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β3 Adrenoceptor-induced cholinergic inhibition in human and rat urinary bladders involves the exchange protein directly activated by cyclic AMP 1 favoring adenosine release

2020Journal article Open access
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dc.contributor.authorSilva, Isabel
dc.contributor.authorMagalhães‐Cardoso, M. Teresa
dc.contributor.authorFerreirinha, Fátima
dc.contributor.authorMoreira, Sílvia
dc.contributor.authorCosta, Ana Filipa
dc.contributor.authorSilva, Diogo
dc.contributor.authorVieira, Cátia
dc.contributor.authorSilva-Ramos, Miguel
dc.contributor.authorCorreia‐de‐Sá, Paulo
dc.date.accessioned2021-11-09T20:51:26Z
dc.date.available2021-11-09T20:51:26Z
dc.date.issued2020
dc.description.abstractBackground and purpose: The mechanism by which β3 receptor agonists (e.g. mirabegron) control bladder overactivity may involve adenosine release from human and rat detrusor smooth muscle. Retrograde activation of adenosine A1 receptors reduces ACh release from cholinergic bladder nerves. β3 -Adrenoceptors usually couple to adenylyl cyclase. Here we investigated, which of the cAMP targets, protein kinase A or the exchange protein directly activated by cAMP (EPAC) could be involved in this cholinergic inhibition of the bladder. Experimental approach: [3 H]ACh and adenosine release from urothelium-denuded detrusor strips of cadaveric human organ donors and rats were measured by liquid scintillation spectrometry and HPLC, respectively. In vivo cystometry was also performed in urethane-anaesthetized rats. Key results: The exchange protein directly activated by cAMP (EPAC) inhibitor, ESI-09, prevented mirabegron- and isoprenaline-induced adenosine release from human and rat detrusor strips respectively. ESI-09, but not the PKA inhibitor, H-89, attenuated inhibition of [3 H]ACh release from stimulated (10 Hz) detrusor strips caused by activating β3 -adrenoceptors, AC (forskolin) and EPAC1 (8-CTP-2Me-cAMP). Isoprenaline-induced inhibition of [3 H]ACh release was also prevented by inhibitors of PKC (chelerythrine and Go6976) and of the equilibrative nucleoside transporter 1 (ENT1; dipyridamole and NBTI), but not by PLC inhibition with U73122. Pretreatment with ESI-09, but not with H-89, prevented the reduction of the voiding frequency caused by isoprenaline and forskolin in vivo. Conclusion and implications: Data suggest that β3 -adrenoceptor-induced inhibition of cholinergic neurotransmission in human and rat urinary bladders involves activation of an EPAC1/PKC pathway downstream cAMP production resulting in adenosine outflow via ENT1.pt_PT
dc.description.sponsorshipThis research was partially supported by Fundação para a Ciência e a Tecnologia (FCT, FEDER funding, projects Grants PTDC/SAU-OSM/104369/2008, REEQ/1168/SAU/2005, REEQ/1264/SAU/2005, Pest-OE/SAU/UI215/2014, UID/BIM/4308/2016, and UID/BIM/4308/2019), Associação Portuguesa de Urologia (APU), and University of Porto/Caixa Geral de Depósitos (Investigação Científica na Pré-Graduação). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. I.S. was in receipt for a PhD Studentship from FCT (Grant SFRH/BD/88855/2012). The authors wish to thank Mrs. Helena Costa e Silva and Belmira Silva for their valuable technical assistance.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationSilva I, Magalhães-Cardoso MT, Ferreirinha F, et al. β3 Adrenoceptor-induced cholinergic inhibition in human and rat urinary bladders involves the exchange protein directly activated by cyclic AMP 1 favoring adenosine release. Br J Pharmacol. 2020;177(7):1589-1608. doi:10.1111/bph.14921pt_PT
dc.identifier.doi10.1111/bph.14921pt_PT
dc.identifier.issn1476-5381
dc.identifier.urihttp://hdl.handle.net/10400.16/2534
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherMacmillian Journals Ltdpt_PT
dc.relation.publisherversionhttps://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bph.14921pt_PT
dc.titleβ3 Adrenoceptor-induced cholinergic inhibition in human and rat urinary bladders involves the exchange protein directly activated by cyclic AMP 1 favoring adenosine releasept_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/5876-PPCDTI/PTDC%2FSAU-OSM%2F104369%2F2008/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/SFRH/SFRH%2FBD%2F88855%2F2012/PT
oaire.citation.conferencePlaceEnglandpt_PT
oaire.citation.endPage1608pt_PT
oaire.citation.issue7pt_PT
oaire.citation.startPage1589pt_PT
oaire.citation.titleBritish Journal of Pharmacologypt_PT
oaire.citation.volume177pt_PT
oaire.fundingStream5876-PPCDTI
oaire.fundingStreamSFRH
person.familyNameSilva-Ramos
person.givenNameMiguel
person.identifier.ciencia-idA71F-0CBC-D7F7
person.identifier.orcid0000-0002-1232-3232
person.identifier.ridN-4077-2013
person.identifier.scopus-author-id22952009900
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
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relation.isAuthorOfPublication.latestForDiscovery41b30044-e671-4c7a-bb70-137a59e963f5
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