Phosphodiesterase 5 enzyme and its inhibitors: update on pharmacological and therapeutical aspects

Cyclic nucleotides are important secondary messengers that control many physiologic processes, including smooth muscle contractility. Phosphodiesterases (PDEs) comprise of a superfamily of metallophosphydrolases that specifically cleave the 3',5'-cyclic phosphate moiety of cAMP and/or cGMP to produce the corresponding 5' nucleotide. Currently 21 PDE genes have been cloned and are classified into 11 families (1-11) according to their sequence of homology, biochemical and pharmacological properties. Phosphodiesterase type 5 (PDE5) is one of the members of the superfamily that specifically cleaves cyclic guanosine monophosphate (cGMP), a key intracellular secondary messenger. It is composed of 875 amino acids and was first identified in lungs, vascular and tracheal smooth muscle, and platelets. PDE5 is selectively inhibited by sildenafil, vardenafil and tadalafil, and less selectively by zaprinast and dipyridamole. PDE5 inhibitors have been reported to possess antiplatelet aggregation, weak cardiac inotropic effects and vascular relaxant properties. The tissue distribution of the PDE5 family is relatively restricted compared with other PDEs. Still, recent immunohistochemical and reverse transcriptase-polymerase chain reaction analysis have demonstrated the presence of anti-PDE5 antibodies and PDE5 transcripts in rat cerebellum, kidney, pancreas, aortic smooth muscle cells, heart, placenta, skeletal muscle, and, to a much lesser extent, in other regions of the brain, liver and lungs. Research in this field is intense, with a goal of identifying and developing new, selective PDE5 inhibitors that would be beneficial in a number of maladies, as well as angina, hypertension and erectile dysfunction (ED).