Cyclic GMP and phosphodiesterase 5 inhibitor therapies: what's on the horizon?

A little more than 6 years ago, the first therapeutic agent targeting cyclic nucleotide phosphodiesterases (PDEs) for the treatment of erectile dysfunction (ED) was introduced into clinical medicine (Boolell et al., 1996). The PDE5 inhibitor sildenafil (Viagra) was the first orally active, effective therapy for the treatment of ED by virtue of its capacity to inhibit cyclic GMP hydrolysis in penile cavernosal and arterial smooth muscle. This Perspective will focus on a “bench-tobedside” view of PDE5 inhibitors, including comments relating to the emergence of newer PDE5 inhibitor drugs, and the extraordinary explosion of research into novel therapeutic uses of PDE5 inhibitors. Figure 1 reviews the role of PDE5 in the metabolism of cyclic GMP and how PDE5 inhibition alters the activity of cellular pathways regulated by cyclic GMP. Cyclic GMP is synthesized in cells by guanylyl cyclases. There are two types of guanylyl cyclase: a membrane-bound, particulate form that is activated by circulating natriuretic peptides and guanylins and a soluble, cytosolic form that is activated by nitric oxide (NO). NO diffuses from cells that express NO synthases, such as neurons and endothelial cells, into target cells, such as smooth muscle cells, to activate soluble guanylyl cyclase. Cyclic GMP interacts with cellular receptors, which, in smooth muscle, include the serine/threonine kinase cyclic GMP-dependent protein kinase (PKG) and the cyclic AMP specific phosphodiesterase 3 (PDE3). The binding of cyclic GMP activates PKG but inhibits PDE3 activity. In cavernosal tissue in particular, but also in most vascular and nonvascular smooth muscle, PDE5 represents a major cyclic GMP-hydrolyzing activity. PDE5 itself is activated by phosphorylation catalyzed by PKG. Phosphorylation increases cyclic GMP binding to noncatalytic cyclic GMP binding GAF domains; this results in the activation of cyclic GMP hydrolysis at distinct catalytic sites. The interactions between PKG and PDE5 insure that cyclic GMP levels do not accumulate too rapidly in the cell. The catalytic cyclic GMP binding sites on PDE5, but not the GAF sites, bind PDE5 inhibitors with high affinity to block cyclic GMP hydrolysis. Therefore, a greater degree of activation of PKG occurs in the cell, and in smooth muscle, enhanced PKG-dependent phosphorylation of a variety of protein substrates inhibits contraction. In this issue of Molecular Pharmacology, Blount et al. (2004) assess the binding properties of the newer PDE5 inhibitors, vardenafil (Levitra) and tadalafil (Cialis), and compare the properties of these compounds with those of sildenafil. The order of potency for inhibition of PDE5 correlates closely with the binding affinity of the drugs for the catalytic sites. Because each of these inhibitors competes with the other inhibitors for access to PDE5, each must bind in the same manner to PDE5. Of particular interest regarding the potent biological effects of these compounds is that cyclic GMP addition increased the binding affinity (inhibitory activity) of the newer inhibitors vardenafil and tadalafil. These results imply that PDE5 inhibitors potentiate their own inhibitory activity by merely elevating cyclic GMP in the cell via PDE5 inhibition. Herein lies the secret to the potent biological effects of these drugs. The kinetic findings in this study also indicate that the three therapeutically available PDE5 inhibitors have the same inhibitory activity toward cyclic GMP hydrolysis. The difference in potency of inhibition, however, indicates that vardenafil and tadalafil may produce biological effects at lower concentrations and perhaps for longer durations. The therapeutic activity of tadalafil, for example, is of longer duration than sildenafil; this may be caused in part by its higher affinity for PDE5. Other factors such as metabolic degradation may affect the duration of action. The availability of different PDE5 inhibitors with different Article, publication date, and citation information can be found at http:// molpharm.aspet.org. DOI: 10.1124/mol.104.001388