotinolol) was administered for three months. Thereafter, the patients were randomised to receive a beta-adrenoceptor blocker with ISA (pindolol or carteolol) for three months or a beta-adrenoceptor blocker without ISA for a further three months. This pattern was continued until all beta-adrenoceptor blockers had been given. At the end of each period, CPK and CPK-MB levels were measured. Of the 78 subjects, muscle cramps occurred in 27 during treatment with pindolol and 32 during treatment with carteolol. No complaints were made by subjects treated with propranolol and arotinolol, but muscle cramps were reported in 2 treated with metoprolol. While muscle cramps were caused both by pindolol and carteolol in 16 subjects, they were caused by either of these drugs in the remainder of the subjects. Muscle cramp occurred mainly in the calves when the patients were in bed at night. Serum CPK and CPK-MB levels increased significantly during treatment with pindolol (control period vs pindolol, CPK = 96 vs 133 IU.ml-1, CPK-MB = 14 vs 18 IU.ml-1) or carteolol (CPK = 117 IU.ml-1, CPK-MB = 18 IU.ml-1) while the levels during treatment with propranolol, arotinolol and metoprolol did not change from those in the control period.(ABSTRACT TRUNCATED AT 250 WORDS)

  3. α₂-Adrenoceptor functionality in postmortem frontal cortex of depressed suicide victims.

    Science.gov (United States)

    Valdizán, Elsa M; Díez-Alarcia, Rebeca; González-Maeso, Javier; Pilar-Cuéllar, Fuencisla; García-Sevilla, Jesús A; Meana, J Javier; Pazos, Angel

    2010-11-01

    Alterations in brain density and signaling associated with monoamine receptors are believed to play a role in depressive disorders. This study evaluates the functional status of α₂(A)-adrenoceptors in postmortem frontal cortex of depressed subjects. G-protein activation and inhibition of adenylyl cyclase (AC) activity induced by the α₂-adrenoceptor agonist UK14304 were measured in triplicate in samples from 15 suicide victims with an antemortem diagnosis of major depression and 15 matched control subjects. Basal [³⁵S] guanosine γ thio-phosphate (GTPγS) binding and cyclic adenosine monophosphate accumulation did not differ between groups. In depressed victims, an increase in [³⁵S] GTPγS binding potency (EC₅₀ = .58 μmol/L vs. EC₅₀ = 3.31 μmol/L; p < .01; depressed vs. control) and a significant reduction in the maximal inhibition of AC activity (I(max) = 27 ± 4% vs. I(max) = 47 ± 5%; p < .01) were observed after incubation with the α(2)-adrenoceptor agonist UK14304. No differences were found between antidepressant-free and antidepressant-treated subjects. A significant relationship between EC₅₀ values for [³⁵S] GTPγS and I(max) values for AC assay was found (n = 30; r = -.43; p < .05). The dual regulation of α(2A)-adrenoceptor signaling pathways raises the possibility that factors affecting the G-protein cycle and/or selective access of Gα(i/o)-protein to AC might be relevant to receptor abnormalities in depression, providing further support for the involvement of α₂(A)-adrenoceptors in the pathogenesis of depression. Copyright © 2010 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  4. α2-Adrenoceptor Functionality in Postmortem Frontal Cortex of Depressed Suicide Victims

    Science.gov (United States)

    Valdizán, Elsa M.; Díez-Alarcia, Rebeca; González-Maeso, Javier; Pilar-Cuéllar, Fuencisla; García-Sevilla, Jesús A.; Meana, J. Javier; Pazos, Angel

    2013-01-01

    Background Alterations in brain density and signaling associated with monoamine receptors are believed to play a role in depressive disorders. This study evaluates the functional status of α2A-adrenoceptors in postmortem frontal cortex of depressed subjects. Methods G-protein activation and inhibition of adenylyl cyclase (AC) activity induced by the α2-adrenoceptor agonist UK14304 were measured in triplicate in samples from 15 suicide victims with an antemortem diagnosis of major depression and 15 matched control subjects. Results Basal [35S] guanosine γ thio-phosphate (GTPγS) binding and cyclic adenosine monophosphate accumulation did not differ between groups. In depressed victims, an increase in [35S] GTPγS binding potency (EC50 = .58 μmol/L vs. EC50 = 3.31 μmol/L; p < .01; depressed vs. control) and a significant reduction in the maximal inhibition of AC activity (Imax = 27 ± 4% vs. Imax = 47 ± 5%; p < .01) were observed after incubation with the α2-adrenoceptor agonist UK14304. No differences were found between antidepressant-free and antidepressant-treated subjects. A significant relationship between EC50 values for [35S] GTPγS and Imax values for AC assay was found (n = 30; r = −.43; p < .05). Conclusions The dual regulation of α2A-adrenoceptor signaling pathways raises the possibility that factors affecting the G-protein cycle and/or selective access of Gαi/o–protein to AC might be relevant to receptor abnormalities in depression, providing further support for the involvement of α2A-adrenoceptors in the pathogenesis of depression. PMID:20864091

  5. Naloxone : actions of an antagonist

    NARCIS (Netherlands)

    Dorp, Eveline Louise Arianna van

    2009-01-01

    The opioid antagonist naloxone has a special place in pharmacology – it has no intrinsic action of its own, but it is able to save lives in the case of life threatening side-effects caused by other drugs. Naloxone is an antagonist for all opioid receptors, but most specifically for the μ-opioid

  6. Effect of prolonged 5-hydroxytryptamine uptake inhibition by paroxetine on cortical β1 and β2-adrenoceptors in rat brain

    International Nuclear Information System (INIS)

    Nelson, D.R.; Palmer, K.J.; Johnson, A.M.

    1990-01-01

    The effects of prolonged oral administration of the antidepressants paroxetine and amitriptyline on rat brain cortical β 1 - and β 2 -adrenoceptor numbers and affinities were investigated using [ 3 H]-CGP 12177. Although amitriptyline, 27 mg/kg, caused a significant 20% reduction in the number of β 1 -adrenoceptors, paroxetine, at does up to 8.9 mg/kg p.o., did not influence binding of [ 3 H]-CGP 12177 to cortical β 1 - or β 2 -adrenoceptors. This study with paroxetine provides further evidence that the down-regulation of central β 1 -adrenoceptors in rat brain after repeated administration is not a property of all antidepressant drugs

  7. Interaction between Antagonist of Cannabinoid Receptor and Antagonist of Adrenergic Receptor on Anxiety in Male Rat

    Directory of Open Access Journals (Sweden)

    Alireza Komaki

    2014-07-01

    Full Text Available Introduction: Anxiety is among the most common and treatable mental disorders. Adrenergic and cannabinoid systems have an important role in the neurobiology of anxiety. The elevated plus-maze (EPM has broadly been used to investigate anxiolytic and anxiogenic compounds. The present study investigated the effects of intraperitoneal (IP injection of cannabinoid CB1 receptor antagonist (AM251 in the presence of alpha-1 adrenergic antagonist (Prazosin on rat behavior in the EPM. Methods: In this study, the data were obtained from male Wistar rat, which weighing 200- 250 g. Animal behavior in EPM were videotaped and saved in computer for 10 min after IP injection of saline, AM251 (0.3 mg/kg, Prazosin (0.3 mg/kg and AM251 + Prazosin, subsequently scored for conventional indices of anxiety. During the test period, the number of open and closed arms entries, the percentage of entries into the open arms of the EPM, and the spent time in open and closed arms were recorded. Diazepam was considered as a positive control drug with anxiolytic effect (0.3, 0.6, 1.2 mg/kg. Results: Diazepam increased the number of open arm entries and the percentage of spent time on the open arms. IP injection of AM251 before EPM trial decreased open arms exploration and open arm entry. Whereas, Prazosin increased open arms exploration and open arm entry. This study showed that both substances in simultaneous injection have conflicting effects on the responses of each of these two compounds in a single injection. Discussion: Injection of CB1 receptor antagonist may have an anxiogenic profile in rat, whereas adrenergic antagonist has an anxiolytic effect. Further investigations are essential for better understanding of anxiolytic and anxiogenic properties and neurobiological mechanisms of action and probable interactions of the two systems.

  8. Chronic citalopram administration desensitizes prefrontal cortex but not somatodendritic α2-adrenoceptors in rat brain.

    Science.gov (United States)

    Fernández-Pastor, Begoña; Ortega, Jorge E; Grandoso, Laura; Castro, Elena; Ugedo, Luisa; Pazos, Ángel; Meana, J Javier

    2017-03-01

    Selective serotonin reuptake inhibitors (SSRIs) regulate brain noradrenergic neurotransmission both at somatodendritic and nerve terminal areas. Previous studies have demonstrated that noradrenaline (NA) reuptake inhibitors are able to desensitize α 2 -adrenoceptor-mediated responses. The present study was undertaken to elucidate the effects of repeated treatment with the SSRI citalopram on the α 2 -adrenoceptor sensitivity in locus coeruleus (LC) and prefrontal cortex (PFC), by using in vivo microdialysis and electrophysiological techniques, and in vitro stimulation of [ 35 S]GTPγS binding autoradiography. Repeated, but not acute, treatment with citalopram (5 mg/kg, i.p., 14 days) increased extracellular NA concentration selectively in PFC. The α 2 -adrenoceptor agonist clonidine (0.3 mg/kg, i.p.), administered to saline-treated animals (1 ml/kg i.p., 14 days) induced NA decrease in LC (E max  = -44 ± 4%; p < 0.001) and in PFC (E max  = -61 ± 5%, p < 0.001). In citalopram chronically-treated rats, clonidine administration exerted a lower decrease of NA (E max  = -25 ± 7%; p < 0.001) in PFC whereas the effect in LC was not different to controls (E max  = -36 ± 4%). Clonidine administration (0.625-20 μg/kg, i.v.) evoked a dose-dependent decrease of the firing activity of LC noradrenergic neurons in both citalopram- (ED 50  = 3.2 ± 0.4 μg/kg) and saline-treated groups (ED 50  = 2.6 ± 0.5 μg/kg). No significant differences between groups were found in ED 50 values. The α 2 -adrenoceptor agonist UK14304 stimulated specific [ 35 S]GTPγS binding in brain sections containing LC (144 ± 14%) and PFC (194 ± 32%) of saline-treated animals. In citalopram-treated animals, this increase did not differ from controls in LC (146 ± 22%) but was lower in PFC (141 ± 8%; p < 0.05). Taken together, long-term citalopram treatment induces a desensitization of α 2 -adrenoceptors acting as axon terminal autoreceptors in PFC

  9. 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...

  10. Afferent Pathway-Mediated Effect of α1 Adrenergic Antagonist, Tamsulosin, on the Neurogenic Bladder After Spinal Cord Injury.

    Science.gov (United States)

    Han, Jin-Hee; Kim, Sung-Eun; Ko, Il-Gyu; Kim, Jayoung; Kim, Khae Hawn

    2017-09-01

    The functions of the lower urinary tract (LUT), such as voiding and storing urine, are dependent on complex central neural networks located in the brain, spinal cord, and peripheral ganglia. Thus, the functions of the LUT are susceptible to various neurologic disorders including spinal cord injury (SCI). SCI at the cervical or thoracic levels disrupts voluntary control of voiding and the normal reflex pathways coordinating bladder and sphincter functions. In this context, it is noteworthy that α1-adrenoceptor blockers have been reported to relieve voiding symptoms and storage symptoms in elderly men with benign prostatic hyperplasia (BPH). Tamsulosin, an α1-adrenoceptor blocker, is also considered the most effective regimen for patients with LUT symptoms such as BPH and overactive bladder (OAB). In the present study, the effects of tamsulosin on the expression of c-Fos, nerve growth factor (NGF), and nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) in the afferent micturition areas, including the pontine micturition center (PMC), the ventrolateral periaqueductal gray matter (vlPAG), and the spinal cord (L5), of rats with an SCI were investigated. SCI was found to remarkably upregulate the expression of c-Fos, NGF, and NADPH-d in the afferent pathway of micturition, the dorsal horn of L5, the vlPAG, and the PMC, resulting in the symptoms of OAB. In contrast, tamsulosin treatment significantly suppressed these neural activities and the production of nitric oxide in the afferent pathways of micturition, and consequently, attenuated the symptoms of OAB. Based on these results, tamsulosin, an α1-adrenoceptor antagonist, could be used to attenuate bladder dysfunction following SCI. However, further studies are needed to elucidate the exact mechanism and effects of tamsulosin on the afferent pathways of micturition.

  11. Activation of β-Adrenoceptors by Dobutamine May Induce a Higher Expression of Peroxisome Proliferator-Activated Receptors δ (PPARδ in Neonatal Rat Cardiomyocytes

    Directory of Open Access Journals (Sweden)

    Ming-Ting Chou

    2012-01-01

    Full Text Available Recent evidence showed the role of peroxisome proliferator-activated receptors (PPARs in cardiac function. Cardiac contraction induced by various agents is critical in restoring the activity of peroxisome proliferator-activated receptors δ (PPARδ in cardiac myopathy. Because dobutamine is an agent widely used to treat heart failure in emergency setting, this study is aimed to investigate the change of PPARδ in response to dobutamine. Neonatal rat cardiomyocytes were used to examine the effects of dobutamine on PPARδ expression levels and cardiac troponin I (cTnI phosphorylation via Western blotting analysis. We show that treatment with dobutamine increased PPARδ expression and cTnI phosphorylation in a time- and dose-dependent manner in neonatal rat cardiomyocytes. These increases were blocked by the antagonist of β1-adrenoceptors. Also, the action of dobutamine was related to the increase of calcium ions and diminished by chelating intracellular calcium. Additionally, dobutamine-induced action was reduced by the inhibition of downstream messengers involved in this calcium-related pathway. Moreover, deletion of PPARδ using siRNA generated the reduction of cTnI phosphorylation in cardiomyocytes treated with dobutamine. Thus, we concluded that PPARδ is increased by dobutamine in cardiac cells.

  12. Comparative Cistromics Reveals Genomic Cross-talk between FOXA1 and ER alpha in Tamoxifen-Associated Endometrial Carcinomas

    NARCIS (Netherlands)

    Droog, Marjolein; Nevedomskaya, Ekaterina; Kim, Yongsoo; Severson, Tesa; Flach, Koen D.; Opdam, Mark; Schuurman, Karianne; Gradowska, Patrycja; Hauptmann, Michael; Dackus, Gwen; Hollema, Harry; Mourits, Marian; Nederlof, Petra; van Boven, Hester; Linn, Sabine C.; Wessels, Lodewyk; van Leeuwen, Flora E.; Zwart, Wilbert

    2016-01-01

    Tamoxifen, a small-molecule antagonist of the transcription factor estrogen receptor alpha (ER alpha) used to treat breast cancer, increases risks of endometrial cancer. However, no parallels of ER alpha transcriptional action in breast and endometrial tumors have been found that might explain this

  13. Involvement of the clock gene Rev-erb alpha in the regulation of glucagon secretion in pancreatic alpha-cells.

    Directory of Open Access Journals (Sweden)

    Elaine Vieira

    Full Text Available Disruption of pancreatic clock genes impairs pancreatic beta-cell function, leading to the onset of diabetes. Despite the importance of pancreatic alpha-cells in the regulation of glucose homeostasis and in diabetes pathophysiology, nothing is known about the role of clock genes in these cells. Here, we identify the clock gene Rev-erb alpha as a new intracellular regulator of glucagon secretion. Rev-erb alpha down-regulation by siRNA (60-70% inhibition in alphaTC1-9 cells inhibited low-glucose induced glucagon secretion (p<0.05 and led to a decrease in key genes of the exocytotic machinery. The Rev-erb alpha agonist GSK4112 increased glucagon secretion (1.6 fold and intracellular calcium signals in alphaTC1-9 cells and mouse primary alpha-cells, whereas the Rev-erb alpha antagonist SR8278 produced the opposite effect. At 0.5 mM glucose, alphaTC1-9 cells exhibited intrinsic circadian Rev-erb alpha expression oscillations that were inhibited by 11 mM glucose. In mouse primary alpha-cells, glucose induced similar effects (p<0.001. High glucose inhibited key genes controlled by AMPK such as Nampt, Sirt1 and PGC-1 alpha in alphaTC1-9 cells (p<0.05. AMPK activation by metformin completely reversed the inhibitory effect of glucose on Nampt-Sirt1-PGC-1 alpha and Rev-erb alpha. Nampt inhibition decreased Sirt1, PGC-1 alpha and Rev-erb alpha mRNA expression (p<0.01 and glucagon release (p<0.05. These findings identify Rev-erb alpha as a new intracellular regulator of glucagon secretion via AMPK/Nampt/Sirt1 pathway.

  14. Selective κ opioid antagonists nor-BNI, GNTI and JDTic have low affinities for non-opioid receptors and transporters.

    Directory of Open Access Journals (Sweden)

    Thomas A Munro

    Full Text Available Nor-BNI, GNTI and JDTic induce selective κ opioid antagonism that is delayed and extremely prolonged, but some other effects are of rapid onset and brief duration. The transient effects of these compounds differ, suggesting that some of them may be mediated by other targets.In binding assays, the three antagonists showed no detectable affinity (K(i≥10 µM for most non-opioid receptors and transporters (26 of 43 tested. There was no non-opioid target for which all three compounds shared detectable affinity, or for which any two shared sub-micromolar affinity. All three compounds showed low nanomolar affinity for κ opioid receptors, with moderate selectivity over μ and δ (3 to 44-fold. Nor-BNI bound weakly to the α(2C-adrenoceptor (K(i = 630 nM. GNTI enhanced calcium mobilization by noradrenaline at the α(1A-adrenoceptor (EC₅₀ = 41 nM, but did not activate the receptor, displace radioligands, or enhance PI hydrolysis. This suggests that it is a functionally-selective allosteric enhancer. GNTI was also a weak M₁ receptor antagonist (K(B = 3.7 µM. JDTic bound to the noradrenaline transporter (K(i = 54 nM, but only weakly inhibited transport (IC₅₀ = 1.1 µM. JDTic also bound to the opioid-like receptor NOP (K(i = 12 nM, but gave little antagonism even at 30 µM. All three compounds exhibited rapid permeation and active efflux across Caco-2 cell monolayers.Across 43 non-opioid CNS targets, only GNTI exhibited a potent functional effect (allosteric enhancement of α(1A-adrenoceptors. This may contribute to GNTI's severe transient effects. Plasma concentrations of nor-BNI and GNTI may be high enough to affect some peripheral non-opioid targets. Nonetheless, κ opioid antagonism persists for weeks or months after these transient effects dissipate. With an adequate pre-administration interval, our results therefore strengthen the evidence that nor-BNI, GNTI and JDTic are highly selective κ opioid antagonists.

  15. Acquisition of Pavlovian Fear Conditioning Using β-Adrenoceptor Activation of the Dorsal Premammillary Nucleus as an Unconditioned Stimulus to Mimic Live Predator-Threat Exposure

    Science.gov (United States)

    Pavesi, Eloisa; Canteras, Newton S; Carobrez, Antônio P

    2011-01-01

    In the present work, we sought to mimic the internal state changes in response to a predator threat by pharmacologically stimulating the brain circuit involved in mediating predator fear responses, and explored whether this stimulation would be a valuable unconditioned stimulus (US) in an olfactory fear conditioning paradigm (OFC). The dorsal premammillary nucleus (PMd) is a key brain structure in the neural processing of anti-predatory defensive behavior and has also been shown to mediate the acquisition and expression of anti-predatory contextual conditioning fear responses. Rats were conditioned by pairing the US, which was an intra-PMd microinjection of isoproterenol (ISO; β-adrenoceptor agonist), with amyl acetate odor—the conditioned stimulus (CS). ISO (10 and 40 nmol) induced the acquisition of the OFC and the second-order association by activation of β-1 receptors in the PMd. Furthermore, similar to what had been found for contextual conditioning to a predator threat, atenolol (β-1 receptor antagonist) in the PMd also impaired the acquisition and expression of OFC promoted by ISO. Considering the strong glutamatergic projections from the PMd to the dorsal periaqueductal gray (dPAG), we tested how the glutamatergic blockade of the dPAG would interfere with the OFC induced by ISO. Accordingly, microinjections of NMDA receptor antagonist (AP5, 6 nmol) into the dPAG were able to block both the acquisition, and partially, the expression of the OFC. In conclusion, we have found that PMd β-1 adrenergic stimulation is a good model to mimic predatory threat-induced internal state changes, and works as a US able to mobilize the same systems involved in the acquisition and expression of predator-related contextual conditioning. PMID:21209611

  16. Alpha-adrenergic receptors in rat skeletal muscle

    DEFF Research Database (Denmark)

    Rattigan, S; Appleby, G J; Edwards, S J

    1986-01-01

    from sarcolemma of soleus muscle (phentolamine greater than phenylephrine greater than idazoxan greater than yohimbine) suggested that the receptors were alpha 1. Binding sites for dihydroalprenolol (beta antagonist) were also more concentrated on red than white muscle and outnumbered prazosin sites...... by approx. 10:1. Binding sites for idazoxan (alpha 2 antagonist) were undetectable. Contamination of sarcolemma-enriched preparations by endothelial tissue indicated by the activity of angiotensin converting enzyme did not correlate with prazosin binding. It is concluded that post-synaptic alpha 1...... adrenergic receptors are present on the sarcolemma of slow oxidative red fibres of rat skeletal muscle. The presence provides the mechanistic basis for apparent alpha-adrenergic effects to increase glucose and oxygen uptake in perfused rat hindquarter....

  17. Non-NMDA receptor antagonist-induced drinking in rat

    Science.gov (United States)

    Xu, Z.; Johnson, A. K.

    1998-01-01

    Glutamate has been implicated in the central control of mechanisms that maintain body fluid homeostasis. The present studies demonstrate that intracerebroventricular (i.c.v.) injections of the non-N-methyl-d-aspartate (NMDA) receptor antagonists 6, 7-dinitroquinoxaline-2,3-dione (DNQX) and 6-cyano-7-nitroquinoxaline-2,3 dione (CNQX) induce drinking in rats. The dipsogenic effect of i.c.v. DNQX was antagonized by the non-NMDA receptor agonist alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA). The water intake induced by DNQX was also blocked by pretreatment with a NMDA receptor antagonist, MK-801, but not by angiotensin type 1 (AT1) or acetylcholine muscarinic receptor antagonists (losartan and atropine). The results indicate that non-NMDA receptors may exert a tonic inhibitory effect within brain circuits that control dipsogenic activity and that functional integrity of NMDA receptors may be required for the non-NMDA receptor antagonists to induce water intake. Copyright 1998 Published by Elsevier Science B.V.

  18. Coexistence of beta 1- and beta 2-adrenoceptors in the rabbit heart: quantitative analysis of the regional distribution by (-)-/sup 3/H-dihydroalprenolol binding

    Energy Technology Data Exchange (ETDEWEB)

    Brodde, O.E.; Leifert, F.J.; Krehl, H.J.

    1982-01-01

    We determined the amount of beta 1- and beta 2-adrenoceptors in right and left atria and ventricles of rabbits. For this purpose inhibition of specific (-)-/sup 3/H-dihydroalprenolol ((-)-/sup 3/H-DHA) binding (5 nM) by beta 1-selective (practolol, metoprolol) and beta 2-selective (zinterol, IPS 339) adrenergic drugs was determined and analyzed by pseudo-Scatchard (Hofstee) plots. For both atria, inhibition of binding by the four selective beta-adrenergic drugs resulted in non-linear Hofstee plots, suggesting the coexistence of both beta-adrenoceptor subtypes. From these plots we calculated a beta 1:beta 2-adrenoceptor ratio of 72:28 for the right atrium and of 82:18 for the left. In contrast, only a very small amount of beta 2-adrenoceptors (approximately 5-7% of the total beta-adrenoceptor population) could be detected in the ventricles. For comparison we analyzed the inhibition of specific (-)-/sup 3/H-DHA binding in tissues with homogeneous population of beta-adrenoceptors (beta 1:guinea pig left ventricle; beta 2: cerebellum of mature rats). For both tissues the four selective beta-adrenergic drugs showed linear Hofstee plots, demonstrating that in tissues with homogeneous beta-receptor population interaction of each drug with the receptor followed simple mass-action kinetics. We conclude that beta 1- and beta 2-adrenoceptors coexist in rabbit atria while the ventricles are predominantly endowed the beta 1-adrenoceptors.

  19. The role of α1- and α2-adrenoceptor subtypes in the vasopressor responses induced by dihydroergotamine in ritanserin-pretreated pithed rats

    NARCIS (Netherlands)

    Rivera-Mancilla, E. (Eduardo); Avilés-Rosas, V.H. (Victor H.); G. Manrique-Maldonado (Guadalupe); A.H. Altamirano-Espinoza (Alain); Villanueva-Castillo, B. (Belinda); A. Maassen van den Brink (Antoinette); C.M. Villalón (Carlos)

    2017-01-01

    textabstractBackground: Dihydroergotamine (DHE) is an acute antimigraine agent that displays affinity for dopamine D2-like receptors, serotonin 5-HT1/2 receptors and α1/α2-adrenoceptors. Since activation of vascular α1/α2-adrenoceptors results in systemic vasopressor responses, the purpose of this

  20. β-Adrenoceptor subtypes and cAMP role in adrenaline- and noradrenaline-induced relaxation in the rat thoracic aorta

    Science.gov (United States)

    Shiina, Shunsuke; Kanemura, Ayaka; Suzuki, Chihiro; Yamaki, Fumiko; Obara, Keisuke; Chino, Daisuke; Tanaka, Yoshio

    2018-01-01

    Object We identified the β-adrenoceptor (β-AR) subtypes responsible for the relaxant responses to adrenaline (AD) and noradrenaline (NA) in the rat thoracic aorta and examined the role of cAMP which is involved in these relaxant responses. Methods The effects of β-AR antagonists or the adenylyl cyclase inhibitor SQ 22,536 on AD- and NA-induced relaxant responses in phenylephrine-induced contraction and increases in cAMP levels were examined in isolated, endothelium-denuded rat thoracic aorta segments. Results AD-induced relaxation was completely suppressed by propranolol (10−7 M) or by ICI-118,551 (10−8 M) plus atenolol (10−6 M), and was also very strongly inhibited by ICI-118,551 (10−8 M) alone. AD (10−5 M) increased tissue cAMP levels by approximately 1.9-fold compared with that in non-stimulated aortic tissue, but did not significantly increase cAMP levels in the presence of ICI-118,551 (10−8 M) or SQ 22,536 (10−4 M). AD-induced relaxation was strongly suppressed by SQ 22,536 (10−4 M). NA-induced relaxation was almost completely suppressed by atenolol (10−6 M) plus ICI-118,551 (10−8 M) although it was hardly affected by ICI-118,551 (10−8 M) alone. NA (10−5 M) increased tissue cAMP levels by approximately 2.2-fold compared with that in non-stimulated aortic tissue, but did not significantly increase cAMP levels in the presence of atenolol (10−6 M) or SQ 22,536 (10−4 M). NA-induced relaxation was strongly suppressed by SQ 22,536 (10−4 M). Conclusion In rat thoracic aorta, AD- and NA-induced relaxations, which are both strongly dependent on increased tissue cAMP levels, are mainly mediated through β2- and β1-adrenoceptors respectively. PMID:29540622

  1. β3-Adrenoceptor Mediates Metabolic Protein Remodeling in a Rabbit Model of Tachypacing-Induced Atrial Fibrillation

    Directory of Open Access Journals (Sweden)

    Yixi Liu

    2013-12-01

    Full Text Available Background: The beta 3-adrenoceptor (β3-AR is closely associated with energy metabolism. This study aimed to explore the role of β3-AR in energy remodeling in a rabbit model of pacing-induced atrial fibrillation (AF. Methods: Rabbits with a sham-operation or pacing-induced AF were used for this study, and the latter group was further divided into three subgroups: 1 the pacing group, 2 the β3-AR agonist (BRL37344-treated group, and 3 the β3-AR antagonist (SR59230A-treated group. Atrial electrogram morphology and surface ECG were used to monitor the induction of AF and atrial effective refractory period (AERP. RT-PCR and western blot (WB were used to show alterations in β3-AR and metabolic-related protein. Results: RT-PCR and WB results showed that β3-AR was significantly upregulated in the pacing group, and that it corresponded with high AF inducibility and significantly decreased AERP200 and ATP production in this group. Inhibition of β3-AR decreased the AF induction rate, reversed AERP200 reduction, and restored ATP levels in the AF rabbits. Further activation of β3-AR using agonist BRL37344 exacerbated AF-induced metabolic disruption. Periodic acid Schiff (PAS and Oil Red O staining showed β3-AR-dependent glycogen and lipid droplet accumulation in cardiac myocytes with AF. Glucose transporter-4 (GLUT-4 and CD36, key transporters of glucose and fatty acids, were downregulated in the pacing group. Expression of carnitine-palmitoyltransferase I (CPT-1, a key regulator in fatty acid metabolism, was also significantly downregulated in the pacing group. Reduced glucose transportation and fatty acid oxidation could be restored by inhibition of β3-AR. Furthermore, key regulators of metabolism, peroxisome proliferator-activated receptor-α (PPARα and PPAR co-activator (PGC-1α can be regulated by pharmacological intervention of the β3-AR. Conclusions: β3-AR is involved in metabolic protein remodeling in AF. PPARα/PGC-1α signaling pathway

  2. Coulomb correction to elastic. alpha. -. alpha. scattering

    Energy Technology Data Exchange (ETDEWEB)

    Bera, P.K.; Jana, A.K.; Haque, N.; Talukdar, B. (Department of Physics, Visva-Bharati University, Santiniketan-731235, West Bengal, India (IN))

    1991-02-01

    The elastic {alpha}-{alpha} scattering is treated within the framework of a generalized phase-function method (GPFM). This generalization consists in absorbing the effect of Coulomb interaction in the comparison functions for developing the phase equation. Based on values of scattering phase shifts computed by the present method, it is concluded that the GPFM provides an uncomplicated approach to rigorous Coulomb correction in the {alpha}-{alpha} scattering.

  3. Intrahepatic expression of interferon alpha & interferon alpha ...

    African Journals Online (AJOL)

    kemrilib

    Alpha m-RNA while 30% only expressed Interferon Alpha Receptor m-RNA. Responders and non-responders to Interferon therapy ... expression of IFN Alpha Receptor mRNA. Regardless of the response to interferon, histological .... generation reverse hybridisation, line probe assay. (Inno-LiPA HCV II; Innogenetics, Ghent,.

  4. Antagonism of Lateral Amygdala Alpha1-Adrenergic Receptors Facilitates Fear Conditioning and Long-Term Potentiation

    Science.gov (United States)

    Lazzaro, Stephanie C.; Hou, Mian; Cunha, Catarina; LeDoux, Joseph E.; Cain, Christopher K.

    2010-01-01

    Norepinephrine receptors have been studied in emotion, memory, and attention. However, the role of alpha1-adrenergic receptors in fear conditioning, a major model of emotional learning, is poorly understood. We examined the effect of terazosin, an alpha1-adrenergic receptor antagonist, on cued fear conditioning. Systemic or intra-lateral amygdala…

  5. Alpha-adrenergic receptors in rat skeletal muscle

    DEFF Research Database (Denmark)

    Rattigan, S; Appleby, G J; Edwards, S J

    1986-01-01

    Sarcolemma-enriched preparations from muscles rich in slow oxidative red fibres contained specific binding sites for the alpha 1 antagonist, prazosin (e.g. soleus Kd 0.13 nM, Bmax 29 fmol/mg protein). Binding sites for prazosin were almost absent from white muscle. Displacement of prazosin bindin...

  6. Bulk is a determinant of oxymetazoline affinity for the alpha1A-adrenergic receptor.

    Science.gov (United States)

    McCune, Dan; Gaivin, Robert; Rorabaugh, Boyd; Perez, Dianne

    2004-01-01

    The alpha1A-adrenergic receptor (AR) has a higher affinity for several agonists and antagonists compared to alpha1B or alpha1D ARs. Mutagenesis studies were used to determine residues potentially responsible for this subtype selectivity. Oxymetazoline has a 50-fold lower affinity for alpha1D ARs compared to alpha1A ARs and also displayed a significant loss of affinity for an alpha1A Leu-290 to Phe mutant. It was concluded that steric interactions between the alpha1D ARs Phe-360 and the bulkytert-butyl group of oxymetazoline partially accounts for this lower affinity. Thus, the alpha1A AR binding pocket may more easily accommodate bulk at the paraposition of the phenyl ring than the alpha1D AR.

  7. [Distribution and significance of α1-adrenoceptor subtypes in patients with chronic prostatitis in prostate, bladder detrusor and posterior urethral tissue].

    Science.gov (United States)

    Yang, Yu; Xie, Hui; Zheng, Jian-jian; Chen, Bi-cheng; He, Qiu-xiang; Shen, Ji-hong

    2010-12-14

    To study the distribution of alpha1-adrenoceptor (α1-AR) subtype in prostate, posterior urethra and bladder detrusor of patients with chronic prostatitis (CP). The prostate specimens were collected at autopsy from 30 organ donors (aged 20-35 years old) dying of non-prostatic diseases. The pathological specimens of prostate peripheral zone were examined. The method of real-time reverse transcriptase polymerase chain reaction (real-time RT-PCR) was employed for quantification of α1a-AR and α1b-AR subtype expression in prostate transition zone and its surrounding zone, posterior urethra and bladder detrusor tissue. Among all donors, there were 24 cases with pathological inflammation in prostatic peripheral zone and 6 with pathological non-inflammation. The mRNA expression of α1-AR subtypes in bladder detrusor and posterior urethra was significantly higher in the inflammation group than in the control group (Pposterior urethra was significantly lower in the inflammation group than in the control group (Pposterior urethra may explain various urodynamic changes in CP and lead to the occurrence and development of CP in prostate, posterior urethra and bladder detrusor.

  8. Angiotensin AT1 - α2C-Adrenoceptor Interaction Disturbs α2A-auto-Inhibition of Catecholamine Release in Hypertensive Rats.

    Science.gov (United States)

    Berg, Torill

    2013-01-01

    α2-Adrenoceptors lower central sympathetic output and peripheral catecholamine release, and thus may prevent sympathetic hyperactivity and hypertension. α2AR also influence vascular tension. These α2AR are malfunctioning in spontaneously hypertensive rats (SHR). Here I tested if an interaction between α2AR subtypes and the angiotensin AT1 receptor (AT1R) precipitated these disorders. Blood pressure was monitored through a femoral artery catheter and cardiac output by ascending aorta flow in anesthetized rats. Catecholamine concentrations were determined in plasma collected at the end of a 15-min tyramine-infusion. Tyramine stimulates norepinephrine release through the re-uptake transporter, thus preventing re-uptake. Presynaptic control of vesicular release is therefore reflected as differences in overflow to plasma. Previous experiments showed surgical stress to activate some secretion of epinephrine, also subjected to α2AR-auto-inhibition. Normotensive rats (WKY) and SHR were pre-treated with (1) vehicle or α2AR-antagonist (L-659,066), followed by fadolmidine (α2C>B>A + α1AR-agonist), ST-91 (α2non-A-selective agonist), or m-nitrobiphenyline (α2CAR-agonist + α2A+B-antagonist), or (2) AT1R-antagonist losartan, losartan + L-659,066, or losartan + clonidine. In WKY, L-659,066 alone, L-659,066 + agonist or losartan + L-659,066 increased catecholamine overflow to plasma after tyramine and eliminated the norepinephrine-induced rise in total peripheral vascular resistance (TPR). In SHR, L-659,066 + fadolmidine/ST-91/m-nitrobiphenyline and losartan + L-659,066 greatly increased, and losartan + clonidine reduced, catecholamine concentrations, and L-659,066 + ST-91, losartan + L-659,066 and losartan + clonidine eliminated the tyramine-induced rise in TPR. Separately, these drugs had no effect in SHR. In conclusion, peripheral α2CAR-stimulation or AT1R-inhibition restored failing α2AAR-mediated auto-inhibition of

  9. ANGIOTENSIN AT1 - α2C-ADRENOCEPTOR INTERACTION DISTURBS α2A-AUTO-INHIBITION OF CATECHOLAMINE RELEASEIN HYPERTENSIVE RATS

    Directory of Open Access Journals (Sweden)

    Torill eBerg

    2013-06-01

    Full Text Available α2-adrenoceptors (AR lower central sympathetic output and peripheral catecholamine release, and thus may prevent sympathetic hyperactivity and hypertension. α2AR also influence vascular tension. These α2AR are malfunctioning in spontaneously hypertensive rats (SHR. Here I tested if an interaction between α2AR subtypes and the angiotensin AT1 receptor (AT1R precipitated these disorders. Blood pressure was monitored through a femoral artery catheter and cardiac output by ascending aorta flow in anaesthetized rats. Catecholamine concentrations were determined in plasma collected at the end of a 15-min tyramine-infusion. Tyramine stimulates norepinephrine release through the re-uptake transporter, thus preventing re-uptake, and presynaptic control of vesicular release is reflected as differences in overflow to plasma. Previous experiments showed surgical stress to activate some secretion of epinephrine, also subjected to α2AR-auto-inhibition. Normotensive rats (WKY and SHR were pre-treated with 1 vehicle or α2AR antagonist (L-659,066, followed by fadolmidine (α2C>B>A+α1AR agonist, ST-91 (α2non-A-selective agonist or m-nitrobiphenyline (α2CAR-agonist+α2A+B-antagonist, or 2 AT1R antagonist losartan, losartan+L-659,066 or losartan+clonidine. In WKY, L-659,066 alone, L-659,066+agonist or losartan+L-659,066 increased catecholamine overflow to plasma after tyramine and eliminated the norepinephrine-induced rise in total peripheral vascular resistance (TPR. In SHR, L-659,066+fadolmidine/ST-91/m-nitrobiphenyline and losartan+L-659,066 greatly increased, and losartan+clonidine reduced, catecholamine concentrations, and L-659,066+ST-91, losartan+L-659,066 and losartan+clonidine eliminated the tyramine-induced rise in TPR. Separately, these drugs had no effect in SHR. In conclusion, peripheral α2CAR-stimulation or AT1R-inhibition restored failing α2AAR-mediated auto-inhibition of norepinephrine and epinephrine release and control of TPR in SHR.

  10. 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...

  11. ANTAGONISTIC POTENTIAL OF FLUORESCENT Pseudomonas ...

    African Journals Online (AJOL)

    Prof. Adipala Ekwamu

    This study focused on the antagonistic potential of fluorescent Pseudomonas in vitro, and its inoculation effect on growth performance of Lycopersicon esculentum in Fusarium oxysporum and Rhizoctonia solani infested soil. Biochemical characteristics of fluorescent Pseudomonas showed that all ten isolates were positive ...

  12. Interaction of metabolic and respiratory acidosis with α and β-adrenoceptor stimulation in rat myocardium.

    Science.gov (United States)

    Biais, Matthieu; Jouffroy, Romain; Carillion, Aude; Feldman, Sarah; Jobart-Malfait, Aude; Riou, Bruno; Amour, Julien

    2012-12-01

    The effects of acute respiratory versus metabolic acidosis on the myocardium and their consequences on adrenoceptor stimulation remain poorly described. We compared the effects of metabolic and respiratory acidosis on inotropy and lusitropy in rat myocardium and their effects on the responses to α- and β-adrenoceptor stimulations. The effects of acute respiratory and metabolic acidosis (pH 7.10) and their interactions with α and β-adrenoceptor stimulations were studied in isolated rat left ventricular papillary muscle (n=8 per group). Intracellular pH was measured using confocal microscopy and a pH-sensitive fluorophore in isolated rat cardiomyocytes. Data are mean percentages of baseline±SD. Respiratory acidosis induced more pronounced negative inotropic effects than metabolic acidosis did both in isotonic (45±3 versus 63±6%, P<0.001) and isometric (44±5 versus 64±3%, P<0.001) conditions concomitant with a greater decrease in intracellular pH (6.85±0.07 versus 7.12±0.07, P<0.001). The response to α-adrenergic stimulation was not modified by respiratory or metabolic acidosis. The inotropic response to β-adrenergic stimulation was impaired only in metabolic acidosis (137±12 versus 200±33%, P<0.001), but this effect was not observed with administration of forskolin or dibutiryl-cyclic adenosine monophosphate. This effect might be explained by a change in transmembrane pH gradient only observed with metabolic acidosis. The lusitropic response to β-adrenergic stimulation was not modified by respiratory or metabolic acidosis. Acute metabolic and respiratory acidosis induce different myocardial effects related to different decreases in intracellular pH. Only metabolic acidosis impairs the positive inotropic effect of β-adrenergic stimulation.

  13. Reactive oxygen species are involved in regulating α1-adrenoceptor-activated vascular smooth muscle contraction

    Directory of Open Access Journals (Sweden)

    Tsai Ming-Ho

    2010-08-01

    Full Text Available Abstract Background Reactive oxygen species (ROS were shown to mediate aberrant contractility in hypertension, yet the physiological roles of ROS in vascular smooth muscle contraction have remained elusive. This study aimed to examine whether ROS regulate α1-adrenoceptor-activated contraction by altering myosin phosphatase activities. Methods Using endothelium-denuded rat tail artery (RTA strips, effects of anti-oxidants on isometric force, ROS production, phosphorylation of the 20-kDa myosin light chain (MLC20, and myosin phosphatase stimulated by α1-adrenoceptor agonist phenylephrine were examined. Results An antioxidant, N-acetyl-L-cysteine (NAC, and two NADPH oxidase inhibitors, apocynin and VAS2870, dose-dependently inhibited contraction activated by phenylephrine. Phenylephrine stimulated superoxide anion production that was diminished by the pretreatment of apocynin, VAS2870, superoxide scavenger tiron or mitochondria inhibitor rotenone, but not by xanthine oxidase inhibitor allopurinol or cyclooxygenase inhibitor indomethacin. Concurrently, NADPH oxidase activity in RTA homogenates increased within 1 min upon phenylephrine stimulation, sustained for 10 min, and was abolished by the co-treatment with apocynin, but not allopurinol or rotenone. Phenylephrine-induced MLC20 phosphorylation was dose-dependently decreased by apocynin. Furthermore, apocynin inhibited phenylephrine-stimulated RhoA translocation to plasma membrane and phosphorylation of both myosin phosphatase regulatory subunit MYPT1Thr855 and myosin phosphatase inhibitor CPI-17Thr38. Conclusions ROS, probably derived from NADPH oxidase and mitochondria, partially regulate α1-adrenoceptor-activated smooth muscle contraction by altering myosin phosphatase-mediated MLC20 phosphorylation through both RhoA/Rho kinase- and CPI-17-dependent pathways.

  14. Adverse reactions of α2-adrenoceptor agonists in cats reported in 2003-2013 in Finland.

    Science.gov (United States)

    Raekallio, Marja R; Virtanen, Marika; Happonen, Irmeli; Vainio, Outi M

    2017-07-01

    To describe suspected adverse drug reactions in cats associated with use of α 2 -adrenoceptor agonists. Retrospective study. A total of 90 cats. Data were collected from reports on adverse reactions to veterinary medicines sent to the Finnish Medicines Agency during 2003-2013. All reports of suspected adverse reactions associated with use of α 2 -adrenoceptor agonists in cats were included. Probable pulmonary oedema was diagnosed based on post mortem or radiological examination, or presence of frothy or excess fluid from the nostrils or trachea. If only dyspnoea and crackles on auscultation were reported, possible pulmonary oedema was presumed. Pulmonary oedema was suspected in 61 cases. Of these cats, 37 were categorised as probable and 24 as possible pulmonary oedema. The first clinical signs had been noted between 1 minute and 2 days (median, 15 minutes) after α 2 -adrenoceptor agonist administration. Many cats probably had no intravenous overhydration when the first clinical signs were detected, as either they presumably had no intravenous cannula or the signs appeared before, during or immediately after cannulation. Of the 61 cats, 43 survived, 14 died and for four the outcome was not clearly stated. Pulmonary oedema is a perilous condition that may appear within minutes of an intramuscular administration of sedative or anaesthetic agent in cats. The symptoms were not caused by intravenous overhydration, at least in cats having no venous cannula when the first clinical signs were detected. Copyright © 2017 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.

  15. Beta-adrenoceptor responsiveness in intact leukocytes from adults and newborn infants; effect of phosphodiesterase inhibitors

    DEFF Research Database (Denmark)

    Foged, N; Bertelsen, Niels Haldor; Johansen, Torben

    1990-01-01

    Intact mononuclear and polymorphonuclear leukocytes from adults and newborn infants were used to estimate the beta 2-adrenoceptor responsiveness in vitro. The accumulation of cAMP in response to receptor stimulation by isoprenaline was used as a measure of the receptor responsiveness. The relevance......-1 inhibits the phosphodiesterase activity almost completely. By use of this concentration no age-dependent changes in the isoprenaline-stimulated cAMP accumulation in mononuclear and polymorphonuclear leukocytes from adults and newborn infants could be demonstrated....

  16. Abediterol (LAS100977), an inhaled long-acting β2-adrenoceptor agonist, has a fast association rate and long residence time at receptor.

    Science.gov (United States)

    Ramos, Israel; Aparici, Mònica; Letosa, Maria; Puig, Carlos; Gavaldà, Amadeu; Huerta, Josep Maria; Espinosa, Sonia; Vilella, Dolors; Miralpeix, Montserrat

    2018-01-15

    This study describes the association rate and residence time of abediterol, a novel long-acting β 2 -adrenoceptor agonist (LABA) in Phase II development for treatment of asthma and COPD, in comparison with indacaterol, olodaterol, vilanterol and salmeterol, for both human β 1 - and β 2 -adrenoceptors. Abediterol association and dissociation rates were monitored directly by using its tritiated form. Moreover, association was determined indirectly using experimental K i and k off obtained from assays performed with unlabelled compound. Dissociation was also studied indirectly by measuring the association rate of 3 H-CGP12177 to beta adrenoceptors previously occupied by unlabelled compounds. Abediterol shows a fast association for the β 2 -adrenoceptor (k on 1.4 × 10 7 ± 1.8 × 10 6 M -1 min -1 ) while its dissociation rate is between 30 and 64 times slower than that of the reference LABA compounds tested, with a residence time of 91.3 ± 13.3min (measured directly) and 185.5 ± 7.5min (measured indirectly). Abediterol shows kinetic selectivity for the β 2 - over the β 1 -adrenoceptor, with a dissociation rate from the β 1 -adrenoceptor similar to the other LABA compounds tested. In conclusion, abediterol is a potent LABA with a fast association rate and a long residence time at β 2 -adrenoceptors. These data are in agreement with the onset and duration of action of abediterol shown in humans. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. [Effect of 1-alpha blockader on maximal oxygen consumption and physical endurance in hypertensive men].

    Science.gov (United States)

    Tomten, S E; Nilsson, S; Kjeldsen, S E; Westheim, A S

    1996-01-10

    The effect of alpha 1 adrenoceptor blockade (doxazosin, 4 mg daily) on maximal oxygen uptake (VO2 max) and physical endurance capacity in 16 mildly hypertensive, athletic men was investigated in a randomized, placebo-controlled, double-blind, two-period of 4 weeks, cross-over study. The maximal work load obtained during graded bicycle ergometer exercise and the VO2 max were reduced by 16 +/- 3 W (mean +/- SE) and 3 +/- 1 ml x kg-1 x min-1 on doxazosin (p track increased by 43 +/- 12 sec (p < 0.05). Thus, alpha 1-blockade moderately reduces VO2 max and physical endurance capacity in mildly hypertensive athletic men. However, lower systolic blood pressure (9 +/- 4 mm Hg, p < 0.05) immediately after running, and unchanged heart rate suggest a safer performance of exercise.

  18. Effects of central imidazolinergic and alpha2-adrenergic activation on water intake

    Directory of Open Access Journals (Sweden)

    Sugawara A.M.

    2001-01-01

    Full Text Available Non-adrenergic ligands that bind to imidazoline receptors (I-R, a selective ligand that binds to alpha2-adrenoceptors (alpha2-AR and mixed ligands that bind to both receptors were tested for their action on water intake behavior of 24-h water-deprived rats. All drugs were injected into the third cerebral ventricle. Except for agmatine (80 nmol, mixed ligands binding to I-R/alpha2-AR such as guanabenz (40 nmol and UK 14304 (20 nmol inhibited water intake by 65% and up to 95%, respectively. The selective non-imidazoline alpha2-AR agonist, alpha-methylnoradrenaline, produced inhibition of water intake similar to that obtained with guanabenz, but at higher doses (80 nmol. The non-adrenergic I-R ligands histamine (160 nmol, mixed histaminergic and imidazoline ligand and imidazole-4-acetic acid (80 nmol, imidazoline ligand did not alter water intake. The results show that selective, non-imidazoline alpha2-AR activation suppresses water intake, and suggest that the action on imidazoline sites by non-adrenergic ligands is not sufficient to inhibit water intake.

  19. Drug‐induced Raynaud's phenomenon: beyond β‐adrenoceptor blockers

    Science.gov (United States)

    Khouri, Charles; Blaise, Sophie; Carpentier, Patrick; Villier, Céline; Cracowski, Jean‐Luc

    2016-01-01

    Aim Drug‐induced Raynaud's phenomenon (RP) has long been associated with the use of different drugs, including cancer chemotherapy or β‐adrenoceptor blockers. However, sources report extremely variable prevalence and the level of evidence for each class is heterogeneous. Moreover, new signals are emerging from case reports and small series. Our objective was therefore to review available evidence about this adverse drug effect and to propose a mechanistic approach of drug‐induced RP. Methods A systematic review of English and French language articles was performed through Medline (1946–2015) and Embase (1974–2015). Further relevant papers were identified from the reference lists of retrieved articles. Results We identified 12 classes of drugs responsible for RP, with a variety of underlying mechanisms such as increased sympathetic activation, endothelial dysfunction, neurotoxicity or decreased red blood cell deformability. Cisplatin and bleomycin were associated with the highest risk, followed by β‐adrenoceptor blockers. Recent data suggest a possible involvement of tyrosine kinase inhibitors (TKI), through an unknown mechanism. Conclusion Drug‐induced RP is a probably underestimated adverse drug event, with limited available evidence regarding its prevalence. Although rare, serious complications like critical digital ischaemia have been reported. When these treatments are started in patients with a history of RP, careful monitoring must be made and, if possible, alternative therapies that do not alter peripheral blood flow should be considered. PMID:26949933

  20. Biodistribution and radiation dosimetry of [N-methyl-11C]mirtazapine, an antidepressant affecting adrenoceptors

    International Nuclear Information System (INIS)

    Marthi, Katalin; Hansen, S.B.; Jakobsen, Steen; Bender, Dirk; Smith, S.B.; Smith, D.F.

    2003-01-01

    Central adrenoceptors cannot currently be studied by PET neuroimaging due to a lack of appropriate radioligands. The fast-acting antidepressant drug mirtazapine, radiolabelled for PET, may be of value for assessing central adrenoceptors, provided that the radiation dosimetry of the radioligand is acceptable. To obtain that information, serial whole-body images were made for up to 70 min following intravenous injection of 326 and 185 MBq [N-methyl- 11 C]mirtazapine (specific activities E.O.S. of 119 and 39 GBq/μmol, respectively) in a healthy volunteer. Ten source organs plus remaining body were considered in estimating absorbed radiation doses calculated using MIRD 3.1. The highest absorbed organ doses were found to the lungs (3.4x10 -2 mGy/MBq), adrenals (1.2x10 -2 mGy/MBq), spleen (1.2x10 -2 mGy/MBq), and gallbladder wall (1.1x10 -2 mGy/MBq). The effective dose was estimated to be 6.8x10 -3 mSv/MBq, which is similar to that produced by several radioligands used routinely for neuroimaging

  1. Pharmacological profile of β3-adrenoceptor agonists in clinical development for the treatment of overactive bladder syndrome

    NARCIS (Netherlands)

    Igawa, Yasuhiko; Michel, Martin C.

    2013-01-01

    β(3)-Adrenoceptor agonists are an emerging drug class for the treatment of the overactive bladder syndrome, and clinical proof-of-concept data have been obtained for three representatives of this class, mirabegron, ritobegron, and solabegron. We review here the pharmacological profile of these three

  2. β3-Adrenoceptor-mediated relaxation of rat and human urinary bladder : roles of BKCa channels and Rho kinase

    NARCIS (Netherlands)

    Cernecka, Hana; Kersten, Kim; Maarsingh, Harm; Elzinga, Carolina R.; de Jong, Igle Jan; Korstanje, Cees; Michel, Martin C.; Schmidt, Martina

    Previous studies suggest that the large-conductance Ca2+-activated K+ (BKCa) channel and Rho-kinase play major roles in the control of urinary bladder tone. Here, we investigated their involvement in beta-adrenoceptor (AR)-mediated relaxation of rat and human bladder. Concentration-response curves

  3. Opioid antagonists with minimal sedation for opioid withdrawal.

    Science.gov (United States)

    Gowing, Linda; Ali, Robert; White, Jason M

    2017-05-29

    Managed withdrawal is a necessary step prior to drug-free treatment or as the endpoint of long-term substitution treatment. To assess the effects of opioid antagonists plus minimal sedation for opioid withdrawal. Comparators were placebo as well as more established approaches to detoxification, such as tapered doses of methadone, adrenergic agonists, buprenorphine and symptomatic medications. We updated our searches of the following databases to December 2016: CENTRAL, MEDLINE, Embase, PsycINFO and Web of Science. We also searched two trials registers and checked the reference lists of included studies for further references to relevant studies. We included randomised and quasi-randomised controlled clinical trials along with prospective controlled cohort studies comparing opioid antagonists plus minimal sedation versus other approaches or different opioid antagonist regimens for withdrawal in opioid-dependent participants. We used standard methodological procedures expected by Cochrane. Ten studies (6 randomised controlled trials and 4 prospective cohort studies, involving 955 participants) met the inclusion criteria for the review. We considered 7 of the 10 studies to be at high risk of bias in at least one of the domains we assessed.Nine studies compared an opioid antagonist-adrenergic agonist combination versus a treatment regimen based primarily on an alpha 2 -adrenergic agonist (clonidine or lofexidine). Other comparisons (placebo, tapered doses of methadone, buprenorphine) made by included studies were too diverse for any meaningful analysis. This review therefore focuses on the nine studies comparing an opioid antagonist (naltrexone or naloxone) plus clonidine or lofexidine versus treatment primarily based on clonidine or lofexidine.Five studies took place in an inpatient setting, two studies were in outpatients with day care, two used day care only for the first day of opioid antagonist administration, and one study described the setting as outpatient

  4. In vitro histamine H/sub 2/-antagonist activity of the novel compound HUK 978

    Energy Technology Data Exchange (ETDEWEB)

    Coombes, J.D.; Norris, D.B.; Rising, T.J.; Ross, B.C.; Steward, A.

    1985-11-04

    Histamine stimulated adenylate cyclase from guinea-pig fundic mucosa and /sup 3/H-tiotidine binding in guinea-pig cerebral cortex were used to assess the in-vitro histamine H/sub 2/-activity of the novel H/sub 2/-antagonist HUK 978. The results showed that HUK 978 was a more potent H/sub 2/-antagonist than either cimetidine or ranitidine. HUK 978 was also shown to be devoid of activity at the histamine H-/sub 1/-receptor, the muscarinic receptor and the ..cap alpha.. and ..beta..-adrenergic receptors.

  5. Reduced CGP12177 binding to cardiac β-adrenoceptors in hyperglycemic high-fat-diet-fed, streptozotocin-induced diabetic rats

    International Nuclear Information System (INIS)

    Thackeray, James T.; Parsa-Nezhad, Maryam; Kenk, Miran; Thorn, Stephanie L.; Kolajova, Maria; Beanlands, Rob S.B.; DaSilva, Jean N.

    2011-01-01

    Introduction: Abnormal sympathetic nervous system and β-adrenoceptor (β-AR) signaling is associated with diabetes. [ 3 H]CGP12177 is a nonselective β-AR antagonist that can be labeled with carbon-11 for positron emission tomography. The aim of this study was to examine the suitability of this tracer for evaluation of altered β-AR expression in diabetic rat hearts. Methods: Ex vivo biodistribution with [ 3 H]CGP12177 was carried out in normal Sprague-Dawley rats for evaluation of specific binding and response to continuous β-AR stimulation by isoproterenol. In a separate group, high-fat-diet feeding imparted insulin resistance and a single intraperitoneal injection of streptozotocin (STZ) or vehicle evoked hyperglycemia (blood glucose >11 mM). [ 3 H]CGP12177 biodistribution was assessed at 2 and 8 weeks post-STZ to measure β-AR binding in heart, 30 min following tracer injection. Western blotting of β-AR subtypes was completed in parallel. Results: Infusion of isoproterenol over 14 days did not affect cardiac binding of [ 3 H]CGP12177. Approximately half of rats treated with STZ exhibited sustained hyperglycemia and progressive hypoinsulinemia. Myocardial [ 3 H]CGP12177 specific binding was unchanged at 2 weeks post-STZ but significantly reduced by 30%-40% at 8 weeks in hyperglycemic but not euglycemic STZ-treated rats compared with vehicle-treated controls. Western blots supported a significant decrease in β 1 -AR in hyperglycemic rats. Conclusions: Reduced cardiac [ 3 H]CGP12177 specific binding in the presence of sustained hyperglycemia corresponds to a decrease in relative β 1 -AR expression. These data indirectly support the use of [ 11 C]CGP12177 for assessment of cardiac dysfunction in diabetes.

  6. Reduced CGP12177 binding to cardiac {beta}-adrenoceptors in hyperglycemic high-fat-diet-fed, streptozotocin-induced diabetic rats

    Energy Technology Data Exchange (ETDEWEB)

    Thackeray, James T.; Parsa-Nezhad, Maryam; Kenk, Miran; Thorn, Stephanie L. [Molecular Function and Imaging Program, National Cardiac PET Centre, Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario, K1Y4W7 (Canada); Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Roger Guindon Hall, Ottawa, Ontario, K1H8M5 (Canada); Kolajova, Maria [Molecular Function and Imaging Program, National Cardiac PET Centre, Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario, K1Y4W7 (Canada); Beanlands, Rob S.B. [Molecular Function and Imaging Program, National Cardiac PET Centre, Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario, K1Y4W7 (Canada); Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Roger Guindon Hall, Ottawa, Ontario, K1H8M5 (Canada); DaSilva, Jean N., E-mail: jdasilva@ottawaheart.ca [Molecular Function and Imaging Program, National Cardiac PET Centre, Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario, K1Y4W7 (Canada); Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Roger Guindon Hall, Ottawa, Ontario, K1H8M5 (Canada)

    2011-10-15

    Introduction: Abnormal sympathetic nervous system and {beta}-adrenoceptor ({beta}-AR) signaling is associated with diabetes. [{sup 3}H]CGP12177 is a nonselective {beta}-AR antagonist that can be labeled with carbon-11 for positron emission tomography. The aim of this study was to examine the suitability of this tracer for evaluation of altered {beta}-AR expression in diabetic rat hearts. Methods: Ex vivo biodistribution with [{sup 3}H]CGP12177 was carried out in normal Sprague-Dawley rats for evaluation of specific binding and response to continuous {beta}-AR stimulation by isoproterenol. In a separate group, high-fat-diet feeding imparted insulin resistance and a single intraperitoneal injection of streptozotocin (STZ) or vehicle evoked hyperglycemia (blood glucose >11 mM). [{sup 3}H]CGP12177 biodistribution was assessed at 2 and 8 weeks post-STZ to measure {beta}-AR binding in heart, 30 min following tracer injection. Western blotting of {beta}-AR subtypes was completed in parallel. Results: Infusion of isoproterenol over 14 days did not affect cardiac binding of [{sup 3}H]CGP12177. Approximately half of rats treated with STZ exhibited sustained hyperglycemia and progressive hypoinsulinemia. Myocardial [{sup 3}H]CGP12177 specific binding was unchanged at 2 weeks post-STZ but significantly reduced by 30%-40% at 8 weeks in hyperglycemic but not euglycemic STZ-treated rats compared with vehicle-treated controls. Western blots supported a significant decrease in {beta}{sub 1}-AR in hyperglycemic rats. Conclusions: Reduced cardiac [{sup 3}H]CGP12177 specific binding in the presence of sustained hyperglycemia corresponds to a decrease in relative {beta}{sub 1}-AR expression. These data indirectly support the use of [{sup 11}C]CGP12177 for assessment of cardiac dysfunction in diabetes.

  7. Therapeutic Potential of Selectively Targeting the α2C-Adrenoceptor in Cognition, Depression, and Schizophrenia—New Developments and Future Perspective

    Directory of Open Access Journals (Sweden)

    Madeleine Monique Uys

    2017-08-01

    Full Text Available α2A- and α2C-adrenoceptors (ARs are the primary α2-AR subtypes involved in central nervous system (CNS function. These receptors are implicated in the pathophysiology of psychiatric illness, particularly those associated with affective, psychotic, and cognitive symptoms. Indeed, non-selective α2-AR blockade is proposed to contribute toward antidepressant (e.g., mirtazapine and atypical antipsychotic (e.g., clozapine drug action. Both α2C- and α2A-AR share autoreceptor functions to exert negative feedback control on noradrenaline (NA release, with α2C-AR heteroreceptors regulating non-noradrenergic transmission (e.g., serotonin, dopamine. While the α2A-AR is widely distributed throughout the CNS, α2C-AR expression is more restricted, suggesting the possibility of significant differences in how these two receptor subtypes modulate regional neurotransmission. However, the α2C-AR plays a more prominent role during states of low endogenous NA activity, while the α2A-AR is relatively more engaged during states of high noradrenergic tone. Although augmentation of conventional antidepressant and antipsychotic therapy with non-selective α2-AR antagonists may improve therapeutic outcome, animal studies report distinct yet often opposing roles for the α2A- and α2C-ARs on behavioral markers of mood and cognition, implying that non-selective α2-AR antagonism may compromise therapeutic utility both in terms of efficacy and side-effect liability. Recently, several highly selective α2C-AR antagonists have been identified that have allowed deeper investigation into the function and utility of the α2C-AR. ORM-13070 is a useful positron emission tomography ligand, ORM-10921 has demonstrated antipsychotic, antidepressant, and pro-cognitive actions in animals, while ORM-12741 is in clinical development for the treatment of cognitive dysfunction and neuropsychiatric symptoms in Alzheimer’s disease. This review will emphasize the importance and

  8. Serelaxin Elicits Bronchodilation and Enhances β-Adrenoceptor-Mediated Airway Relaxation

    Science.gov (United States)

    Lam, Maggie; Royce, Simon G.; Donovan, Chantal; Jelinic, Maria; Parry, Laura J.; Samuel, Chrishan S.; Bourke, Jane E.

    2016-01-01

    Treatment with β-adrenoceptor agonists does not fully overcome the symptoms associated with severe asthma. Serelaxin elicits potent uterine and vascular relaxation via its cognate receptor, RXFP1, and nitric oxide (NO) signaling, and is being clinically evaluated for the treatment of acute heart failure. However, its direct bronchodilator efficacy has yet to be explored. Tracheal rings were prepared from male Sprague-Dawley rats (250–350 g) and tricolor guinea pigs, and precision cut lung slices (PCLSs) containing intrapulmonary airways were prepared from rats only. Recombinant human serelaxin (rhRLX) alone and in combination with rosiglitazone (PPARγ agonist; recently described as a novel dilator) or β-adrenoceptor agonists (isoprenaline, salbutamol) were added either to pre-contracted airways, or before contraction with methacholine or endothelin-1. Regulation of rhRLX responses by epithelial removal, indomethacin (cyclooxygenase inhibitor), L-NAME (nitric oxide synthase inhibitor), SQ22536 (adenylate cyclase inhibitor) and ODQ (guanylate cyclase inhibitor) were also evaluated. Immunohistochemistry was used to localize RXFP1 to airway epithelium and smooth muscle. rhRLX elicited relaxation in rat trachea and PCLS, more slowly than rosiglitazone or isoprenaline, but potentiated relaxation to both these dilators. It markedly increased β-adrenoceptor agonist potency in guinea pig trachea. rhRLX, rosiglitazone, and isoprenaline pretreatment also inhibited the development of rat tracheal contraction. Bronchoprotection by rhRLX increased with longer pre-incubation time, and was partially reduced by epithelial removal, indomethacin and/or L-NAME. SQ22536 and ODQ also partially inhibited rhRLX-mediated relaxation in both intact and epithelial-denuded trachea. RXFP1 expression in the airways was at higher levels in epithelium than smooth muscle. In summary, rhRLX elicits large and small airway relaxation via epithelial-dependent and -independent mechanisms, likely

  9. Alpha blockers: A relook at phenoxybenzamine

    Directory of Open Access Journals (Sweden)

    Sambhunath Das

    2017-01-01

    Full Text Available Phenoxybenzamine (PBZ is an alpha adrenergic antagonist, used for the management of hypertension. PBZ acts by blocking alpha-adrenergic receptors, leading to vasodilatation and low systemic vascular resistance. This helps in control of blood pressure in pheochromocytoma, improvement of systemic oxygen delivery, and optimization of the Qp/Qs in pediatric cardiac surgery such as hypoplastic left heart syndrome and improving perfusion parameters during open heart surgery. The uses have further extended to causalgia, Raynaud's phenomenon, autonomic hyperreflexia, and even for patency of radial artery conduit in coronary artery bypass grafting surgery. However, its prolonged hypotensive effect limits the regular use. In this review, we discussed the mechanism of action, pharmaco-physiology of PBZ, perioperative uses in different clinical setting and controversies for its uses; publications in different scientific journals from the previous years.

  10. Smac mimetics as IAP antagonists.

    Science.gov (United States)

    Fulda, Simone

    2015-03-01

    As the Inhibitor of Apoptosis (IAP) proteins are expressed at high levels in human cancers, they represent promising targets for therapeutic intervention. Small-molecule inhibitors of IAP proteins mimicking the endogenous IAP antagonist Smac, called Smac mimetics, neutralize IAP proteins and thereby promote the induction of cell death. Smac mimetics have been shown in preclinical models of human cancer to directly trigger cancer cell death or to sensitize for cancer cell death induced by a variety of cytotoxic stimuli. Smac mimetics are currently undergoing clinical evaluation in phase I/II trials, demonstrating that therapeutic targeting of IAP proteins has reached the clinical stage. Copyright © 2015 Elsevier Ltd. All rights reserved.

  11. Identification of alpha 2-adrenergic receptor sites in human retinoblastoma (Y-79) and neuroblastoma (SH-SY5Y) cells

    Energy Technology Data Exchange (ETDEWEB)

    Kazmi, S.M.; Mishra, R.K.

    1989-02-15

    The existence of specific alpha 2-adrenergic receptor sites has been shown in human retinoblastoma (Y-79) and neuroblastoma (SH-SH5Y) cells using direct radioligand binding. (/sup 3/H)Rauwolscine, a selective alpha 2-adrenergic receptor antagonist, exhibited high affinity, saturable binding to both Y-79 and SH-SY5Y cell membranes. The binding of alpha 1 specific antagonist, (/sup 3/H)Prazocine, was not detectable in either cell type. Competition studies with antagonists yielded pharmacological characteristics typical of alpha 2-adrenergic receptors: rauwolscine greater than yohimbine greater than phentolamine greater than prazocine. Based on the affinity constants of prazocine and oxymetazoline, it appears that Y-79 cells contain alpha 2A receptor, whereas SH-SY5Y cells probably represent a mixture of alpha 2A and alpha 2B receptors. alpha 2-agonists clonidine and (-)epinephrine inhibition curves yielded high and low affinity states of the receptor in SH-SY5Y cells. Gpp(NH)p and sodium ions reduced the proportion of high affinity sites of alpha 2 receptors. These two neuronal cell lines of human origin would prove useful in elucidating the action and regulation of human alpha 2-adrenergic receptors and their interaction with other receptor systems.

  12. Synthetic peptide antagonists of glucagon

    International Nuclear Information System (INIS)

    Unson, C.G.; Andreu, D.; Gurzenda, E.M.; Merrifield, R.B.

    1987-01-01

    Several glucagon analogs were synthesized in an effort to find derivatives that would bind with high affinity to the glucagon receptor of rat liver membranes but would not activate membrane-bound adenylate cyclase and, therefore, would serve as antagonists of the hormone. Measurements on a series of glucagon/secretin hybrids indicated that replacement of Asp 9 in glucagon by Glu 9 , found in secretin, was the important sequence difference in the N terminus of the two hormones. Further deletion of His 1 and introduction of a C-terminal amide resulted in des-His 1 -[Glu 9 ]glucagon amide, which had a 40% binding affinity relative to that of native glucagon but caused no detectable adenylate cyclase activation in the rat liver membrane. This antagonist completely inhibited the effect of a concentration of glucagon that alone gave a full agonist response. It had an inhibition index of 12. The pA 2 was 7.2. An attempt was made to relate conformation with receptor binding. The peptides were synthesized by solid-phase methods and purified to homogeneity by reverse-phase high-performance liquid chromatography on C 18 -silica columns

  13. Multifactorial control of water and saline intake: role of a2-adrenoceptors

    Directory of Open Access Journals (Sweden)

    L.A. De-Luca Jr.

    1997-04-01

    Full Text Available Water and saline intake is controlled by several mechanisms activated during dehydration. Some mechanisms, such as the production of angiotensin II and unloading of cardiovascular receptors, activate both behaviors, while others, such as the increase in blood osmolality or sodium concentration, activate water, but inhibit saline intake. Aldosterone probably activates only saline intake. Clonidine, an a2-adrenergic agonist, inhibits water and saline intake induced by these mechanisms. One model to describe the interactions between these multiple mechanisms is a wire-block diagram, where the brain circuit that controls each intake is represented by a summing point of its respective inhibiting and activating factors. The a2-adrenoceptors constitute an inhibitory factor common to both summing points

  14. Aortic barodenervation up-regulates α2-adrenoceptors in the nucleus tractus solitarius and rostral ventrolateral medulla: an autoradiographic study

    International Nuclear Information System (INIS)

    Abdel-Rahman, A.A.; El-Mas, M.M.

    1997-01-01

    Earlier findings have shown that α 2 -adrenoceptors in the nucleus tractus solitarius and rostral ventrolateral medulla modulate baroreflexes. The present study investigated whether attenuation of baroreflexes induced by surgical interruption of aortic baroafferents is related to an alteration of α 2 -adrenoceptor binding in these regions of the brainstem. In vitro autoradiography was utilized to assess the density and binding dissociation constant (affinity) of α 2 -adrenoceptors in the rostral ventrolateral medulla and in the middle and rostral portions of the nucleus tractus solitarius of aortic-barodenervated and sham-operated rats. Compared to sham operation, aortic barodenervation caused an acute rise in mean arterial pressure and heart rate and a significant reduction in baroreflex sensitivity. Two days later, mean arterial pressure and heart rate of conscious aortic-barodenervated rats subsided to sham-operated levels, whereas the baroreflex sensitivity remained significantly (P 3 H]rauwolscine (0.5-16 nM) revealed that labeling of α 2 binding sites was saturable and of high affinity. Scatchard analysis of the saturation isotherms obtained from the three brain areas of sham-operated rats showed an uneven distribution of α 2 binding sites; the rostral nucleus tractus solitarius exhibited the highest density and lowest affinity. Aortic barodenervation caused region-dependent changes in the binding activity of α 2 -adrenoceptors. These changes comprised significant (P 2 -adrenoceptors in the middle nucleus tractus solitarius (436±60 vs 240±50 fmol/mg protein) and rostral ventrolateral medulla (350±67 vs 194±35 fmol/mg protein) compared with sham-operated rats; no significant changes occurred in the rostral nucleus tractus solitarius. The affinity of α 2 binding sites was not changed by aortic barodenervation in any of the three brain regions.These findings suggest that attenuation of baroreflexes produced by aortic barodenervation coincides with up

  15. Sub-chronic lead exposure produces β1-adrenoceptor downregulation decreasing arterial pressure reactivity in rats.

    Science.gov (United States)

    Toscano, Cindy Medici; Simões, Maylla Ronacher; Alonso, Maria Jesus; Salaices, Mercedes; Vassallo, Dalton Valentim; Fioresi, Mirian

    2017-07-01

    Lead is considered a causative factor for hypertension and other cardiovascular diseases. To investigate the effects of sub-chronic lead exposure on blood pressure reactivity and cardiac β 1 -adrenoceptor activity and to evaluate whether the effects found in vitro are similar to those found in vivo. Male Wistar rats were randomly distributed into two groups: control rats (Ct) and rats administered drinking water containing 100ppm lead (Pb) for 30days. Blood pressure in the Pb rats increased starting from the first week of treatment until the end of the study [systolic blood pressure, Ct: 122±4 vs. Pb: 143±3mmHg; diastolic blood pressure, Ct: 63±4 vs. Pb: 84±4mmHg]. The heart rate was also increased (Ct: 299±11 vs. Pb: 365±11bpm), but the pressure reactivity to phenylephrine was decreased. Losartan and hexamethonium exhibited a greater reduction in blood pressure of Pb rats than in the Ct rats. Isoproterenol increased the left ventricular systolic and end-diastolic pressure, and heart rate only in Ct rats, suggesting that lead induced β 1 -adrenoceptor downregulation. Indomethacin reduced the blood pressure and heart rate in the Pb rats, suggesting the involvement of cyclooxygenase-derived products (which are associated with reduced nitric oxide bioavailability) in this process. These findings offer further evidence that the effects of sub-chronic lead exposure in vitro can be reproduced in vivo-even at low concentrations-thus triggering mechanisms for the development of hypertension. Therefore, lead should be considered an environmental risk factor for cardiovascular disease. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Metabolic markers following beta-adrenoceptor agonist infusion in footshock-stressed rats

    Directory of Open Access Journals (Sweden)

    J.L. Verago

    2001-09-01

    Full Text Available Stress hormones can alter metabolic functions in adipose tissue and liver, as well as the sensitivity of rat white adipocytes and rat atrial responses to ß-adrenergic agonists. In this study, we examined the effects of three daily footshock stress sessions on the plasma corticosterone, glucose, glycerol and triacylglycerol levels of fed, conscious male rats, and on the plasma glucose, glycerol and triacylglycerol levels of the same rats following iv infusions of ß-adrenergic agonists (isoproterenol: 0.4 nmol kg-1 min-1, noradrenaline: 5.0 µg kg-1 day-1, and BRL 37344 ([±]-[4-(2-[(2-[3-chlorophenyl]-2-hydroxyethylamino]propylphenoxy]acetic acid, a selective ß3-adrenoceptor agonist: 0.4 nmol kg-1 min-1. Plasma corticosterone levels increased significantly after each stress session, while triacylglycerol levels increased after the first session and glucose increased after the second and third sessions. Glycerol levels were unaltered after stress. These results suggest that repeated footshock stress may induce a metabolic shift from triacylglycerol biosynthesis to glucose release by hepatic tissue, with glycerol serving as one of the substrates in both pathways. Stressed rats were more sensitive to infusion of noradrenaline plus prazosin and to infusion of isoproterenol, with elevated plasma glucose, glycerol and triacylglycerol levels. The higher sensitivity of stressed rats to isoproterenol and noradrenaline was probably related to the permissive effect of plasma corticosterone. Only BRL 37344 increased plasma glycerol levels in stressed rats, probably because ß3-adrenoceptors are not involved in hepatic triacylglycerol synthesis, thus allowing glycerol to accumulate in plasma.

  17. Screening alpha-glucosidase and alpha-amylase inhibitors from natural compounds by molecular docking in silico.

    Science.gov (United States)

    Jhong, Chien-Hung; Riyaphan, Jirawat; Lin, Shih-Hung; Chia, Yi-Chen; Weng, Ching-Feng

    2015-01-01

    The alpha-glucosidase inhibitor is a common oral anti-diabetic drug used for controlling carbohydrates normally converted into simple sugars and absorbed by the intestines. However, some adverse clinical effects have been observed. The present study seeks an alternative drug that can regulate the hyperglycemia by down-regulating alpha-glucosidase and alpha-amylase activity by molecular docking approach to screen the hyperglycemia antagonist against alpha-glucosidase and alpha-amylase activities from the 47 natural compounds. The docking data showed that Curcumin, 16-hydroxy-cleroda-3,13-dine-16,15-olide (16-H), Docosanol, Tetracosanol, Antroquinonol, Berberine, Catechin, Quercetin, Actinodaphnine, and Rutin from 47 natural compounds had binding ability towards alpha-amylase and alpha-glucosidase as well. Curcumin had a better biding ability of alpha-amylase than the other natural compounds. Analyzed alpha-glucosidase activity reveals natural compound inhibitors (below 0.5 mM) are Curcumin, Actinodaphnine, 16-H, Quercetin, Berberine, and Catechin when compared to the commercial drug Acarbose (3 mM). A natural compound with alpha-amylase inhibitors (below 0.5 mM) includes Curcumin, Berberine, Docosanol, 16-H, Actinodaphnine/Tetracosanol, Catechin, and Quercetin when compared to Acarbose (1 mM). When taken together, the implication is that molecular docking is a fast and effective way to screen alpha-glucosidase and alpha-amylase inhibitors as lead compounds of natural sources isolated from medicinal plants. © 2015 International Union of Biochemistry and Molecular Biology.

  18. The determination of $\\alpha_s$ by the ALPHA collaboration

    CERN Document Server

    Bruno, Mattia

    2016-01-01

    We review the ALPHA collaboration strategy for obtaining the QCD coupling at high scale. In the three-flavor effective theory it avoids the use of perturbation theory at $\\alpha > 0.2$ and at the same time has the physical scales small compared to the cutoff $1/a$ in all stages of the computation. The result $\\Lambda_\\overline{MS}^{(3)}=332(14)$~MeV is translated to $\\alpha_\\overline{MS}(m_Z)=0.1179(10)(2)$ by use of (high order) perturbative relations between the effective theory couplings at the charm and beauty quark "thresholds". The error of this perturbative step is discussed and estimated as $0.0002$.

  19. Investigation of CGRP receptors and peptide pharmacology in human coronary arteries. Characterization with a nonpeptide antagonist

    DEFF Research Database (Denmark)

    Hasbak, Philip; Saetrum Opgaard, Ole; Eskesen, Karen

    2003-01-01

    . Preincubation with alphaCGRP(8-37) (10(-6) M) and Compound 1 (10(-6) M) caused significant rightward shift of the concentration-response curves for AM and amylin as well with pK B values between 6.6 and 7.5. Preincubation with AM(22-52) had no antagonistic effect on the AM and amylin response, neither did...

  20. The Alpha-1A Adrenergic Receptor in the Rabbit Heart.

    Directory of Open Access Journals (Sweden)

    R Croft Thomas

    Full Text Available The alpha-1A-adrenergic receptor (AR subtype is associated with cardioprotective signaling in the mouse and human heart. The rabbit is useful for cardiac disease modeling, but data on the alpha-1A in the rabbit heart are limited. Our objective was to test for expression and function of the alpha-1A in rabbit heart. By quantitative real-time reverse transcription PCR (qPCR on mRNA from ventricular myocardium of adult male New Zealand White rabbits, the alpha-1B was 99% of total alpha-1-AR mRNA, with <1% alpha-1A and alpha-1D, whereas alpha-1A mRNA was over 50% of total in brain and liver. Saturation radioligand binding identified ~4 fmol total alpha-1-ARs per mg myocardial protein, with 17% alpha-1A by competition with the selective antagonist 5-methylurapidil. The alpha-1D was not detected by competition with BMY-7378, indicating that 83% of alpha-1-ARs were alpha-1B. In isolated left ventricle and right ventricle, the selective alpha-1A agonist A61603 stimulated a negative inotropic effect, versus a positive inotropic effect with the nonselective alpha-1-agonist phenylephrine and the beta-agonist isoproterenol. Blood pressure assay in conscious rabbits using an indwelling aortic telemeter showed that A61603 by bolus intravenous dosing increased mean arterial pressure by 20 mm Hg at 0.14 μg/kg, 10-fold lower than norepinephrine, and chronic A61603 infusion by iPRECIO programmable micro Infusion pump did not increase BP at 22 μg/kg/d. A myocardial slice model useful in human myocardium and an anthracycline cardiotoxicity model useful in mouse were both problematic in rabbit. We conclude that alpha-1A mRNA is very low in rabbit heart, but the receptor is present by binding and mediates a negative inotropic response. Expression and function of the alpha-1A in rabbit heart differ from mouse and human, but the vasopressor response is similar to mouse.

  1. The left ventricular contractility of the rat heart is modulated by changes in flow and a1-adrenoceptor stimulation

    Directory of Open Access Journals (Sweden)

    P.F. Vassallo

    1998-10-01

    Full Text Available Myocardial contractility depends on several mechanisms such as coronary perfusion pressure (CPP and flow as well as on a1-adrenoceptor stimulation. Both effects occur during the sympathetic stimulation mediated by norepinephrine. Norepinephrine increases force development in the heart and produces vasoconstriction increasing arterial pressure and, in turn, CPP. The contribution of each of these factors to the increase in myocardial performance needs to be clarified. Thus, in the present study we used two protocols: in the first we measured mean arterial pressure, left ventricular pressure and rate of rise of left ventricular pressure development in anesthetized rats (N = 10 submitted to phenylephrine (PE stimulation before and after propranolol plus atropine treatment. These observations showed that in vivo a1-adrenergic stimulation increases left ventricular-developed pressure (Pa1-adrenoceptors and increased flow, increased cardiac performance acting simultaneously and synergistically.

  2. Diet-induced changes in subcutaneous adipose tissue blood flow in man: effect of beta-adrenoceptor inhibition

    DEFF Research Database (Denmark)

    Simonsen, L; Bülow, J; Astrup, A

    1990-01-01

    The effect of a carbohydrate-rich meal on subcutaneous adipose tissue blood flow was studied with and without continuous i.v. infusion of propranolol in healthy volunteers. The subcutaneous adipose tissue blood flow was measured with the 133Xe washout method in three different locations......: the forearm, the thigh and the abdomen. The subjects were given a meal consisting of white bread, jam, honey and apple juice (about 2300 kJ). The meal induced a twofold increase in blood flow in the examined tissues. Propranolol abolished the flow increase in the thigh and the abdomen and reduced...... it in the forearm. This indicates that the mechanism for the flow increase is elicited by a stimulation of vascular beta-adrenoceptors in the subcutaneous adipose tissue, since the beta-adrenoceptor inhibition did not affect the overall metabolic and hormonal responses to the meal....

  3. Lyman Alpha Control

    CERN Document Server

    Nielsen, Daniel Stefaniak

    2015-01-01

    This document gives an overview of how to operate the Lyman Alpha Control application written in LabVIEW along with things to watch out for. Overview of the LabVIEW code itself as well as the physical wiring of and connections from/to the NI PCI-6229 DAQ box is also included. The Lyman Alpha Control application is the interface between the ALPHA sequencer and the HighFinesse Wavelength Meter as well as the Lyman Alpha laser setup. The application measures the wavelength of the output light from the Lyman Alpha cavity through the Wavelength Meter. The application can use the Wavelength Meter’s PID capabilities to stabilize the Lyman Alpha laser output as well as switch between up to three frequencies.

  4. New ALPHA-2 magnet

    CERN Multimedia

    Anaïs Schaeffer

    2012-01-01

    On 21 June, members of the ALPHA collaboration celebrated the handover of the first solenoid designed for the ALPHA-2 experiment. The magnet has since been successfully installed and is working well.   Khalid Mansoor, Sumera Yamin and Jeffrey Hangst in front of the new ALPHA-2 solenoid. “This was the first of three identical solenoids that will be installed between now and September, as the rest of the ALPHA-2 device is installed and commissioned,” explains ALPHA spokesperson Jeffrey Hangst. “These magnets are designed to allow us to transfer particles - antiprotons, electrons and positrons - between various parts of the new ALPHA-2 device by controlling the transverse size of the particle bunch that is being transferred.” Sumera Yamin and Khalid Mansoor, two Pakistani scientists from the National Centre for Physics in Islamabad, came to CERN in February specifically to design and manufacture these magnets. “We had the chance to work on act...

  5. Isoproterenol induces vascular oxidative stress and endothelial dysfunction via a Giα-coupled β2-adrenoceptor signaling pathway.

    Directory of Open Access Journals (Sweden)

    Ana P Davel

    Full Text Available OBJECTIVE: Sustained β-adrenergic stimulation is a hallmark of sympathetic hyperactivity in cardiovascular diseases. It is associated with oxidative stress and altered vasoconstrictor tone. This study investigated the β-adrenoceptor subtype and the signaling pathways implicated in the vascular effects of β-adrenoceptor overactivation. METHODS AND RESULTS: Mice lacking the β1- or β2-adrenoceptor subtype (β1KO, β2KO and wild-type (WT were treated with isoproterenol (ISO, 15 μg.g(-1 x day(-1, 7 days. ISO significantly enhanced the maximal vasoconstrictor response (Emax of the aorta to phenylephrine in WT (+34% and β1KO mice (+35% but not in β2KO mice. The nitric oxide synthase (NOS inhibitor L-NAME abolished the differences in phenylephrine response between the groups, suggesting that ISO impaired basal NO availability in the aorta of WT and β1KO mice. Superoxide dismutase (SOD, pertussis toxin (PTx or PD 98,059 (p-ERK 1/2 inhibitor incubation reversed the hypercontractility of aortic rings from ISO-treated WT mice; aortic contraction of ISO-treated β2KO mice was not altered. Immunoblotting revealed increased aortic expression of Giα-3 protein (+50% and phosphorylated ERK1/2 (+90% and decreased eNOS dimer/monomer ratio in ISO-treated WT mice. ISO enhanced the fluorescence response to dihydroethidium (+100% in aortas from WT mice, indicating oxidative stress that was normalized by SOD, PTx and L-NAME. The ISO effects were abolished in β2KO mice. CONCLUSIONS: The β2-adrenoceptor/Giα signaling pathway is implicated in the enhanced vasoconstrictor response and eNOS uncoupling-mediated oxidative stress due to ISO treatment. Thus, long-term β2-AR activation might results in endothelial dysfunction.

  6. 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.

  7. S179D prolactin: antagonistic agony!

    Science.gov (United States)

    Walker, Ameae M

    2007-09-30

    The aims of this review are three-fold: first, to collate what is known about the production and activities of phosphorylated prolactin (PRL), the latter largely, but not exclusively, as illustrated through the use of the molecular mimic, S179D PRL; second, to apply this and related knowledge to produce an updated model of prolactin-receptor interactions that may apply to other members of this cytokine super-family; and third, to promote a shift in the current paradigm for the development of clinically important growth antagonists. This third aim explains the title since, based on results with S179D PRL, it is proposed that agents which signal to antagonistic ends may be better therapeutics than pure antagonists-hence antagonistic agony. Since S179D PRL is not a pure antagonist, we have proposed the term selective prolactin receptor modulator (SPeRM) for this and like molecules.

  8. [Extracorporeal life support in calcium antagonist intoxication].

    Science.gov (United States)

    Groot, M W; Grewal, S; Meeder, H J; van Thiel, R J; den Uil, C A

    2017-01-01

    Intoxication with calcium antagonists is associated with poor outcome. Even mild calcium antagonist overdose may be fatal. A 51-year-old woman and a 51-year-old man came to the Accident and Emergency Department in severe shock after they had taken a calcium antagonist overdose. After extensive medicinal therapy had failed, they both needed extracorporeal life support (ECLS) as a bridge to recovery. In severe calcium antagonist overdose, the combination of vasoplegia and cardiac failure leads to refractory shock. ECLS temporarily supports the circulation and maintains organ perfusion. In this way ECLS functions as a bridge to recovery and may possibly save lives. Timely consultation with and referral to an ECLS centre is recommended in patients with calcium antagonist overdose.

  9. Endotoxin pretreatment modifies peristalsis and attenuates the antipropulsive action of adrenoceptor agonists in the guinea-pig small intestine.

    Science.gov (United States)

    Fruhwald, S; Herk, E; Schöll, G; Shahbazian, A; Hammer, H F; Metzler, H; Holzer, P

    2004-04-01

    The action of endotoxin to alter gastrointestinal motility in vivo may reflect a direct effect on the gut or result from vascular and other systemic manifestations of this sepsis model. Here we examined whether in vivo pretreatment of guinea-pigs with endotoxin modifies peristalsis in the isolated gut and influences the antipropulsive action of adrenoceptor agonists. Distension-induced peristalsis was recorded in fluid-perfused segments of the small intestine taken from animals pretreated intraperitoneally with endotoxin (1 mg kg(-1)Escherichia coli lipopolysaccharide) or vehicle 4 or 20 h before. Clonidine, adrenaline, noradrenaline, dopamine and dobutamine inhibited peristalsis with differential potency. Endotoxin pretreatment lowered the peristaltic pressure threshold and altered other parameters of baseline peristalsis in a time-related manner. The potency and efficacy of clonidine to inhibit peristalsis were markedly decreased after endotoxin administration, while the potency of the other test drugs was less attenuated. The antipropulsive action of clonidine in control segments was reduced by yohimbine and prazosin, whereas in segments from endotoxin-pretreated animals it was antagonized by yohimbine but not prazosin. We conclude that systemic endotoxin pretreatment of guinea-pigs modifies baseline peristalsis by an action on the gut and inhibits the antipropulsive action of adrenoceptor agonists through changes in adrenoceptor activity.

  10. The α(2C)-Del322-325 adrenoceptor polymorphism and the occurrence of left ventricular hypertrophy in hypertensives.

    Science.gov (United States)

    Savva, Jacqueline; Alfakih, Khaled; Galloway, Stacey L; Hall, Alistair S; West, Robert M; Ball, Stephen G; Balmforth, Anthony J; Maqbool, Azhar

    2012-04-01

    Sympathetic activation has a role in the development of left ventricular hypertrophy (LVH). The presynaptic α(2C)-adrenoceptor inhibits the release of norepinephrine from sympathetic nerve terminals in the heart. A deletion polymorphism in the α(2C)-adrenoceptor (α(2C)Del322-325) generates a hypofunctional α(2C)-adrenoceptor, which may result in chronic adrenergic signalling. This study aimed to investigate whether the α(2C)Del322-325 polymorphism was associated with an increased prevalence of LVH in patients with systemic hypertension. Left ventricular mass was measured in 205 patients with systemic hypertension and 60 normal volunteers using a 1.5-T Philips MRI system. Genotyping was performed using a restriction fragment length polymorphism assay. No significant difference was observed between the distribution of the α(2C)Del322-325 genotypes in hypertensive patients with LVH compared with those without LVH. Adjusting for confounding variables the odds ratio (OR) of being ins/del for the α(2C)Del322-325 and having LVH was 0.49 (95% CI 0.14-1.69, p = 0.256). These observations suggest that there is little evidence for an association between α(2C)Del322-325 polymorphism and an increased prevalence of LVH in patients with systemic hypertension.

  11. Alpha Shapes and Proteins

    DEFF Research Database (Denmark)

    Winter, Pawel; Sterner, Henrik; Sterner, Peter

    2009-01-01

    We provide a unified description of (weighted) alpha shapes, beta shapes and the corresponding simplicialcomplexes. We discuss their applicability to various protein-related problems. We also discuss filtrations of alpha shapes and touch upon related persistence issues.We claim that the full...... potential of alpha-shapes and related geometrical constructs in protein-related problems yet remains to be realized and verified. We suggest parallel algorithms for (weighted) alpha shapes, and we argue that future use of filtrations and kinetic variants for larger proteins will need such implementation....

  12. CGRP receptors mediating CGRP-, adrenomedullin- and amylin-induced relaxation in porcine coronary arteries. Characterization with 'Compound 1' (WO98/11128), a non-peptide antagonist

    DEFF Research Database (Denmark)

    Hasbak, P; Sams, A; Schifter, S

    2001-01-01

    . The partial porcine mRNA sequences shared 82 - 92% nucleotide identity with human sequences. 3. The human peptides alphaCGRP, betaCGRP, AM and amylin induced relaxation with pEC(50) values of 8.1, 8.1, 6.7 and 6.1 M respectively. 4. The antagonistic properties of a novel non-peptide CGRP antagonist 'Compound...

  13. Plasma glucose, insulin, free fatty acids, lactate and cortisol concentrations in dexmedetomidine-sedated dogs with or without MK-467: a peripheral α-2 adrenoceptor antagonist.

    Science.gov (United States)

    Restitutti, F; Raekallio, M; Vainionpää, M; Kuusela, E; Vainio, O

    2012-08-01

    Six healthy laboratory Beagles were treated IV with 10 μg/kg dexmedetomidine (DEX) or 10 μg/kg dexmedetomidine combined with 500 μg/kg MK-467 in the same syringe (DMK) in a randomised cross-over design with a 14 day washout. Blood was collected immediately before treatment and 35, 60 and 120 min post-injection through a central venous catheter. The plasma concentrations of glucose, insulin, non-esterified free fatty acids (NEFAs), lactate and cortisol were determined. A repeated-measures ANOVA test was used to compare treatments and effects for each sample time point. Significant differences between treatments were found for plasma glucose (P=0.037) and insulin (P=0.009). DEX significantly increased plasma glucose at 120 min, but reduced plasma insulin at 35 and 60 min. NEFA decreased for both treatments at 35 min. This reduction was transient for DMK, whereas it persisted during the follow up period for DEX. Plasma lactate concentrations increased at 35 and 60 min with DEX. Neither treatment altered plasma cortisol concentrations. The addition of MK-467 to dexmedetomidine prevented or abolished most metabolic changes in healthy Beagles. Copyright © 2011 Elsevier Ltd. All rights reserved.

  14. The predictive factors of α1-D/A adrenoceptor antagonist, naftopidil, dose increase therapy for male lower urinary tract symptoms caused by benign prostatic hyperplasia: INFORM study

    Directory of Open Access Journals (Sweden)

    Yasushi Tanuma

    2017-01-01

    Conclusions: The short term of naftopidil 50 mg therapy was ineffective for the patients who had large PVR. The predictive factor of this dose increase therapy might be a dynamic variable in 50 mg/day of dose period, but not a baseline variable at the time of 75 mg/day dosage starts.

  15. Targeted Alpha Therapy: From Alpha to Omega

    International Nuclear Information System (INIS)

    Allen, Barry J; Clarke, Raymond; Huang Chenyu

    2013-01-01

    This review covers the broad spectrum of Targeted Alpha Therapy (TAT) research in Australia; from in vitro and in vivo studies to clinical trials. The principle of tumour anti-vascular alpha therapy (TAVAT) is discussed in terms of its validation by Monte Carlo calculations of vascular models and the potential role of biological dosimetry is examined. Summmary of this review is as follows: 1. The essence of TAT 2. Therapeutic objectives 3. TAVAT and Monte Carlo microdosimetry 4. Biological dosimetry 5. Preclinical studies 6. Clinical trials 7. What next? 8. Obstacles. (author)

  16. Opioid antagonists for alcohol dependence.

    Science.gov (United States)

    Rösner, Susanne; Hackl-Herrwerth, Andrea; Leucht, Stefan; Vecchi, Simona; Srisurapanont, Manit; Soyka, Michael

    2010-12-08

    Alcohol dependence belongs to the globally leading health risk factors. Therapeutic success of psychosocial programs for relapse prevention is moderate and could be increased by an adjuvant treatment with the opioid antagonists naltrexone and nalmefene. To determine the effectiveness and tolerability of opioid antagonists in the treatment of alcohol dependence. We searched the Cochrane Drugs and Alcohol Group (CDAG) Specialized Register, PubMed, EMBASE and CINAHL in January 2010 and inquired manufacturers and researchers for unpublished trials. All double-blind randomised controlled trials (RCTs) which compare the effects of naltrexone or nalmefene with placebo or active control on drinking-related outcomes. Two authors independently extracted outcome data. Trial quality was assessed by one author and cross-checked by a second author. Based on a total of 50 RCTs with 7793 patients, naltrexone reduced the risk of heavy drinking to 83% of the risk in the placebo group RR 0.83 (95% CI 0.76 to 0.90) and decreased drinking days by about 4%, MD -3.89 (95% CI -5.75 to -2.04). Significant effects were also demonstrated for the secondary outcomes of the review including heavy drinking days, MD - 3.25 (95% CI -5.51 to -0.99), consumed amount of alcohol, MD - 10.83 (95% CI -19.69 to -1.97) and gamma-glutamyltransferase, MD - 10.37 (95% CI -18.99 to -1.75), while effects on return to any drinking, RR 0.96 (95 CI 0.92 to 1.00) missed statistical significance. Side effects of naltrexone were mainly gastrointestinal problems (e.g. nausea: RD 0.10; 95% CI 0.07 to 0.13) and sedative effects (e.g. daytime sleepiness: RD 0.09; 95% CI 0.05 to 0.14). Based on a limited study sample, effects of injectable naltrexone and nalmefene missed statistical significance. Effects of industry-sponsored studies, RR 0.90 (95% CI 0.78 to 1.05) did not significantly differ from those of non-profit funded trials, RR 0.84 (95% CI 0.77 to 0.91) and the linear regression test did not indicate publication

  17. Nicotine enhances expression of the alpha 3, alpha 4, alpha 5, and alpha 7 nicotinic receptors modulating calcium metabolism and regulating adhesion and motility of respiratory epithelial cells.

    Science.gov (United States)

    Zia, S; Ndoye, A; Nguyen, V T; Grando, S A

    1997-09-01

    The purpose of this study was to investigate the possibility of direct toxic effects of nicotine (Nic) on human bronchial epithelial cells (BEC) suggested by our previous findings of functional nicotinic acetylcholine receptors (nAChRs) in the epithelial cells lining mucocutaneous membranes. We now demonstrate for the first time that human and murine BEC both in vivo and in vitro express functional nAChRs, and that classic alpha 3, alpha 4, alpha 5 and alpha 7 subunits can contribute to formation of these acetylcholine-gated ion channels. In human bronchial and mouse lung tissues, and in cultures of human BEC, the nAChRs were visualized by subunit-specific antibodies on the cell membranes, particularly at the sites of cell-to-cell contacts. The epithelial cells of submucosal glands abundantly expressed alpha 7 nAChRs. Smoking significantly (p epithelial nAChRs apparently involve regulation of cell-to-cell communications, adhesion and motility, because Mec caused rapid and profound changes in these cell functions which were reversible by Nic. An over exposure of BEC to Nic, however, produced an antagonist-like effect, suggesting that the pathobiological effects of Nic toxicity might result from both activation of nAChR channels and nAChR desensitization. We conclude that medical consequences of smoking can be mediated by direct toxic effects of inhaled Nic on the respiratory tissues wherein Nic specifically binds to and activates the nicotinic ion channels present on the cell surfaces of BEC. We believe that outside the neural system Nic interferes with functioning of non-neuronal cholinergic networks by displacing from nAChR its natural ligand acetylcholine which acts as a local hormone or cytokine in a variety of non-neuronal locations.

  18. Role of angiotensin II type 1 receptor antagonists in the treatment of hypertension in patients aged >or=65 years.

    Science.gov (United States)

    Gradman, Alan H

    2009-01-01

    Systolic blood pressure (SBP) increases with age, and hypertension affects approximately two-thirds of adults in the US aged >60 years. Blood pressure (BP) increases as a consequence of age-related structural changes in large arteries, which lead to loss of elasticity and reduced vascular compliance. Increased pulse wave velocity augments SBP, resulting in a high prevalence of isolated systolic hypertension. Because age itself elevates cardiovascular risk, effective treatment of hypertension in an older (aged >or=65 years) patient population prevents many more events per 1000 patients treated than treatment of younger hypertensive patients. Recommendations for treating hypertension are similar in older patients compared with the general population. The Seventh Report of the Joint National Committee on Detection, Prevention, Evaluation, and Treatment of High Blood Pressure recommends target BP goals of hypertension, and treatment goals to include patients with coronary artery disease, other types of vascular disease and heart failure. Randomized clinical trials have demonstrated the efficacy of calcium channel antagonists (calcium channel blockers [CCBs]), low-dose diuretics, ACE inhibitors and angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]) in reducing the risk of stroke and other adverse cardiovascular outcomes in older patients; beta-adrenoceptor antagonists are less effective in terms of endpoint reduction. The majority of older patients require two or more drugs to achieve BP goals. Despite active treatment, half of these patients do not achieve target BP, in part because of the reluctance of physicians to intensify treatment, a phenomenon referred to as 'clinical inertia'. ARBs are effective antihypertensive agents in older patients and have been shown to reduce cardiovascular endpoints in patients with hypertension, diabetic nephropathy, cerebrovascular disease and heart failure. ARBs produce additive BP reduction when

  19. Alpha1-antitrypsin deficiency

    DEFF Research Database (Denmark)

    Stolk, Jan; Seersholm, Niels; Kalsheker, Noor

    2006-01-01

    The Alpha One International Registry (AIR), a multinational research program focused on alpha1-antitrypsin (AAT) deficiency, was formed in response to a World Health Organization recommendation. Each of the nearly 20 participating countries maintains a national registry of patients with AAT defic...... epidemiology, inflammatory and signalling processes, therapeutic advances, and lung imaging techniques....

  20. Alpha clustering in nuclei

    International Nuclear Information System (INIS)

    Hodgson, P.E.

    1990-01-01

    The effects of nucleon clustering in nuclei are described, with reference to both nuclear structure and nuclear reactions, and the advantages of using the cluster formalism to describe a range of phenomena are discussed. It is shown that bound and scattering alpha-particle states can be described in a unified way using an energy-dependent alpha-nucleus potential. (author)

  1. A synthetic combinatorial strategy for developing a-conotoxin analogs as potent a7 nicotinic acetylcholine receptor antagonists

    DEFF Research Database (Denmark)

    Armishaw, Christopher J; Singh, Narender; Medina-Franco, Jose L

    2010-01-01

    ) nAChR Fluo-4/Ca2+ assay, allowing amino acids that confer antagonistic activity for this receptor to be identified. A second series of individual alpha-conotoxin analogs based on the combinations of defined active amino acid residues from positional scan synthetic combinatorial library screening...... of an acetylcholine-binding protein. Finally, a third series of refined analogs was synthesized based on modeling studies, which led to several analogs with refined pharmacological properties. Of the 96 individual alpha-conotoxin analogs synthesized, three displayed > or =10-fold increases in antagonist potency...

  2. PXR antagonists and implication in drug metabolism

    Science.gov (United States)

    Mani, Sridhar; Dou, Wei; Redinbo, Matthew R.

    2013-01-01

    Adopted orphan nuclear receptor (NR), pregnane X receptor (PXR), plays a central role in the regulation of xeno- and endobiotic metabolism. Since the discovery of the functional role of PXR in 1998, there is evolving evidence for the role of PXR agonists in abrogating metabolic pathophysiology (e.g., cholestasis, hypercholesterolemia, and inflammation). However, more recently, it is clear that PXR is also an important mediator of adverse xeno- (e.g., enhances acetaminophen toxicity) and endobiotic (e.g., hepatic steatosis) metabolic phenotypes. Moreover, in cancer therapeutics, PXR activation can induce drug resistance, and there is growing evidence for tissue-specific enhancement of the malignant phenotype. Thus, in these instances, there may be a role for PXR antagonists. However, as opposed to the discovery efforts for PXR agonists, there are only a few antagonists described. The mode of action of these antagonists (e.g., sulforaphane) remains less clear. Our laboratory efforts have focused on this question. Since the original discovery of azoles analogs as PXR antagonists, we have preliminarily defined an important PXR antagonist pharmacophore and developed less-toxic PXR antagonists. In this review, we describe our published and unpublished findings on recent structure-function studies involving the azole chemical scaffold. Further work in the future is needed to fully define potent, more-selective PXR antagonists that may be useful in clinical application. PMID:23330542

  3. Blood flow distribution with adrenergic and histaminergic antagonists

    Energy Technology Data Exchange (ETDEWEB)

    Baker, C.H.; Davis, D.L.; Sutton, E.T.

    1989-03-01

    Superficial fibular nerve stimulation (SFNS) causes increased pre- and post-capillary resistances as well as increased capillary permeability in the dog hind paw. These responses indicate possible adrenergic and histaminergic interactions. The distribution of blood flow between capillaries and arteriovenous anastomoses (AVA) may depend on the relative effects of these neural inputs. Right hind paws of anesthetized heparinized dogs were vascularly and neurally isolated and perfused with controlled pressure. Blood flow distribution was calculated from the venous recovery of 85Sr-labeled microspheres (15 microns). The mean transit times of 131I-albumin and 85Sr-labeled microspheres were calculated. The effects of adrenergic and histaminergic antagonists with and without SFNS were determined. Phentolamine blocked the entire response to SFNS. Prazosin attenuated increases in total and AVA resistance. Yohimbine prevented increased total resistance, attenuated the AVA resistance increase, and revealed a decrease in capillary circuit resistance. Pyrilamine attenuated total resistance increase while SFNS increased capillary and AVA resistances. Metiamide had no effect on blood flow distribution with SFNS. The increase in AVA resistance with SFNS apparently resulted from a combination of alpha 1 and alpha 2 receptor stimulation but not histaminergic effects.

  4. Blood flow distribution with adrenergic and histaminergic antagonists

    International Nuclear Information System (INIS)

    Baker, C.H.; Davis, D.L.; Sutton, E.T.

    1989-01-01

    Superficial fibular nerve stimulation (SFNS) causes increased pre- and post-capillary resistances as well as increased capillary permeability in the dog hind paw. These responses indicate possible adrenergic and histaminergic interactions. The distribution of blood flow between capillaries and arteriovenous anastomoses (AVA) may depend on the relative effects of these neural inputs. Right hind paws of anesthetized heparinized dogs were vascularly and neurally isolated and perfused with controlled pressure. Blood flow distribution was calculated from the venous recovery of 85Sr-labeled microspheres (15 microns). The mean transit times of 131I-albumin and 85Sr-labeled microspheres were calculated. The effects of adrenergic and histaminergic antagonists with and without SFNS were determined. Phentolamine blocked the entire response to SFNS. Prazosin attenuated increases in total and AVA resistance. Yohimbine prevented increased total resistance, attenuated the AVA resistance increase, and revealed a decrease in capillary circuit resistance. Pyrilamine attenuated total resistance increase while SFNS increased capillary and AVA resistances. Metiamide had no effect on blood flow distribution with SFNS. The increase in AVA resistance with SFNS apparently resulted from a combination of alpha 1 and alpha 2 receptor stimulation but not histaminergic effects

  5. Genetics Home Reference: alpha thalassemia

    Science.gov (United States)

    ... Facebook Twitter Home Health Conditions Alpha thalassemia Alpha thalassemia Printable PDF Open All Close All Enable Javascript to view the expand/collapse boxes. Description Alpha thalassemia is a blood disorder that reduces the production ...

  6. Quantifying the effects of diuretics and β-adrenoceptor blockers on glycaemic control in diabetes mellitus – a systematic review and meta-analysis

    Science.gov (United States)

    Hirst, Jennifer A; Farmer, Andrew J; Feakins, Benjamin G; Aronson, Jeffrey K; Stevens, Richard J

    2015-01-01

    Aims Although there are reports that β-adrenoceptor antagonists (beta-blockers) and diuretics can affect glycaemic control in people with diabetes mellitus, there is no clear information on how blood glucose concentrations may change and by how much. We report results from a systematic review to quantify the effects of these antihypertensive drugs on glycaemic control in adults with established diabetes. Methods We systematically reviewed the literature to identify randomized controlled trials in which glycaemic control was studied in adults with diabetes taking either beta-blockers or diuretics. We combined data on HbA1c and fasting blood glucose using fixed effects meta-analysis. Results From 3864 papers retrieved, we found 10 studies of beta-blockers and 12 studies of diuretics to include in the meta-analysis. One study included both comparisons, totalling 21 included reports. Beta-blockers increased fasting blood glucose concentrations by 0.64 mmol l−1 (95% CI 0.24, 1.03) and diuretics by 0.77 mmol l−1 (95% CI 0.14, 1.39) compared with placebo. Effect sizes were largest in trials of non-selective beta-blockers (1.33, 95% CI 0.72, 1.95) and thiazide diuretics (1.69, 95% CI 0.60, 2.69). Beta-blockers increased HbA1c concentrations by 0.75% (95% CI 0.30, 1.20) and diuretics by 0.24% (95% CI −0.17, 0.65) compared with placebo. There was no significant difference in the number of hypoglycaemic events between beta-blockers and placebo in three trials. Conclusions Randomized trials suggest that thiazide diuretics and non-selective beta-blockers increase fasting blood glucose and HbA1c concentrations in patients with diabetes by moderate amounts. These data will inform prescribing and monitoring of beta-blockers and diuretics in patients with diabetes. PMID:25377481

  7. Quantifying the effects of diuretics and β-adrenoceptor blockers on glycaemic control in diabetes mellitus - a systematic review and meta-analysis.

    Science.gov (United States)

    Hirst, Jennifer A; Farmer, Andrew J; Feakins, Benjamin G; Aronson, Jeffrey K; Stevens, Richard J

    2015-05-01

    Although there are reports that β-adrenoceptor antagonists (beta-blockers) and diuretics can affect glycaemic control in people with diabetes mellitus, there is no clear information on how blood glucose concentrations may change and by how much. We report results from a systematic review to quantify the effects of these antihypertensive drugs on glycaemic control in adults with established diabetes. We systematically reviewed the literature to identify randomized controlled trials in which glycaemic control was studied in adults with diabetes taking either beta-blockers or diuretics. We combined data on HbA1c and fasting blood glucose using fixed effects meta-analysis. From 3864 papers retrieved, we found 10 studies of beta-blockers and 12 studies of diuretics to include in the meta-analysis. One study included both comparisons, totalling 21 included reports. Beta-blockers increased fasting blood glucose concentrations by 0.64 mmol l(-1) (95% CI 0.24, 1.03) and diuretics by 0.77 mmol l(-1) (95% CI 0.14, 1.39) compared with placebo. Effect sizes were largest in trials of non-selective beta-blockers (1.33, 95% CI 0.72, 1.95) and thiazide diuretics (1.69, 95% CI 0.60, 2.69). Beta-blockers increased HbA1c concentrations by 0.75% (95% CI 0.30, 1.20) and diuretics by 0.24% (95% CI -0.17, 0.65) compared with placebo. There was no significant difference in the number of hypoglycaemic events between beta-blockers and placebo in three trials. Randomized trials suggest that thiazide diuretics and non-selective beta-blockers increase fasting blood glucose and HbA1c concentrations in patients with diabetes by moderate amounts. These data will inform prescribing and monitoring of beta-blockers and diuretics in patients with diabetes. © 2014 The British Pharmacological Society.

  8. Binding kinetics of five drugs to beta2-adrenoceptor using peak profiling method and nonlinear chromatography.

    Science.gov (United States)

    Liang, Yuan; Wang, Jing; Fei, Fuhuan; Sun, Huanmei; Liu, Ting; Li, Qian; Zhao, Xinfeng; Zheng, Xiaohui

    2018-02-23

    Investigations of drug-protein interactions have advanced our knowledge of ways to design more rational drugs. In addition to extensive thermodynamic studies, ongoing works are needed to enhance the exploration of drug-protein binding kinetics. In this work, the beta2-adrenoceptor (β 2 -AR) was immobilized on N, N'-carbonyldiimidazole activated amino polystyrene microspheres to prepare an affinity column (4.6 mm × 5.0 cm, 8 μm). The β 2 -AR column was utilized to determine the binding kinetics of five drugs to the receptor. Introducing peak profiling method into this receptor chromatographic analysis, we determined the dissociation rate constants (k d ) of salbutamol, terbutaline, methoxyphenamine, isoprenaline hydrochloride and ephedrine hydrochloride to β 2 -AR to be 15 (±1), 22 (±1), 3.3 (±0.2), 2.3 (±0.2) and 2.1 (±0.1) s -1 , respectively. The employment of nonlinear chromatography (NLC) in this case exhibited the same rank order of k d values for the five drugs bound to β 2 -AR. We confirmed that both the peak profiling method and NLC were capable of routine measurement of receptor-drug binding kinetics. Compared with the peak profiling method, NLC was advantageous in the simultaneous assessment of the kinetic and apparent thermodynamic parameters. It will become a powerful method for high throughput drug-receptor interaction analysis. Copyright © 2018 Elsevier B.V. All rights reserved.

  9. Enantiomers of bronchodilating beta2-adrenoceptor agonists: is there a cause for concern?

    Science.gov (United States)

    Waldeck, B

    1999-05-01

    All bronchodilating beta2-adrenoceptor agonists in current clinical use are derivatives of adrenaline and are available as racemates. Whereas the vast majority of the pharmacologic and clinical documentation has been made with the racemates, there are a few studies with the individual enantiomers. It thus appears that all established pharmacologic effects of racemic beta2-agonists reside in the (R)-enantiomer, with the (S)-enantiomer being virtually inactive. In recent years the suspicion has been raised that the (S)-enantiomer of the beta2-agonists is responsible for induction of airway hyperreactivity. This suspicion is based primarily on results obtained in guinea pigs exposed to (S)-enantiomers of beta2-agonists. A number of experiments in vitro have been undertaken to find a mechanism of action for these observations in vivo. Most of the results obtained are equivocal. However, the observation that (S)-salbutamol may cause mobilization of intracellular Ca2+, apparently by means of a cholinergic mechanism, deserves further investigation. The clinical studies are focused on the enantiomers of salbutamol. They confirm the preclinical findings that the pulmonary, as well as the extrapulmonary, effects of salbutamol reside in the (R)-enantiomer. The studies available so far do not convincingly show clinically significant airway hyperreactivity after exposure to the (S)-enantiomer. Further studies are needed to settle this issue.

  10. GABAA receptor partial agonists and antagonists

    DEFF Research Database (Denmark)

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

    2015-01-01

    to the local temporal pattern of GABA impact, enabling phasic or tonic inhibition. Specific GABAAR antagonists are essential tools for physiological and pharmacological elucidation of the different type of GABAAR inhibition. However, distinct selectivity among the receptor subtypes (populations) has been shown...... 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...

  11. Calcium antagonists for aneurysmal subarachnoid haemorrhage

    NARCIS (Netherlands)

    Dorhout Mees, S. M.; Rinkel, G. J. E.; Feigin, V. L.; Algra, A.; van den Bergh, W. M.; Vermeulen, M.; van Gijn, J.

    2007-01-01

    BACKGROUND: Secondary ischaemia is a frequent cause of poor outcome in patients with subarachnoid haemorrhage (SAH). Its pathogenesis has been incompletely elucidated, but vasospasm probably is a contributing factor. Experimental studies have suggested that calcium antagonists can prevent or reverse

  12. Antagonist wear by polished zirconia crowns.

    Science.gov (United States)

    Hartkamp, Oliver; Lohbauer, Ulrich; Reich, Sven

    The aim of this in vivo study was to measure antagonist wear caused by polished monolithic posterior zirconia crowns over a 24-month period using the intraoral digital impression (IDI) technique. Thirteen zirconia crowns were placed in nine patients. The crowns and adjacent teeth were captured using an intraoral scanner (Lava C.O.S.). The corresponding antagonist teeth and the respective neighboring teeth were also scanned. Scanning was performed immediately after the restoration (baseline) as well as 12 and 24 months after crown placement. Geomagic Qualify software was used to superimpose the follow-up data sets onto the corresponding baseline data set, identify wear sites, and measure maximum vertical height loss in each individual wear site. Overall antagonist wear was then determined as the mean of wear rates measured in all of the individual antagonist units. In addition, wear rates in enamel and ceramic antagonists were analyzed as part of the scope of this study. The maximum mean wear with standard deviation (SD) in the overall sample with a total of nine patients, 13 antagonist units, and 98 evaluable wear sites was 86 ± 23 µm at 12 months, and 103 ± 39 µm at 24 months. The maximum mean wear in the enamel antagonist subgroup was 87 ± 41 µm at 12 months, and 115 ± 71 µm at 24 months; and in the ceramic antagonist subgroup 107 ± 22 µm at 12 months, and 120 ± 27 µm at 24 months. The wear rates determined in this study are comparable to those of existing studies. The IDI technique of wear analysis can be carried out in a practical manner and produces useful results.

  13. Polymorphisms in the interleukin-1 gene influence the stratum corneum interleukin-1 alpha concentration in uninvolved skin of patients with chronic irritant contact dermatitis

    NARCIS (Netherlands)

    de Jongh, Cindy M.; Khrenova, Liubov; Kezic, Sanja; Rustemeyer, Thomas; Verberk, Maarten M.; John, Swen M.

    2008-01-01

    BACKGROUND: Interleukin (IL)-1 alpha and its receptor antagonist IL-1 ra play a role in skin inflammation. Several polymorphisms in the IL1 gene cluster, coding for IL-1 alpha, IL-1 ra, and IL-1 beta, influence their protein expression. Within this cluster, strong linkage disequilibrium has been

  14. Effect of beta2-adrenoceptor agonists and other cAMP-elevating agents on inflammatory gene expression in human ASM cells: a role for protein kinase A.

    Science.gov (United States)

    Kaur, Manminder; Holden, Neil S; Wilson, Sylvia M; Sukkar, Maria B; Chung, Kian Fan; Barnes, Peter J; Newton, Robert; Giembycz, Mark A

    2008-09-01

    In diseases such as asthma, airway smooth muscle (ASM) cells play a synthetic role by secreting inflammatory mediators such as granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-6, or IL-8 and by expressing surface adhesion molecules, including ICAM-1. In the present study, PGE(2), forskolin, and short-acting (salbutamol) and long-acting (salmeterol and formoterol) beta(2)-adrenoceptor agonists reduced the expression of ICAM-1 and the release of GM-CSF evoked by IL-1beta in ASM cells. IL-1beta-induced IL-8 release was also repressed by PGE(2) and forskolin, whereas the beta(2)-adrenoceptor agonists were ineffective. In each case, repression of these inflammatory indexes was prevented by adenoviral overexpression of PKIalpha, a highly selective PKA inhibitor. These data indicate a PKA-dependent mechanism of repression and suggest that agents that elevate intracellular cAMP, and thereby activate PKA, may have a widespread anti-inflammatory effect in ASM cells. Since ICAM-1 and GM-CSF are highly NF-kappaB-dependent genes, we used an adenoviral-delivered NF-kappaB-dependent luciferase reporter to examine the effects of forskolin and the beta(2)-adrenoceptor agonists on NF-kappaB activation. There was no effect on luciferase activity measured in the presence of forskolin or beta(2)-adrenoceptor agonists. This finding is consistent with the observation that IL-1beta-induced expression of IL-6, a known NF-kappaB-dependent gene in ASM, was also unaffected by beta(2)-adrenoceptor agonists, forskolin, PGE(2), 8-bromo-cAMP, or rolipram. Collectively, these results indicate that repression of IL-1beta-induced ICAM-1 expression and GM-CSF release by cAMP-elevating agents, including beta(2)-adrenoceptor agonists, may not occur through a generic effect on NF-kappaB.

  15. Alpha Thalassemia (For Parents)

    Science.gov (United States)

    ... the body has a problem producing alpha globin Beta thalassemia : when the body has a problem producing beta ... Transfusion Blood Test: Hemoglobin Electrophoresis Sickle Cell Disease Beta Thalassemia Blood All About Genetics Prenatal Genetic Counseling Genetic ...

  16. Alpha7 nicotinic receptor mediated protection against ethanol-induced cytotoxicity in PC12 cells.

    Science.gov (United States)

    Li, Y; King, M A; Grimes, J; Smith, N; de Fiebre, C M; Meyer, E M

    1999-01-16

    Ethanol caused a concentration-dependent loss of PC12 cells over a 24 h interval, accompanied by an increase in intracellular calcium. The specific alpha7 nicotinic receptor partial agonist DMXB attenuated both of these ethanol-induced actions at a concentration (3 microM) found previously to protect against apoptotic and necrotic cell loss. The alpha7 nicotinic receptor antagonist methylylaconitine blocked the neuroprotective action of DMXB when applied with but not 30 min after the agonist. These results indicate that activation of alpha7 nicotinic receptors may be therapeutically useful in preventing ethanol-neurotoxicity. Copyright 1999 Elsevier Science B.V.

  17. ALPHA-2: the sequel

    CERN Multimedia

    Katarina Anthony

    2012-01-01

    While many experiments are methodically planning for intense works over the long shutdown, there is one experiment that is already working at full steam: ALPHA-2. Its final components arrived last month and will completely replace the previous ALPHA set-up. Unlike its predecessor, this next generation experiment has been specifically designed to measure the properties of antimatter.   The ALPHA team lower the new superconducting solenoid magnet into place. The ALPHA collaboration is working at full speed to complete the ALPHA-2 set-up for mid-November – this will give them a few weeks of running before the AD shutdown on 17 December. “We really want to get some experience with this device this year so that, if we need to make any changes, we will have time during the long shutdown in which to make them,” says Jeffrey Hangst, ALPHA spokesperson. “Rather than starting the 2014 run in the commissioning stage, we will be up and running from the get go.&...

  18. The effects of beta-adrenoceptor activation on contraction in isolated fast- and slow-twitch skeletal muscle fibres of the rat.

    OpenAIRE

    Cairns, S. P.; Dulhunty, A. F.

    1993-01-01

    1. The aim of the experiments was to examined the effects of beta-adrenoceptor activation on twitch and tetanic contractions in fast- and slow-twitch mammalian skeletal muscle fibres. Isometric force was recorded from bundles of intact fibres isolated from the normal and denervated slow-twitch soleus and normal fast-twitch sternomastoid muscles of the rat. 2. Terbutaline (10 microM), a beta 2-adrenoceptor agonist, induced an average 15% potentiation of peak twitch and peak tetanic force in no...

  19. New imidazoline/α(2)-adrenoceptors affecting compounds-4(5)-(2-aminoethyl)imidazoline (dihydrohistamine) derivatives. Synthesis and receptor affinity studies.

    Science.gov (United States)

    Treder, Adam P; Andruszkiewicz, Ryszard; Zgoda, Włodzimierz; Walkowiak, Aleksandra; Ford, Celeste; Hudson, Alan L

    2011-01-01

    Compilation of agmatine structure and imidazoline moiety leads to a new group of imidazoline/α(2)-adrenoceptor ligands, 4(5)-(2-aminoethyl)imidazoline derivatives. In this study the exploration of previously unknown 4(5)-(2-aminoethyl)imidazolines including the analogues of reported imidazoline and α(2)-aderenoceptors ligands: clonidine, rilmenidine, idazoxan, efaroxan, antazoline, tracizoline is described. The synthesis of a variety of novel 4(5)-(2-aminoethyl)imidazolines and their I(1), I(2), α(2)-adrenoceptors affinities are reported. Copyright © 2010 Elsevier Ltd. All rights reserved.

  20. Clenbuterol activates the central IL-1 system via the β2-adrenoceptor without provoking inflammatory response related behaviours in rats.

    Science.gov (United States)

    Ryan, Karen M; Griffin, Éadaoin W; Ryan, Katie J; Tanveer, Riffat; Vanattou-Saifoudine, Natacha; McNamee, Eoin N; Fallon, Emer; Heffernan, Sheena; Harkin, Andrew; Connor, Thomas J

    2016-08-01

    The long-acting, highly lipophilic, β2-adrenoceptor agonist clenbuterol may represent a suitable therapeutic agent for the treatment of neuroinflammation as it drives an anti-inflammatory response within the CNS. However, clenbuterol is also known to increase the expression of IL-1β in the brain, a potent neuromodulator that plays a role in provoking sickness related symptoms including anxiety and depression-related behaviours. Here we demonstrate that, compared to the immunological stimulus lipopolysaccharide (LPS, 250μg/kg), clenbuterol (0.5mg/kg) selectively up-regulates expression of the central IL-1 system resulting in a mild stress-like response which is accompanied by a reduction in locomotor activity and food consumption in rats. We provide further evidence that clenbuterol-induced activation of the central IL-1 system occurs in a controlled and selective manner in tandem with its negative regulators IL-1ra and IL-1RII. Furthermore, we demonstrate that peripheral β2-adrenoceptors mediate the suppression of locomotor activity and food consumption induced by clenbuterol and that these effects are not linked to the central induction of IL-1β. Moreover, despite increasing central IL-1β expression, chronic administration of clenbuterol (0.03mg/kg; twice daily for 21days) fails to induce anxiety or depressive-like behaviour in rats in contrast to reports of the ability of exogenously administered IL-1 to induce these symptoms in rodents. Overall, our findings suggest that clenbuterol or other selective β2-adrenoceptor agonists could have the potential to combat neuroinflammatory or neurodegenerative disorders without inducing unwanted symptoms of depression and anxiety. Copyright © 2016 Elsevier Inc. All rights reserved.

  1. Hydro-ethanolic Extract of Portulaca oleracea Affects Beta-adrenoceptors of Guinea Pig Tracheal Smooth Muscle

    Science.gov (United States)

    Boskabady, Mohammad Hossein; Hashemzehi, Milad; Khazdair, Mohammad Reza; Askari, Vahid Reza

    2016-01-01

    Thestimulatory effect of the extract of Portulaca oleracea (P. olerace) on β-adrenoceptor of tracheal smooth muscle was examined.To examine β-adrenoceptor stimulatory effect, concentration response curve to isoprenaline was obtained in pre-contracted tracheal smooth muscle in the presence of three concentrations of aqueous-ethanolic extract, propranolol, and saline. Values of EC50 (the effective concentration of isoprenaline, causing 50% of maximum response) and dose ratio-1(CR-1) were measured. This effect was tested innon-incubated tracheal smooth muscle (group 1) and incubated tissues with chlorpheniramine (group 2). Concentration-response curves to isoprenaline in the presence of two higher concentrations of the extract in group 1 and all three concentrations in group 2 showed leftward shifts compared to isoprenaline curves produced in the presence of saline in both groups. EC50 obtained in the presence of propranolol was significantly higher than that of saline in both groups of experiments (p<0.05 for both cases). However, the EC50 obtained in the presence of two higher concentrations of the extract in group 1 and lower concentration in group 2 were non-significantly but those obtained of medium and high extract concentrations in the group 2 were significantly (p<0.05 for both cases)lower than those of saline. The values of (CR-1) obtained in the presence of all concentrations of the extract in groups1 and 2 were significantly lower than that of propranolol (p<0.05 to p<0.001).The results indicated a stimulatory effect of the P. olerace extract on ß 2-adrenoceptors of tracheal smooth muscle. PMID:28243284

  2. Expression of triplicated and quadruplicated alpha globin genes in sheep.

    Science.gov (United States)

    Vestri, R; Pieragostini, E; Yang, F; di Gregorio, P; Rando, A; Masina, P

    1991-01-01

    In the sheep alpha alpha alpha globin gene haplotype, the three genes display from the 5' to the 3' end the percentage efficiencies of about 30:14:6, as indicated by the amounts of the three types of alpha chain produced in the alpha alpha alpha/alpha alpha alpha homozygotes. The 3' gene in the alpha alpha alpha alpha haplotype appears to have an efficiency around 1%, as suggested by analysis of one quadruple alpha homozygote. Moreover, the total outputs of the alpha alpha alpha as well as of the alpha alpha alpha alpha haplotypes do not substantially differ from that of the common alpha alpha haplotype.

  3. Correlation between phosphatidylinositol labeling and contraction in rabbit aorta: effect of alpha-1 adrenergic activation

    Energy Technology Data Exchange (ETDEWEB)

    Villalobos-Molina, R.; Uc, M.; Hong, E.; Garcia-Sainz, J.A.

    1982-07-01

    Activation of rabbit aortic strips with alpha adrenergic agonists increased the labeling (with (/sup 32/P)Pi) of phosphatidylinositol (PI) and phosphatidic acid and contracted the vascular preparations in dose-related fashion. Epinephrine, norepinephrine and methoxamine produced maximal effects, whereas clonidine behaved as partial agonist and B-HT 933 (2-amino-6-ethyl-4,5,7,8-tetrahydro-6H-oxazole-(5,4-d) azepin dihydrochloride) was almost without activity in the two experimental models used. Phenylephrine was a full agonist in producing contraction, but failed to elicit the maximal increase in PI labeling. The EC50 values to produce contraction of aortic strips were lower for all agonists than those required to increase the incorporation of radioactive phosphate into PI, but there was a good correlation between the two sets of data. The increased PI labeling and contraction of aortic strips induced by epinephrine were antagonized by prazosin and yohimbine in dose-related fashion, but the first alpha blocker was about three orders of magnitude more potent than the second in antagonizing the two effects. The present results indicate that both stimulation of PI labeling and contraction are mediated through activation of alpha-1 adrenoceptors in rabbit aorta.

  4. Correlation between phosphatidylinositol labeling and contraction in rabbit aorta: effect of alpha-1 adrenergic activation

    International Nuclear Information System (INIS)

    Villalobos-Molina, R.; Uc, M.; Hong, E.; Garcia-Sainz, J.A.

    1982-01-01

    Activation of rabbit aortic strips with alpha adrenergic agonists increased the labeling (with [ 32 P]Pi) of phosphatidylinositol (PI) and phosphatidic acid and contracted the vascular preparations in dose-related fashion. Epinephrine, norepinephrine and methoxamine produced maximal effects, whereas clonidine behaved as partial agonist and B-HT 933 (2-amino-6-ethyl-4,5,7,8-tetrahydro-6H-oxazole-[5,4-d] azepin dihydrochloride) was almost without activity in the two experimental models used. Phenylephrine was a full agonist in producing contraction, but failed to elicit the maximal increase in PI labeling. The EC50 values to produce contraction of aortic strips were lower for all agonists than those required to increase the incorporation of radioactive phosphate into PI, but there was a good correlation between the two sets of data. The increased PI labeling and contraction of aortic strips induced by epinephrine were antagonized by prazosin and yohimbine in dose-related fashion, but the first alpha blocker was about three orders of magnitude more potent than the second in antagonizing the two effects. The present results indicate that both stimulation of PI labeling and contraction are mediated through activation of alpha-1 adrenoceptors in rabbit aorta

  5. Modification of certain pharmacological effects of ethanol by lipophilic alpha-1 adrenergic agonists

    Energy Technology Data Exchange (ETDEWEB)

    Menon, M.K.; Dinovo, E.C.; Haddox, V.G.

    1987-09-28

    The influence of four centrally-acting alpha-1 adrenoceptor agonists, namely, 2(2-chloro-5-trifluoromethylphenylimino) imidazolidine (St 587), cirazoline, (-) 1,2,3,4-tetrahydro-8-methoxy-5-methylthio-2-naphthalenamine ((-)SKF 89748A) and 2-(2-methylindazol-4-imino)imidazolidine (Sgd 101/75) on the pharmacological effects of ethanol was investigated. All four drugs reduced the duration of ethanol-induced hypnosis in C57B1/6 mice, this effect being proportional to their relative potencies to exert central alpha-1 agonism. In prazosin-pretreated mice, St 587 failed to reduce the hypnotic effect of ethanol, which provided strong evidence for the role of alpha-1 agonism for the hypnosis reducing effect of St 587. Hyperactivity induced in C57B1/6 mice by a subhypnotic dose of ethanol and St 587 was reported earlier. In the present study, St 587, cirazoline and (-)SKF 89748A produced similar response, but no correlation between this effect and ethanol hypnosis blockade could be established. 19 references, 8 figures, 2 tables.

  6. A model for short alpha-neurotoxin bound to nicotinic acetylcholine receptor from Torpedo californica: comparison with long-chain alpha-neurotoxins and alpha-conotoxins.

    Science.gov (United States)

    Mordvintsev, D Yu; Polyak, Ya L; Levtsova, O V; Tourleigh, Ye V; Kasheverov, I E; Shaitan, K V; Utkin, Yu N; Tsetlin, V I

    2005-12-01

    Short-chain alpha-neurotoxins from snakes are highly selective antagonists of the muscle-type nicotinic acetylcholine receptors (nAChR). Although their spatial structures are known and abundant information on topology of binding to nAChR is obtained by labeling and mutagenesis studies, the accurate structure of the complex is not yet known. Here, we present a model for a short alpha-neurotoxin, neurotoxin II from Naja oxiana (NTII), bound to Torpedo californica nAChR. It was built by comparative modeling, docking and molecular dynamics using 1H NMR structure of NTII, cross-linking and mutagenesis data, cryoelectron microscopy structure of Torpedo marmorata nAChR [Unwin, N., 2005. Refined structure of the nicotinic acetylcholine receptor at 4A resolution. J. Mol. Biol. 346, 967-989] and X-ray structures of acetylcholine-binding protein (AChBP) with agonists [Celie, P.H., van Rossum-Fikkert, S.E., van Dijk, W.J., Brejc, K., Smit, A.B., Sixma, T.K., 2004. Nicotine and carbamylcholine binding to nicotinic acetylcholine receptors as studied in AChBP crystal structures. Neuron 41 (6), 907-914] and antagonists: alpha-cobratoxin, a long-chain alpha-neurotoxin [Bourne, Y., Talley, T.T., Hansen, S.B., Taylor, P., Marchot, P., 2005. Crystal structure of Cbtx-AChBP complex reveals essential interactions between snake alpha-neurotoxins and nicotinic receptors. EMBO J. 24 (8), 1512-1522] and alpha-conotoxin [Celie, P.H., Kasheverov, I.E., Mordvintsev, D.Y., Hogg, R.C., van Nierop, P., van Elk, R., van Rossum-Fikkert, S.E., Zhmak, M.N., Bertrand, D., Tsetlin, V., Sixma, T.K., Smit, A.B., 2005. Crystal structure of nicotinic acetylcholine receptor homolog AChBP in complex with an alpha-conotoxin PnIA variant. Nat. Struct. Mol. Biol. 12 (7), 582-588]. In complex with the receptor, NTII was located at about 30 A from the membrane surface, the tip of its loop II plunges into the ligand-binding pocket between the alpha/gamma or alpha/delta nAChR subunits, while the loops I and III

  7. Differential phosphorylation, desensitization, and internalization of α1A-adrenoceptors activated by norepinephrine and oxymetazoline.

    Science.gov (United States)

    Akinaga, Juliana; Lima, Vanessa; Kiguti, Luiz Ricardo de Almeida; Hebeler-Barbosa, Flávia; Alcántara-Hernández, Rocío; García-Sáinz, J Adolfo; Pupo, André Sampaio

    2013-04-01

    Loss of response on repetitive drug exposure (i.e., tachyphylaxis) is a particular problem for the vasoconstrictor effects of medications containing oxymetazoline (OXY), an α1-adrenoceptor (AR) agonist of the imidazoline class. One cause of tachyphylaxis is receptor desensitization, usually accompanied by phosphorylation and internalization. It is well established that α1A-ARs are less phosphorylated, desensitized, and internalized on exposure to the phenethylamines norepinephrine (NE), epinephrine, or phenylephrine (PE) than are the α1B and α1D subtypes. However, here we show in human embryonic kidney-293 cells that the low-efficacy agonist OXY induces G protein-coupled receptor kinase 2-dependent α1A-AR phosphorylation, followed by rapid desensitization and internalization (∼40% internalization after 5 minutes of stimulation), whereas phosphorylation of α1A-ARs exposed to NE depends to a large extent on protein kinase C activity and is not followed by desensitization, and the receptors undergo delayed internalization (∼35% after 60 minutes of stimulation). Native α1A-ARs from rat tail artery and vas deferens are also desensitized by OXY, but not by NE or PE, indicating that this property of OXY is not limited to recombinant receptors expressed in cell systems. The results of the present study are clearly indicative of agonist-directed α1A-AR regulation. OXY shows functional selectivity relative to NE and PE at α1A-ARs, leading to significant receptor desensitization and internalization, which is important in view of the therapeutic vasoconstrictor effects of this drug and the varied biologic process regulated by α1A-ARs.

  8. Calcineurin mediates alpha-adrenergic stimulation of Na+,K(+)-ATPase activity in renal tubule cells.

    Science.gov (United States)

    Aperia, A; Ibarra, F; Svensson, L B; Klee, C; Greengard, P

    1992-01-01

    The alpha-adrenergic agonist oxymetazoline increased Na+,K(+)-ATPase activity of single proximal convoluted tubules dissected from rat kidney. Activation of the enzyme by oxymetazoline was prevented by either the alpha 1-adrenergic antagonist prazosin or the alpha 2-adrenergic antagonist yohimbine and was mimicked by the calcium ionophore A23187. The effect of oxymetazoline on Na+,K(+)-ATPase activity was prevented by a specific peptide inhibitor of calcineurin, as well as by FK 506, an immunosuppressant agent known to inhibit calcineurin; these results indicate that the action of oxymetazoline is mediated via activation of calcineurin (a calcium/calmodulin-dependent protein phosphatase). Activation of the Na+,K(+)-ATPase by either oxymetazoline or A23187 was associated with a greater than 2-fold increase in its affinity for Na+. The results provide a biochemical mechanism by which norepinephrine, released from renal nerve terminals, stimulates Na+ retention. PMID:1380157

  9. Coronary dilation with nitrocompounds and calcium antagonists.

    Science.gov (United States)

    Jost, S; Rafflenbeul, W; Lichtlen, P R

    1990-01-01

    The vasodilatory effects of nitrocompounds and calcium antagonists on epicardial coronary arteries represent substantial antianginal mechanisms in the presence of coronary vasospasm or eccentric coronary stenoses. With high doses of nitrocompounds, angiographically normal coronary segments can be dilated by an average of approx. 30%, some coronary stenoses even by up to 100%, usually without severe reduction of blood pressure. With calcium antagonists, a similar extent of dilation of normal coronary arteries and eccentric stenoses can be obtained. Our own group demonstrated an average dilation of normal coronary arteries of about 20% after intravenous administration of dihydropyridine calcium antagonists; however, the average systolic blood pressure dropped below 100 mmHg after these compounds. Hence, although in isolated human coronary arteries high concentrations of calcium antagonists were shown to induce a considerably greater vasodilation than nitrocompounds, the early drop in blood pressure prohibits a higher dosage of calcium antagonists in vivo. In the presence of coronary artery disease, particularly when associated with coronary vasospasm, a combination of the two groups of compounds might be recommendable, since an addition of the effects of coronary vasomotor tone is likely. Furthermore, the antianginal effects of a reduction of preload and afterload are complementary.

  10. Examination of chlorpromazine and other amphipathic drugs on the activity of lipopolysaccharide antagonists, E5564 and E5531.

    Science.gov (United States)

    Yang, H; Daun, J M; Rose, J R; Christ, W J; Gusovsky, F; Chow, J C

    2000-01-01

    The synthetic antagonists of lipopolysaccharide (LPS), E5531 and E5564, are analogs of the lipid A portion of LPS that not only lack agonistic activity but also inhibit the biological effects of LPS both in vitro and in vivo. The effects of LPS and these synthetic antagonists have been localized to the recently described Toll-like receptor 4 (TLR4). A recent report indicated that the naturally occurring LPS antagonist Rhodobacter sphaeroides LPS loses its antagonist properties and gains pro-inflammatory qualities in the presence of chlorpromazine and other amphipathic drugs. To determine whether these reported actions occur with our chemically defined LPS antagonists, we examined the effects of chlorpromazine, fluphenazine, trifluoperazine, and lidocaine on the antagonism elicited by RsLPS and E5531 in U373 cells, which produce IL-6 in response to LPS. We also tested the effects of these amphipathic molecules on the LPS-neutralizing activity of RsLPS and E5564 on LPS-induced TNF-alpha release in human whole blood. The results indicate that neither chlorpromazine, fluphenazine, trifluoperazine nor lidocaine alter the activity of E5531 or E5564 in an in vitro cell system or human whole blood. Furthermore, chlorpromazine did not affect the antagonistic activity of RsLPS or E5564 on IL-6 generation by peripheral blood mononuclear cells. Thus, based on these data, our purified synthetic LPS-antagonists do not appear to lose their antagonistic properties and/or become agonists in the presence of amphipathic agents or drugs.

  11. Postcountershock myocardial damage after pretreatment with adrenergic and calcium channel antagonists in halothane-anesthetized dogs

    Energy Technology Data Exchange (ETDEWEB)

    Gaba, D.M.; Metz, S.; Maze, M.

    1985-05-01

    Transthoracic electric countershock can cause necrotic myocardial lesions in humans as well as experimental animals. The authors investigated the effect on postcountershock myocardial damage of pretreatment with prazosin, an alpha-1 antagonist; L-metoprolol, a beta-1 antagonist, and verapamil, a calcium channel-blocking agent. Twenty dogs were anesthetized with halothane and given two transthoracic countershocks of 295 delivered joules each after drug or vehicle treatment. Myocardial injury was quantitated 24 h following countershock by measuring the uptake of technetium-99m pyrophosphate in the myocardium. Elevated technetium-99m pyrophosphate uptake occurred in visible lesions in most dogs regardless of drug treatment. For each of four parameters of myocardial damage there was no statistically significant difference between control animals and those treated with prazosin, metoprolol, or verapamil. These data suggest that adrenergic or calcium channel-mediated mechanisms are not involved in the pathogenesis of postcountershock myocardial damage.

  12. Antidepressant-like effects of nicotinic acetylcholine receptor antagonists, but not agonists, in the mouse forced swim and mouse tail suspension tests

    DEFF Research Database (Denmark)

    Andreasen T., Jesper; Olsen, G M; Wiborg, O

    2009-01-01

    AChR subtype/s involved remains unknown. In this study, we systematically compared the effects of non-selective and selective nicotinic agonists and antagonists in two different tests for antidepressant effects in mice: the tail suspension test and the forced swim test. Compounds: nicotine, RJR-2403 (alpha4...

  13. Monte Carlo alpha calculation

    Energy Technology Data Exchange (ETDEWEB)

    Brockway, D.; Soran, P.; Whalen, P.

    1985-01-01

    A Monte Carlo algorithm to efficiently calculate static alpha eigenvalues, N = ne/sup ..cap alpha..t/, for supercritical systems has been developed and tested. A direct Monte Carlo approach to calculating a static alpha is to simply follow the buildup in time of neutrons in a supercritical system and evaluate the logarithmic derivative of the neutron population with respect to time. This procedure is expensive, and the solution is very noisy and almost useless for a system near critical. The modified approach is to convert the time-dependent problem to a static ..cap alpha../sup -/eigenvalue problem and regress ..cap alpha.. on solutions of a/sup -/ k/sup -/eigenvalue problem. In practice, this procedure is much more efficient than the direct calculation, and produces much more accurate results. Because the Monte Carlo codes are intrinsically three-dimensional and use elaborate continuous-energy cross sections, this technique is now used as a standard for evaluating other calculational techniques in odd geometries or with group cross sections.

  14. ETA-receptor antagonists or allosteric modulators?

    DEFF Research Database (Denmark)

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

    2011-01-01

    . In resistance arteries, the long-lasting contractile effects can only be partly and reversibly relaxed by low-molecular-weight ET(A) antagonists (ERAs). However, the neuropeptide calcitonin-gene-related peptide selectively terminates binding of ET1 to ET(A). We propose that ET1 binds polyvalently to ET......(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...

  15. Inhibition of Brain Swelling after Ischemia-Reperfusion by β-Adrenergic Antagonists: Correlation with Increased K+ and Decreased Ca2+ Concentrations in Extracellular Fluid

    Directory of Open Access Journals (Sweden)

    Dan Song

    2014-01-01

    Full Text Available Infarct size and brain edema following ischemia/reperfusion are reduced by inhibitors of the Na+, K+, 2Cl−, and water cotransporter NKCC1 and by β1-adrenoceptor antagonists. NKCC1 is a secondary active transporter, mainly localized in astrocytes, driven by transmembrane Na+/K+ gradients generated by the Na+,K+-ATPase. The astrocytic Na+,K+-ATPase is stimulated by small increases in extracellular K+ concentration and by the β-adrenergic agonist isoproterenol. Larger K+ increases, as occurring during ischemia, also stimulate NKCC1, creating cell swelling. This study showed no edema after 3 hr medial cerebral artery occlusion but pronounced edema after 8 hr reperfusion. The edema was abolished by inhibitors of specifically β1-adrenergic pathways, indicating failure of K+-mediated, but not β1-adrenoceptor-mediated, stimulation of Na+,K+-ATPase/NKCC1 transport during reoxygenation. Ninety percent reduction of extracellular Ca2+ concentration occurs in ischemia. Ca2+ omission abolished K+ uptake in normoxic cultures of astrocytes after addition of 5 mM KCl. A large decrease in ouabain potency on K+ uptake in cultured astrocytes was also demonstrated in Ca2+-depleted media, and endogenous ouabains are needed for astrocytic K+ uptake. Thus, among the ionic changes induced by ischemia, the decrease in extracellular Ca2+ causes failure of the high-K+-stimulated Na+,K+-ATPase/NKCC1 ion/water uptake, making β1-adrenergic activation the only stimulus and its inhibition effective against edema.

  16. Influence of hyperpolarization caused by high salt diet on β-adrenoceptor-mediated responses in rat pulmonary artery.

    Science.gov (United States)

    Mahajan, Puneet; Tabrizchi, Reza

    2012-07-01

    The effect of high salt diet on β-adrenoceptor-mediated response was assessed in rat-isolated pulmonary arteries. Isoprenaline-induced relaxations were not different in tissues from rats on either, high salt or regular diets. However, acidic buffer (pH 6.4) alone and in combination with Ba2+ or Nω-nitro-L-arginine methyl ester (L-NAME) significantly attenuated isoprenaline-induced relaxations in tissues from rats on high salt compared with those on a regular diet. Also, Ba2+ and ouabain together produced a significantly greater inhibition of isoprenaline-induced relaxation in tissues from rats on high salt when compared with those on the regular diet. The resting membrane potential of smooth muscle cells of pulmonary arteries of rats on high salt diet compared with regular diet was more negative (ie, hyperpolarized) than that on the regular diet. This hyperpolarization was reversed on exposure of blood vessels to acidic buffer and/or Ba2+ and ouabain combined but not L-NAME. Treatment with isoprenaline did not cause further hyperpolarization of smooth muscle cells of arteries from rats on the high salt diet. Taken together, the electrical changes due to the high salt diet can be attributed to the opening of K+ channels (2 pore acid-sensitive K+ channels and K(ir2.1)) and the activation of Na+/K+-ATPase. Furthermore, hyperpolarization observed after consumption of high salt diet seems to preserve β-adrenoceptor-mediated vasorelaxation.

  17. β3-Adrenoceptor agonists for overactive bladder syndrome: Role of translational pharmacology in a repositioning clinical drug development project.

    Science.gov (United States)

    Michel, Martin C; Korstanje, Cees

    2016-03-01

    β3-Adrenoceptor agonists were originally considered as a promising drug class for the treatment of obesity and/or type 2 diabetes. When these development efforts failed, they were repositioned for the treatment of the overactive bladder syndrome. Based on the example of the β3-adrenoceptor agonist mirabegron, but also taking into consideration evidence obtained with ritobegron and solabegron, we discuss challenges facing a translational pharmacology program accompanying clinical drug development for a first-in-class molecule. Challenges included generic ones such as ligand selectivity, species differences and drug target gene polymorphisms. Challenges that are more specific included changing concepts of the underlying pathophysiology of the target condition while clinical development was under way; moreover, a paucity of public domain tools for the study of the drug target and aspects of receptor agonists as drugs had to be addressed. Nonetheless, a successful first-in-class launch was accomplished. Looking back at this translational pharmacology program, we conclude that a specifically tailored and highly flexible approach is required. However, several of the lessons learned may also be applicable to translational pharmacology programs in other indications. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. Monte Carlo alpha deposition

    International Nuclear Information System (INIS)

    Talley, T.L.; Evans, F.

    1988-01-01

    Prior work demonstrated the importance of nuclear scattering to fusion product energy deposition in hot plasmas. This suggests careful examination of nuclear physics details in burning plasma simulations. An existing Monte Carlo fast ion transport code is being expanded to be a test bed for this examination. An initial extension, the energy deposition of fast alpha particles in a hot deuterium plasma, is reported. The deposition times and deposition ranges are modified by allowing nuclear scattering. Up to 10% of the initial alpha particle energy is carried to greater ranges and times by the more mobile recoil deuterons. 4 refs., 5 figs., 2 tabs

  19. Buffett’s Alpha

    DEFF Research Database (Denmark)

    Frazzini, Andrea; Kabiller, David; Heje Pedersen, Lasse

    Berkshire Hathaway has realized a Sharpe ratio of 0.76, higher than any other stock or mutual fund with a history of more than 30 years, and Berkshire has a significant alpha to traditional risk factors. However, we find that the alpha becomes insignificant when controlling for exposures to Betting......-Against-Beta and Quality-Minus-Junk factors. Further, we estimate that Buffett’s leverage is about 1.6-to-1 on average. Buffett’s returns appear to be neither luck nor magic, but, rather, reward for the use of leverage combined with a focus on cheap, safe, quality stocks. Decomposing Berkshires’ portfolio into ownership...

  20. Safety and tolerability of β3-adrenoceptor agonists in the treatment of overactive bladder syndrome - insight from transcriptosome and experimental studies

    NARCIS (Netherlands)

    Michel, Martin C.; Gravas, Stavros

    2016-01-01

    We have reviewed the safety and tolerability of β3-adrenoceptor agonists, specifically mirabegron and solabegron, a newly emerging drug class for the treatment of the overactive bladder syndrome. We discuss them mechanistically in the context of expression and other preclinical data. Based on a

  1. Stereoselectivity at the B2-adrenoceptor on macrophages is a major determinant of the anti-inflammatory effects of B2-agonists

    NARCIS (Netherlands)

    Izeboud, C.A.; Vermeulen, R.M.; Zwart, A.; Vos, H.P.; Miert, A.S.J.P.A.M. van; Witkamp, R.F.

    2000-01-01

    Previous research has shown that β-adrenoceptor (β-AR) agonists have potent anti-inflammatory capabilities, e.g. represented by suppression of release of the proinflammatory cytokines. Aim of this research was to determine whether the effects of β-agonists on LPS-induced TNFα and IL-10 release are

  2. Involvement of beta 3-adrenoceptor in altered beta-adrenergic response in senescent heart: role of nitric oxide synthase 1-derived nitric oxide.

    Science.gov (United States)

    Birenbaum, Aurélie; Tesse, Angela; Loyer, Xavier; Michelet, Pierre; Andriantsitohaina, Ramaroson; Heymes, Christophe; Riou, Bruno; Amour, Julien

    2008-12-01

    In senescent heart, beta-adrenergic response is altered in parallel with beta1- and beta2-adrenoceptor down-regulation. A negative inotropic effect of beta3-adrenoceptor could be involved. In this study, the authors tested the hypothesis that beta3-adrenoceptor plays a role in beta-adrenergic dysfunction in senescent heart. beta-Adrenergic responses were investigated in vivo (echocardiography-dobutamine, electron paramagnetic resonance) and in vitro (isolated left ventricular papillary muscle, electron paramagnetic resonance) in young adult (3-month-old) and senescent (24-month-old) rats. Nitric oxide synthase (NOS) immunolabeling (confocal microscopy), nitric oxide production (electron paramagnetic resonance) and beta-adrenoceptor Western blots were performed in vitro. Data are mean percentages of baseline +/- SD. An impaired positive inotropic effect (isoproterenol) was confirmed in senescent hearts in vivo (117 +/- 23 vs. 162 +/- 16%; P < 0.05) and in vitro (127 +/- 10 vs. 179 +/- 15%; P < 0.05). In the young adult group, the positive inotropic effect was not significantly modified by the nonselective NOS inhibitor N-nitro-L-arginine methylester (L-NAME; 183 +/- 19%), the selective NOS1 inhibitor vinyl-L-N-5(1-imino-3-butenyl)-L-ornithine (L-VNIO; 172 +/- 13%), or the selective NOS2 inhibitor 1400W (183 +/- 19%). In the senescent group, in parallel with beta3-adrenoceptor up-regulation and increased nitric oxide production, the positive inotropic effect was partially restored by L-NAME (151 +/- 8%; P < 0.05) and L-VNIO (149 +/- 7%; P < 0.05) but not by 1400W (132 +/- 11%; not significant). The positive inotropic effect induced by dibutyryl-cyclic adenosine monophosphate was decreased in the senescent group with the specific beta3-adrenoceptor agonist BRL 37344 (167 +/- 10 vs. 142 +/- 10%; P < 0.05). NOS1 and NOS2 were significantly up-regulated in the senescent rat. In senescent cardiomyopathy, beta3-adrenoceptor overexpression plays an important role in the

  3. Rapid Eye Movement Sleep Deprivation Associated Increase in Na-K ATPase Activity in the Rat Brain is Due to Noradrenaline Induced α1-Adrenoceptor Mediated Increased α-Subunit of the Enzyme.

    Science.gov (United States)

    Amar, Megha; Mallick, Birendra Nath

    2015-08-01

    Rapid eye movement sleep (REMS) modulates Na-K ATPase activity and maintains brain excitability. REMS deprivation (REMSD)-associated increased Na-K ATPase activity is mediated by noradrenaline (NA) acting on α1-adrenoceptor (AR) in the brain. It was shown that NA-induced increased Na-K ATPase activity was due to allosteric modulation as well as increased turnover of the enzyme. Although the former has been studied in detail, our understanding on the latter was lacking, which we have studied. Male Wistar rats were REMS deprived for 4-days by classical flower-pot method; suitable control experiments were conducted. In another set, α1-AR antagonist prazosin (PRZ) was i.p. injected 48 h REMSD onward. At the end of experiments rats were sacrificed by cervical dislocation and brains were removed. Synaptosomes prepared from the brains were used to estimate Na-K ATPase activity as well as protein expressions of different isoforms of the enzyme subunits using western blot. REMSD significantly increased synaptosomal Na-K ATPase activity and that was due to differential increase in the expressions of α1-, α2- and α3-isoforms, but not that of β1- and β2-isoforms. PRZ reduced the REMSD-induced increased Na-K ATPase activity and protein expressions. We also observed that the increased Na-K ATPase subunit expression was not due to enhanced mRNA synthesis, which suggests the possibility of post-transcriptional regulation. Thus, the findings suggest that REMSD-associated increased Na-K ATPase activity is due to elevated level of α-subunit of the enzyme and that is induced by NA acting on α1-AR mediated mRNA-stabilization.

  4. Pre- and postsynaptic mechanisms in the clonidine- and oxymetazoline-induced inhibition of gastric motility in the rat.

    Science.gov (United States)

    Zádori, Zoltán S; Shujaa, Nashwan; Fülöp, Katalin; Dunkel, Petra; Gyires, Klára

    2007-10-01

    The inhibitory effect of clonidine (non-selective alpha2-adrenoceptor agonist) and oxymetazoline (alpha2A-adrenoceptor selective agonist) was compared on basal and stimulated gastric motor activity (gastric tone and contractions) using the balloon method in the rat. It was shown that oxymetazoline (0.2-1.7 micromol/kg, i.v.) decreased the basal motility, while clonidine (1.9-3.8 micromol/kg, i.v.) failed to affect it. When motility was stimulated centrally by insulin (5 IU/rat, i.v.), both clonidine (1.9-3.8 micromol/kg, i.v.) and oxymetazoline (0.1-3.4 micromol/kg, i.v.) inhibited the gastric motor activity. However, while the effect of clonidine was antagonized by the non-selective alpha2-adrenoceptor antagonist yohimbine (5 micromol/kg, i.v.) and the alpha2A-adrenoceptor selective antagonist BRL 44408 (3 micromol/kg, i.v.), the effect of oxymetazoline was only partially affected. Prazosin (alpha1- and alpha2B-adrenoceptor antagonist, 0.07-0.28 micromol/kg, i.v.) also failed to reverse the effect of oxymetazoline. Furthermore, when gastric motility was stimulated peripherally by activation of postsynaptic cholinergic muscarinic receptors by the combination of carbachol (0.14 micromol/kg, i.v.) and hexamethonium (37 micromol/kg, i.v.), clonidine (3.8 micromol/kg, i.v.) failed to affect the increased motor activity, however, oxymetazoline (0.8-3.4 micromol/kg, i.v.) exerted a pronounced inhibition. These results suggest that different mechanisms may be involved in the inhibitory effect of clonidine and oxymetazoline; while clonidine reduces the gastric motility by activation of presynaptic alpha2-adrenoceptors, postsynaptic component in the effect of oxymetazoline has also been raised.

  5. Case Study - Alpha

    Directory of Open Access Journals (Sweden)

    Stephen Leybourne

    2016-11-01

    Full Text Available This case study was developed from an actual scenario by Dr. Steve Leybourne of Boston University.  The case documents the historical evolution of an organization, and has been used successfully in courses dealing with organizational and cultural change, and the utilization of ‘soft skills’ in project-based management. This is a short case, ideal for classroom use and discussion.  The issues are easily accessible to students, and there is a single wide ranging question that allows for the inclusion of many issues surrounding strategic decision-making, and behavioural and cultural change. Alpha was one of the earlier companies in the USA to invest in large, edge-of-town superstores, with plentiful free vehicle parking, selling food and related household products. Alpha was created in the 1950s as a subsidiary of a major publicly quoted retail group.  It started business by opening a string of very large discount stores in converted industrial and warehouse premises in the south of the United States. In the early days shoppers were offered a limited range of very competitively priced products. When Alpha went public in 1981 it was the fourth largest food retailer in the US, selling an ever-widening range of food and non-food products.  Its success continued to be based on high volume, low margins and good value for money, under the slogan of ‘Alpha Price.’

  6. Alpha-mannosidosis

    DEFF Research Database (Denmark)

    Borgwardt, Line; Stensland, Hilde Monica Frostad Riise; Olsen, Klaus Juul

    2015-01-01

    of the three subgroups of genotype/subcellular localisation and the clinical and biochemical data were done to investigate the potential relationship between genotype and phenotype in alpha-mannosidosis. Statistical analyses were performed using the SPSS software. Analyses of covariance were performed...

  7. Functional selectivity of central Gα-subunit proteins in mediating the cardiovascular and renal excretory responses evoked by central α(2) -adrenoceptor activation in vivo.

    Science.gov (United States)

    Wainford, R D; Kapusta, D R

    2012-05-01

    Activation of brain α(2) -adrenoceptors in conscious rodents decreases heart rate (HR) and mean arterial blood pressure (MAP) and increases urine output and urinary sodium excretion. In vitro, α(2) -adrenoceptor stimulation activates Gα(i(1-3)) , Gα(o) and Gα(s) -subunit protein-gated signal transduction pathways. Here we have investigated whether these same Gα-subunit protein-gated pathways mediate the cardiovascular and renal excretory responses to central α(2) -adrenoceptor activation in conscious Sprague-Dawley rats. Rats were pre-treated by intracerebroventricular injection (i.c.v.) with an oligodeoxynucleotide (ODN) targeted to a Gα(i1) , Gα(i2) , Gα(i3) , Gα(o) , Gα(s) or a scrambled (SCR) ODN sequence (25 µg, 24 h). On the day of study, the α(2) -adrenoceptor agonist guanabenz (50 µg) or saline vehicle, was injected i.c.v. into ODN-pre-treated conscious rats. MAP and HR were recorded, and urine was collected for 150 min. In vehicle- and SCR ODN-pre-treated rats, i.c.v. guanabenz decreased MAP and HR, and produced marked diuretic and natriuretic responses. Selective ODN-mediated down-regulation of brain Gα(i2) -subunit proteins abolished the central guanabenz-induced hypotension and natriuresis. In contrast, following selective Gα(s) down-regulation, the characteristic hypotensive response to i.c.v. guanabenz was converted to an immediate increase in MAP. The bradycardic and diuretic responses to i.c.v. guanabenz were not blocked by pre-treatment with any ODN. There was functional selectivity of Gα(i2) and Gα(s) subunit protein-gated signal transduction pathways in mediating the hypotensive and natriuretic, but not bradycardic or diuretic, responses evoked by central α(2) -adrenoceptor activation in vivo. Published 2011. This article is a U.S. Government work and is in the public domain in the USA.

  8. CRTH2 antagonists in asthma: current perspectives

    Directory of Open Access Journals (Sweden)

    Singh D

    2017-12-01

    Full Text Available Dave Singh, Arjun Ravi, Thomas Southworth Division of Infection, Immunity and Respiratory Medicine, The Medicines Evaluation Unit, Manchester Academic Health Science Centre, Manchester University NHS Foundation Trust, The University of Manchester, Manchester, UK Abstract: Chemoattractant receptor-homologous molecule expressed on TH2 cells (CRTH2 binds to prostaglandin D2. CRTH2 is expressed on various cell types including eosinophils, mast cells, and basophils. CRTH2 and prostaglandin D2 are involved in allergic inflammation and eosinophil activation. Orally administered CRTH2 antagonists are in clinical development for the treatment of asthma. The biology and clinical trial data indicate that CRTH2 antagonists should be targeted toward eosinophilic asthma. This article reviews the clinical evidence for CRTH2 involvement in asthma pathophysiology and clinical trials of CRTH2 antagonists in asthma. CRTH2 antagonists could provide a practical alternative to biological treatments for patients with severe asthma. Future perspectives for this class of drug are considered, including the selection of the subgroup of patients most likely to show a meaningful treatment response. Keywords: CRTH2, clinical trial, eosinophilic asthma, prostaglandin D2

  9. Carbon adaptation influence the antagonistic ability of ...

    African Journals Online (AJOL)

    Influences of carbon adaptation on antagonistic activities of three Pseudomonas aeruginosa strains V4, V7 and V10 against Fusarium oxysporum f. sp. melonis were determined in this study. Results from this study showed that the P. aeruginosa strains and their adapted strains significantly inhibited the growth of mycelium ...

  10. Calcium antagonists for aneurysmal subarachnoid haemorrhage

    NARCIS (Netherlands)

    Rinkel, G. J. E.; Feigin, V. L.; Algra, A.; van den Bergh, W. M.; Vermeulen, M.; van Gijn, J.

    2005-01-01

    BACKGROUND: Secondary ischaemia is a frequent cause of poor outcome in patients with subarachnoid haemorrhage (SAH). Its pathogenesis has not been elucidated yet, but may be related to vasospasm. Experimental studies have indicated that calcium antagonists can prevent or reverse vasospasm and have

  11. Antagonistic properties of microogranisms associated with cassava ...

    African Journals Online (AJOL)

    The antagonistic properties of indigenous microflora from cassava starch, flour and grated cassava were investigated using the conventional streak, novel ring and well diffusion methods. Antagonism was measured by zone of inhibition between the fungal plug and bacterial streak/ring. Bacillus species were more effective ...

  12. Tumor necrosis factor alpha converting enzyme: an encouraging target for various inflammatory disorders.

    Science.gov (United States)

    Bahia, Malkeet S; Silakari, Om

    2010-05-01

    Tumor necrosis factor alpha is one of the most common pro-inflammatory cytokines responsible for various inflammatory disorders. It plays an important role in the origin and progression of rheumatoid arthritis and also in other autoimmune disease conditions. Some anti-tumor necrosis factor alpha antibodies like Enbrel, Humira and Remicade have been successfully used in these disease conditions as antagonists of tumor necrosis factor alpha. Inhibition of generation of active form of tumor necrosis factor alpha is a promising therapy for various inflammatory disorders. Therefore, the inhibition of an enzyme (tumor necrosis factor alpha converting enzyme), which is responsible for processing inactive form of tumor necrosis factor alpha into its active soluble form, is an encouraging target. Many tumor necrosis factor alpha converting enzyme inhibitors have been the candidates of clinical trials but none of them have reached in to the market because of their broad spectrum inhibitory activity for other matrix metalloproteases. Selectivity of tumor necrosis factor alpha converting enzyme inhibition over matrix metalloproteases is of utmost importance. If selectivity is achieved successfully, side-effects can be over-ruled and this approach may become a novel therapy for treatment of rheumatoid arthritis and other inflammatory disorders. This cytokine not only plays a pivotal role in inflammatory conditions but also in some cancerous conditions. Thus, successful targeting of tumor necrosis factor alpha converting enzyme may result in multifunctional therapy.

  13. Relationship between the autoantibody and expression of β3-adrenoceptor in lung and heart.

    Directory of Open Access Journals (Sweden)

    Guobin Miao

    Full Text Available BACKGROUND: Evidences suggest that β3 -adrenoceptor (β3-AR plays an important role in heart failure (HF, although no data is reported indicating how these effects may change with the increasing age. Pulmonary congestion and edema are the major life-threatening complications associated with HF. The purpose of this study is to explore the relationship between the anti-β3-AR autoantibody and the expression of β3-AR in the lungs and heart for both aged patients and rats with HF. METHODS: Synthetic β3-AR peptides served as the target antigens in ELISA were used to screen the anti-β3-AR autoantibody in aged patients and rats. Two aged rat models were constructed based on aortic banding and sham-operation. The expression of β3-AR mRNA and protein in the lung and heart was measured in intervention and non-intervention groups by Western blot analysis at the baseline, 5(th, 7(th, 9(th and 11(th week, respectively. RESULTS: The frequency and titer of anti-β3-AR autoantibody in aged patients and rats with HF were higher than those in the control group (p<0.05. The expression of β3-AR mRNA and protein in pulmonary tissues decreased continually from the 7(th week (p<0.05, followed by HF observed during the 9(th week. The expression of β3-AR in myocardial tissues continued to increase after the 9(th week (p<0.05, and the expression of both β3-AR mRNA and protein in the BRL group [HF group with BRL37344 (4-[-[2-hydroxy-(3-chlorophenylethyl-amino] phenoxyacetic acid (a β3-AR agonist injection] was positively correlated with BRL37344 when compared with non-BRL group (HF group without BRL37344 injection (p<0.05. CONCLUSION: Anti-β3-AR autoantibody was detected in aged patients and rats with HF. The expression of β3-AR mRNA and protein in pulmonary tissues decreased continually, and began earlier than in the heart, but its expression in myocardial tissues increased continually and could be further promoted by β3-AR agonist.

  14. Antagonist-Elicited Cannabis Withdrawal in Humans

    Science.gov (United States)

    Gorelick, David A.; Goodwin, Robert S.; Schwilke, Eugene; Schwope, David M.; Darwin, William D.; Kelly, Deanna L.; McMahon, Robert P.; Liu, Fang; Ortemann-Renon, Catherine; Bonnet, Denis; Huestis, Marilyn A.

    2013-01-01

    Cannabinoid CB1 receptor antagonists have potential therapeutic benefits, but antagonist-elicited cannabis withdrawal has not been reported in humans. Ten male daily cannabis smokers received 8 days of increasingly frequent 20-mg oral Δ9-tetrahydrocannabinol (THC) dosages (40–120 mg/d) around-the-clock to standardize cannabis dependence while residing on a closed research unit. On the ninth day, double-blind placebo or 20- (suggested therapeutic dose) or 40-mg oral rimonabant, a CB1-cannabinoid receptor antagonist, was administered. Cannabis withdrawal signs and symptoms were assessed before and for 23.5 hours after rimonabant. Rimonabant, THC, and 11-hydroxy-THC plasma concentrations were quantified by mass spectrometry. The first 6 subjects received 20-mg rimonabant (1 placebo); the remaining 4 subjects received 40-mg rimonabant (1 placebo). Fourteen subjects enrolled; 10 completed before premature termination because of withdrawal of rimonabant from clinical development. Three of 5 subjects in the 20-mg group, 1 of 3 in the 40-mg group, and none of 2 in the placebo group met the prespecified withdrawal criterion of 150% increase or higher in at least 3 visual analog scales for cannabis withdrawal symptoms within 3 hours of rimonabant dosing. There were no significant associations between visual analog scale, heart rate, or blood pressure changes and peak rimonabant plasma concentration, area-under-the-rimonabant-concentration-by-time curve (0–8 hours), or peak rimonabant/THC or rimonabant/(THC + 11-hydroxy-THC) plasma concentration ratios. In summary, prespecified criteria for antagonist-elicited cannabis withdrawal were not observed at the 20- or 40-mg rimonabant doses. These data do not preclude antagonist-elicited withdrawal at higher rimonabant doses. PMID:21869692

  15. Antagonist-elicited cannabis withdrawal in humans.

    Science.gov (United States)

    Gorelick, David A; Goodwin, Robert S; Schwilke, Eugene; Schwope, David M; Darwin, William D; Kelly, Deanna L; McMahon, Robert P; Liu, Fang; Ortemann-Renon, Catherine; Bonnet, Denis; Huestis, Marilyn A

    2011-10-01

    Cannabinoid CB1 receptor antagonists have potential therapeutic benefits, but antagonist-elicited cannabis withdrawal has not been reported in humans. Ten male daily cannabis smokers received 8 days of increasingly frequent 20-mg oral Δ⁹-tetrahydrocannabinol (THC) dosages (40-120 mg/d) around-the-clock to standardize cannabis dependence while residing on a closed research unit. On the ninth day, double-blind placebo or 20- (suggested therapeutic dose) or 40-mg oral rimonabant, a CB1-cannabinoid receptor antagonist, was administered. Cannabis withdrawal signs and symptoms were assessed before and for 23.5 hours after rimonabant. Rimonabant, THC, and 11-hydroxy-THC plasma concentrations were quantified by mass spectrometry. The first 6 subjects received 20-mg rimonabant (1 placebo); the remaining 4 subjects received 40-mg rimonabant (1 placebo). Fourteen subjects enrolled; 10 completed before premature termination because of withdrawal of rimonabant from clinical development. Three of 5 subjects in the 20-mg group, 1 of 3 in the 40-mg group, and none of 2 in the placebo group met the prespecified withdrawal criterion of 150% increase or higher in at least 3 visual analog scales for cannabis withdrawal symptoms within 3 hours of rimonabant dosing. There were no significant associations between visual analog scale, heart rate, or blood pressure changes and peak rimonabant plasma concentration, area-under-the-rimonabant-concentration-by-time curve (0-8 hours), or peak rimonabant/THC or rimonabant/(THC + 11-hydroxy-THC) plasma concentration ratios. In summary, prespecified criteria for antagonist-elicited cannabis withdrawal were not observed at the 20- or 40-mg rimonabant doses. These data do not preclude antagonist-elicited withdrawal at higher rimonabant doses.

  16. Combining elements from two antagonists of formyl peptide receptor 2 generates more potent peptidomimetic antagonists

    DEFF Research Database (Denmark)

    Skovbakke, Sarah Line; Holdfeldt, Andre; Nielsen, Christina

    2017-01-01

    Structural optimization of a peptidomimetic antagonist of formyl peptide receptor 2 (FPR2) was explored by an approach involving combination of elements from the two most potent FPR2 antagonists described: a Rhodamine B-conjugated 10-residue gelsonin-derived peptide (i.e., PBP10, Rh......B-QRLFQVKGRR-OH) and the palmitoylated α-peptide/β-peptoid hybrid Pam-(Lys-βNspe)6-NH2. This generated an array of hybrid compounds from which a new subclass of receptor-selective antagonists was identified. The most potent representatives displayed activity in the low nanomolar range. The resulting stable and potent FPR2-selective...... antagonists (i.e., RhB-(Lys-βNphe)n-NH2; n = 4–6) are expected to become valuable tools in further elucidation of the physiological role of FPR2 in health and disease....

  17. Pharmacokinetics and Pharmacodynamics of Tamsulosin in its Modified-Release and Oral Controlled Absorption System Formulations

    NARCIS (Netherlands)

    Franco-Salinas, Gabriela; de La Rosette, Jean J. M. C. H.; Michel, Martin C.

    2010-01-01

    Tamsulosin is an alpha(1)-adrenoceptor antagonist used for the treatment of lower urinary tract symptoms that are suggestive of benign prostatic hyperplasia. It is mostly used in a modified-release (M R) Formulation. but an oral controlled absorption system (OCAS) and a 'without-water' tablet

  18. A potential aphrodisiac for female macaques.

    Science.gov (United States)

    Pertovaara, Antti; Linnankoski, Ilkka; Artchakov, Denis; Rämä, Pia; Carlson, Synnöve

    2004-09-01

    Earlier studies suggest that alpha2-adrenoceptor antagonists and dopamine receptor agonists may enhance sexual activity in human and nonhuman male primates. It is not known whether these compounds influence the sexual behavior of female primates. We determined whether the administration of a selective alpha2-adrenoceptor antagonist (atipamezole), a dopamine receptor agonist (apomorphine), or their combination to female Macaca arctoides (stumptail macaque) monkeys produces changes in sexual behavior of the female with a male. Following the administration of drugs to the female, the behavior of the female with a male stumptail was observed for 30 min. Atipamezole dose dependently (0.03-0.3 mg/kg im) increased short-time mounting behavior of the male and the total number of copulations. Apomorphine alone (0.125-0.25 mg/kg) or in combination with atipamezole had no significant effects on sexual behavior. The result indicates that a selective alpha2-adrenoceptor antagonist administered in the female stumptail increases sexual behavior of the male with the female. A plausible explanation for this finding is that a selective alpha2-adrenoceptor antagonist increases sexual arousal in female stumptails and this, possibly due to a change in psychosocial behavior of the female, triggers increased sexual activity in males.

  19. Similarities and differences between calcium antagonists: pharmacological aspects

    NARCIS (Netherlands)

    van Zwieten, P. A.; Pfaffendorf, M.

    1993-01-01

    Characteristics of three different calcium antagonist groups: Most important calcium antagonists used to treat cardiovascular disease belong to one of three main groups, phenylalkylamines, dihydropyridines and benzothiazepines. The best known drug in each group is verapamil, nifedipine and

  20. Protective effects of calcium antagonists in different organs and tissues

    NARCIS (Netherlands)

    van Zwieten, P. A.

    1993-01-01

    The therapeutic efficacy of calcium antagonists in ischemic disorders of various tissues is attributed to vasodilator and antivasoconstrictor activities. A direct, energy-conserving, antiischemic effect of certain calcium antagonists has been claimed repeatedly by basic scientists. The clinical

  1. Demystifying AlphaGo Zero as AlphaGo GAN

    OpenAIRE

    Dong, Xiao; Wu, Jiasong; Zhou, Ling

    2017-01-01

    The astonishing success of AlphaGo Zero\\cite{Silver_AlphaGo} invokes a worldwide discussion of the future of our human society with a mixed mood of hope, anxiousness, excitement and fear. We try to dymystify AlphaGo Zero by a qualitative analysis to indicate that AlphaGo Zero can be understood as a specially structured GAN system which is expected to possess an inherent good convergence property. Thus we deduct the success of AlphaGo Zero may not be a sign of a new generation of AI.

  2. $\\alpha$-Representation for QCD

    OpenAIRE

    Tuan, Richard Hong

    1998-01-01

    An $\\alpha$-parameter representation is derived for gauge field theories.It involves, relative to a scalar field theory, only constants and derivatives with respect to the $\\alpha$-parameters. Simple rules are given to obtain the $\\alpha$-representation for a Feynman graph with an arbitrary number of loops in gauge theories in the Feynman gauge.

  3. Alpha Theta Meditation: Phenomenological, neurophysiologic ...

    African Journals Online (AJOL)

    Alpha Theta Meditation: Phenomenological, neurophysiologic, mindfulness, mood, health and sport implications. ... the single alpha theta meditation was associated with elevated alpha and theta activity, as well as decrease in negative mood perceptions, especially with regard to anxiety, sadness and confusion scores.

  4. A monoclonal antibody raised against a thermo-stabilised β1-adrenoceptor interacts with extracellular loop 2 and acts as a negative allosteric modulator of a sub-set of β1-adrenoceptors expressed in stable cell lines.

    Science.gov (United States)

    Soave, Mark; Cseke, Gabriella; Hutchings, Catherine J; Brown, Alastair J H; Woolard, Jeanette; Hill, Stephen J

    2018-01-01

    Recent interest has focused on antibodies that can discriminate between different receptor conformations. Here we have characterised the effect of a monoclonal antibody (mAb3), raised against a purified thermo-stabilised turkey β 1 -adrenoceptor (β 1 AR-m23 StaR), on β 1 -ARs expressed in CHO-K1 or HEK 293 cells. Immunohistochemical and radioligand-binding studies demonstrated that mAb3 was able to bind to ECL2 of the tβ 1 -AR, but not its human homologue. Specific binding of mAb3 to tβ 1 -AR was inhibited by a peptide based on the turkey, but not the human, ECL2 sequence. Studies with [ 3 H]-CGP 12177 demonstrated that mAb3 prevented the binding of orthosteric ligands to a subset (circa 40%) of turkey β 1 -receptors expressed in both CHO K1 and HEK 293 cells. MAb3 significantly reduced the maximum specific binding capacity of [ 3 H]-CGP-12177 without influencing its binding affinity. Substitution of ECL2 of tβ 1 -AR with its human equivalent, or mutation of residues D186S, P187D, Q188E prevented the inhibition of [ 3 H]-CGP 12177 binding by mAb3. MAb3 also elicited a negative allosteric effect on agonist-stimulated cAMP responses. The identity of the subset of turkey β 1 -adrenoceptors influenced by mAb3 remains to be established but mAb3 should become an important tool to investigate the nature of β 1 -AR conformational states and oligomeric complexes. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  5. Alpha scintillation radon counting

    International Nuclear Information System (INIS)

    Lucas, H.F. Jr.

    1977-01-01

    Radon counting chambers which utilize the alpha-scintillation properties of silver activated zinc sulfide are simple to construct, have a high efficiency, and, with proper design, may be relatively insensitive to variations in the pressure or purity of the counter filling. Chambers which were constructed from glass, metal, or plastic in a wide variety of shapes and sizes were evaluated for the accuracy and the precision of the radon counting. The principles affecting the alpha-scintillation radon counting chamber design and an analytic system suitable for a large scale study of the 222 Rn and 226 Ra content of either air or other environmental samples are described. Particular note is taken of those factors which affect the accuracy and the precision of the method for monitoring radioactivity around uranium mines

  6. Ginkgolide X is a potent antagonist of anionic Cys-loop receptors with a unique selectivity profile at glycine receptors

    DEFF Research Database (Denmark)

    Jensen, Anders Asbjørn; Bergmann, Marianne Lerbæk; Sander, Tommy

    2010-01-01

    The novel ginkgolide analog ginkgolide X was characterized functionally at human glycine and gamma-aminobutyric acid type A receptors (GlyRs and GABAARs, respectively) in the fluorescence-based FLIPR Membrane Potential assay. The compound inhibited the signalling of all GABAAR subtypes included...... in the study with high nanomolar/low micromolar IC50 values, except the rho1 receptor at which it was a significantly weaker antagonist. Ginkgolide X also displayed high nanomolar/low micromolar IC50 values at the homomeric alpha1 and alpha2 GlyRs, whereas it was inactive at the heteromeric alpha1beta...... identified as the primary molecular determinant of the selectivity profile of ginkgolide X, and a 6' M2 ring consisting of five Thr residues was found to be of key importance for its activity at the GABAAR. Conformational analysis and docking of low-energy conformations of the native ginkgolide...

  7. Combining Alphas via Bounded Regression

    Directory of Open Access Journals (Sweden)

    Zura Kakushadze

    2015-11-01

    Full Text Available We give an explicit algorithm and source code for combining alpha streams via bounded regression. In practical applications, typically, there is insufficient history to compute a sample covariance matrix (SCM for a large number of alphas. To compute alpha allocation weights, one then resorts to (weighted regression over SCM principal components. Regression often produces alpha weights with insufficient diversification and/or skewed distribution against, e.g., turnover. This can be rectified by imposing bounds on alpha weights within the regression procedure. Bounded regression can also be applied to stock and other asset portfolio construction. We discuss illustrative examples.

  8. Differential constrictor responses of cephalic and caudal vasculature to α-adrenoceptor agonist after hind limb unloading.

    Science.gov (United States)

    Hutchings, Simon R; Kim, Jong Moo; Song, Dongzhe; Pang, Catherine C Y

    2010-11-01

    We examined the effects of hind limb unloading (HLU, 14 days) on constriction of carotid and iliac arterial beds in vivo in thiobutabarbital-anaesthetized rats and isolated carotid and iliac arteries in vitro. Both control and HLU rats had similar arterial pressure and carotid and iliac arterial flows. The HLU rats had increased carotid arterial but reduced iliac arterial constriction in response to methoxamine (α1-adrenoceptor agonist) in vivo. In contrast, constriction in response to methoxamine was reduced in the isolated carotid and unchanged in the iliac artery of HLU rats relative to control rats. Thus, HLU is associated with increased constriction of carotid arterial bed but reduced constriction of the isolated carotid artery, and reduced constriction of iliac arterial bed but unchanged constriction of the isolated iliac artery. These results show differential influence of HLU on constriction of cephalic and caudal arterial beds, and differential effect on constrictions of arterial beds relative to conduit arteries.

  9. Prefrontal cortical α2A-adrenoceptors and a possible primate model of attention deficit and hyperactivity disorder.

    Science.gov (United States)

    Ma, Chao-Lin; Sun, Xuan; Luo, Fei; Li, Bao-Ming

    2015-04-01

    Attention deficit and hyperactivity disorder (ADHD), a prevalent syndrome in children worldwide, is characterized by impulsivity, inappropriate inattention, and/or hyperactivity. It seriously afflicts cognitive development in childhood, and may lead to chronic under-achievement, academic failure, problematic peer relationships, and low self-esteem. There are at least three challenges for the treatment of ADHD. First, the neurobiological bases of its symptoms are still not clear. Second, the commonly prescribed medications, most showing short-term therapeutic efficacy but with a high risk of serious side-effects, are mainly based on a dopamine mechanism. Third, more novel and efficient animal models, especially in nonhuman primates, are required to accelerate the development of new medications. In this article, we review research progress in the related fields, focusing on our previous studies showing that blockade of prefrontal cortical α2A-adrenoceptors in monkeys produces almost all the typical behavioral symptoms of ADHD.

  10. Antagonistic parent-offspring co-adaptation.

    Directory of Open Access Journals (Sweden)

    Mathias Kölliker

    2010-01-01

    Full Text Available 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.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.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.

  11. Antagonist potential of Trichoderma indigenous isolates for ...

    African Journals Online (AJOL)

    STORAGESEVER

    2009-10-19

    Oct 19, 2009 ... Full Length Research Paper. Antagonist potential of Trichoderma indigenous isolates for biological control of Phytophthora palmivora the causative agent of black pod disease on cocoa (Theobroma cacao L.) in Côte d'Ivoire. J. Mpika1,4*, I. B. Kébé1, A. E. Issali2, F.K. N'Guessan1, S. Druzhinina3, ...

  12. Functional characterisation of the human alpha1 glycine receptor in a fluorescence-based membrane potential assay

    DEFF Research Database (Denmark)

    Jensen, Anders A.; Kristiansen, Uffe

    2004-01-01

    screening assay. In the patch-clamp assay, the alpha1 GlyR exhibited the properties expected from a strychnine-sensitive glycine-gated chloride channel. In the FMP assay exposure of the cell line to GlyR agonists elicited a concentration-dependent increase in fluorescent intensity, a signal that could...... and RU 5135>strychnine>brucine>PMBA=picrotoxin>atropine for the antagonists. The actions of three allosteric modulators at the alpha1 GlyR cell line were also characterised in the FMP assay. Micromolar concentrations of Zn2+ inhibited alpha1 GlyR signalling but in contrast to previous reports the metal...

  13. Medicinal Chemistry of Competitive Kainate Receptor Antagonists

    Science.gov (United States)

    2010-01-01

    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

  14. The sexually antagonistic genes of Drosophila melanogaster.

    Directory of Open Access Journals (Sweden)

    Paolo Innocenti

    2010-03-01

    Full Text Available When selective pressures differ between males and females, the genes experiencing these conflicting evolutionary forces are said to be sexually antagonistic. Although the phenotypic effect of these genes has been documented in both wild and laboratory populations, their identity, number, and location remains unknown. Here, by combining data on sex-specific fitness and genome-wide transcript abundance in a quantitative genetic framework, we identified a group of candidate genes experiencing sexually antagonistic selection in the adult, which correspond to 8% of Drosophila melanogaster genes. As predicted, the X chromosome is enriched for these genes, but surprisingly they represent only a small proportion of the total number of sex-biased transcripts, indicating that the latter is a poor predictor of sexual antagonism. Furthermore, the majority of genes whose expression profiles showed a significant relationship with either male or female adult fitness are also sexually antagonistic. These results provide a first insight into the genetic basis of intralocus sexual conflict and indicate that genetic variation for fitness is dominated and maintained by sexual antagonism, potentially neutralizing any indirect genetic benefits of sexual selection.

  15. Pharmacological analysis of calcium antagonist receptors

    International Nuclear Information System (INIS)

    Reynolds, I.J.

    1987-01-01

    This work focuses on two aspects of the action of calcium antagonist drugs, namely, the interaction of drugs with receptors for verapamil-like calcium antagonists, and the interactions of drugs with voltage-sensitive calcium fluxes in rat brain synaptosomes. From binding studies I have found that the ligand of choice for labeling the verapamil receptor is (-)[ 3 H]desmethoxy-verapamil. This drug labels potently, reversibly and stereoselectively two receptors in membranes prepared from rat brain and rabbit skeletal muscle tissues. In equilibrium studies dihydropyridine calcium antagonists interact in a non-competitive fashion, while many non-DHPs are apparently competitive. In-depth kinetic studies in skeletal muscle membranes indicate that the two receptors are linked in a negative heterotropic fashion, and that low-affinity binding of (-) [ 3 H]desmethoxy-verapamil may be to the diltiazem receptor. However, these studies were not able to distinguish between the hypothesis that diltiazem binds to spatially separate, allosterically coupled receptors, and the hypothesis that diltiazem binds to a subsite of the verapamil receptor

  16. NMDA Receptor Antagonists for Treatment of Depression

    Directory of Open Access Journals (Sweden)

    Zeynep Ates-Alagoz

    2013-04-01

    Full Text Available Depression is a psychiatric disorder that affects millions of people worldwide. Individuals battling this disorder commonly experience high rates of relapse, persistent residual symptoms, functional impairment, and diminished well-being. Medications have important utility in stabilizing moods and daily functions of many individuals. However, only one third of patients had considerable improvement with a standard antidepressant after 2 months and all patients had to deal with numerous side effects. The N-methyl-d-aspartate (NMDA receptor family has received special attention because of its critical role in psychiatric disorders. Direct targeting of the NMDA receptor could result in more rapid antidepressant effects. Antidepressant-like effects of NMDA receptor antagonists have been demonstrated in different animal models. MK-801 (a use-dependent channel blocker, and CGP 37849 (an NMDA receptor antagonist have shown antidepressant properties in preclinical studies, either alone or combined with traditional antidepressants. A recent development is use of ketamine clinically for refractory depression. The purpose of this review is to examine and analyze current literature on the role of NMDA receptor antagonists for treatment of depression and whether this is a feasible route in drug discovery.

  17. Adrenergic receptor effects and antihypertensive actions of beta-adrenoceptor-blocking agents with ancillary properties.

    Science.gov (United States)

    Imai, S; Nakahara, H; Nakazawa, M; Takeda, K

    1988-01-01

    The acute antihypertensive effects and possible underlying mechanisms of 3 beta-adrenergic-blocking drugs with alpha-blocking activity, i.e. labetalol, drugs with alpha-blocking activity, i.e. labetalol, nipradilol and arotinolol, were studied in conscious spontaneously hypertensive rats (SHR) and compared with the effects of prazosin, propranolol and hydralazine. Prazosin produced a dose-dependent antihypertensive effect which paralleled inhibition of the pressor response to phenylephrine. Labetalol (30 mg/kg), nipradilol (30 and 100 mg/kg) and arotinolol (30 and 100 mg/kg) also produced a fall in blood pressure. However, inhibition of the pressor response to phenylephrine was not seen in association with the antihypertensive effect after the lower dose of nipradilol and arotinolol. Propranolol (100 mg/kg) did not lower blood pressure. These results suggest that a mechanism(s) other than an alpha-adrenergic-blocking effect plays a role in the acute antihypertensive effects produced by the lower dose of nipradilol and arotinolol.

  18. Influence of the low thyroid state in diabetes mellitus on cardiac function and inotropic responsiveness to alpha 1-adrenoceptor stimulation: comparison with the role of hypothyroidism alone

    NARCIS (Netherlands)

    Beenen, O. H.; Pfaffendorf, M.; van Zwieten, P. A.

    1996-01-01

    The hypothyroid state accompanying diabetes mellitus has been suggested to be partly responsible for the diabetes-induced metabolic, hemodynamic, and pharmacological cardiovascular changes. We assessed the effectivity of streptozotocin (STZ) to induce diabetes mellitus and a hypothyroid state.

  19. Alpha1a-Adrenoceptor Genetic Variant Triggers Vascular Smooth Muscle Cell Hyperproliferation and Agonist Induced Hypertrophy via EGFR Transactivation Pathway.

    Directory of Open Access Journals (Sweden)

    Irina Gradinaru

    Full Text Available α1a Adrenergic receptors (α1aARs are the predominant AR subtype in human vascular smooth muscle cells (SMCs. α1aARs in resistance vessels are crucial in the control of blood pressure, yet the impact of naturally occurring human α1aAR genetic variants in cardiovascular disorders remains poorly understood. To this end, we present novel findings demonstrating that 3D cultures of vascular SMCs expressing human α1aAR-247R (247R genetic variant demonstrate significantly increased SMC contractility compared with cells expressing the α1aAR-WT (WT receptor. Stable expression of 247R genetic variant also triggers MMP/EGFR-transactivation dependent serum- and agonist-independent (constitutive hyperproliferation and agonist-dependent hypertrophy of SMCs. Agonist stimulation reduces contractility Using pathway-specific inhibitors we determined that the observed hyperproliferation of 247R-expressing cells is triggered via β-arrestin1/Src/MMP-2/EGFR/ERK-dependent mechanism. MMP-2-specific siRNA inhibited 247R-triggered hyperproliferation indicating MMP-2 involvement in 247R-triggered hyperproliferation in SMCs. β-arrestin1-specific shRNA also inhibited 247R-triggered hyperproliferation but did not affect hypertrophy in 247R-expressing SMCs, indicating that agonist-dependent hypertrophy is independent of β-arrestin1. Our data reveal that in different cardiovascular cells the same human receptor genetic variant can activate alternative modulators of the same signaling pathway. Thus, our findings in SMCs demonstrate that depending on the type of cells expressing the same receptor (or receptor variant, different target-specific inhibitors could be used to modulate aberrant hyperproliferative or hypertrophic pathways in order to restore normal phenotype.

  20. Effect of Block of alpha(1)-adrenoceptors on Overall Motor Activity but not on Spatial Cognition in the Object-Position Recognition Task

    Czech Academy of Sciences Publication Activity Database

    Levčík, David; Stuchlík, Aleš; Klement, Daniel

    2013-01-01

    Roč. 62, č. 5 (2013), s. 561-567 ISSN 0862-8408 R&D Projects: GA ČR(CZ) GBP304/12/G069; GA MZd(CZ) NT13386 Grant - others:Rada Programu interní podpory projektů mezinárodní spolupráce AV ČR(CZ) M200111204 Institutional support: RVO:67985823 Keywords : recognition * prazosin * rat * learning Subject RIV: FH - Neurology Impact factor: 1.487, year: 2013

  1. From the Cover: Glutamate antagonists limit tumor growth

    Science.gov (United States)

    Rzeski, Wojciech; Turski, Lechoslaw; Ikonomidou, Chrysanthy

    2001-05-01

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

  2. Treatment of alpha bearing wastes

    International Nuclear Information System (INIS)

    1988-01-01

    This report deals with the current state of the art of alpha waste treatment, which is an integral part of the overall nuclear waste management system. The International Atomic Energy Agency (IAEA) defines alpha bearing waste as 'waste containing one or more alpha emitting radionuclides, usually actinides, in quantities above acceptable limits'. The limits are established by national regulatory bodies. The limits above which wastes are considered as alpha contaminated refer to the concentrations of alpha emitters that need special consideration for occupational exposures and/or potential safety, health, or environmental impact during one or more steps from generation through disposal. Owing to the widespread use of waste segregation by source - that is, based upon the 'suspect origin' of the material - significant volumes of waste are being handled as alpha contaminated which, in fact, do not require such consideration by reason of risk or environmental concern. The quantification of de minimis concepts by national regulatory bodies could largely contribute to the safe reduction of waste volumes and associated costs. Other factors which could significantly contribute to the reduction of alpha waste arisings are an increased application of assaying and sorting, instrumentation and the use of feedback mechanisms to control or modify the processes which generate these wastes. Alpha bearing wastes are generated during fabrication and reprocessing of nuclear fuels, decommissioning of alpha contaminated facilities, and other activities. Most alpha wastes are contact handled, but a small portion may require shielding or remote handling because of high levels of neutron (n), beta (β), or gamma (γ) emissions associated with the waste material. This report describes the sources and characteristics of alpha wastes and strategies for alpha waste management. General descriptions of treatment processes for solid and liquid alpha wastes are included. 71 refs, 14 figs, 9 tabs

  3. The alpha effect

    International Nuclear Information System (INIS)

    Anon.

    1982-01-01

    Much of the recent interest in RAM system reliability stems from concern over alpha particle soft error rates reported for the initial 64 k RAMs. With increasing memory density likely in the next few years the problem of soft errors is rearing its head again. A few years ago ITT carried out experiments on 16k RAMs and found no significant problems. However, recent tests have shown a raise in the number of soft errors with 64k RAMs, and the launch of 256k and 512k memories is likely to make the problem acute

  4. Alpha-mannosidosis

    Directory of Open Access Journals (Sweden)

    Nilssen Øivind

    2008-07-01

    Full Text Available Abstract Alpha-mannosidosis is an inherited lysosomal storage disorder characterized by immune deficiency, facial and skeletal abnormalities, hearing impairment, and intellectual disability. It occurs in approximately 1 of 500,000 live births. The children are often born apparently normal, and their condition worsens progressively. Some children are born with ankle equinus or develop hydrocephalus in the first year of life. Main features are immune deficiency (manifested by recurrent infections, especially in the first decade of life, skeletal abnormalities (mild-to-moderate dysostosis multiplex, scoliosis and deformation of the sternum, hearing impairment (moderate-to-severe sensorineural hearing loss, gradual impairment of mental functions and speech, and often, periods of psychosis. Associated motor function disturbances include muscular weakness, joint abnormalities and ataxia. The facial trait include large head with prominent forehead, rounded eyebrows, flattened nasal bridge, macroglossia, widely spaced teeth, and prognathism. Slight strabismus is common. The clinical variability is significant, representing a continuum in severity. The disorder is caused by lysosomal alpha-mannosidase deficiency. Alpha-mannosidosis is inherited in an autosomal recessive fashion and is caused by mutations in the MAN2B1 gene located on chromosome 19 (19 p13.2-q12. Diagnosis is made by measuring acid alpha-mannosidase activity in leukocytes or other nucleated cells and can be confirmed by genetic testing. Elevated urinary secretion of mannose-rich oligosaccharides is suggestive, but not diagnostic. Differential diagnoses are mainly the other lysosomal storage diseases like the mucopolysaccharidoses. Genetic counseling should be given to explain the nature of the disease and to detect carriers. Antenatal diagnosis is possible, based on both biochemical and genetic methods. The management should be pro-active, preventing complications and treating

  5. Alpha-Amylase Activity in Blood Increases after Pharmacological, But Not Psychological, Activation of the Adrenergic System.

    Directory of Open Access Journals (Sweden)

    Urs M Nater

    Full Text Available Alpha-amylase in both blood and saliva has been used as a diagnostic parameter. While studies examining alpha-amylase activity in saliva have shown that it is sensitive to physiological and psychological challenge of the adrenergic system, no challenge studies have attempted to elucidate the role of the adrenergic system in alpha-amylase activity in blood. We set out to examine the impact of psychological and pharmacological challenge on alpha-amylase in blood in two separate studies.In study 1, healthy subjects were examined in a placebo-controlled, double-blind paradigm using yohimbine, an alpha2-adrenergic antagonist. In study 2, subjects were examined in a standardized rest-controlled psychosocial stress protocol. Alpha-amylase activity in blood was repeatedly measured in both studies.Results of study 1 showed that alpha-amylase in blood is subject to stronger increases after injection of yohimbine compared to placebo. In study 2, results showed that there was no significant effect of psychological stress compared to rest.Alpha-amylase in blood increases after pharmacological activation of the adrenergic pathways suggesting that sympathetic receptors are responsible for these changes. Psychological stress, however, does not seem to have an impact on alpha-amylase in blood. Our findings provide insight into the mechanisms underlying activity changes in alpha-amylase in blood in healthy individuals.

  6. Dataset of mRNA levels for dopaminergic receptors, adrenoceptors and tyrosine hydroxylase in lymphocytes from subjects with clinically isolated syndromes

    Directory of Open Access Journals (Sweden)

    Marco Cosentino

    2016-12-01

    Full Text Available This data article presents a dataset of mRNA levels for dopaminergic receptors, adrenoceptors and for tyrosine hydoxylase, the rate-limiting enzyme in the synthesis of catecholamines, in peripheral blood mononuclear cells as well as in CD4+ T effector and regulatory cells from subjects with clinically isolated syndromes (CIS, which is a first episode of neurological disturbance(s suggestive of multiple sclerosis. CIS subjects are divided into two groups according to their eventual progression, after 12 months from CIS, to clinically established multiple sclerosis. The data reported are related to the article entitled "Dopaminergic receptors and adrenoceptors in circulating lymphocytes as putative biomarkers for the early onset and progression of multiple sclerosis" (M. Cosentino, M. Zaffaroni, M. Legnaro, R. Bombelli, L. Schembri, D. Baroncini, A. Bianchi, R. Clerici, M. Guidotti, P. Banfi, G. Bono, F. Marino, 2016 [1].

  7. A model for short alpha-neurotoxin bound to nicotinic acetylcholine receptor from Torpedo californica.

    Science.gov (United States)

    Mordvintsev, Dmitry Y; Polyak, Yakov L; Kuzmine, Dmitry A; Levtsova, Olga V; Tourleigh, Yegor V; Kasheverov, Igor E

    2006-01-01

    Short- and long-chain alpha-neurotoxins from snake venoms are potent blockers of nicotinic acetylcholine receptors (nAChRs). Short alpha-neurotoxins consist of 60-62 amino acid residues and include 4 disulfide bridges, whereas long alpha-neurotoxins have 66-75 residues and 5 disulfides. The spatial structure of these toxins is built by three loops, I-III "fingers," confined by four disulfide bridges; the fifth disulfide of long-chain alpha-neurotoxins is situated close to the tip of central loop II. An accurate knowledge of the mode of alpha-neurotoxin-nAChR interaction is important for rational design of new nAChR agonists and antagonists for medical purposes. Ideas on the topography of toxin-nAChR complexes were based until recently on nAChR interactions with selectively labeled alpha-neurotoxins, mutations in toxins, nAChR, or both. Recently, crystal structures have been solved for the Torpedo marmorata nAChR (4A[Unwin, 2005]) and for the acetylcholine-binding protein (AChBP) complexed with mollusk alpha-conotoxin (2.4 A[Celie et al., 2005]) or alpha-cobratoxin, long-chain alpha-neurotoxin (4 A [Bourne et al., 2005]). However, there were no angstrom-resolution models for complexes of short-chain alpha-neurotoxins. Here, we report the model of the Torpedo californica nAChR extracellular domain complexed to a short-chain alpha-neurotoxin II (NTII) from Naja oxiana cobra venom.

  8. Anticonvulsant and reproductive toxicological studies of the imidazole-based histamine H3R antagonist 2-18 in mice

    Directory of Open Access Journals (Sweden)

    Bastaki SM

    2018-01-01

    Full Text Available Salim M Bastaki,1 Yousef M Abdulrazzaq,2 Mohamed Shafiullah,1 Małgorzata Więcek,3 Katarzyna Kieć-Kononowicz,3 Bassem Sadek1 1Department of Pharmacology and Therapeutics, College of Medicine and Health Science, United Arab Emirates University, Al Ain, 2Department of Medical Education, Dubai Health Authority, Dubai, UAE; 3Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna, Kraków, Poland Abstract: The imidazole-based H3R antagonist 2-18 with high in vitro H3R antagonist affinity, excellent in vitro selectivity profile, and high in vivo H3R antagonist potency was tested for its anticonvulsant effect in maximal electroshock (MES-induced convulsions in mice having valproic acid (VPA as a reference antiepileptic drug (AED. Additionally, H3R antagonist 2-18 was evaluated for its reproductive toxicity in the same animal species. The results show that acute systemic administration (intraperitoneal; i.p. of H3R antagonist 2-18 (7.5, 15, 30, and 60 mg/kg, i.p. significantly and dose dependently protected male as well as female mice against MES-induced convulsion. The protective action observed for H3R antagonist 2-18 in both mice sexes was comparable to that of VPA and was reversed when mice were pretreated with the selective H3R agonist (R-alpha-methylhistamine (RAMH, 10 mg/kg, i.p.. Moreover, the results show that acute systemic administration of single (7.5, 15, 30, or 60 mg/kg, i.p. or multiple doses (15×3 mg/kg, i.p. of H3R antagonist 2-18 on gestation day (GD 8 or 13 did not affect the maternal body weight of mice when compared with the control group. Furthermore, no significant differences were observed in the average number of implantations and resorptions between the control and H3R antagonist 2-18-treated group at the early stages of gestation and the organogenesis period. However, oral treatment with H3R antagonist 2-18 (15 mg/kg on GD 8 induced a reduced number of

  9. Combination decongestion therapy in hospitalized heart failure: loop diuretics, mineralocorticoid receptor antagonists and vasopressin antagonists.

    Science.gov (United States)

    Vaduganathan, Muthiah; Mentz, Robert J; Greene, Stephen J; Senni, Michele; Sato, Naoki; Nodari, Savina; Butler, Javed; Gheorghiade, Mihai

    2015-01-01

    Congestion is the most common reason for admissions and readmissions for heart failure (HF). The vast majority of hospitalized HF patients appear to respond readily to loop diuretics, but available data suggest that a significant proportion are being discharged with persistent evidence of congestion. Although novel therapies targeting congestion should continue to be developed, currently available agents may be utilized more optimally to facilitate complete decongestion. The combination of loop diuretics, natriuretic doses of mineralocorticoid receptor antagonists and vasopressin antagonists represents a regimen of currently available therapies that affects early and persistent decongestion, while limiting the associated risks of electrolyte disturbances, hemodynamic fluctuations, renal dysfunction and mortality.

  10. Investigation of orexin-2 selective receptor antagonists: Structural modifications resulting in dual orexin receptor antagonists.

    Science.gov (United States)

    Skudlarek, Jason W; DiMarco, Christina N; Babaoglu, Kerim; Roecker, Anthony J; Bruno, Joseph G; Pausch, Mark A; O'Brien, Julie A; Cabalu, Tamara D; Stevens, Joanne; Brunner, Joseph; Tannenbaum, Pamela L; Wuelfing, W Peter; Garson, Susan L; Fox, Steven V; Savitz, Alan T; Harrell, Charles M; Gotter, Anthony L; Winrow, Christopher J; Renger, John J; Kuduk, Scott D; Coleman, Paul J

    2017-03-15

    In an ongoing effort to explore the use of orexin receptor antagonists for the treatment of insomnia, dual orexin receptor antagonists (DORAs) were structurally modified, resulting in compounds selective for the OX 2 R subtype and culminating in the discovery of 23, a highly potent, OX 2 R-selective molecule that exhibited a promising in vivo profile. Further structural modification led to an unexpected restoration of OX 1 R antagonism. Herein, these changes are discussed and a rationale for selectivity based on computational modeling is proposed. Copyright © 2017 Elsevier Ltd. All rights reserved.

  11. A comparison of β-adrenoceptors and muscarinic cholinergic receptors in tissues of brown bullhead catfish (Ameiurus nebulosus) from the black river and old woman creek, Ohio

    Science.gov (United States)

    Steevens, Jeffery A.; Baumann, Paul C.; Jones, Susan B.

    1996-01-01

    β-Adrenoceptors (βARs) and muscarinic cholinergic receptors were measured in brain, gill, and heart tissues of brown bullhead catfish exposed to polycyclic aromatic hydrocarbons in the Black River, Ohio, USA, and were compared to values from Old Woman Creek, Ohio, a reference site. A decreased number of βARs were found in the gill from Black River fish, possibly indicating a compensatory response subsequent to chemical stress.

  12. Effects of ovarian steroids upon responses mediated by adrenoceptors in separated layers of the myometrium and in the costo-uterine muscle of the guinea-pig

    Science.gov (United States)

    Hartley, Margaret L.; Pennefather, Jocelyn N.; Story, Margot E.

    1983-01-01

    1 This study describes the effects of ovarian steroid hormones upon the responses to adrenoceptor agonists of isolated myometrium, separated into its longitudinal and circular layers, and of costo-uterine muscle from guinea-pigs. The preparations were field-stimulated at 100 s intervals, and the adrenoceptor agonists phenylephrine and isoprenaline produced enhancement or inhibition of the evoked contractions. 2 Isoprenaline produced propranolol-sensitive inhibitory effects in longitudinal and circular myometrium and costo-uterine muscle preparations from animals from all experimental groups: i.e. from nonsteroid-treated animals (ovariectomized and intact); intact animals treated with either oestrogen or progesterone alone; ovariectomized animals treated with oestrogen; ovariectomized and intact animals treated with progesterone following oestrogen priming; and from animals 1-4 days post-partum. Longitudinal myometrial preparations from progesterone-treated oestrogen-primed and from post-partum animals were most sensitive to this agonist. 3 Phenylephrine produced phentolamine-sensitive excitatory effects in circular myometrial and costo-uterine muscle preparations from animals from all the experimental groups. In contrast, propranolol-sensitive inhibitory responses to phenylephrine occurred in longitudinal myometrial preparations taken from animals treated with progesterone following oestrogen priming, and from post-partum animals. Longitudinal myometrium from animals from the remaining experimental groups exhibited phentolamine-sensitive excitatory responses to phenylephrine. 4 The basis for the selective effect upon the longitudinal myometrium of exposure to progesterone following a period of oestrogen priming, is discussed. The results described are consistent with the possibility that in the longitudinal layer of guinea-pig uterus exposed to progesterone following oestrogen priming there is an increase in the proportion of β-adrenoceptors in this layer. This

  13. Alpha activity measurement with lsc

    International Nuclear Information System (INIS)

    Dobrin, R. I.; Dulama, C. N.; Ciocirlan, C. N.; Toma, A.; Stoica, S. M.; Valeca, M.

    2013-01-01

    Recently, we showed that the alpha activity in liquid samples can be measured using a liquid scintillation analyzer without alpha/beta discrimination capability. The purpose of this work was to evaluate the performances of the method and to optimize the procedure of the sample preparation. A series of tests was performed to validate the procedure of alpha emitting radionuclides extraction in aqueous samples with Actinide Resin, especially regarding to the contact time required to extract all alpha nuclides. The main conclusions were that a minimum 18 hours stirring time is needed to achieve a percent recovery of the alpha nuclides grater than 90% and that the counting efficiency of alphas measurements with LSC is nearly 100%. (authors)

  14. Reduction of periodontal pathogens adhesion by antagonistic strains.

    Science.gov (United States)

    Van Hoogmoed, C G; Geertsema-Doornbusch, G I; Teughels, W; Quirynen, M; Busscher, H J; Van der Mei, H C

    2008-02-01

    Periodontitis results from a shift in the subgingival microflora into a more pathogenic direction with Porphyromonas gingivalis, Prevotella intermedia, and Actinobacillus actinomycetemcomitans considered as periodontopathogens. In many cases, treatment procures only a temporary shift towards a less pathogenic microflora. An alternative treatment could be the deliberate colonization of pockets with antagonistic microorganisms to control the adhesion of periodontopathogens. The aim of this study was to identify bacterial strains that reduce adhesion of periodontopathogens to surfaces. Streptococcus sanguinis, Streptococcus crista, Streptococcus salivarius, Streptococcus mitis, Actinomyces naeslundii, and Haemophilus parainfluenzae were evaluated as potential antagonists against P. gingivalis ATCC 33277, P. intermedia ATCC 49046, and A. actinomycetemcomitans ATCC 43718 as periodontopathogens. Adhesion of periodontopathogens to the bottom plate of a parallel plate flow chamber was studied in the absence (control) and the presence of pre-adhering antagonistic strains up to a surface coverage of 5%. The largest reduction caused by antagonistic strains was observed for P. gingivalis. All antagonistic strains except S. crista ATCC 49999 inhibited the adhesion of P. gingivalis by at least 1.6 cells per adhering antagonist, with the largest significant reduction observed for A. naeslundii ATCC 51655 (3.8 cells per adhering antagonist). Adhering antagonists had a minimal effect on the adhesion of A. actinomycetemcomitans ATCC 43718. Intermediate but significant reductions were perceived for P. intermedia, most notably caused by S. mitis BMS. The adhesion of P. gingivalis was inhibited best by antagonistic strains, while S. mitis BMS appeared to be the most successful antagonist.

  15. Synthesis and evaluation of 1'-[[sup 18]F]fluorometoprolol as a potential tracer for the visualization of [beta]-adrenoceptors with PET

    Energy Technology Data Exchange (ETDEWEB)

    Groot, T.J. de; Waarde, A. van; Elsinga, P.H.; Visser, G.M.; Vaalburg, Willem (Groningen Univ. Hospital (Netherlands)); Brodde, O.-E. (Essen Univ. (Germany). Biochemisches Forschungslabor)

    1993-07-01

    ([+-])-1'[[sup 18]F]Fluorometoprol 4 was prepared from desisopropylmetoprolol and [[sup 18]F]fluoroisopropyl tosylate 2 with a radiochemical yield of 2% [corrected for decay to end of bombardment (EOB), synthesis time 90 min]. Synthon 2 was prepared from (S)-1,2-propanediol di(p-toluenesulfonate) in 45% radiochemical yield. Compound 4 shows in two in vitro assays a similar affinity at [beta]-adrenoceptors (about 0.3 [mu]M) as metroprolol 5, but with a slightly higher [beta][sub 1]/[beta][sub 2]-adrenoceptor selectivity ratio (48.6 vs 30.7). In vivo experiments with 4 showed almost no receptor-mediated uptake in the heart probably because the affinity of (fluoro)metoprolol for the [beta][sub 1]-adrenoceptors is too low for successful imaging. However, the in vitro experiments suggest that the fluoroisopropyl group is suitable for the synthesis of [[sup 18]F]fluorinated [beta][sub 1]-adrenergic receptor binding ligands. (Author).

  16. Cutting edge: bone morphogenetic protein antagonists Drm/Gremlin and Dan interact with Slits and act as negative regulators of monocyte chemotaxis.

    Science.gov (United States)

    Chen, Bo; Blair, Donald G; Plisov, Sergei; Vasiliev, Gennady; Perantoni, Alan O; Chen, Qian; Athanasiou, Meropi; Wu, Jane Y; Oppenheim, Joost J; Yang, De

    2004-11-15

    Drm/Gremlin and Dan, two homologous secreted antagonists of bone morphogenic proteins, have been shown to regulate early development, tumorigenesis, and renal pathophysiology. In this study, we report that Drm and Dan physically and functionally interact with Slit1 and Slit2 proteins. Drm binding to Slits depends on its glycosylation and is not interfered with by bone morphogenic proteins. Importantly, Drm and Dan function as inhibitors for monocyte migration induced by stromal cell-derived factor 1alpha (SDF-1alpha) or fMLP. The inhibition of SDF-1alpha-induced monocyte chemotaxis by Dan is not due to blocking the binding of SDF-1alpha to its receptor. Thus, the results identify that Drm and Dan can interact with Slit proteins and act as inhibitors of monocyte chemotaxis, demonstrating a previously unidentified biological role for these proteins.

  17. Diphenyl Purine Derivatives as Peripherally Selective Cannabinoid Receptor 1 Antagonists

    Science.gov (United States)

    Fulp, Alan; Bortoff, Katherine; Zhang, Yanan; Seltzman, Herbert; Mathews, James; Snyder, Rodney; Fennell, Tim; Maitra, Rangan

    2015-01-01

    Cannabinoid receptor 1 (CB1) antagonists are potentially useful for the treatment of several diseases. However, clinical development of several CB1 antagonists was halted due to central nervous system (CNS)-related side effects including depression and suicidal ideation in some users. Recently, studies have indicated that selective regulation of CB1 receptors in the periphery is a viable strategy for treating several important disorders. Past efforts to develop peripherally selective antagonists of CB1 have largely targeted rimonabant, an inverse agonist of CB1. Reported here are our efforts toward developing a peripherally selective CB1 antagonist based on the otenabant scaffold. Even though otenabant penetrates the CNS, it is unique among CB1 antagonists that have been clinically tested because it has properties that are normally associated with peripherally selective compounds. Our efforts have resulted in an orally absorbed compound that is a potent and selective CB1 antagonist with limited penetration into the CNS. PMID:23098108

  18. Alpha wastes treatment

    International Nuclear Information System (INIS)

    Thouvenot, P.

    2000-01-01

    Alter 2004, the alpha wastes issued from the Commissariat a l'Energie Atomique installations will be sent to the CEDRA plant. The aims of this installation are decontamination and wastes storage. Because of recent environmental regulations concerning ozone layer depletion, the use of CFC 113 in the decontamination unit, as previously planned, is impossible. Two alternatives processes are studied: the AVD process and an aqueous process including surfactants. Best formulations for both processes are defined issuing degreasing kinetics. It is observed that a good degreasing efficiency is linked to a good decontamination efficiency. Best results are obtained with the aqueous process. Furthermore, from the point of view of an existing waste treatment unit, the aqueous process turns out to be more suitable than the AVD process. (author)

  19. Hypocretin antagonists in insomnia treatment and beyond.

    Science.gov (United States)

    Ruoff, Chad; Cao, Michelle; Guilleminault, Christian

    2011-01-01

    Hypocretin neuropeptides have been shown to regulate transitions between wakefulness and sleep through stabilization of sleep promoting GABAergic and wake promoting cholinergic/monoaminergic neural pathways. Hypocretin also influences other physiologic processes such as metabolism, appetite, learning and memory, reward and addiction, and ventilatory drive. The discovery of hypocretin and its effect upon the sleep-wake cycle has led to the development of a new class of pharmacologic agents that antagonize the physiologic effects of hypocretin (i.e. hypocretin antagonists). Further investigation of these agents may lead to novel therapies for insomnia without the side-effect profile of currently available hypnotics (e.g. impaired cognition, confusional arousals, and motor balance difficulties). However, antagonizing a system that regulates the sleep-wake cycle while also influencing non-sleep physiologic processes may create an entirely different but equally concerning side-effect profile such as transient loss of muscle tone (i.e. cataplexy) and a dampened respiratory drive. In this review, we will discuss the discovery of hypocretin and its receptors, hypocretin and the sleep-wake cycle, hypocretin antagonists in the treatment of insomnia, and other implicated functions of the hypocretin system.

  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. 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

  2. Novel 4-phenylpiperidine-2,6-dione derivatives. Ligands for α1-adrenoceptor subtypes

    KAUST Repository

    Romeo, Giuseppe F.

    2011-07-01

    A number of new 4-phenylpiperidine-2,6-diones bearing at the 1-position an ω-[4-(substituted phenyl)piperazin-1-yl]alkyl moiety were designed and synthesized as ligands for the α1-adrenergic receptor (α1-AR) subtypes. Some synthesized compounds, tested in binding assays for the human cloned α1A-, α1B-, and α1D-AR subtypes, displayed affinities in the nanomolar range. Highest affinity values were found in derivatives having a butyl connecting chain between the 4-phenylpiperidine-2,6-dione and the phenylpiperazinyl moieties. 1-[4-[4-(2-Methoxyphenyl)piperazin-1-yl]butyl]-4-phenylpiperidine-2,6- dione (34) showed the best affinity for the α1A-AR (pK i = 8.74) and 10-fold selectivity compared to the other two α1-AR subtypes. Some representative compounds were also tested in order to evaluate their effects on the signal transduction pathway coupled to α1-AR subtypes. They all blocked norepinephrine-induced stimulation of inositol phospholipid hydrolysis, thus behaving as antagonists. Binding data were used to refine a previously developed pharmacophoric model for α1D-ARs. The revised model shows a highly predictive power and could be useful for the future design of high affinity α1D-AR ligands. © 2011 Elsevier Masson SAS. All rights reserved.

  3. Mind Your p's and Alphas.

    Science.gov (United States)

    Stallings, William M.

    In the educational research literature alpha, the a priori level of significance, and p, the a posteriori probability of obtaining a test statistic of at least a certain value when the null hypothesis is true, are often confused. Explanations for this confusion are offered. Paradoxically, alpha retains a prominent place in textbook discussions of…

  4. Summary of Alpha Particle Transport

    Energy Technology Data Exchange (ETDEWEB)

    Medley, S.S.; White, R.B.; Zweben, S.J.

    1998-08-19

    This paper summarizes the talks on alpha particle transport which were presented at the 5th International Atomic Energy Agency's Technical Committee Meeting on "Alpha Particles in Fusion Research" held at the Joint European Torus, England in September 1997.

  5. Proteinaceous alpha-araylase inhibitors

    DEFF Research Database (Denmark)

    Svensson, Birte; Fukuda, Kenji; Nielsen, P.K.

    2004-01-01

    Proteins that inhibit alpha-amylases have been isolated from plants and microorganisms. These inhibitors can have natural roles in the control of endogenous a-amylase activity or in defence against pathogens and pests; certain inhibitors are reported to be antinutritional factors. The alpha-amylase...... inhibitors belong to seven different protein structural families, most of which also contain evolutionary related proteins without inhibitory activity. Two families include bifunctional inhibitors acting both on alpha-amylases and proteases. High-resolution structures are available of target alpha-amylases...... in complex with inhibitors from five families. These structures indicate major diversity but also some similarity in the structural basis of alpha-amylase inhibition. Mutational analysis of the mechanism of inhibition was performed in a few cases and various protein engineering and biotechnological...

  6. Endogenous acetylcholine modulates impulsive action via alpha4beta2 nicotinic acetylcholine receptors in rats.

    Science.gov (United States)

    Tsutsui-Kimura, Iku; Ohmura, Yu; Izumi, Takeshi; Yamaguchi, Taku; Yoshida, Takayuki; Yoshioka, Mitsuhiro

    2010-09-01

    Nicotine has been well established as an impulsive action-inducing agent, but it remains unknown whether endogenous acetylcholine affects impulsive action via nicotinic acetylcholine receptors. In the present study, the 3-choice serial reaction time task (3-CSRTT), a simple and valid assessment of impulsive action, was employed. Male Wistar/ST rats were trained to detect and respond to 1-s flashes of light presented in one of three holes until stable performance was achieved. Following training on the 3-CSRTT, rats received intracerebroventricular injections of the preferential alpha4beta2 nicotinic acetylcholine receptor antagonist dihydro-beta-erythroidine (DHbetaE; 0, 3, 10, and 30 microg) or the selective alpha7 nicotinic acetylcholine receptor antagonist methyllycaconitine (MLA; 0, 3, 10, and 30 microg) 5 min before test sessions. Injection of 10 microg of DHbetaE significantly suppressed premature responses, an index of impulsive-like action, without changing other behavioral parameters. On the other hand, MLA infusions failed to affect impulsive-like action at any dose. These results suggest that the central alpha4beta2 nicotinic acetylcholine receptors that enable a provoking effect of endogenous acetylcholine play a critical role in impulsive action. Substances that modulate nicotinic acetylcholine receptors, especially the alpha4beta2 subtype, may be beneficial for the treatment of psychiatric disorders characterized by lack of inhibitory control. Copyright (c) 2010 Elsevier B.V. All rights reserved.

  7. Decreased adrenoceptor stimulation in heart failure rats reduces NGF expression by cardiac parasympathetic neurons.

    Science.gov (United States)

    Hasan, Wohaib; Smith, Peter G

    2014-04-01

    Postganglionic cardiac parasympathetic and sympathetic nerves are physically proximate in atrial cardiac tissue allowing reciprocal inhibition of neurotransmitter release, depending on demands from central cardiovascular centers or reflex pathways. Parasympathetic cardiac ganglion (CG) neurons synthesize and release the sympathetic neurotrophin nerve growth factor (NGF), which may serve to maintain these close connections. In this study we investigated whether NGF synthesis by CG neurons is altered in heart failure, and whether norepinephrine from sympathetic neurons promotes NGF synthesis. NGF and proNGF immunoreactivity in CG neurons in heart failure rats following chronic coronary artery ligation was investigated. NGF immunoreactivity was decreased significantly in heart failure rats compared to sham-operated animals, whereas proNGF expression was unchanged. Changes in neurochemistry of CG neurons included attenuated expression of the cholinergic marker vesicular acetylcholine transporter, and increased expression of the neuropeptide vasoactive intestinal polypeptide. To further investigate norepinephrine's role in promoting NGF synthesis, we cultured CG neurons treated with adrenergic receptor (AR) agonists. An 82% increase in NGF mRNA levels was detected after 1h of isoproterenol (β-AR agonist) treatment, which increased an additional 22% at 24h. Antagonist treatment blocked isoproterenol-induced increases in NGF transcripts. In contrast, the α-AR agonist phenylephrine did not alter NGF mRNA expression. These results are consistent with β-AR mediated maintenance of NGF synthesis in CG neurons. In heart failure, a decrease in NGF synthesis by CG neurons may potentially contribute to reduced connections with adjacent sympathetic nerves. Copyright © 2013 Elsevier B.V. All rights reserved.

  8. Interaction of alpha-conotoxin ImII and its analogs with nicotinic receptors and acetylcholine-binding proteins: additional binding sites on Torpedo receptor.

    Science.gov (United States)

    Kasheverov, Igor E; Zhmak, Maxim N; Fish, Alexander; Rucktooa, Prakash; Khruschov, Alexey Yu; Osipov, Alexey V; Ziganshin, Rustam H; D'hoedt, Dieter; Bertrand, Daniel; Sixma, Titia K; Smit, August B; Tsetlin, Victor I

    2009-11-01

    alpha-Conotoxins interact with nicotinic acetylcholine receptors (nAChRs) and acetylcholine-binding proteins (AChBPs) at the sites for agonists/competitive antagonists. alpha-Conotoxins blocking muscle-type or alpha7 nAChRs compete with alpha-bungarotoxin. However, alpha-conotoxin ImII, a close homolog of the alpha7 nAChR-targeting alpha-conotoxin ImI, blocked alpha7 and muscle nAChRs without displacing alpha-bungarotoxin (Ellison et al. 2003, 2004), suggesting binding at a different site. We synthesized alpha-conotoxin ImII, its ribbon isomer (ImIIiso), 'mutant' ImII(W10Y) and found similar potencies in blocking human alpha7 and muscle nAChRs in Xenopus oocytes. Both isomers displaced [(125)I]-alpha-bungarotoxin from human alpha7 nAChRs in the cell line GH(4)C(1) (IC(50) 17 and 23 microM, respectively) and from Lymnaea stagnalis and Aplysia californica AChBPs (IC(50) 2.0-9.0 microM). According to SPR measurements, both isomers bound to immobilized AChBPs and competed with AChBP for immobilized alpha-bungarotoxin (K(d) and IC(50) 2.5-8.2 microM). On Torpedo nAChR, alpha-conotoxin [(125)I]-ImII(W10Y) revealed specific binding (K(d) 1.5-6.1 microM) and could be displaced by alpha-conotoxin ImII, ImIIiso and ImII(W10Y) with IC(50) 2.7, 2.2 and 3.1 microM, respectively. As alpha-cobratoxin and alpha-conotoxin ImI displaced [(125)I]-ImII(W10Y) only at higher concentrations (IC(50)> or = 90 microM), our results indicate that alpha-conotoxin ImII and its congeners have an additional binding site on Torpedo nAChR distinct from the site for agonists/competitive antagonists.

  9. 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.

  10. Antiallergic effects of H1-receptor antagonists.

    Science.gov (United States)

    Baroody, F M; Naclerio, R M

    2000-01-01

    The primary mechanism of antihistamine action in the treatment of allergic diseases is believed to be competitive antagonism of histamine binding to cellular receptors (specifically, the H1-receptors), which are present on nerve endings, smooth muscles, and glandular cells. This notion is supported by the fact that structurally unrelated drugs antagonize the H1-receptor and provide clinical benefit. However, H1-receptor antagonism may not be their sole mechanism of action in treating allergic rhinitis. On the basis of in vitro and animal experiments, drugs classified as H1-receptor antagonists have long been recognized to have additional pharmacological properties. Most first-generation H1-antihistamines have anticholinergic, sedative, local anaesthetic, and anti-5-HT effects, which might favourably affect the symptoms of the allergic response but also contribute to side-effects. These additional properties are not uniformly distributed among drugs classified as H1-receptor antagonists. Azatadine, for example, inhibits in vitro IgE-mediated histamine and leukotriene (LT) release from mast cells and basophils. In human challenge models, terfenadine, azatadine, and loratadine reduce IgE-mediated histamine release. Cetirizine reduces eosinophilic infiltration at the site of antigen challenge in the skin, but not the nose. In a nasal antigen challenge model, cetirizine pretreatment did not affect the levels of histamine and prostaglandin D2 recovered in postchallenge lavages, whereas the levels of albumin, N-tosyl-L-arginine methyl ester (TAME) esterase activity, and LTs were reduced. Terfenadine, cetirizine, and loratadine blocked allergen-induced hyperresponsiveness to methacholine. In view of the complexity of the pathophysiology of allergy, a number of H1 antagonists with additional properties are currently under development for allergic diseases. Mizolastine, a new H1-receptor antagonist, has been shown to have additional actions that should help reduce the

  11. Calcium antagonists and the diabetic hypertensive patient

    DEFF Research Database (Denmark)

    Parving, H H; Rossing, P

    1993-01-01

    reduces albuminuria, delays the progression of nephropathy, and postpones renal insufficiency in diabetic nephropathy. Calcium antagonists and angiotensin converting enzyme inhibitors induce an acute increase in the glomerular filtration rate, renal plasma flow, and renal sodium excretion......Roughly 40% of all diabetic patients, whether insulin dependent or not, develop persistent albuminuria (over 300 mg/24 hr), a decrease in the glomerular filtration rate, and elevated blood pressure, ie, diabetic nephropathy. Diabetic nephropathy is the single most important cause of end stage renal...... disease in the Western world, and accounts for over a quarter of all end stage renal disease. It also is a major cause of the increased morbidity and mortality seen in diabetic patients; for example, the cost of end stage renal care in the United States currently exceeds +1.8 billion per year for diabetic...

  12. Assay method for organic calcium antagonist drugs and a kit for such an assay

    International Nuclear Information System (INIS)

    Snyder, S. H.; Gould, R. J.

    1985-01-01

    A method for measuring the level of organic calcium antagonist drug in a body fluid comprises preparing a mixture of a radioactive calcium antagonist drug, a body fluid containing a calcium antagonist drug and a calcium antagonist receptor material, measuring the radioactivity of the radioactive calcium antagonist drug bound to said calcium antagonist receptor material and deriving the concentration of the calcium antagonist drug in the body fluid from a standard curve indicating the concentration of calcium antagonist drug versus inhibition of binding of said radioactive calcium antagonist drug to said receptor sites caused by the calcium antagonist drug in said body fluid. A kit for measuring the level of an organic calcium drug comprises a receptacle containing a radioactive calcium antagonist drug, a calcium antagonist receptor material and a standard amount of a nonradioactive calcium antagonist drug

  13. Investigation of Drug-Drug Interactions Between Ritobegron, a Selective β3 -Adrenoceptor Agonist, With Probenecid in Healthy Men.

    Science.gov (United States)

    Abe, Yoshikazu; Nakano, Yuki; Kanazawa, Toru; Furihata, Takao; Endo, Takuro; Kobayashi, Mamoru

    2016-05-01

    We evaluated the effects of probenecid, a potent organic anion transporter 1 (OAT1) and OAT3 inhibitor, on the pharmacokinetics and safety of ritobegron, a selective β3 -adrenoceptor agonist, in healthy men. Twelve healthy men were administered a single oral dose of ritobegron (20 mg) alone or in combination with probenecid 2 hours before administration of ritobegron. In the combination sequence, additional doses of probenecid were administered 4 and 10 hours after the administration of ritobegron. Probenecid increased the Cmax of KUC-7322, an active form of ritobegron, and the AUC0-48  h by 1.39 and 2.93 times, respectively. Probenecid prolonged the t1/2 of KUC-7322 from 1.6 to 3.4 hours and decreased the renal clearance and cumulative fraction of KUC-7322 excreted in urine from 18.5 to 4.9 L/h and from 64.7% to 49.7%, respectively. Coadministration of probenecid did not influence adverse events, blood pressure, pulse rate, or heart rate relative to ritobegron alone. Although probenecid inhibited renal tubule secretion of KUC-7322 via OAT3 and increased KUC-7322 exposure, it did not influence adverse effects or vital signs. Therefore, clinically significant drug-drug interactions are unlikely to occur when probenecid is administered in combination with OAT3 inhibitors or substrates. © 2015, The American College of Clinical Pharmacology.

  14. Determinants of Ligand Subtype-Selectivity at α1A-Adrenoceptor Revealed Using Saturation Transfer Difference (STD) NMR.

    Science.gov (United States)

    Yong, Kelvin J; Vaid, Tasneem M; Shilling, Patrick J; Wu, Feng-Jie; Williams, Lisa M; Deluigi, Mattia; Plückthun, Andreas; Bathgate, Ross A D; Gooley, Paul R; Scott, Daniel J

    2018-03-22

    α 1A - and α 1B -adrenoceptors (α 1A -AR and α 1B -AR) are closely related G protein-coupled receptors (GPCRs) that modulate the cardiovascular and nervous systems in response to binding epinephrine and norepinephrine. The GPCR gene superfamily is made up of numerous subfamilies that, like α 1A -AR and α 1B -AR, are activated by the same endogenous agonists but may modulate different physiological processes. A major challenge in GPCR research and drug discovery is determining how compounds interact with receptors at the molecular level, especially to assist in the optimization of drug leads. Nuclear magnetic resonance spectroscopy (NMR) can provide great insight into ligand-binding epitopes, modes, and kinetics. Ideally, ligand-based NMR methods require purified, well-behaved protein samples. The instability of GPCRs upon purification in detergents, however, makes the application of NMR to study ligand binding challenging. Here, stabilized α 1A -AR and α 1B -AR variants were engineered using Cellular High-throughput Encapsulation, Solubilization, and Screening (CHESS), allowing the analysis of ligand binding with Saturation Transfer Difference NMR (STD NMR). STD NMR was used to map the binding epitopes of epinephrine and A-61603 to both receptors, revealing the molecular determinants for the selectivity of A-61603 for α 1A -AR over α 1B -AR. The use of stabilized GPCRs for ligand-observed NMR experiments will lead to a deeper understanding of binding processes and assist structure-based drug design.

  15. Involvement of the α1-adrenoceptor in sleep-waking and sleep loss-induced anxiety behavior in zebrafish.

    Science.gov (United States)

    Singh, A; Subhashini, N; Sharma, S; Mallick, B N

    2013-08-15

    Sleep is a universal phenomenon in vertebrates, and its loss affects various behaviors. Independent studies have reported that sleep loss increases anxiety; however, the detailed mechanism is unknown. Because sleep deprivation increases noradrenalin (NA), which modulates many behaviors and induces patho-physiological changes, this study utilized zebrafish as a model to investigate whether sleep loss-induced increased anxiety is modulated by NA. Continuous behavioral quiescence for at least 6s was considered to represent sleep in zebrafish; although some authors termed it as a sleep-like state, in this study we have termed it as sleep. The activity of fish that signified sleep-waking was recorded in light-dark, during continuous dark and light; the latter induced sleep loss in fish. The latency, number of entries, time spent and distance travelled in the light chamber were assessed in a light-dark box test to estimate the anxiety behavior of normal, sleep-deprived and prazosin (PRZ)-treated fish. Zebrafish showed increased waking during light and complete loss of sleep upon continuous exposure to light for 24h. PRZ significantly increased sleep in normal fish. Sleep-deprived fish showed an increased preference for dark (expression of increased anxiety), and this effect was prevented by PRZ, which increased sleep as well. Our findings suggest that sleep loss-induced anxiety-like behavior in zebrafish is likely to be mediated by NA's action on the α1-adrenoceptor. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

  16. Altered cardiac gene expression of noradrenaline enzymes, transporter and β-adrenoceptors in rat model of rheumatoid arthritis.

    Science.gov (United States)

    Dronjak, Sladjana; Stefanovic, Bojana; Jovanovic, Predrag; Spasojevic, Natasa; Jankovic, Milica; Jeremic, Ivica; Hoffmann, Markus

    2017-12-01

    Baseline sympathetic activity was found to be elevated in rheumatoid arthritis (RA) patients and it is related to increased cardiovascular risk in these patients. Although many studies have highlighted the association between RA and increased cardiac sympathetic activity, the underlying mechanistic links remain unclear. The aim of the present study was to understand how diseases-triggered changes in gene expression may result in maladaptive physiological changes. Our results suggest that the equilibrium between noradrenaline synthesis, release and reuptake was disrupted in the ventricles of arthritic rats. In the acute phase of the arthritic process, decreased gene expression of MAO-A might lead to accumulation of noradrenaline in myocardial interstitial space, whereas increased gene expression of NET protected cardiomyocytes from the deleterious effects of enhanced noradrenaline. During the chronic phase, reduced expression of β 1 -adrenoceptor and decreased efficiency of noradrenaline reuptake contribute to progressive damage of the myocardium and limits heart efficiency. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Pharmacological modulation of beta-adrenoceptor function in patients with coexisting chronic obstructive pulmonary disease and chronic heart failure.

    Science.gov (United States)

    Matera, Maria Gabriella; Martuscelli, Eugenio; Cazzola, Mario

    2010-02-01

    Pharmacological modulation of beta-adrenoceptor function is one of the critical issues in the treatment of patients with concurrent chronic obstructive pulmonary disease (COPD) and chronic heart failure (CHF). A volume of published evidence sustains the role of long-acting beta(2)-agonists in the treatment of stable COPD, but beta-agonists seem to be detrimental when used for long term in CHF. beta(2)-agonists may exacerbate heart failure and, in any case, they induce adverse cardiac effects in COPD patients with pre-existing cardiovascular disease. The adverse effects of beta(2)-agonists are likely to be exacerbated in COPD patients with coexistent CHF. beta-Blockers are the standard treatment in CHF, but they can worsen FEV(1) and airway hyperresponsiveness and reluctance exists to prescribe these agents to COPD patients, despite the anticipated beneficial cardiovascular effects. Although the literature is reassuring, there are currently no prospective long-term studies on the safety of beta-blockers in COPD. Therefore, although beta-blockers can be introduced in any medical setting for treating patients with concurrent COPD and CHF, it still seems appropriate to only use those beta-blockers that are more selective for the beta(1)-AR but without ISA at the lowest dose and to titrate them slowly with attention to lung function and symptoms, adding an inhaled antimuscarinic agent when bronchodilation is needed. Copyright 2009 Elsevier Ltd. All rights reserved.

  18. Antagonistic activity of marine sponges associated Actinobacteria

    Directory of Open Access Journals (Sweden)

    Selvakumar Dharmaraj

    2016-06-01

    Full Text Available 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

  19. ALPHA freezes antiprotons

    CERN Multimedia

    CERN Bulletin

    2010-01-01

    Laboratories like CERN can routinely produce many different types of antiparticles. In 1995, the PS210 experiment formed the first antihydrogen atoms and a few years later, in 2002, ATRAP and ATHENA were already able to produce several thousand of them. However, no experiment in the world has succeeded in ‘trapping’ these anti-atoms in order to study them. This is the goal of the ALPHA experiment, which has recently managed to cool down the antiprotons to just a few Kelvin. This represents a major step towards trapping the anti-atom, thus opening a new avenue into the investigation of antimatter properties.   Members of the ALPHA collaboration working on the apparatus in the Antiproton Decelerator experimental hall at CERN. Just like the atom, the anti-atom is neutral. Unlike the atom, the anti-atom is made up of antiprotons (as opposed to protons in the atom) and positrons (as opposed to electrons). In order to thoroughly study the properties of the anti-atoms, scien...

  20. Alpha-1-antitrypsin deficiency.

    Science.gov (United States)

    Bals, Robert

    2010-10-01

    Alpha-1-antitrypsin deficiency (AATD) is a rare genetic disorder associated with the development of liver and lung disease. AAT is a 52-kD glycoprotein, produced mainly by hepatocytes and secreted into the blood. Agglomeration of the AAT-protein in hepatocytes can result in liver disease. Exposure to smoke is the major risk factor for the development of lung disease characterised as early chronic obstructive lung disease (COPD). Diagnosis is based on the analysis of the AAT genotype and phenotype. The measurement of the AAT serum level is useful as screening test. Liver biopsy is not necessary to establish the diagnosis. Therapy for AAT-related liver disease is supportive, a specific therapy is not available. AATD is a rare condition (1:5000-10000) and, as a consequence, data and information on diagnosis and treatment are not easily accessible. This chapter provides a comprehensive overview on AATD, covering basic biology, diagnostic and therapeutic approaches. Copyright © 2010 Elsevier Ltd. All rights reserved.

  1. Measurement of $\\alpha_{s}$ with Radiative Hadronic Events

    CERN Document Server

    Abbiendi, G; Åkesson, P F; Alexander, G; Anagnostou, G; Anderson, K J; Asai, S; Axen, D; Bailey, I; Barberio, E; Barillari, T; Barlow, R J; Batley, R J; Bechtle, P; Behnke, T; Bell, K W; Bell, P J; Bella, G; Bellerive, A; Benelli, G; Bethke, S; Biebel, O; Boeriu, O; Bock, P; Boutemeur, M; Braibant, S; Brown, R M; Burckhart, H J; Campana, S; Capiluppi, P; Carnegie, R K; Carter, A A; Carter, J R; Chang, C Y; Charlton, D G; Ciocca, C; Csilling, A; Cuffiani, M; Dado, S; Dallavalle, M; de Roeck, A; De Wolf, E A; Desch, K; Dienes, B; Dubbert, J; Duchovni, E; Duckeck, G; Duerdoth, I P; Etzion, E; Fabbri, F; Ferrari, P; Fiedler, F; Fleck, I; Ford, M; Frey, A; Gagnon, P; Gary, J W; Geich-Gimbel, C; Giacomelli, G; Giacomelli, P; Giunta, M; Goldberg, J; Gross, E; Grunhaus, J; Gruwé, M; Sen-Gupta, A; Hajdu, C; Hamann, M; Hanson, G G; Harel, A; Hauschild, M; Hawkes, C M; Hawkings, R; Herten, G; Heuer, R D; Hill, J C; Horváth, D; Igo-Kemenes, P; Ishii, K; Jeremie, H; Jovanovic, P; Junk, T R; Kanzaki, J; Karlen, D; Kawagoe, K; Kawamoto, T; Keeler, R K; Kellogg, R G; Kennedy, B W; Kluth, S; Kobayashi, T; Kobel, M; Komamiya, S; Kramer, T; Krasznahorkays, A Jr; Krieger, P; Von Krogh, J; Kühl, T; Kupper, M; Lafferty, G D; Landsman, H; Lanske, D; Lellouch, D; Letts, J; Levinson, L; Lillich, J; Lloyd, S L; Loebinger, F K; Lü, J; Ludwig, A; Ludwig, J; Mader, W; Marcellini, S; Martin, A J; Mashimo, T; Mättig, P; McKenna, J; McPherson, R A; Meijers, F; Menges, W; Merritt, F S; Mes, H; Meyer, N; Michelini, A; Mihara, S; Mikenberg, G; Miller, D J; Mohr, W; Mori, T; Mutter, A; Nagai, K; Nakamura, I; Nanjo, H; Neal, H A; O'Neale, S W; Oh, A; Oreglia, M J; Orito, S; Pahl, C; Pásztor, G; Pater, J R; Pilcher, J E; Pinfold, J L; Plane, D E; Pooth, O; Przybycien, M; Quadt, A; Rabbertz, K; Rembser, C; Renkel, P; Roney, J M; Rossi, A M; Rozen, Y; Runge, K; Sachs, K; Saeki, T; Sarkisyan-Grinbaum, E; Schaile, A D; Schaile, O; Scharff-Hansen, P; Schiecks, J; Schörner-Sadenius, T; Schröder, M; Schumacher, M; Seuster, R; Shears, T G; Shen, B C; Sherwood, P; Skuja, A; Smith, A M; Sobie, R J; Söldner-Rembold, S; Spanó, F; Stahl, A; Strom, D; Ströhmer, R; Tarem, S; Tasevsky, M; Teuscher, R; Thomson, M A; Torrence, E; Toya, D; Trigger, I; Trócsányi, Z L; Tsur, E; Turner-Watson, M F; Ueda, I; Ujvári, B; Vollmer, C F; Vannerem, P; Vertesi, R; Verzocchi, M; Voss, H; Vossebeld, J; Ward, C P; Ward, D R; Watkins, P M; Watson, A T; Watson, N K; Wells, P S; Wengler, T; Wermes, N; Wilson, G W; Wilson, J A; Wolf, G; Wyatt, T R; Yamashita, S; Zer-Zion, D; Zivkovic, L

    2008-01-01

    Hadronic final states with a hard isolated photon are studied using data taken at centre-of-mass energies around the mass of the Z0 boson with the OPAL detector at LEP. The strong coupling alpha S is extracted by comparing data and QCD predictions for event shape observables at average reduced centre-of-mass energies ranging from 24 GeV to 78 GeV, and the energy dependence of alpha S is studied. Our results are consistent with the running of alpha S as predicted by QCD and show that within the uncertainties of our analysis event shapes in hadronic Z0 decays with hard and isolated photon radiation can be described by QCD at reduced centre-of-mass energies. Combining all values from different event shape observables and energies gives alpha S (Mz)=0.1182 pm 0.0015(stat.) pm 0.0101(syst.).

  2. Pharmacological characterisation of strychnine and brucine analogues at glycine and alpha7 nicotinic acetylcholine receptors

    DEFF Research Database (Denmark)

    Jensen, Anders A.; Gharagozloo, Parviz; Birdsall, Nigel J M

    2006-01-01

    Strychnine and brucine from the plant Strychnos nux vomica have been shown to have interesting pharmacological effects on several neurotransmitter receptors, including some members of the superfamily of ligand-gated ion channels. In this study, we have characterised the pharmacological properties...... of tertiary and quaternary analogues as well as bisquaternary dimers of strychnine and brucine at human alpha1 and alpha1beta glycine receptors and at a chimera consisting of the amino-terminal domain of the alpha7 nicotinic receptor (containing the orthosteric ligand binding site) and the ion channel domain...... of the 5-HT3A serotonin receptor. Although the majority of the analogues displayed significantly increased Ki values at the glycine receptors compared to strychnine and brucine, a few retained the high antagonist potencies of the parent compounds. However, mirroring the pharmacological profiles...

  3. Effect of a Hypocretin/Orexin Antagonist on Neurocognitive Performance

    Science.gov (United States)

    2013-12-18

    Effectiveness Directorate, Biosciences and Protection Division, Warfighter Fatigue Countermeasures Branch. 35. Golden, C.J. (1978). Stroop Color and Word Test: A...0080 TITLE: Effect of a Hypocretin/Orexin Antagonist on Neurocognitive Performance PRINCIPAL INVESTIGATOR: Dr. Thomas Neylan...31August2013 4. TITLE AND SUBTITLE Effect of a Hypocretin/Orexin Antagonist on Neurocognitive Performance 5a. CONTRACT NUMBER W81XWH

  4. Using waste of Tofu production improved antagonistic activities of a ...

    African Journals Online (AJOL)

    Mrs. Hoa

    2012-10-04

    Oct 4, 2012 ... screened for their antagonistic activity against 10 races of Xoo causing rice bacterial blight disease. Three actinomycete strains ... antagonistic activity of VN10-A-44 against the Xoo pathogen and to make use of tofu waste for large- ..... vitamins and some essential amino acids which are very important for ...

  5. Thrombin-receptor antagonist vorapaxar in acute coronary syndromes

    DEFF Research Database (Denmark)

    Tricoci, Pierluigi; Huang, Zhen; Held, Claes

    2012-01-01

    Vorapaxar is a new oral protease-activated-receptor 1 (PAR-1) antagonist that inhibits thrombin-induced platelet activation.......Vorapaxar is a new oral protease-activated-receptor 1 (PAR-1) antagonist that inhibits thrombin-induced platelet activation....

  6. Evaluation of antagonistic fungi against charcoal rot of sunflower ...

    African Journals Online (AJOL)

    In vitro, sensitivity of Macrophomina phaseolina (Tassi) Goid determined through inhibition zone technique to various antagonistic fungi viz., Aspergillus niger, Aspergillus flavus, Trichoderma viride, Trichoderma harzianum and Penicillium capsulatum amended into PDA medium. All the antagonists reduced the colony ...

  7. Calcium antagonists for ischemic stroke: a systematic review

    NARCIS (Netherlands)

    Horn, J.; Limburg, M.

    2001-01-01

    BACKGROUND AND PURPOSE: Stroke is a common disease, and many trials with calcium antagonists as possible neuroprotective agents have been conducted. The aim of this review is to determine whether calcium antagonists reduce the risk of death or dependency after acute ischemic stroke. METHODS: Acute

  8. 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…

  9. What Powers Lyman alpha Blobs?

    OpenAIRE

    Ao, Y.; Matsuda, Y.; Beelen, A.; Henkel, C.; Cen, R.; De Breuck, C.; Francis, P.; Kovacs, A.; Lagache, G.; Lehnert, M.; Mao, M.; Menten, K. M.; Norris, R.; Omont, A.; Tatemastu, K.

    2015-01-01

    Lyman alpha blobs (LABs) are spatially extended lyman alpha nebulae seen at high redshift. The origin of Lyman alpha emission in the LABs is still unclear and under debate. To study their heating mechanism(s), we present Australia Telescope Compact Array (ATCA) observations of the 20 cm radio emission and Herschel PACS and SPIRE measurements of the far-infrared (FIR) emission towards the four LABs in the protocluster J2143-4423 at z=2.38. Among the four LABs, B6 and B7 are detected in the rad...

  10. Alpha heating in toroidal devices

    Energy Technology Data Exchange (ETDEWEB)

    Miley, G.H.

    1978-01-01

    Ignition (or near-ignition) by alpha heating is a key objective for the achievement of economic fusion reactors. While good confinement of high-energy alphas appears possible in larger reactors, near-term tokamak-type ignition experiments as well as some concepts for small reactors (e.g., the Field-Reversed Mirror or FRM) potentially face marginal situations. Consequently, there is a strong motivation to develop methods to evaluate alpha losses and heating profiles in some detail. Such studies for a TFTR-size tokamak and for a small FRM are described here.

  11. Dronerarone acts as a selective inhibitor of 3,5,3'-triiodothyronine binding to thyroid hormone receptor-alpha1: in vitro and in vivo evidence

    NARCIS (Netherlands)

    van Beeren, H. C.; Jong, W. M. C.; Kaptein, E.; Visser, T. J.; Bakker, O.; Wiersinga, W. M.

    2003-01-01

    Dronedarone (Dron), without iodine, was developed as an alternative to the iodine-containing antiarrhythmic drug amiodarone (AM). AM acts, via its major metabolite desethylamiodarone, in vitro and in vivo as a thyroid hormone receptor alpha(1) (TRalpha(1)) and TRbeta(1) antagonist. Here we

  12. Impact of the Tamsulosin in Alpha Adrenergic Receptor of Airways at Patients with Increased Bronchial Reactibility.

    Science.gov (United States)

    Mustafa, Lirim; Ilazi, Ali; Dauti, Arta; Islami, Pellumb; Kastrati, Bashkim; Islami, Hilmi

    2015-08-01

    In this work, effect of tamsulosin as antagonist of alpha1A and alpha1B adrenergic receptor and effect of agonists of beta2 adrenergic receptor-salbutamol in patients with increased bronchial reactibility was studied. Parameters of the lung function are determined with Body plethysmography six (6) hours after administration of tamsulosin. Raw and ITGV were registered and specific resistance (SRaw) was calculated as well. Tamsulosin was administered in per os manner as a preparation in the shape of the capsules with a brand name of "Prolosin", produced by Niche Generics Limited, Hitchin, Herts. After six (6) hours of administration of tamsulosin, results gained indicate that blockage of alpha1A and alpha1B-adrenergic receptor (0.8 mg per os) has not changed significantly (p > 0.1) the bronchomotor tonus of tracheobronchial tree in comparison to the check-up that has inhaled salbutamol agonist of adrenergic beta2 receptor (2 inh. x 0.2 mg), (p tamsulosin. This suggests that even after six hours of administration of tamsulosin, and determining of lung function parameters, the activity of alpha1A and alpha1B-adrenergic receptor in the smooth bronchial musculature has not changed in patients with increased bronchial reactibility.

  13. Antagonistic interactions between psychrotrophic cultivable bacteria isolated from Antarctic sponges: a preliminary analysis.

    Science.gov (United States)

    Mangano, Santina; Michaud, Luigi; Caruso, Consolazione; Brilli, Matteo; Bruni, Vivia; Fani, Renato; Lo Giudice, Angelina

    2009-01-01

    The present work was aimed at studying antagonistic interactions existing among cultivable bacteria associated with the Antarctic sponges Anoxycalyx joubini and Lissodendoryx nobilis. Overall, bacterial isolates were affiliated with the alpha- and gamma-Proteobacteria (17.3 and 65.3%, respectively), the CFB group of Bacteroidetes (10.7%) and the Actinobacteria (6.7%) by 16S rDNA sequencing. The two sponges harbored microorganisms belonging to different species/genera and previously retrieved from polar marine environments. Antagonistic interactions, assayed by the cross-streak method and statistically analyzed using the "network theory" approach, were checked among isolates associated with the same sponge as well as between isolates retrieved from the two sponge species ("cross-niche inhibition"). Results suggest that antagonism could play a significant role in shaping bacterial communities within sponge tissues. Data from this study confirm previous observations on the antibacterial activity of Antarctic microorganisms and represent a baseline for further investigation of both the ecological role and biotechnological exploitation of Antarctic sponge-associated bacteria.

  14. Preclinical anticonvulsant and neuroprotective profile of 8319, a non-competitive NMDA antagonist

    International Nuclear Information System (INIS)

    Fielding, S.; Wilker, J.C.; Chernack, J.; Ramirez, V.; Wilmot, C.A.; Martin, L.L.; Payack, J.F.; Cornfeldt, M.L.; Rudolphi, K.A.; Rush, D.K.

    1990-01-01

    8319, ((+-)-2-Amino-N-ethyl-alpha-(3-methyl-2-thienyl)benzeneethanamine 2HCl), is a novel compound with the profile of a non-competitive NMDA antagonist. The compound displaced [3H] TCP with high affinity (IC50 = 43 nM), but was inactive at the NMDA, benzodiazepine and GABA sites; in vivo, 8319 showed good efficacy as an anticonvulsant and potential neuroprotective agent. It blocked seizures induced by NMDLA, supramaximal electroshock, pentylenetetrazol (PTZ), picrotoxin, and thiosemicarbazide with ED50's of 1-20 mg/kg ip. As a neuroprotective agent, 8319 (30-100 mg/kg sc) prevented the death of dorsal hippocampal pyramidal cells induced by direct injection of 20 nmol NMDA. At 15 mg/kg ip, the compound was also effective against hippocampal neuronal necrosis induced via bilateral occlusion of the carotid arteries in gerbils. In summary, 8319 is a noncompetitive NMDA antagonist with good anticonvulsant activity and may possess neuroprotective properties useful in the treatment of brain ischemia

  15. Current position of 5HT3 antagonists and the additional value of NK1 antagonists; a new class of antiemetics

    NARCIS (Netherlands)

    R. de Wit (Ronald)

    2003-01-01

    textabstractThe advent of the 5HT3 receptor antagonists (5HT3 antagonists) in the 1990s and the combination with dexamethasone has resulted in acute emesis protection in 70% of patients receiving highly emetogenic chemotherapy. Despite complete protection in the acute phase, however, 40% of patients

  16. Effect of beta-adrenoceptor blockers on human ether-a-go-go-related gene (HERG) potassium channels

    DEFF Research Database (Denmark)

    Dupuis, Delphine S; Klaerke, Dan A; Olesen, Søren-Peter

    2005-01-01

    -1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol hydrochloride) blocked the HERG channel with similar affinity, whereas the beta1-receptor antagonists metoprolol and atenolol showed weak effects. Further, the four compounds blocked HERG channels expressed in a mammalian HEK293 cell line...

  17. Binding properties of alpha-1 adrenergic receptors in rat cerebral cortex: similarity to smooth muscle

    Energy Technology Data Exchange (ETDEWEB)

    Minneman, K.P.

    1983-12-01

    The characteristics of alpha-1 adrenergic receptors in rat cerebral cortex were examined using the radioiodinated alpha-1 adrenergic receptor antagonist ((/sup 125/I)BE). (/sup 125/I)BE labeled a single class of high-affinity binding sites in a particulate fraction of rat cerebral cortex with mass action kinetics and a KD of 57 pM. The binding of (/sup 125/I)BE was inhibited by various alpha adrenergic receptor antagonists, partial agonists and full agonists. The potency of these compounds in competing for the (/sup 125/I)BE binding sites suggested that (/sup 125/I)BE was labeling alpha-1 adrenergic receptors in rat cerebral cortex. In the absence of a physiological concentration of NaCl in the assay medium there was a small (20%) decrease in the density of (/sup 125/I)BE binding sites with no effect on the KD value. The absence of NaCl also caused a 4-fold increase in the potency of norepinephrine in competing for (/sup 125/I)BE binding sites. All drugs competed for (/sup 125/I) BE binding sites with Hill coefficients greater than 0.86, except for oxymetazoline which had a Hill coefficient of 0.77. Scatchard analysis of specific (/sup 125/I)BE binding in the presence of various competing drugs showed that the inhibition by both agonists and antagonists was purely competitive, but the inhibition by oxymetazoline was complex. Treatment of the particulate fraction of rat cerebral cortex with 0.2 to 200 nM phenoxybenzamine for 10 min caused a dose-dependent decrease in the density of (/sup 125/I) BE binding sites which could be mostly blocked by the presence of norepinephrine during the phenoxybenzamine exposure.

  18. Binding of (3H)dihydroergocryptine to an alpha-adrenergic site in the stalk median eminence of the steer

    Energy Technology Data Exchange (ETDEWEB)

    Chen, H.T.; Roberts, J.M.; Weiner, R.I.

    1981-12-01

    Dihydroergocryptine (DHE), a potent dopamine agonist and alpha-adrenergic antagonist, has been used as a radioligand to characterize both dopamine and alpha-adrenergic receptors. In the present study, the binding of (3H)DHE to particulate fractions of the steer stalk median eminence was characterized using a filtration assay. Specific binding was defined by the presence of 10 microM phentolamine or by an iterative nonlinear hyperbolic curve-fitting program. Scatchard analysis of equilibrium isotherms of specific binding defined a single high affinity (Kd . 1.78 +/- 0.22 nM), saturable (maximum binding, 481 +/- 39 fmol/mg protein), stereoselective binding site. The Kd, calculated from the ratio of the rate constants k2 and k1, was 2.8 +/- 0.14 nM. The rank order of potency of agonists to compete for (3H)DHE binding (l-epinephrine greater than l-norepinephrine greater than dopamine greater than l-isoproterenol) was consistent with interactions at an alpha-adrenergic site. The rank order of potency of alpha-antagonists (phentolamine greater than yohimbine greater than prazosin) suggested that this was an alpha 2-adrenergic receptor. The affinity of dopamine agonists for the (3H)DHE-binding site was 10-fold lower relative to their potency at known dopamine receptors, while the affinity of dopaminergic antagonists was 100-fold lower. Furthermore, Scatchard analysis of specific (3H)DHE binding in the presence of a concentration of spiperone which should saturate dopamine receptors, only decreased the number of binding sites by 9%. These data demonstrate the presence of large numbers of alpha-adrenergic receptors in the stalk median eminence of the steer. Only a small number of dopaminergic binding sites for (3H)DHE appeared to be present.

  19. The novel β3-adrenoceptor agonist mirabegron reduces carbachol-induced contractile activity in detrusor tissue from patients with bladder outflow obstruction with or without detrusor overactivity

    DEFF Research Database (Denmark)

    Svalø, Julie; Nordling, Jørgen; Bouchelouche, Kirsten

    2013-01-01

    prostatic hyperplasia undergoing cystoscopy and from patients undergoing radical prostatectomy/cystectomy (in total 33 donors). Detrusor contractility was evaluated by organ bath studies and strips were incubated with carbachol (1μM) to induce and enhance tension. Both mirabegron and isoprenaline reduced...... preparations from patients with bladder outflow obstruction (BOO) with and without detrusor overactivity (DO), and from patients with normal bladder function. We compared the effects to those of isoprenaline, a non-selective β-adrenoceptor agonist. Detrusor specimens were obtained from patients with benign...

  20. Chronic sympathetic activation promotes downregulation of ß-adrenoceptor-mediated effects in the guinea pig heart independently of structural remodeling and systolic dysfunction

    DEFF Research Database (Denmark)

    Soltysinska, Ewa; Thiele, Stefanie; Osadchiy, Oleg

    2011-01-01

    pathway upon chronic infusion of isoproterenol, a ß-adrenoceptor agonist, at a dose producing no structural left ventricular (LV) remodeling and systolic dysfunction. Subcutaneous isoproterenol infusion (400 µg kg(-1) h(-1) over 16 days) to guinea pigs using osmotic minipumps produced no change in cardiac...... developed pressure increase, less shortening of LV epicardial monophasic action potential and effective refractory period, and less myocardial cyclic adenosine monophosphate elevation, in response to isoproterenol exposure, when compared to saline-treated controls. Pharmacological responses to forskolin...