Cellular Physiology and Biochemistry

Original Paper

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Phosphodiesterase 5A Inhibition Decreases NHE-1 Activity Without Altering Steady State pHi: Role of Phosphatases

Díaz R.G. · Nolly M.B. · Massarutti C. · Casarini M.J. · Garciarena C.D. · Ennis I.L. · Cingolani H.E. · Pérez N.G.

Author affiliations

1Centro de Investigaciones Cardiovasculares, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, La Plata, Argentina

Corresponding Author

Dr. Néstor Gustavo Pérez

Centro de Investigaciones Cardiovasculares

Facultad de Ciencias Médicas, UNLP

Calle 60 y 120 (1900) La Plata (Argentina)

Tel/Fax. +54-221 483-4833, E-Mail gperez@med.unlp.edu.ar

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Cell Physiol Biochem 2010;26:531–540

Abstract

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 pHi 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 pHi but significantly blunted pHi 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 pHi 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.

© 2010 S. Karger AG, Basel




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Article / Publication Details

First-Page Preview
Abstract of Original Paper

Accepted: August 25, 2010
Published online: October 29, 2010
Issue release date: October 2010

Number of Print Pages: 10
Number of Figures: 0
Number of Tables: 0

ISSN: 1015-8987 (Print)
eISSN: 1421-9778 (Online)

For additional information: https://www.karger.com/CPB


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