Phosphodiesterase 5 mechanisms and therapeutic applications.
The nitric oxide (NO)-dependent signal transduction system, which is an essential mediatory pathway for penile erection, contains several molecular targets available for pharmacologic manipulation to treat erectile dysfunction (ED). The most prominent target identified thus far is phosphodiesterase 5 (PDE5), which enzymatically converts the intracellular second messenger molecule cyclic guanosine monophosphate (cGMP) to its inactive form. By its preservation, cGMP activates cGMP-dependent protein kinase I, which pivotally drives a biochemical cascade resulting in corporal smooth muscle relaxation and, hence, penile erection. This system mechanistically requires the synthesis of cGMP, secondary to the production and release of NO during sexual arousal. Accordingly, PDE5 inhibitors augment the erectile response. Key to erectogenesis are the relatively high concentrations of PDE5 enzymes in the corporal smooth muscle of the penis relative to other structures of the body. At present, 3 PDE5 inhibitors are approved for the therapeutic management of ED. All 3 have been studied extensively, both at the molecular pharmacologic level and in clinical trials. They have shown excellent clinical efficacy and safety. This presentation affirms the value of PDE5 inhibition as a therapeutic strategy for ED.
Burnett
Arthur L
AL
Department of Urology, The James Buchanan Brady Urological Institute, The Johns Hopkins Hospital, Baltimore, Maryland 21287-2411, USA. aburnett@jhmi.edu
D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D007172:Erectile Dysfunction / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D006801:Humans; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism / Q000502:physiology*
D010726:Phosphodiesterase Inhibitors; D009569:Nitric Oxide; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human