Mirabegron elicits rat corpus cavernosum relaxation and increases in vivo erectile response
Autor(a) principal: | |
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Data de Publicação: | 2019 |
Outros Autores: | , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UNESP |
Texto Completo: | http://dx.doi.org/10.1016/j.ejphar.2019.172447 http://hdl.handle.net/11449/187789 |
Resumo: | Mirabegron is the first β3-adrenoceptor agonist approved on the market and may offer beneficial pharmacological action in patients with overactive bladder and erectile dysfunction. Here, we further investigate the mechanisms by which mirabegron induces rat corpus cavernosum (CC) relaxation. Adult male Wistar rats were used. The CC were isolated for in vitro functional assays and β-adrenoceptors subtypes mRNA expression evaluation. Animals were treated orally with mirabegron (30 mg/kg, 3 h), tadalafil (10 mg/kg, 3 h) or both for intracavernous pressure (ICP). Intracellular levels of cAMP and cGMP were also determined. The β1-, β2- and β3-adrenoceptors subtypes were expressed in rat CC. Mirabegron produced concentration-dependent CC relaxations that were unaffected by the β1-, β2- or β3-adrenoceptor antagonists atenolol (1 μM), ICI-118,551 (1 μM) and L748,337 (10 μM), respectively. Mirabegron-induced relaxations were not affected by the phosphodiesterase type 4 inhibitor, rolipram, or the adenylyl cyclase selective inhibitor, SQ 22,536. Potassium channel- or calcium influx-blockade are not involved in mirabegron-induced relaxations. In contrast, mirabegron produced rightward shifts in the contractile response induced by the α1-adrenoceptor agonist, phenylephrine. Finally, cavernous nerve stimulation caused frequency-dependent ICP increases, which were significantly increased in rats treated with mirabegron in a similar degree of tadalafil-treated rat, without promoting a significant cAMP or cGMP accumulation. Together, our results demonstrate that mirabegron induced CC relaxation through α1-adrenoceptor blockade. Care should be taken to translate the effect of mirabegron into the clinic, especially when using rat as an animal model of erectile dysfunction. |
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Mirabegron elicits rat corpus cavernosum relaxation and increases in vivo erectile responseCyclic AMPCyclic GMPErectile dysfunctionIntracavernous pressureMirabegronTadalafilMirabegron is the first β3-adrenoceptor agonist approved on the market and may offer beneficial pharmacological action in patients with overactive bladder and erectile dysfunction. Here, we further investigate the mechanisms by which mirabegron induces rat corpus cavernosum (CC) relaxation. Adult male Wistar rats were used. The CC were isolated for in vitro functional assays and β-adrenoceptors subtypes mRNA expression evaluation. Animals were treated orally with mirabegron (30 mg/kg, 3 h), tadalafil (10 mg/kg, 3 h) or both for intracavernous pressure (ICP). Intracellular levels of cAMP and cGMP were also determined. The β1-, β2- and β3-adrenoceptors subtypes were expressed in rat CC. Mirabegron produced concentration-dependent CC relaxations that were unaffected by the β1-, β2- or β3-adrenoceptor antagonists atenolol (1 μM), ICI-118,551 (1 μM) and L748,337 (10 μM), respectively. Mirabegron-induced relaxations were not affected by the phosphodiesterase type 4 inhibitor, rolipram, or the adenylyl cyclase selective inhibitor, SQ 22,536. Potassium channel- or calcium influx-blockade are not involved in mirabegron-induced relaxations. In contrast, mirabegron produced rightward shifts in the contractile response induced by the α1-adrenoceptor agonist, phenylephrine. Finally, cavernous nerve stimulation caused frequency-dependent ICP increases, which were significantly increased in rats treated with mirabegron in a similar degree of tadalafil-treated rat, without promoting a significant cAMP or cGMP accumulation. Together, our results demonstrate that mirabegron induced CC relaxation through α1-adrenoceptor blockade. Care should be taken to translate the effect of mirabegron into the clinic, especially when using rat as an animal model of erectile dysfunction.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Department of Pharmacology Faculty of Medical Sciences University of Campinas (UNICAMP)Department of Pharmacology Institute of Biosciences São Paulo State University (UNESP)Department of Pharmacology Institute of Biosciences São Paulo State University (UNESP)FAPESP: 2013/13907–4FAPESP: 2017/15175–1FAPESP: 2018/09765–3Universidade Estadual de Campinas (UNICAMP)Universidade Estadual Paulista (Unesp)de Oliveira, Mariana G.Rojas-Moscoso, Julio AlejandroBertollotto, Gabriela M.Candido, Tuany Z.Kiguti, Luiz Ricardo de A.Pupo, André S. [UNESP]Antunes, EdsonDe Nucci, GilbertoMónica, Fabíola Z.2019-10-06T15:47:16Z2019-10-06T15:47:16Z2019-09-05info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttp://dx.doi.org/10.1016/j.ejphar.2019.172447European Journal of Pharmacology, v. 858.1879-07120014-2999http://hdl.handle.net/11449/18778910.1016/j.ejphar.2019.1724472-s2.0-85067626097Scopusreponame:Repositório Institucional da UNESPinstname:Universidade Estadual Paulista (UNESP)instacron:UNESPengEuropean Journal of Pharmacologyinfo:eu-repo/semantics/openAccess2021-10-22T21:10:07Zoai:repositorio.unesp.br:11449/187789Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestopendoar:29462024-08-05T19:13:32.942789Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)false |
dc.title.none.fl_str_mv |
Mirabegron elicits rat corpus cavernosum relaxation and increases in vivo erectile response |
title |
Mirabegron elicits rat corpus cavernosum relaxation and increases in vivo erectile response |
spellingShingle |
Mirabegron elicits rat corpus cavernosum relaxation and increases in vivo erectile response de Oliveira, Mariana G. Cyclic AMP Cyclic GMP Erectile dysfunction Intracavernous pressure Mirabegron Tadalafil |
title_short |
Mirabegron elicits rat corpus cavernosum relaxation and increases in vivo erectile response |
title_full |
Mirabegron elicits rat corpus cavernosum relaxation and increases in vivo erectile response |
title_fullStr |
Mirabegron elicits rat corpus cavernosum relaxation and increases in vivo erectile response |
title_full_unstemmed |
Mirabegron elicits rat corpus cavernosum relaxation and increases in vivo erectile response |
title_sort |
Mirabegron elicits rat corpus cavernosum relaxation and increases in vivo erectile response |
author |
de Oliveira, Mariana G. |
author_facet |
de Oliveira, Mariana G. Rojas-Moscoso, Julio Alejandro Bertollotto, Gabriela M. Candido, Tuany Z. Kiguti, Luiz Ricardo de A. Pupo, André S. [UNESP] Antunes, Edson De Nucci, Gilberto Mónica, Fabíola Z. |
author_role |
author |
author2 |
Rojas-Moscoso, Julio Alejandro Bertollotto, Gabriela M. Candido, Tuany Z. Kiguti, Luiz Ricardo de A. Pupo, André S. [UNESP] Antunes, Edson De Nucci, Gilberto Mónica, Fabíola Z. |
author2_role |
author author author author author author author author |
dc.contributor.none.fl_str_mv |
Universidade Estadual de Campinas (UNICAMP) Universidade Estadual Paulista (Unesp) |
dc.contributor.author.fl_str_mv |
de Oliveira, Mariana G. Rojas-Moscoso, Julio Alejandro Bertollotto, Gabriela M. Candido, Tuany Z. Kiguti, Luiz Ricardo de A. Pupo, André S. [UNESP] Antunes, Edson De Nucci, Gilberto Mónica, Fabíola Z. |
dc.subject.por.fl_str_mv |
Cyclic AMP Cyclic GMP Erectile dysfunction Intracavernous pressure Mirabegron Tadalafil |
topic |
Cyclic AMP Cyclic GMP Erectile dysfunction Intracavernous pressure Mirabegron Tadalafil |
description |
Mirabegron is the first β3-adrenoceptor agonist approved on the market and may offer beneficial pharmacological action in patients with overactive bladder and erectile dysfunction. Here, we further investigate the mechanisms by which mirabegron induces rat corpus cavernosum (CC) relaxation. Adult male Wistar rats were used. The CC were isolated for in vitro functional assays and β-adrenoceptors subtypes mRNA expression evaluation. Animals were treated orally with mirabegron (30 mg/kg, 3 h), tadalafil (10 mg/kg, 3 h) or both for intracavernous pressure (ICP). Intracellular levels of cAMP and cGMP were also determined. The β1-, β2- and β3-adrenoceptors subtypes were expressed in rat CC. Mirabegron produced concentration-dependent CC relaxations that were unaffected by the β1-, β2- or β3-adrenoceptor antagonists atenolol (1 μM), ICI-118,551 (1 μM) and L748,337 (10 μM), respectively. Mirabegron-induced relaxations were not affected by the phosphodiesterase type 4 inhibitor, rolipram, or the adenylyl cyclase selective inhibitor, SQ 22,536. Potassium channel- or calcium influx-blockade are not involved in mirabegron-induced relaxations. In contrast, mirabegron produced rightward shifts in the contractile response induced by the α1-adrenoceptor agonist, phenylephrine. Finally, cavernous nerve stimulation caused frequency-dependent ICP increases, which were significantly increased in rats treated with mirabegron in a similar degree of tadalafil-treated rat, without promoting a significant cAMP or cGMP accumulation. Together, our results demonstrate that mirabegron induced CC relaxation through α1-adrenoceptor blockade. Care should be taken to translate the effect of mirabegron into the clinic, especially when using rat as an animal model of erectile dysfunction. |
publishDate |
2019 |
dc.date.none.fl_str_mv |
2019-10-06T15:47:16Z 2019-10-06T15:47:16Z 2019-09-05 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://dx.doi.org/10.1016/j.ejphar.2019.172447 European Journal of Pharmacology, v. 858. 1879-0712 0014-2999 http://hdl.handle.net/11449/187789 10.1016/j.ejphar.2019.172447 2-s2.0-85067626097 |
url |
http://dx.doi.org/10.1016/j.ejphar.2019.172447 http://hdl.handle.net/11449/187789 |
identifier_str_mv |
European Journal of Pharmacology, v. 858. 1879-0712 0014-2999 10.1016/j.ejphar.2019.172447 2-s2.0-85067626097 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
European Journal of Pharmacology |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.source.none.fl_str_mv |
Scopus reponame:Repositório Institucional da UNESP instname:Universidade Estadual Paulista (UNESP) instacron:UNESP |
instname_str |
Universidade Estadual Paulista (UNESP) |
instacron_str |
UNESP |
institution |
UNESP |
reponame_str |
Repositório Institucional da UNESP |
collection |
Repositório Institucional da UNESP |
repository.name.fl_str_mv |
Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP) |
repository.mail.fl_str_mv |
|
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1808129036567707648 |