Phosphodiesterase 5A inhibition decreases NHE-1 activity without altering steady state pH<SUB>i</SUB>: Role of phosphatases

Autores
Díaz, Romina Gisel; Nolly, Mariela; Massarutti, Carolina; Casarini, María Jesús; Garciarena, Carolina Denis; Ennis, Irene Lucía; Cingolani, Horacio Eugenio; Pérez, Néstor Gustavo
Año de publicación
2010
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Background/Aims: This study aimed to identify the signaling pathway for the proposed link between phosphodiesterase-5A (PDE5A) inhibition and decreased cardiac Na + /H + exchanger (NHE-1) activity. Methods: NHE-1 activity was assessed in rat isolated papillary muscles by the Na + -dependent initial pH i recovery from a sustained acidosis (ammonium prepulse). ERK1/2, p90RSK and NHE-1 phosphorylation state during acidosis was determined. Results: PDE5A inhibition (1 μmol/L sildenafil, SIL) did not modify basal pH i but significantly blunted pH i recovery after sustained acidosis. Although preventing ERK1/2- p90RSK signaling pathway (10 μmol/L U0126) mimicked SIL effect, SIL did not blunt the acidosis-mediated increase in kinases activation. SIL+U0126 did not show additive effect on NHE-1 activity. Then, we hypothesized that SIL could be activating phophasatases (PP1 and/or PP2A) to directly dephosphorylate NHE-1 despite preserved ERK1/2-p90RSK activation. Non-specific phosphatases inhibition (1 μmol/L okadaic acid) canceled SIL effect on pH i recovery from acidosis. Same result was observed by inhibiting PP2A either with a lower dose of okadaic acid (1 nmol/L) or, more specifically, with 100 μmol/L endothall. Consistently, NHE-1 phosphorylation at Ser703 increased after acidosis, SIL prevented this effect and PP2A inhibition (endothall) reverted SIL effect. Conclusion: We suggest that PDE5A inhibitors decrease NHE-1 phosphorylation and activity through a mechanism that involves PP2A activation.
Facultad de Ciencias Médicas
Materia
Ciencias Médicas
NHE-1
Phosphodiesterase 5A
Protein kinase G
Protein phosphatase 2A
Nivel de accesibilidad
acceso abierto
Condiciones de uso
http://creativecommons.org/licenses/by-nc-sa/4.0/
Repositorio
SEDICI (UNLP)
Institución
Universidad Nacional de La Plata
OAI Identificador
oai:sedici.unlp.edu.ar:10915/82462
Acceder
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oai_identifier_str oai:sedici.unlp.edu.ar:10915/82462
network_acronym_str SEDICI
repository_id_str 1329
network_name_str SEDICI (UNLP)
spelling Phosphodiesterase 5A inhibition decreases NHE-1 activity without altering steady state pH<SUB>i</SUB>: Role of phosphatasesDíaz, Romina GiselNolly, MarielaMassarutti, CarolinaCasarini, María JesúsGarciarena, Carolina DenisEnnis, Irene LucíaCingolani, Horacio EugenioPérez, Néstor GustavoCiencias MédicasNHE-1Phosphodiesterase 5AProtein kinase GProtein phosphatase 2ABackground/Aims: This study aimed to identify the signaling pathway for the proposed link between phosphodiesterase-5A (PDE5A) inhibition and decreased cardiac Na + /H + exchanger (NHE-1) activity. Methods: NHE-1 activity was assessed in rat isolated papillary muscles by the Na + -dependent initial pH i recovery from a sustained acidosis (ammonium prepulse). ERK1/2, p90RSK and NHE-1 phosphorylation state during acidosis was determined. Results: PDE5A inhibition (1 μmol/L sildenafil, SIL) did not modify basal pH i but significantly blunted pH i recovery after sustained acidosis. Although preventing ERK1/2- p90RSK signaling pathway (10 μmol/L U0126) mimicked SIL effect, SIL did not blunt the acidosis-mediated increase in kinases activation. SIL+U0126 did not show additive effect on NHE-1 activity. Then, we hypothesized that SIL could be activating phophasatases (PP1 and/or PP2A) to directly dephosphorylate NHE-1 despite preserved ERK1/2-p90RSK activation. Non-specific phosphatases inhibition (1 μmol/L okadaic acid) canceled SIL effect on pH i recovery from acidosis. Same result was observed by inhibiting PP2A either with a lower dose of okadaic acid (1 nmol/L) or, more specifically, with 100 μmol/L endothall. Consistently, NHE-1 phosphorylation at Ser703 increased after acidosis, SIL prevented this effect and PP2A inhibition (endothall) reverted SIL effect. Conclusion: We suggest that PDE5A inhibitors decrease NHE-1 phosphorylation and activity through a mechanism that involves PP2A activation.Facultad de Ciencias Médicas2010info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionArticulohttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdf531-540http://sedici.unlp.edu.ar/handle/10915/82462enginfo:eu-repo/semantics/altIdentifier/issn/1015-8987info:eu-repo/semantics/altIdentifier/doi/10.1159/000322321info:eu-repo/semantics/openAccesshttp://creativecommons.org/licenses/by-nc-sa/4.0/Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0)reponame:SEDICI (UNLP)instname:Universidad Nacional de La Platainstacron:UNLP2025-09-29T11:15:31Zoai:sedici.unlp.edu.ar:10915/82462Institucionalhttp://sedici.unlp.edu.ar/Universidad públicaNo correspondehttp://sedici.unlp.edu.ar/oai/snrdalira@sedici.unlp.edu.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:13292025-09-29 11:15:31.466SEDICI (UNLP) - Universidad Nacional de La Platafalse
dc.title.none.fl_str_mv Phosphodiesterase 5A inhibition decreases NHE-1 activity without altering steady state pH<SUB>i</SUB>: Role of phosphatases
title Phosphodiesterase 5A inhibition decreases NHE-1 activity without altering steady state pH<SUB>i</SUB>: Role of phosphatases
spellingShingle Phosphodiesterase 5A inhibition decreases NHE-1 activity without altering steady state pH<SUB>i</SUB>: Role of phosphatases
Díaz, Romina Gisel
Ciencias Médicas
NHE-1
Phosphodiesterase 5A
Protein kinase G
Protein phosphatase 2A
title_short Phosphodiesterase 5A inhibition decreases NHE-1 activity without altering steady state pH<SUB>i</SUB>: Role of phosphatases
title_full Phosphodiesterase 5A inhibition decreases NHE-1 activity without altering steady state pH<SUB>i</SUB>: Role of phosphatases
title_fullStr Phosphodiesterase 5A inhibition decreases NHE-1 activity without altering steady state pH<SUB>i</SUB>: Role of phosphatases
title_full_unstemmed Phosphodiesterase 5A inhibition decreases NHE-1 activity without altering steady state pH<SUB>i</SUB>: Role of phosphatases
title_sort Phosphodiesterase 5A inhibition decreases NHE-1 activity without altering steady state pH<SUB>i</SUB>: Role of phosphatases
dc.creator.none.fl_str_mv Díaz, Romina Gisel
Nolly, Mariela
Massarutti, Carolina
Casarini, María Jesús
Garciarena, Carolina Denis
Ennis, Irene Lucía
Cingolani, Horacio Eugenio
Pérez, Néstor Gustavo
author Díaz, Romina Gisel
author_facet Díaz, Romina Gisel
Nolly, Mariela
Massarutti, Carolina
Casarini, María Jesús
Garciarena, Carolina Denis
Ennis, Irene Lucía
Cingolani, Horacio Eugenio
Pérez, Néstor Gustavo
author_role author
author2 Nolly, Mariela
Massarutti, Carolina
Casarini, María Jesús
Garciarena, Carolina Denis
Ennis, Irene Lucía
Cingolani, Horacio Eugenio
Pérez, Néstor Gustavo
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Ciencias Médicas
NHE-1
Phosphodiesterase 5A
Protein kinase G
Protein phosphatase 2A
topic Ciencias Médicas
NHE-1
Phosphodiesterase 5A
Protein kinase G
Protein phosphatase 2A
dc.description.none.fl_txt_mv Background/Aims: This study aimed to identify the signaling pathway for the proposed link between phosphodiesterase-5A (PDE5A) inhibition and decreased cardiac Na + /H + exchanger (NHE-1) activity. Methods: NHE-1 activity was assessed in rat isolated papillary muscles by the Na + -dependent initial pH i recovery from a sustained acidosis (ammonium prepulse). ERK1/2, p90RSK and NHE-1 phosphorylation state during acidosis was determined. Results: PDE5A inhibition (1 μmol/L sildenafil, SIL) did not modify basal pH i but significantly blunted pH i recovery after sustained acidosis. Although preventing ERK1/2- p90RSK signaling pathway (10 μmol/L U0126) mimicked SIL effect, SIL did not blunt the acidosis-mediated increase in kinases activation. SIL+U0126 did not show additive effect on NHE-1 activity. Then, we hypothesized that SIL could be activating phophasatases (PP1 and/or PP2A) to directly dephosphorylate NHE-1 despite preserved ERK1/2-p90RSK activation. Non-specific phosphatases inhibition (1 μmol/L okadaic acid) canceled SIL effect on pH i recovery from acidosis. Same result was observed by inhibiting PP2A either with a lower dose of okadaic acid (1 nmol/L) or, more specifically, with 100 μmol/L endothall. Consistently, NHE-1 phosphorylation at Ser703 increased after acidosis, SIL prevented this effect and PP2A inhibition (endothall) reverted SIL effect. Conclusion: We suggest that PDE5A inhibitors decrease NHE-1 phosphorylation and activity through a mechanism that involves PP2A activation.
Facultad de Ciencias Médicas
description Background/Aims: This study aimed to identify the signaling pathway for the proposed link between phosphodiesterase-5A (PDE5A) inhibition and decreased cardiac Na + /H + exchanger (NHE-1) activity. Methods: NHE-1 activity was assessed in rat isolated papillary muscles by the Na + -dependent initial pH i recovery from a sustained acidosis (ammonium prepulse). ERK1/2, p90RSK and NHE-1 phosphorylation state during acidosis was determined. Results: PDE5A inhibition (1 μmol/L sildenafil, SIL) did not modify basal pH i but significantly blunted pH i recovery after sustained acidosis. Although preventing ERK1/2- p90RSK signaling pathway (10 μmol/L U0126) mimicked SIL effect, SIL did not blunt the acidosis-mediated increase in kinases activation. SIL+U0126 did not show additive effect on NHE-1 activity. Then, we hypothesized that SIL could be activating phophasatases (PP1 and/or PP2A) to directly dephosphorylate NHE-1 despite preserved ERK1/2-p90RSK activation. Non-specific phosphatases inhibition (1 μmol/L okadaic acid) canceled SIL effect on pH i recovery from acidosis. Same result was observed by inhibiting PP2A either with a lower dose of okadaic acid (1 nmol/L) or, more specifically, with 100 μmol/L endothall. Consistently, NHE-1 phosphorylation at Ser703 increased after acidosis, SIL prevented this effect and PP2A inhibition (endothall) reverted SIL effect. Conclusion: We suggest that PDE5A inhibitors decrease NHE-1 phosphorylation and activity through a mechanism that involves PP2A activation.
publishDate 2010
dc.date.none.fl_str_mv 2010
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
Articulo
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://sedici.unlp.edu.ar/handle/10915/82462
url http://sedici.unlp.edu.ar/handle/10915/82462
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/issn/1015-8987
info:eu-repo/semantics/altIdentifier/doi/10.1159/000322321
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
http://creativecommons.org/licenses/by-nc-sa/4.0/
Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0)
eu_rights_str_mv openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by-nc-sa/4.0/
Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0)
dc.format.none.fl_str_mv application/pdf
531-540
dc.source.none.fl_str_mv reponame:SEDICI (UNLP)
instname:Universidad Nacional de La Plata
instacron:UNLP
reponame_str SEDICI (UNLP)
collection SEDICI (UNLP)
instname_str Universidad Nacional de La Plata
instacron_str UNLP
institution UNLP
repository.name.fl_str_mv SEDICI (UNLP) - Universidad Nacional de La Plata
repository.mail.fl_str_mv alira@sedici.unlp.edu.ar
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score 13.070432

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