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Article: Protective effects of a glucocorticoid on downregulation of pulmonary β2-adrenergic receptors in vivo

TitleProtective effects of a glucocorticoid on downregulation of pulmonary β2-adrenergic receptors in vivo
Authors
Issue Date1995
PublisherAmerican Society for Clinical Investigation. The Journal's web site is located at http://www.jci.org
Citation
Journal Of Clinical Investigation, 1995, v. 96 n. 1, p. 99-106 How to Cite?
AbstractWe investigated the in vivo effects of a glucocorticoid on β-agonist- induced downregulation of β1- and β2-adrenergic receptors (determined by [125I]iodocyanopindolol binding), mRNA expression (assessed by Northern blotting), and gene transcription (using nuclear run-on assays) in rat lung. Dexamethasone (Dex) (0.2 mg/kg/d, days 1-8) increased β1- and β2-receptor numbers by 70 and 69% above control, respectively, but did not change their mRNA expression. Isoproterenol (Iso) (0.96 mg/kg/d, days 2-8) decreased β1- and β2-receptor numbers by 48 and 51%, respectively, and also reduced mRNA expression by 69 and 57%, respectively. The combination of Dex and Iso resulted in no net change in β2-receptor number and its mRNA expression, although there was a significant reduction in β1-receptor number and mRNA expression. The mapping of β1- and β2-receptors by receptor autoradiography confirmed these findings over alveoli, epithelium, endothelium, and airway and vascular smooth muscle. We also measured the activation of the transcription factor, cyclic AMP response element binding protein (CREB) using an electrophoretic mobility shift assay. CREB-like DNA- binding activity was decreased after Iso treatment but this decrease was prevented after treatment with Dex. Nuclear run-on assays revealed that the transcription rate of the β1-receptor gene did not alter after Dex treatment, but was reduced after Iso treatment. The transcription rate of the β2-receptor gene was increased after Dex treatment by approximately twofold, but there was no change after Iso treatment. We conclude that glucocorticoids can prevent homologous downregulation of β2-receptor number and mRNA expression at the transcriptional level without affecting β1- receptors and that the transcription factor CREB may be involved in this phenomenon. Such an effect may have clinical implications for preventing the development of tolerance to β2-agonists in asthmatic patients treated with β-agonist bronchodilators.
Persistent Identifierhttp://hdl.handle.net/10722/162101
ISSN
2015 Impact Factor: 12.575
2015 SCImago Journal Rankings: 8.764
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorMak, JCWen_US
dc.contributor.authorNishikawa, Men_US
dc.contributor.authorShirasaki, Hen_US
dc.contributor.authorMiyayasu, Ken_US
dc.contributor.authorBarnes, PJen_US
dc.date.accessioned2012-09-05T05:17:20Z-
dc.date.available2012-09-05T05:17:20Z-
dc.date.issued1995en_US
dc.identifier.citationJournal Of Clinical Investigation, 1995, v. 96 n. 1, p. 99-106en_US
dc.identifier.issn0021-9738en_US
dc.identifier.urihttp://hdl.handle.net/10722/162101-
dc.description.abstractWe investigated the in vivo effects of a glucocorticoid on β-agonist- induced downregulation of β1- and β2-adrenergic receptors (determined by [125I]iodocyanopindolol binding), mRNA expression (assessed by Northern blotting), and gene transcription (using nuclear run-on assays) in rat lung. Dexamethasone (Dex) (0.2 mg/kg/d, days 1-8) increased β1- and β2-receptor numbers by 70 and 69% above control, respectively, but did not change their mRNA expression. Isoproterenol (Iso) (0.96 mg/kg/d, days 2-8) decreased β1- and β2-receptor numbers by 48 and 51%, respectively, and also reduced mRNA expression by 69 and 57%, respectively. The combination of Dex and Iso resulted in no net change in β2-receptor number and its mRNA expression, although there was a significant reduction in β1-receptor number and mRNA expression. The mapping of β1- and β2-receptors by receptor autoradiography confirmed these findings over alveoli, epithelium, endothelium, and airway and vascular smooth muscle. We also measured the activation of the transcription factor, cyclic AMP response element binding protein (CREB) using an electrophoretic mobility shift assay. CREB-like DNA- binding activity was decreased after Iso treatment but this decrease was prevented after treatment with Dex. Nuclear run-on assays revealed that the transcription rate of the β1-receptor gene did not alter after Dex treatment, but was reduced after Iso treatment. The transcription rate of the β2-receptor gene was increased after Dex treatment by approximately twofold, but there was no change after Iso treatment. We conclude that glucocorticoids can prevent homologous downregulation of β2-receptor number and mRNA expression at the transcriptional level without affecting β1- receptors and that the transcription factor CREB may be involved in this phenomenon. Such an effect may have clinical implications for preventing the development of tolerance to β2-agonists in asthmatic patients treated with β-agonist bronchodilators.en_US
dc.languageengen_US
dc.publisherAmerican Society for Clinical Investigation. The Journal's web site is located at http://www.jci.orgen_US
dc.relation.ispartofJournal of Clinical Investigationen_US
dc.subject.meshAnimalsen_US
dc.subject.meshAutoradiographyen_US
dc.subject.meshBlotting, Northernen_US
dc.subject.meshDna - Metabolismen_US
dc.subject.meshDown-Regulationen_US
dc.subject.meshElectrophoresisen_US
dc.subject.meshGlucocorticoids - Pharmacologyen_US
dc.subject.meshLung - Chemistry - Drug Effectsen_US
dc.subject.meshMaleen_US
dc.subject.meshRatsen_US
dc.subject.meshRats, Wistaren_US
dc.subject.meshReceptors, Adrenergic, Beta-1 - Analysis - Drug Effects - Geneticsen_US
dc.subject.meshReceptors, Adrenergic, Beta-2 - Analysis - Drug Effects - Geneticsen_US
dc.titleProtective effects of a glucocorticoid on downregulation of pulmonary β2-adrenergic receptors in vivoen_US
dc.typeArticleen_US
dc.identifier.emailMak, JCW:judymak@hku.hken_US
dc.identifier.authorityMak, JCW=rp00352en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1172/JCI118084-
dc.identifier.pmid7615841-
dc.identifier.scopuseid_2-s2.0-0029115523en_US
dc.identifier.volume96en_US
dc.identifier.issue1en_US
dc.identifier.spage99en_US
dc.identifier.epage106en_US
dc.identifier.isiWOS:A1995RH89400014-
dc.publisher.placeUnited Statesen_US
dc.identifier.scopusauthoridMak, JCW=7103323094en_US
dc.identifier.scopusauthoridNishikawa, M=7402607361en_US
dc.identifier.scopusauthoridShirasaki, H=7004586584en_US
dc.identifier.scopusauthoridMiyayasu, K=6507160403en_US
dc.identifier.scopusauthoridBarnes, PJ=36064679400en_US

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