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Article: Chronic systemic administration of salmeterol to rats promotes pulmonary β 2-adrenoceptor desensitization and down-regulation of G sα

TitleChronic systemic administration of salmeterol to rats promotes pulmonary β 2-adrenoceptor desensitization and down-regulation of G sα
Authors
Issue Date2001
PublisherJohn Wiley & Sons Ltd. The Journal's web site is located at http://www.wiley.com/bw/journal.asp?ref=0007-1188&site=1
Citation
British Journal Of Pharmacology, 2001, v. 132 n. 6, p. 1261-1270 How to Cite?
Abstract1. The aim of the present study was to examine the effects of chronic infusion of the long-acting agonist salmeterol on pulmonary β 2-adrenoceptor function in Sprague-Dawley rats in vivo and to elucidate the molecular basis of any altered state. 2. Systemic administration of rats with salmeterol for 7 days compromised the ability of salmeterol and prostaglandin E 2 (PGE 2), given acutely by the intravenous route, to protect against ACh-induced bronchoconstriction when compared to rats treated identically with vehicle. 3. β1- and β 2-adrenoceptor density was significantly reduced in lung membranes harvested from salmeterol-treated animals, which was associated with impaired salmeterol- and PGE 2-induced cyclic AMP accumulation ex vivo. 4. Three variants of G sα that migrated as 42, 44 and 52 kDa peptides on SDS polyacrylamide gels were detected in lung membranes prepared from both groups of rats but the intensity of each isoform was markedly reduced in rats that received salmeterol. 5. The activity of cytosolic, but not membrane-associated, G-protein receptor-coupled kinase was elevated in the lung of salmeterol-treated rats when compared to vehicle-treated animals. 6. The ability of salmeterol, administered systemically, to protect the airways of untreated rats against ACh-induced bronchoconstriction was short-acting (t off ∼45 min), which contrasts with its long-acting nature when given to asthmatic subjects by inhalation. 7. These results indicate that chronic treatment of rats with salmeterol results in heterologous desensitization of pulmonary G s-coupled receptors. In light of previous data obtained in rats treated chronically with salbutamol, we propose that a primary mechanism responsible for this effect is a reduction in membrane-associated G sα. The short-acting nature of salmeterol, when administered systemically, and the reduction in β-adrenoceptor number may be due to metabolism to a biologically-active, short-acting and non-selective β-adrenoceptor agonist.
Persistent Identifierhttp://hdl.handle.net/10722/162501
ISSN
2015 Impact Factor: 5.259
2015 SCImago Journal Rankings: 2.368
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorFinney, PAen_US
dc.contributor.authorDonnelly, LEen_US
dc.contributor.authorBelvisi, MGen_US
dc.contributor.authorChuang, TTen_US
dc.contributor.authorBirrell, Men_US
dc.contributor.authorHarris, Aen_US
dc.contributor.authorMak, JCWen_US
dc.contributor.authorScorer, Cen_US
dc.contributor.authorBarnes, PJen_US
dc.contributor.authorAdcock, IMen_US
dc.contributor.authorGiembycz, MAen_US
dc.date.accessioned2012-09-05T05:20:34Z-
dc.date.available2012-09-05T05:20:34Z-
dc.date.issued2001en_US
dc.identifier.citationBritish Journal Of Pharmacology, 2001, v. 132 n. 6, p. 1261-1270en_US
dc.identifier.issn0007-1188en_US
dc.identifier.urihttp://hdl.handle.net/10722/162501-
dc.description.abstract1. The aim of the present study was to examine the effects of chronic infusion of the long-acting agonist salmeterol on pulmonary β 2-adrenoceptor function in Sprague-Dawley rats in vivo and to elucidate the molecular basis of any altered state. 2. Systemic administration of rats with salmeterol for 7 days compromised the ability of salmeterol and prostaglandin E 2 (PGE 2), given acutely by the intravenous route, to protect against ACh-induced bronchoconstriction when compared to rats treated identically with vehicle. 3. β1- and β 2-adrenoceptor density was significantly reduced in lung membranes harvested from salmeterol-treated animals, which was associated with impaired salmeterol- and PGE 2-induced cyclic AMP accumulation ex vivo. 4. Three variants of G sα that migrated as 42, 44 and 52 kDa peptides on SDS polyacrylamide gels were detected in lung membranes prepared from both groups of rats but the intensity of each isoform was markedly reduced in rats that received salmeterol. 5. The activity of cytosolic, but not membrane-associated, G-protein receptor-coupled kinase was elevated in the lung of salmeterol-treated rats when compared to vehicle-treated animals. 6. The ability of salmeterol, administered systemically, to protect the airways of untreated rats against ACh-induced bronchoconstriction was short-acting (t off ∼45 min), which contrasts with its long-acting nature when given to asthmatic subjects by inhalation. 7. These results indicate that chronic treatment of rats with salmeterol results in heterologous desensitization of pulmonary G s-coupled receptors. In light of previous data obtained in rats treated chronically with salbutamol, we propose that a primary mechanism responsible for this effect is a reduction in membrane-associated G sα. The short-acting nature of salmeterol, when administered systemically, and the reduction in β-adrenoceptor number may be due to metabolism to a biologically-active, short-acting and non-selective β-adrenoceptor agonist.en_US
dc.languageengen_US
dc.publisherJohn Wiley & Sons Ltd. The Journal's web site is located at http://www.wiley.com/bw/journal.asp?ref=0007-1188&site=1en_US
dc.relation.ispartofBritish Journal of Pharmacologyen_US
dc.subject.meshAcetylcholine - Pharmacologyen_US
dc.subject.meshAdrenergic Beta-Agonists - Administration & Dosage - Pharmacologyen_US
dc.subject.meshAlbuterol - Administration & Dosage - Analogs & Derivatives - Pharmacologyen_US
dc.subject.meshAnimalsen_US
dc.subject.meshBronchoconstriction - Drug Effectsen_US
dc.subject.meshCyclic Amp - Metabolismen_US
dc.subject.meshCyclic Amp-Dependent Protein Kinases - Metabolismen_US
dc.subject.meshDinoprostone - Pharmacologyen_US
dc.subject.meshDown-Regulationen_US
dc.subject.meshDrug Interactionsen_US
dc.subject.meshGtp-Binding Protein Alpha Subunits, Gi-Go - Biosynthesisen_US
dc.subject.meshGtp-Binding Protein Alpha Subunits, Gs - Biosynthesisen_US
dc.subject.meshGene Expression - Drug Effectsen_US
dc.subject.meshInjections, Intravenousen_US
dc.subject.meshLung - Drug Effects - Metabolismen_US
dc.subject.meshMaleen_US
dc.subject.meshProtective Agents - Pharmacologyen_US
dc.subject.meshRna, Messenger - Drug Effects - Metabolismen_US
dc.subject.meshRatsen_US
dc.subject.meshRats, Sprague-Dawleyen_US
dc.subject.meshReceptors, Adrenergic, Beta-1 - Genetics - Metabolismen_US
dc.subject.meshReceptors, Adrenergic, Beta-2 - Genetics - Metabolismen_US
dc.subject.meshBeta-Adrenergic Receptor Kinasesen_US
dc.titleChronic systemic administration of salmeterol to rats promotes pulmonary β 2-adrenoceptor desensitization and down-regulation of G sαen_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.doi10.1038/sj.bjp.0703946-
dc.identifier.pmid11250877-
dc.identifier.scopuseid_2-s2.0-0035081856en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-0035081856&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume132en_US
dc.identifier.issue6en_US
dc.identifier.spage1261en_US
dc.identifier.epage1270en_US
dc.identifier.isiWOS:000167499200013-
dc.publisher.placeUnited Kingdomen_US
dc.identifier.scopusauthoridFinney, PA=7003602458en_US
dc.identifier.scopusauthoridDonnelly, LE=7102000743en_US
dc.identifier.scopusauthoridBelvisi, MG=35400532900en_US
dc.identifier.scopusauthoridChuang, TT=7202737767en_US
dc.identifier.scopusauthoridBirrell, M=6603002622en_US
dc.identifier.scopusauthoridHarris, A=7404039326en_US
dc.identifier.scopusauthoridMak, JCW=7103323094en_US
dc.identifier.scopusauthoridScorer, C=6701564019en_US
dc.identifier.scopusauthoridBarnes, PJ=36064679400en_US
dc.identifier.scopusauthoridAdcock, IM=7007066538en_US
dc.identifier.scopusauthoridGiembycz, MA=7007035171en_US

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