Phosphodiesterases (PDEs) are a superfamily of enzymes. This superfamily is further classified into 11 families, PDE1 - PDE11, on the basis of regulatory properties, amino acid sequences, substrate specificities, pharmacological properties and tissue distribution. Their function is to degrade intracellular second messengers such as cyclic adenine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) which leads to several biological processes like effect on intracellular calcium level by the Ca2+ pathway.
Phosphodiesterase 5 (PDE5) is widely expressed in several tissues in the body for example brain, lung, kidney, urinary bladder, smooth muscle and platelets. It is possible to prevent cGMP hydrolysis by inhibiting PDE5 and therefore treat diseases associated with low cGMP levels, because of this, PDE5 is an ideal target for the development of inhibitors. The therapeutic effects of PDE5 inhibition have been demonstrated in several cardiovascular conditions, chronic kidney disease and diabetes mellitus.
The major PDE5 inhibitors (a subset of the phosphodiesterase inhibitors) are sildenafil, tadalafil, vardenafil, and avanafil, and although all share the same mechanism of action each has unique pharmacokinetic and pharmacodynamic properties which dictate their suitability in various conditions and their side effect profile.
General
The human genome contains at least 21 genes involved in determining the intracellular levels of cAMP and cGMP by the expression of phosphodiesterase proteins or PDE's. These PDE's are grouped into at least 11 functional subfamilies, named PDE1-PDE11. PDEs are enzymes that hydrolyze cyclic adenosine 3,5-monophosphate (cAMP) and cyclic guanosine 3,5-monophospahate (cGMP), which are intracellular second messengers, into AMP and GMP. These second messengers control many physiological processes. The cAMP is formed from ATP by the enzyme adenylyl cyclase and cGMP is formed from GTP by the enzyme guanylyl cyclase which are either membrane bound or soluble in the cytosol. When soluble it functions as a receptor for nitric oxide (NO) (see figure 1). Formation of cGMP initiates several reactions in the body including influence on cGMP ion channels, cGMP binding proteins and protein kinase G (PKG). The effect on PKG reduces levels of calcium leading to relaxation of smooth muscles (see figure 2). The PDE5 enzyme is specific for cGMP which means it only hydrolyzes cGMP but not cAMP. The selectivity is mediated through an intricate network of hydrogen bonding which is favorable for cGMP but unfavorable for cAMP in PDE5. By inhibition of PDE5 enzyme the cGMP concentration will be raised and can therefore increase the relaxation of smooth muscles. PDE5 has only one subtype, PDE5A, of which there are 4 isoforms in humans called PDE5A1-4. The difference in PDE5A1-3 isoforms is only in the 5´ end of the mRNA and corresponding N-terminal of the protein.
Distribution of PDE5 in the body
In humans the distribution of PDE5A1 and PDE5A2 isoforms is the same and can be found in the brain, lung tissue, heart, liver, kidneys, bladder, prostate, urethra, penis, uterus and skeletal muscles. PDE5A2 is more common than PDE5A1. PDE5A3 is not as widespread as the other two isoforms, and is only found in smooth muscle tissues, it is found in the heart, bladder, prostate, urethra, penis and uterus, Exact distribution of PDE5A4 isoform was not found in the literature. PDE5 enzyme in humans has also been reported in platelets, gastrointestinal epithelial cells, Purkinje cells of cerebellum, corpus cavernosum, pancreas, placenta and colon, clitoral corpus cavernosum as well as vaginal smooth muscle and epithelium.