CIC   05421
CENTRO DE INVESTIGACIONES CARDIOVASCULARES "DR. HORACIO EUGENIO CINGOLANI"
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Cardioprotective effects of phosphodiesterase-5A inhibition after myocardial
Autor/es:
PÉREZ NG; PIAGGIO MR; ENNIS IL; GARCIARENA CD; MORALES C; ESCUDERO EM; CINGOLANI OH; CHIAPPE DE CINGOLANI G; YANG X-P; CINGOLANI HE
Lugar:
Colby-Sawyer College, New London, New Hampshire, EEUU.
Reunión:
Congreso; Gordon Research Conference on Cardiac Regulatory Mechanisms; 2006
Institución organizadora:
Gordon Conference
Resumen:
Cardiac performance after myocardial infarction (MI) is consequence of infarct size (IS) and structural remodeling of surviving tissue. Pharmacological interventions may improve function by decreasing IS and/or preventing remodeling. Inhibition of phosphodiesterase-5A by sildenafil (SIL) increases protein kinase G (PKG) activity and improves left ventricular (LV) remodeling in pressure-overloaded hearts. We hypothesized that phosphodiesterase-5A inhibition may improve remodeling post-MI by a PKG-mediated Na+/H+ exchanger (NHE-1) inhibition. MI was induced by left anterior descending coronary artery ligation in Wistar rats, which were randomized to placebo or SIL (100 mg/kg/day) treatment. After six weeks, fractional shortening (FS), LV pressure and its first derivative, myocytes cross sectional area (CSA) and fibrosis, LV brain natriuretic peptide (BNP) and NHE-1 expression and NHE-1 activity were  determined. MI increased heart weight to body weight ratio, myocyte CSA, interstitial fibrosis and BNP and NHE-1 expression. These effects were prevented by SIL. Neither a significant change in IS nor in systolic LV pressure was detected. MI decreased FS and the (+dP/dt)/P ratio, effects which were prevented by SIL. pHi recovery following an acid load was significantly faster in post-MI hearts (vs. sham) while SIL significantly inhibited NHE-1 activity. Acute phosphodiesterase-5A inhibition in non-infarcted heart muscle by SIL or phosphodiesterase-5A inhibitor (EMD360527/5) also inhibited NHE-1 activity, while PKG inhibition (KT5823) restored normal NHE-1 activity. In conclusion, chronic phosphodiesterase-5A inhibition post-EMI increases PKG activity and attenuates LV dysfunction and remodeling. Since PKG activity appears to inhibit NHE-1 activity and the protective effect of NHE-1 inhibition is known, we suggest a possible causal link between decreased NHE-1 activity and the protective effects of SIL. . Inhibition of phosphodiesterase-5A by sildenafil (SIL) increases protein kinase G (PKG) activity and improves left ventricular (LV) remodeling in pressure-overloaded hearts. We hypothesized that phosphodiesterase-5A inhibition may improve remodeling post-MI by a PKG-mediated Na+/H+ exchanger (NHE-1) inhibition. MI was induced by left anterior descending coronary artery ligation in Wistar rats, which were randomized to placebo or SIL (100 mg/kg/day) treatment. After six weeks, fractional shortening (FS), LV pressure and its first derivative, myocytes cross sectional area (CSA) and fibrosis, LV brain natriuretic peptide (BNP) and NHE-1 expression and NHE-1 activity were  determined. MI increased heart weight to body weight ratio, myocyte CSA, interstitial fibrosis and BNP and NHE-1 expression. These effects were prevented by SIL. Neither a significant change in IS nor in systolic LV pressure was detected. MI decreased FS and the (+dP/dt)/P ratio, effects which were prevented by SIL. pHi recovery following an acid load was significantly faster in post-MI hearts (vs. sham) while SIL significantly inhibited NHE-1 activity. Acute phosphodiesterase-5A inhibition in non-infarcted heart muscle by SIL or phosphodiesterase-5A inhibitor (EMD360527/5) also inhibited NHE-1 activity, while PKG inhibition (KT5823) restored normal NHE-1 activity. In conclusion, chronic phosphodiesterase-5A inhibition post-EMI increases PKG activity and attenuates LV dysfunction and remodeling. Since PKG activity appears to inhibit NHE-1 activity and the protective effect of NHE-1 inhibition is known, we suggest a possible causal link between decreased NHE-1 activity and the protective effects of SIL.
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