**1.1 PDE-5 Inhibitors**

Sildenafil citrate (ViagraTM) is the first PDE-5 inhibitor approved for treatment of erectile dysfunction. The discovery of this drug in 1989 was the result of extensive research on chemical agents that hold potential promise in the treatment of coronary heart disease. Initial clinical studies on sildenafil in the early 1990s were not promising with respect to its anti-anginal potential. However, a remarkable side effect was reported by a number of volunteers participating in these investigations; sildenafil seemed to enhance penile erections, which soon thereafter became the main focus of further studies. More than 10 million men worldwide have been treated with sildenafil since its market debut in 1998. Sildenafil is highly specific for PDE-5 inhibition with relatively minor cross-reactivity with PDE-6 (Laties & Fraunfelder, 1999). It has a chemical structure similar to cGMP and inhibits PDE-5 by binding to the cGMP-catalytic sites (Corbin & Francis, 2002) thereby allowing the accumulation of cGMP in the erectile tissue. Two additional agents in this class (vardenafil [LevitraTM] (Porst et al., 2001) and tadalafil [CialisTM]) have also been developed and approved by the FDA for treatment of erectile dysfunction and recently sildenafil and tadalafil were approved for treatment of pulmonary arterial hypertension (PAH) (Corbin & Francis, 2002). PDE-5 inhibitors are structurally similar to cGMP and therefore compete with cGMP for binding to PDE-5 at the catalytic site (reviewed in Kukreja et al., 2005). Interestingly, PDE expression has been reported to change in pathologic conditions. For instance, in patients with cardiovascular disease or diabetes, nitric oxide (NO) levels are

Phosphodiesterase-5 Inhibitors Improve Left Ventricular Function in Failing Hearts 99

was evaluated by echocardiography using the Vevo770TM imaging system (VisualSonics, Inc., Toronto, Canada). A 30-MHz probe was utilized to obtain two-dimensional, M-mode and Doppler imaging from parasternal short-axis view at the level of the papillary muscles and the apical four-chamber view (Schiller et al., 1989). M-mode images of the LV were obtained and systolic and diastolic wall thickness (anterior and posterior) and LV endsystolic and end-diastolic diameters (LVESD and LVEDD, respectively) were measured.

Figure 2 is representative of M-mode images from mice on day 28 post MI. The hearts from sham and sildenafil-treated mice exhibited a smaller LV cavity and thicker infarct wall compared to the saline-treated mice. Increase in LVEDD, LVESD and a decrease in anterior wall diastolic thickness (AWDT), anterior wall systolic thickness (AWST) and fractional shortening (FS) in saline- and sildenafil-treated mice (vs. baseline and sham) were observed

**Sham 28 days Saline 28 days**

**Sildenafil 28 days**

Sildenafil-treated mice had smaller LVEDD, LVESD, greater FS, and lower Tei index (reflecting better myocardial performance) on day 7 and 28 as compared to saline-treated group (P<0.05, Figure 3). Sildenafil-treated animals also had a shorter isovolumetric relaxation time (reflective of lower LV end-diastolic pressure) 28 days after AMI when compared to saline-treated animals (11±3 vs. 27±7 ms, respectively, P=0.03), which was not different from sham operated animals (10±3, P=NS). AWDT and AWST were also greater in sildenafil-treated animals (vs. saline-treated animals, P<0.05) on day 7 and 28 post MI showing a protective effect in the peri-infarct region, while no differences in PWDT and PWST were seen. Aneurysmatic dilatation of the anterior wall and apex was observed on day 28 in 90% of saline-treated mice and 62% of sildenafil treated animals (P>0.05).

Fig. 2. M-mode images from mouse LV treated with sildenafil or vehicle 28 days after MI

**1 mm 1 mm**

**1 mm**

on day 7 and 28.

suboptimal due to endothelial dysfunction [damaged NO synthase (NOS)], and recently myocardial PDE-5 expression has been shown to increase in patients with heart failure (Pokreisz et al., 2009). In this regard, targeting PDE-5 is a promising therapeutic approach for treatment of cardiovascular disease and dysfunction.
