Abstract 2271: Sildenafil (Viagra) Attenuates Ischemic Cardiomyopathy and Improves Left Ventricular Function in Mice
Background: Phosphodiesterase-5 (PDE-5) inhibitor sildenafil has potent cardioprotective effect following ischemia/reperfusion injury. We hypothesized that chronic treatment with sildenafil would attenuate myocardial infarction (MI)-induced remodeling and left ventricular (LV) dysfunction.
Methods and Results: Adult male ICR mice underwent MI by ligation of the left anterior descending coronary artery (LAD) and were treated with sildenafil (0.71 mg/kg; ip; BID) or volume-matched saline for 4 weeks. Infarct size, measured by TTC staining, was smaller in sildenafil-treated group (40.0 ± 4.6%) as compared to saline-treated controls (69.6 ± 4.1%, P<0.05) 24 hr after LAD ligation. [NG-nitro-L-arginine methyl ester (L-NAME)], a non-selective NOS inhibitor, blocked the protective effect of sildenafil (infarct size 60.2 ± 1.6%, P<0.05 vs. sildenafil). The apoptotic index, measured by TUNEL assay, was 2.4 ± 0.3% in the saline group vs. 1.2 ± 0.1% in sildenafil-treated mice (P<0.05) on day 7 and 2.0 ± 0.2% for saline vs. 1.2 ± 0.1 for sildenafil (P<0.05) on day 28. LV end-diastolic diameter, measured by echocardiography, increased from 3.6 ± 0.1 mm to 5.2 ± 0.2 mm and 5.5 ± 0.1 mm on days 7 and 28 in the saline group (P>0.05). The dilatation after infarction was less pronounced in sildenafil-treated animals (4.4 ± 0.2 mm and 4.4 ± 0.1 mm on days 7 and 28, respectively, P>0.05). Fractional shortening (FS) decreased from baseline value of 47 ± 2% to 15 ± 3% and 18 ± 3% on days 7 and 28 post-MI, respectively, in saline-treated group. However, the decrease in FS in the sildenafil-treated animals was less pronounced (28 ± 3% and 30 ± 3% on days 7 and 28, respectively). Survival rate was lower in the saline group (36%) as compared to the sildenafil group (93%, P<0.05). Also, a marked decline in the development of cardiac hypertrophy (ratio of heart to body weight) was observed with sildenafil which paralleled the decrease in pulmonary edema.
Conclusion: For the first time, these results show that sildenafil attenuates ischemic cardiomyopathy in mice by limiting necrosis, apoptosis and preserving LV function possibly through NO dependent pathway. We propose that sildenafil and potentially other PDE-5 inhibitors can be promising drugs for prevention of heart failure in patients with MI.