cGMP-specific phosphodiesterase type 5

PDE5 is an enzyme that accepts cGMP and breaks it down. Sildenafil, vardenafil and tadalafil are inhibitors of this enzyme, which bind to the catalytic site of PDE5. Both inhibitors bind with high affinity and specificity, and cGMP-binding to the allosteric sites stimulates binding of PDE5 inhibitors at the catalytic site. The kinetics of inhibitor binding and inhibition of catalysis imply the existence of two PDE5 conformers, and results of native gel electrophoresis reveal that PDE5 exists in two apparently distinct conformations, i.e., an extended conformer and a more compact conformer.

PDE5 activity is modulated by a rapidly reversible redox switch. Chemical reduction of PDE5 relieves autoinhibition of enzyme functions; allosteric cGMP-binding activity is increased 10-fold, and catalytic activity is increased ~3-fold. The redox effect on allosteric cGMP-binding occurs in the isolated regulatory domain. A change in the state of reduction of PDE5 or the isolated regulatory domain is associated with an apparent conformational change similar to that caused by phosphorylation.

PDE5 is expressed in human colonic cells and in intestinal tissue and its activity is regulated by intracellular cGMP levels in these cells that increase on GCC activation. This presumably occurs through binding of cGMP to the GAF domains in the N-terminus of PDE5, resulting in allosteric activation of the enzyme.

The mechanism of action of E4021 on both the nonactivated and activated forms of rod PDE6 because both states are relevant to understanding how PDE5-selective inhibitors may alter signal transduction pathways in photoreceptor cells. PDE5-selective inhibitors may show good discrimination of PDE5 from most other PDE isoforms.

In addition to human corpus cavernosum smooth muscle, PDE5 is also found in lower concentrations in other tissues including platelets, vascular and visceral smooth muscle, and skeletal muscle. The inhibition of PDE5 in these tissues by sildenafil may be the basis for the enhanced platelet antiaggregatory activity of nitric oxide observed in vitro, an inhibition of platelet thrombus formation in vivo and peripheral arterial-venous dilatation in vivo.

Immunohistology has shown that PDE5 localizes in heart cells at the sarcomere z-disk, but can also be found in diffuse amounts in the cytosol.[9] Increased expression of PDE5 has also been measured in hypertrophic disease and has been linked to oxidative stress, and PDE5 inhibition has shown beneficial effects in the failing heart.[10] In an experiment, PDE5 overexpression was found to contribute to worsened pathological remodeling after mouse cardiomyocytes experienced myocardial infarction.[11] The role of PDE5 in heart failure and cardiac treatment involving PDE5 inhibitors have been major areas of focus for both lab and clinical studies.[12]

There are now four oral erectile dysfunction (ED) drugs: Viagra (sildenafil) by Pfizer, Levitra (vardenafil) by Bayer Pharmaceutical and Glaxo-Smith-Kline-Beecham/Schering Plough, Cialis (tadalafil) by Lilly-ICOS, and Stendra (avanafil) by Auxilium Pharmaceuticals.

For all practical purposes, these drugs including Viagra, Levitra, and Cialis are the first line of oral treatment for males with erectile dysfunction. In certain circumstances in which the males are young, no comorbidities are recognized, and laboratory tests are normal, one should look for the underlying cause of their erectile dysfunction before instituting treatment since the disease process may be more serious than the ED itself. In some cases, treatment of the underlying cause may resolve the sexual dysfunction.

Particular caution should be used when prescribing PDE5 inhibitors for erectile dysfunction for patients receiving protease inhibitors, including Reyataz. Coadministration of a protease inhibitor with a PDE5 inhibitor is expected to substantially increase the PDE5 inhibitor concentration and may result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, visual changes, and priapism.

PDE5-inhibiting drugs are very effective. PDE5 inhibitor drugs appear to work in men regardless of why they have erectile dysfunction — including vascular disease, nerve problems, and even psychological causes. PDE5-inhibiting drugs can cause a number of minor side-effects, including headache, lightheadedness, dizziness, flushing, nasal congestion, and changes in vision. In 2011, the Food and Drug Administration (FDA) issued additional guidance on regulations related to cGMP manufacture and packaging.[13]

Sildenafil

Main article: Sildenafil

Bulk bag of counterfeit Viagra

Sildenafil (marketed as Viagra) was the first PDE5 inhibitor on the market. Originally created as a treatment for high blood pressure in 1989, it was found to have a secondary use as an effective PDE5 inhibitor, enabling men who use it to gain stronger erections after arousal. The FDA approved Viagra on March 27, 1998.[14] Discovered by Pfizer, sildenafil is a potent and selective inhibitor of cGMP-specific phosphodiesterase type 5 (PDE5), which is responsible for degradation of cGMP in the corpus cavernosum in the penis. This means that, when sildenafil is present in the organism, normal sexual stimulation leads to increased levels of cGMP in the corpus cavernosum, which leads to better erections. Without sexual stimulation and no activation of the NO/cGMP system, sildenafil should not cause an erection.

Studies in vitro have shown that sildenafil is selective for PDE5.[15] Its effect is more potent on PDE5 than on other known phosphodiesterases (10-fold for PDE6, >80-fold for PDE1, >700-fold for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11). The approximately 4,000-fold selectivity for PDE5 versus PDE3 is important because PDE3 is involved in control of cardiac contractility. Sildenafil is only about 10-fold as potent for PDE5 compared to PDE6, an enzyme found in the retina that is involved in the phototransduction pathway of the retina. This lower selectivity is thought to be the basis for abnormalities related to color vision observed with higher doses or plasma levels.[16]

• PDE5 drug design
• PDE5 inhibitor
• Phosphodiesterase
• Icariin

• The cGMP Specific Phosphodiesterase Type 5 Enzyme
• Pfizer Pharmaceutical
• New Scientist article on Viagra and the female 'G spot' Archived 2008-10-06 at the Wayback Machine
• Human PDE5A genome location and PDE5A gene details page in the UCSC Genome Browser.