The cGMP pool in the cell is tightly controlled by PDEs, which specifically cleave the 3′,5′-cyclic phosphate moiety of cyclic adenosine monophosphate (cAMP) and/or cGMP to produce the corresponding 5' nucleotide. Currently, 21 PDE genes have been cloned and are classified into 11 families according to their sequence of homology, biochemical, and pharmacological properties (6). The PDEs vary in their substrate specificity for cAMP and cGMP: PDE-5, PDE-6, and PDE-9 are specific for cGMP; PDE-4, PDE-7, and PDE-8 are specific for cAMP; and PDE-1, PDE-2, PDE-3, PDE-10, and PDE-11 have mixed specificity for cAMP/cGMP (7). PDE-5 selectively hydrolyzes cGMP, and its inhibition increases cGMP bioavailability. The abundance of PDE-5 in smooth muscles and its role in regulating their contractile tone has made PDE-5 an important drug target for the treatment of erectile dysfunction (6), leading to the development of potent PDE-5 inhibitors, such as sildenafil (Viagra and Revatio, Pfizer, New York, New York), vardenafil (Levitra, Bayer Schering Pharma AG, Leverkusen, Germany), and tadalafil (Cialis and Adcirca, Eli Lilly Canada Inc., Toronto, Ontario, Canada). Revatio and Adcirca have also been approved for the treatment of pulmonary hypertension. Earlier studies found that PDE-5 is not present in normal cardiomyocytes (8- 9), although later investigations revealed its expression in canine (10), mouse cardiomyocytes (1,11- 12), and human heart (13- 14). PDE-5 expression is increased in hypertrophic human right ventricle, as well as failing left ventricular tissue (13- 15). A gene silencing model also confirmed PDE-5 protein expression (16), whereas a recent report still questioned its presence in adult mouse cardiac myocytes (17). Because cGMP-hydrolytic activity is also attributable to PDE-1 and PDE-3, Vandeput et al. (14) suggested that the effects of sildenafil on cGMP hydrolysis were due to inhibition of both PDE-5 and PDE-1 in the left ventricles of normal and failing mouse hearts.