Inhibition of phosphodiesterase-5A by sildenafil attenuates dysfunction after myocardial infarction and decreases Na+/H+ exchanger expression

PÉREZ NG; ENNIS IL; GARCIARENA CD; PINILLA A; ESCUDERO EM; CINGOLANI O; CHIAPPE DE CINGOLANI GE; CINGOLANI HE; YANG XP

Dallas, Texas EE.UU.

Congreso; 2005 Scientific Sessions of The American Heart Association; 2005

American Heart Association

Inhibition of phosphodiesterase-5A (PDE5A) by sildenafil (S) improves left ventricular remodeling in pressure-overloaded hearts. Accordingly, we hypothesized that by virtue of its effects it would improve remodeling after myocardial infarction (MI). Methods and Results: MI was induced by ligation of the left anterior descending coronary artery in 3-4 months-old-male Wistar rats. Immediately after coronary ligation, rats were randomized to placebo or S (100 mg/Kg/day), orally administered in drinking water for 6 weeks. After completion of treatment and before sacrifying the animals, fractional shortening (FS), determined by echocardiography, and hemodynamic contractility parameters were determined. Myocytes cross sectional area (CSA) as well as left ventricle brain natriuretic peptide (BNP) and Na+/H+ exchanger (NHE-1) expression were also measured. PDE5A inhibition was confirmed by measuring left ventricle protein kinase G (PKG) activity after treatment (in fmol PO4/min/mg protein: sham 5.64±0.23 n=4, MI 4.85±0.29 n=5, MI+S 6.73±0.42 n=5, P<0.05 MI+S vs sham and MI, ANOVA). S treatment significantly increased FS and +dP/dt/IP (where IP is LV pressure at which +dP/dt occurs) and decreased BNP and NHE expression, without significant changes in left ventricular mass (LVM) or myocytes CSA (Table). LVM (mg) CSA (mm2) FS (%) +dP/dt (mmHg/s) +dP/dt/IP (s-1) LVDd (mm) LVSd (mm) BNP (% of sham) NHE-1 (% of sham) MI 655±25 n=5 18.1±0.8 n=4 45±2 n=5 4575±987 n=7 89±6 n=7 6.2±0.3 n=5 3.4±0.2 n=5 166±22 n=4 267±11 n=5 MI+S 618±20 n=4 16.2±0.3 n=4 64±4* n=4 5501±600 n=5 112±2* n=5 6.2±0.2 n=4 2.2±0.2* n=4 75±14* n=4 179±19* n=5 Table. LVDd and LVSd: left ventricle diastolic and systolic diameter respectively. *Indicates P<0.05 vs MI. Conclusions: These data suggest that chronic inhibition of PDE5A for 6 weeks after myocardial infarction in the rat increases PKG activity and attenuates dysfunction after MI without affecting ventricular remodeling. Since it is widely accepted that inhibition of NHE-1 attenuates post ischemic functional disarrangements and it has been suggested that PKG activation blunts the enhanced activity of the NHE-1, a causal link between the decrease in the NHE-1 expression and the protective effect of PDE5A inhibition may be suggested.