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PDE4 and PDE5 regulate cyclic nucleotides relaxing effects in human umbilical arteries

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dc.contributor.authorVerde, Ignacio
dc.contributor.authorSilva, António José Santos
dc.contributor.authorCairrão, Elisa
dc.contributor.authorMorgado, Manuel
dc.contributor.authorÁlvarez, Ezequielpt
dc.date.accessioned2010-04-28T10:07:30Z
dc.date.available2010-04-28T10:07:30Z
dc.date.issued2008
dc.description.abstractCyclic nucleotides (cAMP and cGMP) are the main second messengers linked to vasodilatation. They are synthesized by cyclases and degraded by different types of phosphodiesterases (PDE). The effect of PDE inhibition and cyclases stimulation on 5-hydroxytryptamine (5-HT; 1 microM) and histamine (10 microM) contracted arteries was analysed. Stimulation of guanylate cyclase or adenylate cyclase relaxed the histamine- and 5-HT-induced contractions indicating that intracellular increase of cyclic nucleotides leads to vasodilatation of the human umbilical artery. We investigated the role of different PDE families in the regulation of this effect. The presence of the different PDE types in human umbilical artery smooth muscle was analysed by RT-PCR and the expression of PDE1B, PDE3A, PDE3B, PDE4C, PDE4D and PDE5A was detected. The unspecific PDE inhibitor 3-isobutyl-1-methylxanthine (IBMX; 50 microM) relaxed histamine-contracted human umbilical artery on 47.4+/-7.2%. This effect seems to be due to PDE4 and PDE5 inhibition because among the selective PDE inhibitors used only the PDE4 inhibitor (rolipram; 1 microM) and the PDE5 inhibitors (dipyridamole and T0156; 3 microM and 1 microM respectively) induced significant relaxation (39.0+/-8.7, 30.4+/-6.0 and 36.3+/-2.8 respectively). IBMX, dipyridamole and T0156 produced similar relaxation on 5-HT-induced contraction. After forskolin, the addition of IBMX or rolipram increased the effect of the adenylate cyclase stimulator and almost completely relaxed the human umbilical artery contracted by histamine (92.5+/-4.9 and 90.9+/-4.7 respectively), suggesting a main role of PDE4. The data obtained with 5-HT contracted arteries confirmed this, because only rolipram and IBMX significantly increased the forskolin vasodilator effect. The administration of dipyridamole and T0156 after sodium nitroprusside (SNP) induced a significant increase of the SNP relaxant effect on histamine-contracted arteries, but PDE1 and PDE3 inhibition did not increase the effect of the guanylate cyclase stimulator. Similar effects were obtained in 5-HT contracted arteries, the SNP induced relaxation was increased by the PDE5 inhibition, but not by PDE1 or PDE3 inhibition. In summary, our results demonstrate that: 1) the increase of cAMP and/or cGMP levels induces relaxation of the human umbilical vascular smooth muscle; 2) four families of PDE are expressed in this smooth muscle: PDE1, PDE3, PDE4 and PDE5; 3) between these families, PDE4 and PDE5 are the key enzymes involved in the regulation of the relaxation associated to cAMP and cGMP, respectively.
dc.identifier.urihttp://hdl.handle.net/10400.6/623
dc.languageeng
dc.titlePDE4 and PDE5 regulate cyclic nucleotides relaxing effects in human umbilical arteriespt
dc.typejournal article
dspace.entity.typePublication
oaire.citation.issue582:102-109pt
oaire.citation.titleEuropean Journal of Pharmacologypt
person.familyNameVerde
person.familyNameSantos-Silva AJ
person.familyNameCairrao Rodrigues Oliveira
person.familyNameNunes Vicente Passos Morgado
person.givenNameIgnacio
person.givenNameAntónio José dos Santos Silva
person.givenNameMaria Elisa
person.givenNameManuel Augusto
person.identifierAAB-1164-2020
person.identifierAAG-4910-2021
person.identifier.ciencia-idD012-1D7C-791A
person.identifier.ciencia-id0611-71B8-191E
person.identifier.ciencia-id7617-9FDC-2D9D
person.identifier.orcid0000-0003-3492-5725
person.identifier.orcid0000-0002-8200-1052
person.identifier.orcid0000-0002-4823-5701
person.identifier.orcid0000-0003-2112-2835
person.identifier.ridM-3991-2013
person.identifier.scopus-author-id55913729400
person.identifier.scopus-author-idScopus Author ID: 23476537500
person.identifier.scopus-author-id55955252600
rcaap.rightsopenAccess
rcaap.typearticlept
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relation.isAuthorOfPublication.latestForDiscovery211cd7f0-41c8-4799-874d-a94f3f0385cd

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