Allosteric interaction of the anticholinergic drug [N-(4-phenyl)-phenacyl-1-hyoscyamine] (Phenthonium) with nicotinic receptors of post-ganglionic sympathetic neurons of the rat vas deferens

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dc.contributor.authorMunhoz, Egberto
dc.contributor.authorDe Lima, Thereza C. M.
dc.contributor.authorSouccar, Caden
dc.contributor.authorLapa, Antonio J.
dc.contributor.authorLima-Landman, Maria Teresa R. [UNIFESP]
dc.contributor.institutionUniversidade Federal de São Paulo (UNIFESP)
dc.contributor.institutionUniversidade Federal de Santa Catarina (UFSC)
dc.date.accessioned2016-01-24T13:58:37Z
dc.date.available2016-01-24T13:58:37Z
dc.date.issued2009-08-15
dc.description.abstractPhenthonium (Phen), a quaternary analog of hyoscyamine, is a blocker of muscarinic activity and an allosteric blocker of alpha(1)2 beta gamma epsilon nicotinic receptors. Specifically, Phenthonium increases the spontaneous release of acetylcholine at the motor endplate without depolarizing the muscle or inhibiting cholinesterase activity. This paper compares Phenthonium's effects on sympathetic transmission and on ganglionic nicotinic receptor activation. Neurotransmitter release and twitch of the rat vas deferens were induced either by electrical stimulation or by 1,1-dimethyl-4-phenylpiperazine (DMPP) activation of nicotinic receptors. Contractions independent of transmitter release were induced by noradrenaline and adenosine 5'-triphosphate (ATP). Phenthonium inhibited transmitter release and depressed twitch without changing the responsiveness to noradrenaline or ATP. Twitch depression did not occur after K(+)-channel blockade with 4-aminopyridine (4-AP) or charybdotoxin. DMPP had a similar effect, but high concentrations induced contraction of non-stimulated organs. Incubation of Phenthonium inhibited further DMPP twitch depression and non-competitively depressed the contractile responses elicited by DMPP. Furthermore, mecamylamine, but neither methyllycaconitine nor atropine, blocked the contraction elicited by DMPP. Phenthonium and DMPP are K(+)-channel openers that primarily inhibit sympathetic transmission. Contraction induced by DMPP was probably mediated by neuronal nicotinic receptor other than the alpha 7 subtype. the blockade of DMPP contractile response was unrelated to Phenthonium's antimuscarinic or K(+)-channel opening activities. Since Phenthonium's quaternary chemical structure limits its membrane diffusion, the non-competitive inhibition of DMPP excitatory responses should be linked to allosteric interaction with neuronal nicotinic receptors that putatively qualify Phenthonium as a novel modulator of cholinergic synapses. (C) 2009 Elsevier B.V. All rights reserved.en
dc.description.affiliationUniversidade Federal de São Paulo, Nat Prod Sect, Dept Pharmacol, Escola Paulista Med, BR-04044020 São Paulo, Brazil
dc.description.affiliationUniv Fed Santa Catarina, Dept Pharmacol, Florianopolis, SC, Brazil
dc.description.affiliationUnifespUniversidade Federal de São Paulo, Nat Prod Sect, Dept Pharmacol, Escola Paulista Med, BR-04044020 São Paulo, Brazil
dc.description.sourceWeb of Science
dc.description.sponsorshipFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.description.sponsorshipConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
dc.description.sponsorshipFADA-UNIFESP, Brazil
dc.format.extent229-235
dc.identifierhttp://dx.doi.org/10.1016/j.ejphar.2009.06.007
dc.identifier.citationEuropean Journal of Pharmacology. Amsterdam: Elsevier B.V., v. 616, n. 1-3, p. 229-235, 2009.
dc.identifier.doi10.1016/j.ejphar.2009.06.007
dc.identifier.issn0014-2999
dc.identifier.urihttp://repositorio.unifesp.br/handle/11600/31743
dc.identifier.wosWOS:000269933100034
dc.language.isoeng
dc.publisherElsevier B.V.
dc.relation.ispartofEuropean Journal of Pharmacology
dc.rightsinfo:eu-repo/semantics/restrictedAccess
dc.rights.licensehttp://www.elsevier.com/about/open-access/open-access-policies/article-posting-policy
dc.subjectPhenthoniumen
dc.subjectGanglionic nicotinic receptoren
dc.subjectRat vas deferensen
dc.subjectNeurotransmitter releaseen
dc.subjectDMPPen
dc.subjectPotassium channelen
dc.titleAllosteric interaction of the anticholinergic drug [N-(4-phenyl)-phenacyl-1-hyoscyamine] (Phenthonium) with nicotinic receptors of post-ganglionic sympathetic neurons of the rat vas deferensen
dc.typeinfo:eu-repo/semantics/article
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