INVESTIGADORES
ENNIS Irene Lucia
artículos
Título:
Activity of the Na+/H+ Exchanger by Phosphodiesterase 5A Inhibition Is Attributed to an Increase in Protein Phosphatase Activity
Autor/es:
YEVES AM; GARCIARENA CD; NOLLY MB; CHIAPPE DE CINGOLANI GE; CINGOLANI HE; ENNIS IL
Revista:
HYPERTENSION
Editorial:
LIPPINCOTT WILLIAMS & WILKINS
Referencias:
Año: 2010 vol. 56 p. 690 - 695
ISSN:
0194-911X
Resumen:
The beneficial effect of phosphodiesterase 5A inhibition in
ischemia/reperfusion injury and cardiac hypertrophy is well established.
Inhibition of the cardiac Na(+)/H(+) exchanger (NHE-1) exerts
beneficial effects on these same conditions, and a possible link between
these therapeutic strategies was suggested. Experiments were performed
in isolated cat cardiomyocytes to gain insight into the intracellular
pathway involved in the reduction of NHE-1 activity by phosphodiesterase
5A inhibition. NHE-1 activity was assessed by the rate of intracellular
pH recovery from a sustained acidic load in the absence of bicarbonate.
Phosphodiesterase 5A inhibition with sildenafil (1 μmol/L) did not
affect basal intracellular pH; yet, it did decrease proton efflux (J(H);
in millimoles per liter per minute) after the acidic load (proton
efflux: 6.97±0.43 in control versus 3.31±0.58 with sildenafil;
P<0.05). The blockade of both protein phosphatase 1 and 2A with 100
nmol/L of okadaic acid reverted the sildenafil effect (proton efflux:
6.77±0.82). In contrast, selective inhibition of protein phosphatase 2A
(1 nmol/L of okadaic acid or 100 μmol/L of endothall) did not (3.86±1.0
and 2.61±1.2), suggesting that only protein phosphatase 1 was involved
in sildenafil-induced NHE-1 inhibition. Moreover, sildenafil prevented
the acidosis-induced increase in NHE-1 phosphorylation without affecting
activation of the extracellular signal-regulated kinase 1/2-p90(RSK)
pathway. Our results suggest that phosphodiesterase 5A inhibition
decreases NHE-1 activity, during intracellular pH recovery after an
acidic load, by a protein phosphatase 1-dependent reduction in NHE-1
phosphorylation.