المؤلفون: Schellenberg LM; University of Leipzig, Faculty of Veterinary Medicine, Institute of Pharmacology, Pharmacy and Toxicology, An den Tierkliniken 15, 04103, Leipzig, Germany., Bonicelli J; University of Leipzig, Faculty of Veterinary Medicine, Institute of Pharmacology, Pharmacy and Toxicology, An den Tierkliniken 15, 04103, Leipzig, Germany., Hochheim I; University of Leipzig, Faculty of Veterinary Medicine, Institute of Pharmacology, Pharmacy and Toxicology, An den Tierkliniken 15, 04103, Leipzig, Germany., Regenthal R; Rudolf-Boehm-Institute of Pharmacology and Toxicology, Clinical Pharmacology, Faculty of Medicine, Leipzig University, Leipzig, Germany. Electronic address: ralf.regenthal@medizin.uni-leipzig.de., Abraham G; University of Leipzig, Faculty of Veterinary Medicine, Institute of Pharmacology, Pharmacy and Toxicology, An den Tierkliniken 15, 04103, Leipzig, Germany. Electronic address: gabraham@rz.uni-leipzig.de.

المصدر: Pulmonary pharmacology & therapeutics [Pulm Pharmacol Ther] 2020 Apr; Vol. 61, pp. 101897. Date of Electronic Publication: 2020 Jan 18.

نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't

بيانات الدورية: Publisher: Academic Press Country of Publication: England NLM ID: 9715279 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1522-9629 (Electronic) Linking ISSN: 10945539 NLM ISO Abbreviation: Pulm Pharmacol Ther Subsets: MEDLINE

مواضيع طبية MeSH: Adrenergic beta-Antagonists/*metabolism , Bronchi/*metabolism , Epithelial Cells/*metabolism , Receptors, Adrenergic, beta/*metabolism, Animals ; Cells, Cultured ; Cyclic AMP/metabolism ; Horses ; Imidazoles/metabolism ; Iodocyanopindolol/metabolism ; Isoproterenol/pharmacology ; Primary Cell Culture ; Propanolamines/metabolism ; Receptors, Adrenergic, beta-1/metabolism ; Receptors, Adrenergic, beta-2/metabolism

مستخلص: The β-adrenergic receptor (β-AR) plays an important role in regulating a variety of cell and organ functions in different animal species and is an important target in asthma pathogenesis and therapy. The β-AR expression and function in equine bronchial epithelial cells (EBEC) were not known but innervation and significant decrease in receptor level were reported in the equine bronchial tissues from asthmatic horses. ¹²⁵ I-iodocyanopindolol (ICYP) binding studies were undertaken in primary freshly isolated and cultured EBEC to identify the presence of the β-ARs. The receptor distribution was assessed using subtype-selective β-AR antagonists (ICI 118 551 (β 2 ) and CGP 20712A (β 1 ). The β-AR function was confirmed by measuring the agonist-induced intracellular cAMP accumulation in freshly isolated and cultured EBEC. In both freshly isolated and cultured EBEC, the specific ICYP binding was saturable and of high affinity. The maximal receptor density (B max ) was 9763 ± 140 binding sites/cell (mean ± SEM, n = 7) and 10575 ± 194 binding sites/cell (mean ± SEM, n = 5) in freshly isolated and cultured EBEC, respectively. The receptor affinity to the ligand (K D ) was also not different between the two cell conditions. ICI 118.551 displaced ICYP with 25 000-fold higher affinity than CGP 20712A. Moreover, in both fresh isolated and cultured EBEC, cAMP-accumulation was stimulated with a rank-order of potency of isoproterenol > adrenaline > noradrenaline. These results highlight the β 2 -AR to be a key subtype in both freshly isolated and cultured primary EBEC.
Competing Interests: Declaration of competing interest None.
(Copyright © 2020 Elsevier Ltd. All rights reserved.)

المؤلفون: Richard C; Centre de recherche, Centre hospitalier de l'université de Montréal (CHUM), Canada., Shabbir W; Institute of Pharmacology and Toxicology, University of Vienna, Vienna, Austria., Ferraro P; Centre de recherche, Centre hospitalier de l'université de Montréal (CHUM), Canada; Département de chirurgie, Université de Montréal, Montréal, Québec, Canada., Massé C; Centre de recherche, Centre hospitalier de l'université de Montréal (CHUM), Canada; Institut de recherches cliniques de Montréal (IRCM), Montréal, Quebec, Canada., Berthiaume Y; Centre de recherche, Centre hospitalier de l'université de Montréal (CHUM), Canada; Département de médecine, Université de Montréal, Montréal, Québec, Canada; Institut de recherches cliniques de Montréal (IRCM), Montréal, Quebec, Canada. Electronic address: yves.berthiaume@umontreal.ca.

المصدر: Respiratory physiology & neurobiology [Respir Physiol Neurobiol] 2019 Jan; Vol. 259, pp. 104-110. Date of Electronic Publication: 2018 Aug 29.

نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't

بيانات الدورية: Publisher: Elsevier Science Country of Publication: Netherlands NLM ID: 101140022 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1878-1519 (Electronic) Linking ISSN: 15699048 NLM ISO Abbreviation: Respir Physiol Neurobiol Subsets: MEDLINE

مواضيع طبية MeSH: Lung Injury*/etiology , Lung Injury*/physiopathology, Pulmonary Alveoli/*physiopathology , Receptors, Adrenergic, beta-2/*therapeutic use , Reperfusion Injury/*complications, Aminophylline/pharmacology ; Animals ; Blood Pressure/drug effects ; Bronchodilator Agents/pharmacology ; Cyclic AMP/pharmacology ; Disease Models, Animal ; Dogs ; Dose-Response Relationship, Drug ; Epithelial Sodium Channels/metabolism ; Female ; Heart Rate/drug effects ; Imidazoles/therapeutic use ; Iodine Radioisotopes/pharmacokinetics ; Iodocyanopindolol/pharmacokinetics ; Male ; Propanolamines/therapeutic use ; Protein Binding/drug effects ; Pulmonary Edema/etiology ; RNA, Messenger

مستخلص: While alveolar liquid clearance (ALC) mediated by the β 2 -adrenergic receptor (β 2 -AR) plays an important role in lung edema resolution in certain models of lung injury, in more severe lung injury models, this response might disappear. Indeed, we have shown that in an ischemia-reperfusion-induced lung injury model, β 2 -agonists do not enhance ALC. The objective of this study was to determine if downregulation of the β 2 -AR could explain the lack of response to β 2 -agonists in this lung injury model. In an in vivo canine model of lung transplantation, we observed no change in β 2 -AR concentration or affinity in the injured transplanted lungs compared to the native lungs. Furthermore, we could not enhance ALC in transplanted lungs with dcAMP + aminophylline, a treatment that bypasses the β 2 -adrenergic receptor and is known to stimulate ALC in normal lungs. However, transplantation decreased αENaC expression in the lungs by 50%. We conclude that the lack of response to β 2 -agonists in ischemia-reperfusion-induced lung injury is not associated with significant downregulation of the β 2 -adrenergic receptors but is attributable to decreased expression of the ENaC channel, which is essential for sodium transport and alveolar liquid clearance in the lung.
(Copyright © 2018 Elsevier B.V. All rights reserved.)

المؤلفون: Abraham G; Institute of Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine, University of Leipzig, Germany., Broddet OE, Ungemach FR

المصدر: Equine veterinary journal [Equine Vet J] 2001 Sep; Vol. 33 (5), pp. 487-93.

نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't

بيانات الدورية: Publisher: Wiley Country of Publication: United States NLM ID: 0173320 Publication Model: Print Cited Medium: Print ISSN: 0425-1644 (Print) Linking ISSN: 04251644 NLM ISO Abbreviation: Equine Vet J Subsets: MEDLINE

مواضيع طبية MeSH: Adrenergic beta-Antagonists* , Iodocyanopindolol*, Horses/*physiology , Lymphocytes/*metabolism , Receptors, Adrenergic, beta/*classification , Receptors, Adrenergic, beta/*isolation & purification, Animals ; Binding Sites/physiology ; Cyclic AMP/metabolism ; Iodine Radioisotopes ; Kinetics ; Ligands ; Stereoisomerism

مستخلص: In this study, beta-adrenoceptors of intact equine lymphocytes were identified and subclassified by (-)-[125I]-iodocyanopindolol (ICYP) binding. ICYP binding to intact equine lymphocytes was rapid, saturable (maximal number of binding sites 320 +/- 20 ICYP binding sites/cell, n = 12) and of high affinity (KD value for ICYP 14.4 +/- 1.7 pmol/l, n = 12). Binding was stereospecific as shown by the 10 times greater potency of (-)-propranolol to inhibit binding than its (+)-isomer. Beta-adrenoceptor agonists inhibited ICYP binding with an order of potency: (-)-isoprenaline >(-)-adrenaline >(-)-noradrenaline; the same order of potency was obtained for agonist-induced stimulation of lymphocyte cyclic AMP content. The selective beta2-adrenoceptor antagonist ICI 118,551 was about 1000 times more potent in inhibiting ICYP binding than was the beta1-selective adrenoceptor antagonist CGP 20712A. It is, therefore, concluded that in intact equine lymphocytes, ICYP labels a class of functional beta-adrenoceptors that belong predominantly (>90%) to the beta2-adrenoceptor subtype; a small (<10%) beta1-adrenoceptor component, however, cannot be ruled out completely. ICYP binding to equine lymphocytes might be a suitable model to study function and regulation of the beta-adrenoceptor system in the horse in vivo. The aim of this study was to characterise the beta-adrenoreceptor subtypes present on equine lymphocytes.

المؤلفون: Meng K; School of Pharmaceutical and Life Sciences, Changzhou University, Jiangsu 213164, China., Shim P; Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA., Wang Q; School of Pharmaceutical and Life Sciences, Changzhou University, Jiangsu 213164, China., Zhao S; School of Pharmaceutical and Life Sciences, Changzhou University, Jiangsu 213164, China., Gu T; School of Pharmaceutical and Life Sciences, Changzhou University, Jiangsu 213164, China., Kahsai AW; Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA., Ahn S; Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA., Chen X; School of Pharmaceutical and Life Sciences, Changzhou University, Jiangsu 213164, China. Electronic address: xinchen@cczu.edu.cn.

المصدر: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2018 May 15; Vol. 26 (9), pp. 2320-2330. Date of Electronic Publication: 2018 Mar 15.

نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't

بيانات الدورية: Publisher: Elsevier Science Country of Publication: England NLM ID: 9413298 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1464-3391 (Electronic) Linking ISSN: 09680896 NLM ISO Abbreviation: Bioorg Med Chem Subsets: MEDLINE

مواضيع طبية MeSH: Adrenergic beta-2 Receptor Antagonists/*pharmacology , Dipeptides/*pharmacology , Receptors, Adrenergic, beta-2/*metabolism, Adrenergic beta-2 Receptor Antagonists/chemical synthesis ; Adrenergic beta-2 Receptor Antagonists/chemistry ; Allosteric Regulation ; Allosteric Site/drug effects ; Binding, Competitive ; Cell Line, Tumor ; Dipeptides/chemical synthesis ; Dipeptides/chemistry ; Dose-Response Relationship, Drug ; Drug Design ; GTP-Binding Protein alpha Subunits, Gs/metabolism ; HEK293 Cells ; Humans ; Iodine Radioisotopes ; Iodocyanopindolol/chemistry ; Signal Transduction/drug effects ; Structure-Activity Relationship ; beta-Arrestins/metabolism

مستخلص: The β 2 -adrenergic receptor (β 2 AR), a G protein-coupled receptor, is an important therapeutic target. We recently described Cmpd-15, the first small molecule negative allosteric modulator (NAM) for the β 2 AR. Herein we report in details the design, synthesis and structure-activity relationships (SAR) of seven Cmpd-15 derivatives. Furthermore, we provide in a dose-response paradigm, the details of the effects of these derivatives in modulating agonist-induced β 2 AR activities (G-protein-mediated cAMP production and β-arrestin recruitment to the receptor) as well as the binding affinity of an orthosteric agonist in radio-ligand competition binding assay. Our results show that some modifications, including removal of the formamide group in the para-formamido phenylalanine region and bromine in the meta-bromobenzyl methylbenzamide region caused dramatic reduction in the functional activity of Cmpd-15. These SAR results provide valuable insights into the mechanism of action of the NAM Cmpd-15 as well as the basis for future development of more potent and selective modulators for the β 2 AR based on the chemical scaffold of Cmpd-15.
(Copyright © 2018 Elsevier Ltd. All rights reserved.)

المؤلفون: Hoffmann S; Institute of Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine, Leipzig University, D-04103 Leipzig, Germany., Müller T; Department for Public Health and Food Hygiene, Mutzschen, Germany., Abraham G; Institute of Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine, Leipzig University, D-04103 Leipzig, Germany. Electronic address: gabraham@rz.uni-leipzig.de.

المصدر: Veterinary journal (London, England : 1997) [Vet J] 2015 Jun; Vol. 204 (3), pp. 363-5. Date of Electronic Publication: 2015 Feb 26.

نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't

بيانات الدورية: Publisher: Balliere Tindall Country of Publication: England NLM ID: 9706281 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1532-2971 (Electronic) Linking ISSN: 10900233 NLM ISO Abbreviation: Vet J Subsets: MEDLINE

مواضيع طبية MeSH: Gene Expression Regulation/*physiology , Myocardium/*metabolism , Receptors, Adrenergic, beta/*metabolism , Turkeys/*metabolism, Aging ; Animals ; Iodocyanopindolol/metabolism ; Protein Binding ; Receptors, Adrenergic, beta/genetics

مستخلص: The presence, distribution and characteristics of chamber-specific β-adrenergic receptors in adult turkey hearts were investigated by radioligand binding studies using (-)-[(125)I]-iodocyanopindolol (ICYP). The β1-selective (CGP 20712A) and β2-selective (ICI 118.551) antagonists as well as the nonselective β-agonists isoproterenol, epinephrine and norepinephrine were used in displacement studies. In all cardiac chambers, ICI 118.551 and CGP 20712A displacement curves were monophasic and steep, with the affinity of CGP 20712A higher than that of ICI 118.551, indicating the exclusive presence of the β1-adrenergic receptor subtype. The agonist rank order of potency was isoproterenol > norepinephrine ≥ epinephrine, typical for the β1-receptor subtype. In all chambers, the density of β-adrenergic receptors was ~40 fmol/mg protein and the KD was ~30 pM. The study revealed similar β-adrenergic receptor density mainly of the β1-subtype in all cardiac chambers, indicating that this receptor subtype could contribute equally to regulate cardiac physiological function and pathophysiology.
(Copyright © 2015 Elsevier Ltd. All rights reserved.)

المؤلفون: Sykes DA; Novartis Institutes for Biomedical Research, West Sussex, UK., Charlton SJ

المصدر: British journal of pharmacology [Br J Pharmacol] 2012 Apr; Vol. 165 (8), pp. 2672-83.

نوع المنشور: Journal Article

بيانات الدورية: Publisher: Wiley Country of Publication: England NLM ID: 7502536 Publication Model: Print Cited Medium: Internet ISSN: 1476-5381 (Electronic) Linking ISSN: 00071188 NLM ISO Abbreviation: Br J Pharmacol Subsets: MEDLINE

مواضيع طبية MeSH: Adrenergic beta-2 Receptor Agonists/*metabolism , Receptors, Adrenergic, beta-2/*metabolism, Administration, Inhalation ; Adrenergic beta-Antagonists/metabolism ; Animals ; Binding, Competitive ; CHO Cells ; Cell Membrane/metabolism ; Cricetinae ; Cricetulus ; Dihydroalprenolol/analogs & derivatives ; Dihydroalprenolol/metabolism ; Humans ; Iodocyanopindolol/metabolism ; Kinetics ; Radioligand Assay

مستخلص: Background and Purpose: β(2) -Adrenoceptor agonists are important bronchodilators used for the treatment of chronic obstructive pulmonary disease and asthma. Clinical data on β(2) -adrenoceptor agonists show a range of onset and duration of action. We have investigated whether the receptor binding kinetics of β(2) -adrenoceptor agonists can explain their observed onset of action and duration of effect in the clinic.
Experimental Approach: [(3) H]-DHA was used to label β(2) -adrenoceptors expressed in CHO-cell membranes (K(d) of 0.084 nM). Competition kinetic experiments were performed in the presence of unlabelled β(2) agonists at 37°C in HBSS containing GTP. To determine the kinetic parameters, three concentrations (10, 3 and 1 ×K(i) ) of the unlabelled compound were employed against a fixed concentration of [(3) H]-DHA (0.6 nM).
Key Results: The clinically used β(2) -adrenoceptor agonists exhibited a range of association and dissociation rates. The kinetic K(d) and the competition K(i) values of the eight β(2) -adrenoceptor agonists examined were strongly correlated, suggesting that the method had produced accurate k(off) and k(on) rates. The kinetic on-rate was highly correlated with equilibrium binding affinity.
Conclusions and Implications: Although the β(2) -adrenoceptor agonists displayed a range of kinetic rate parameters, simulations at relevant drug concentrations suggest that receptor kinetics do not play an important role in determining onset of action in the clinic. In addition, it is unlikely that receptor kinetics exert an important influence on the duration of action of these agonists, as indacaterol (once daily dosing) had a shorter residency time at the receptor than salmeterol (twice daily dosing).
(© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.)

المؤلفون: Kassahun WT; Department of Surgery II, Faculty of Medicine, University of Leipzig, Leipzig, Germany. Woubet.Kassahun@uniklinik-leipzig.de, Guenl B, Ungemach FR, Jonas S, Abraham G

المصدر: Pharmacology [Pharmacology] 2012; Vol. 89 (5-6), pp. 313-20.

نوع المنشور: Journal Article

بيانات الدورية: Publisher: Karger Country of Publication: Switzerland NLM ID: 0152016 Publication Model: Print Cited Medium: Internet ISSN: 1423-0313 (Electronic) Linking ISSN: 00317012 NLM ISO Abbreviation: Pharmacology Subsets: MEDLINE

مواضيع طبية MeSH: Carcinoma, Hepatocellular/*metabolism , Liver Neoplasms/*metabolism , Receptors, Adrenergic, beta-2/*metabolism, Adrenergic beta-Agonists/pharmacology ; Adrenergic beta-Antagonists/pharmacology ; Adult ; Aged ; Female ; Humans ; Imidazoles/pharmacology ; Iodocyanopindolol/pharmacology ; Liver/drug effects ; Liver/metabolism ; Male ; Middle Aged ; Propanolamines/pharmacology

مستخلص: Aim: Hepatocellular carcinoma (HCC) is one of the most common cancers and a leading cause of death worldwide. There are now multiple lines of evidence demonstrating that the β-adrenoceptor ( β-AR) signaling plays an important role in the progression and metastasis of cancer and may become a novel target for cancer therapy. Little information exists regarding the status of β-ARs and their postreceptor intracellular signaling cascade in the development of human HCC. This study was conducted to detect the expression signal transduction of the β-ARs in liver membranes obtained from patients with HCC and elucidate their possible implication on HCC development.
Methods: The β-AR density and subtype distribution were determined by receptor binding studies. Protein levels of the β(2)-AR and G(s)(α) protein were determined by Western blot analysis. The receptor coupling efficiency and biochemical activities of the adenylate cyclase(AC) was also determined.
Results: In HCC liver membranes, the β(2)-AR density was higher than the density in the nonadjacent nontumor liver membranes. The β(2)-AR protein expression was 1.5-fold increased as compared with nonmalignant controls, and positively correlated with the receptor density. The G s protein expression as well as the receptor, AC and G protein-stimulated activation of the cAMP formation was reduced in HCC.
Conclusion: The β(2)-AR was upregulated in human HCC. Despite this upregulation of the receptor,there was an altered postreceptor signal transduction in HCC liver. The mechanisms responsible for this change in the growth of HCC and the nature of this alteration remain unclear.

المؤلفون: Kopka K; Department of Nuclear Medicine, Albert-Schweitzer-Str. 33, University Hospital Münster, 48149, Münster, Germany. kopka@uni-muenster.de, Wagner S, Riemann B, Law MP, Puke C, Luthra SK, Pike VW, Wichter T, Schmitz W, Schober O, Schäfers M

المصدر: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2003 Aug 05; Vol. 11 (16), pp. 3513-27.

نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't

بيانات الدورية: Publisher: Elsevier Science Country of Publication: England NLM ID: 9413298 Publication Model: Print Cited Medium: Print ISSN: 0968-0896 (Print) Linking ISSN: 09680896 NLM ISO Abbreviation: Bioorg Med Chem Subsets: MEDLINE

مواضيع طبية MeSH: Radioligand Assay/*methods , Receptors, Adrenergic, beta-1/*analysis , Receptors, Adrenergic, beta-1/*metabolism, Adrenergic beta-1 Receptor Antagonists ; Animals ; Heart Ventricles/metabolism ; Humans ; Inhibitory Concentration 50 ; Iodocyanopindolol/metabolism ; Iodocyanopindolol/pharmacology ; Ligands ; Mice ; Molecular Structure ; Myocardium/metabolism ; Propanolamines/metabolism ; Propanolamines/pharmacology ; Substrate Specificity ; Time Factors ; Tomography, Emission-Computed ; Tomography, Emission-Computed, Single-Photon

مستخلص: In general, the failing human heart is characterized by a selective reduction in beta(1)-adrenoceptors (beta(1)-ARs) without change in beta(2)-AR density. Medical imaging techniques, either single photon emission computed tomography (SPECT) or positron emission tomography (PET) with appropriate radioligands, offer the possibility of assessing beta-adrenoceptor density non-invasively in humans. To date, neither a SPECT nor a PET radioligand is available for the selective imaging of cardiac beta(1)-ARs. The aim of this study was to develop potential high affinity beta(1)-selective AR radioligands for the non-invasive in vivo imaging of the beta(1)-AR density in the human heart using SPECT or PET. A variety of racemic N-aryl-N'-[2-[3-aryloxy-2-hydroxy-propylamino]-ethyl]-urea derivatives and chain-elongated analogues, related to the established beta(1)-AR antagonist, ICI 89,406 8i, were synthesized. Competition studies using the non-selective AR ligand, [(125)I]iodocyanopindolol ([(125)I]ICYP), and ventricular membrane preparations of wild-type mice revealed nine ligands with higher beta(1)-AR affinities (up to 76-fold) and beta(1)-AR selectivities (up to 139-fold) than 8i. Mostly, these ligands possess a 2-substituted phenoxy group and a 4-substituted phenyl residue in contrast to the lead compound 8i. The non-radioactive counterparts of the desired SPECT- and PET-radiotracers were synthesized as reference compounds [e.g., 8f, 8g, 8h and 8l as the non-radioactive analogues of the radioiodinated SPECT radioligands, 8e and 8h as the non-radioactive compounds of C-11 labelled PET-tracers (C-11 in the methoxy group)]. The established library of high affinity beta(1)-selective AR antagonists was screened for chemical precursors for the radiosynthesis of the mentioned radioligands. Furthermore, the library consists of some comparison compounds that are unsubstituted, allyl- and alkyl-substituted or chain-elongated (e.g., 8a, 8j, 8o and 8r-t). Future steps will include radiolabelling and pharmacokinetic evaluation of the beta(1)-selective target compounds, which could be applied as sympathetic innervation agents for in vivo investigations and diagnostics in patients suffering from cardiac diseases like heart failure and ventricular arrhythmias.

المؤلفون: Shanahan NA; Committee on Neurobiology, University of Chicago, IL 60637, USA., Velez LP, Masten VL, Dulawa SC

المصدر: Biological psychiatry [Biol Psychiatry] 2011 Dec 01; Vol. 70 (11), pp. 1039-48. Date of Electronic Publication: 2011 Sep 13.

نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't

بيانات الدورية: Publisher: Elsevier Country of Publication: United States NLM ID: 0213264 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-2402 (Electronic) Linking ISSN: 00063223 NLM ISO Abbreviation: Biol Psychiatry Subsets: MEDLINE

مواضيع طبية MeSH: Obsessive-Compulsive Disorder/*pathology , Prefrontal Cortex/*metabolism , Receptor, Serotonin, 5-HT1B/*metabolism, 8-Hydroxy-2-(di-n-propylamino)tetralin/toxicity ; Acoustic Stimulation/adverse effects ; Adrenergic Uptake Inhibitors/pharmacology ; Adrenergic Uptake Inhibitors/therapeutic use ; Adrenergic beta-Antagonists/pharmacokinetics ; Animals ; Clomipramine/pharmacology ; Clomipramine/therapeutic use ; Desipramine/pharmacology ; Desipramine/therapeutic use ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Drug Interactions ; Exploratory Behavior/drug effects ; Female ; Guanosine 5'-O-(3-Thiotriphosphate)/pharmacokinetics ; Indoles/toxicity ; Iodocyanopindolol/pharmacokinetics ; Isotopes/pharmacokinetics ; Mice ; Mice, Inbred BALB C ; Neural Inhibition/drug effects ; Obsessive-Compulsive Disorder/chemically induced ; Obsessive-Compulsive Disorder/drug therapy ; Serotonin Receptor Agonists/toxicity ; Selective Serotonin Reuptake Inhibitors/pharmacology ; Selective Serotonin Reuptake Inhibitors/therapeutic use ; Swimming/psychology ; Time Factors

مستخلص: Background: Perseveration and sensorimotor gating deficits are core features of obsessive-compulsive disorder (OCD). Serotonin 1B receptor (5-HT1BR) agonists exacerbate OCD symptoms in patients and induce perseveration and sensorimotor gating deficits in mice. Serotonin reuptake inhibitors (SRIs), but not noradrenaline reuptake inhibitors (NRIs), reduce OCD symptoms following 4 to 8 weeks of treatment. Using mice, we compared the effects of chronic SRI versus NRI treatment on 5-HT1BR-induced OCD-like behavior and 5-HT1BR sensitivity in orbitofrontal-subcortical OCD circuits. Furthermore, we localized the 5-HT1BR population that mediates OCD-like behavior.
Methods: Mice chronically received the SRI clomipramine or the NRI desipramine and were examined for 5-HT1BR-induced OCD-like behavior or 5-HT1BR binding and G-protein coupling in caudate putamen, nucleus accumbens, and orbitofrontal cortex. Separate mice were tested for OCD- or depression-like behavior following 4, 14, 21, 28, or 56 days of SRI treatment. Finally, OCD-like behavior was assessed following intra-orbitofrontal 5-HT1BR agonist infusion or intra-orbitofrontal 5-HT1BR antagonist infusion coupled with systemic 5-HT1BR agonist treatment.
Results: Effective, but not ineffective, OCD treatments reduced OCD-like behavior in mice with a time course that parallels the delayed therapeutic onset in OCD patients and downregulated 5-HT1BR expression in the orbitofrontal cortex. Intra-orbitofrontal 5-HT1BR agonist infusion induced OCD-like behavior, and intra-orbitofrontal 5-HT1BR antagonist infusion blocked OCD-like effects of systemic 5-HT1BR agonist treatment.
Conclusions: These results indicate that orbitofrontal 5-HT1BRs are necessary and sufficient to induce OCD-like behavior in mice and that SRI pharmacotherapy reduces OCD-like behavior by desensitizing orbitofrontal 5-HT1BRs. Our findings suggest an essential role for orbitofrontal 5-HT1BRs in OCD pathophysiology and treatment.
(Published by Elsevier Inc.)

المؤلفون: Abraham G; University of Leipzig, Faculty of Veterinary Medicine, Institute of Pharmacology, Pharmacy and Toxicology, An den Tierkliniken 15, 04103 Leipzig, Germany. gabraham@rz.uni-leipzig.de, Shibeshi W, Ungemach FR

المصدر: Pulmonary pharmacology & therapeutics [Pulm Pharmacol Ther] 2011 Feb; Vol. 24 (1), pp. 174-81. Date of Electronic Publication: 2010 Jun 25.

نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't

بيانات الدورية: Publisher: Academic Press Country of Publication: England NLM ID: 9715279 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1522-9629 (Electronic) Linking ISSN: 10945539 NLM ISO Abbreviation: Pulm Pharmacol Ther Subsets: MEDLINE

مواضيع طبية MeSH: Receptors, Adrenergic, beta/*analysis , Trachea/*chemistry, Animals ; Cells, Cultured ; Cyclic AMP/biosynthesis ; Epithelial Cells/chemistry ; Female ; Horses ; Iodocyanopindolol/metabolism ; Male

مستخلص: Responses and functions of airway epithelial cells are stimulated by β₂-agonists via the β₂-adrenergic receptors (β₂-ARs)-G(s)-protein-cAMP-system, thus, affecting airway inflammation such as in asthma and equine recurrent airway obstruction (RAO). Though horses can be used as large animal model for human asthma, evaluation of the expression and functions of the β-AR system in primary equine airway epithelial cells has not been yet carried out. Thus, for the first time, we determined the β-AR density and subtype distribution by [¹²⁵I]-iodocyanopindolol (ICYP) binding, examined β-AR function by cAMP assay as well as their expression by western blot analysis and immunocytochemical staining in primary equine tracheal epithelial cells (ETEC). Cells were collected from 19 horses and cultured subsequently. The specific ICYP binding was saturable and of high affinity: in freshly isolated cells the receptor density (B(max)) and ICYP affinity (K(D)) for β-ARs were 12727 ± 883 binding sites/cell and 31.78 ± 6.57 pM, respectively, and in cultured ETEC 3730 ± 212 binding sites/cell and 15.26 ± 3.37 pM, respectively. The β-AR subtype assessed by β₁-selective (CGP 20712A) and β₂-selective (ICI 118.551) adrenergic receptor antagonists demonstrated that the β₂-AR subtype predominated (>95%) in both cell populations (p < 0.001). The β-AR agonists increased cAMP formation with a rank order of potency: isoproterenol > epinephrine > norepinephrine. ICI 118.551 (100 nM) significantly blocked (p < 0.05) isoproterenol-induced cAMP accumulation but not CGP 20712A (300 nM). Western blot analyses and immunocytochemical staining further indicated the expression of the β(2)-AR subtype in both cell preparations. Our data indicate that in acutely dissociated and primary cultured ETEC the β(2)-AR-AC system is expressed, but varies considerably between the two preparations.
(Copyright © 2010 Elsevier Ltd. All rights reserved.)