Abstract 227: Na+/H+ Exchanger Blockade is Involved in the Protection Afforded by Phosphodiesterase-5A Inhibition by Sildenafil after Myocardial Infarction
Since Na+/H+ exchanger (NHE-1) inhibition induces cardioprotection against myocardial infarction (MI) at least comparable to ischemic preconditioning, the possibility of a link between phosphodiesterase-5A (PDE5A) inhibition and NHE-1 activity was explored in a rat model of MI. MI was induced by left anterior descending coronary artery ligation in 3– 4 months-old-male Wistar rats. Immediately after surgery, the animals were randomized to placebo or sildenafil (S, 100 mg/Kg/day), orally administered in drinking water for 6 weeks. After this period, the increase in left ventricular (LV) protein kinase G-1 (PKG-1) activity in the MI+S group confirmed PDE5A inhibition: (in fmol PO4/min/μg protein) MI 4.85±0.29 vs MI+S 6.73±0.42 (n=5 each, P<0.05). Infarct size did not statistically change after S treatment (MI: 40±10% vs MI+S: 31±7%, n=4 each), but myocytes cross sectional area, collagen volume fraction and brain natriuretic peptide were significantly reduced after PDE5A inhibition (from 250±34 to 159±6 μm2, n=5; from 3.28±032 to 2.45±0.13%, n=5; and from 166±22 to 75±14% of control, n=4, respectively, P<0.05 all). The cardiac performance assessed by the +dP/dt/IP index (where IP is LV pressure at which +dP/dt occurs), showed a significant recovery after S treatment (89±6, n=7 vs 112±2 s−1, n=5, P<0.05). The NHE-1 expression was increased in the MI group (in agreement with previous reports) and it was significantly reduced by S treatment (from 267±11 to 179±19 % of control, n=5 each, P<0.05). The NHE-1 activity was evaluated in isolated papillary muscles by the Na+-dependent pHi recovery after an acute and sustained acid load (ammonium prepulse technique) in the nominal absence of bicarbonate. No changes in the maximal induced acidification or the intrinsic buffer capacity were detected between groups. S treatment induced a dramatic inhibition of the NHE-1 (maxdpHi/dt: 0.212±0.026 in MI vs 0.004±0.002 pH units/min in MI+S, n=5 each, P<0.05). Taken the results together, we conclude that NHE-1 inhibition by PKG-1 activation influences remodeling after MI and may be involved in the protective effect of S after MI.