| Autor: |
Díaz, Romina G., Nolly, Mariela B., Massarutti, Carolina, Casarini, María J., Garciarena, Carolina D., Ennis, Irene L., Cingolani, Horacio E., Pérez, Néstor G. |
| Předmět: |
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| Zdroj: |
Cellular Physiology & Biochemistry (Karger AG); 2010, Vol. 26 Issue 4/5, p531-540, 10p |
| Abstrakt: |
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. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR] |
| Databáze: |
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