Phosphodiesterase 5A inhibition decreases NHE-1 activity without altering steady state pHi: Role of phosphatases
| Autor: | Díaz Gómez, Andrea Romina, Nolly, Mariela Beatriz, Massarutti, Carolina, Casarini, María J., Garciarena, Carolina Denis, Ennis, Irene Lucia, Cingolani, Horacio Eugenio, Perez, Nestor Gustavo |
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| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: | |
| Zdroj: | SEDICI (UNLP) Universidad Nacional de La Plata instacron:UNLP CONICET Digital (CONICET) Consejo Nacional de Investigaciones Científicas y Técnicas instacron:CONICET |
| Popis: | 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 |
| Databáze: | OpenAIRE |
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