CONICET | Buscador de Institutos y Recursos Humanos

AbstractThe beneficial effect of phosphodiesterase 5A inhibition in ischemia/reperfusion injury and cardiac hypertrophyis well established. Inhibition of the cardiac Na/H exchanger (NHE-1) exerts beneficial effects on these sameconditions, and a possible link between these therapeutic strategies was suggested. Experiments were performed inisolated cat cardiomyocytes to gain insight into the intracellular pathway involved in the reduction of NHE-1 activityby phosphodiesterase 5A inhibition. NHE-1 activity was assessed by the rate of intracellular pH recovery from asustained acidic load in the absence of bicarbonate. Phosphodiesterase 5A inhibition with sildenafil (1 mol/L) did notaffect basal intracellular pH; yet, it did decrease proton efflux (JH; in millimoles per liter per minute) after the acidicload (proton efflux: 6.970.43 in control versus 3.310.58 with sildenafil; P0.05). The blockade of both proteinphosphatase 1 and 2A with 100 nmol/L of okadaic acid reverted the sildenafil effect (proton efflux: 6.770.82). Incontrast, selective inhibition of protein phosphatase 2A (1 nmol/L of okadaic acid or 100 mol/L of endothall) did not(3.861.0 and 2.611.2), suggesting that only protein phosphatase 1 was involved in sildenafil-induced NHE-1inhibition. Moreover, sildenafil prevented the acidosis-induced increase in NHE-1 phosphorylation without affectingactivation of the extracellular signalregulated kinase 1/2-p90RSK pathway. Our results suggest that phosphodiesterase5A inhibition decreases NHE-1 activity, during intracellular pH recovery after an acidic load, by a protein phosphatase1dependent reduction in NHE-1 phosphorylation. (Hypertension. 2010;56:690-695.)Key Words: signal transduction ion transport phosphatases intracellular acidosis phosphorylation