Phosphodiesterase type 5 as a pharmacologic target in erectile dysfunction.
The scientific rationale of pharmacologically inhibiting phosphodiesterase type 5 (PDE5) in the treatment of erectile dysfunction (ED) is reviewed. Published literature on the nitric oxide-cyclic guanosine monophosphate (cGMP) pathway for penile erection and on PDE5 inhibition using sildenafil as the model for pharmacologic PDE5 inhibition are assessed. The key second messenger in the mediation of penile erection is cGMP. PDE5 is the predominant PDE in the corpus cavernosum, and cGMP is its primary substrate. Therefore, in men with ED, elevation of cGMP in corpus cavernosal tissue via selective inhibition of cGMP-specific PDE5 is a means of improving erectile function at minimal risk of adverse events. This approach is validated by the clinical efficacy and safety of sildenafil, the pioneering drug for selective PDE5 inhibitor therapy for ED. Sildenafil exhibits inhibitory potency against PDE5 and a 10-fold lower dose-related inhibitory potency against rod outer segment PDE6, the predominant PDE in the phototransduction cascade in rods. Thus, its pharmacologic profile is predictable, with close correlation between pharmacodynamic and pharmacokinetic properties. Clinically, sildenafil improves erectile function in a large percentage of men with ED. The most common adverse events are due to PDE5 inhibition in vascular and visceral smooth muscle; similar adverse events are expected during therapeutic use of all PDE5 inhibitors. As free sildenafil plasma concentrations approach concentrations sufficient to inhibit retinal PDE6, usually at higher therapeutic doses, transient, reversible visual adverse events can occur, albeit infrequently. Selective inhibition of PDE5 is a rational therapeutic approach in ED, as proved by the clinical success of sildenafil.
Corbin
Jackie D
JD
Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0615, USA. jackie.corbin@mcmail.vanderbilt.edu
Francis
Sharron H
SH
Webb
David J
DJ
D015106:3',5'-Cyclic-GMP Phosphodiesterases; D006152:Cyclic GMP / Q000502:physiology*; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D007172:Erectile Dysfunction / Q000188:drug therapy* / Q000209:etiology; D006801:Humans; D008297:Male; D009569:Nitric Oxide / Q000502:physiology*; D010410:Penile Erection / Q000187:drug effects / Q000502:physiology*; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use*; D010727:Phosphoric Diester Hydrolases / Q000502:physiology; D010879:Piperazines / Q000627:therapeutic use*; D011687:Purines; D000068677:Sildenafil Citrate; D013450:Sulfones; D014665:Vasodilator Agents / Q000627:therapeutic use*
D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014665:Vasodilator Agents; D009569:Nitric Oxide; D000068677:Sildenafil Citrate; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human; D006152:Cyclic GMP