cGMP-specific phosphodiesterase type 5
This article needs additional citations for verification. (December 2012) |
Ensembl | |||||||||
---|---|---|---|---|---|---|---|---|---|
UniProt | |||||||||
RefSeq (mRNA) | |||||||||
RefSeq (protein) | |||||||||
Location (UCSC) | Chr 4: 119.49 – 119.63 Mb | Chr 3: 122.52 – 122.65 Mb | |||||||
PubMed search | [3] | [4] |
View/Edit Human | View/Edit Mouse |
Cyclic guanosine monophosphate-specific phosphodiesterase type 5 is an enzyme (EC 3.1.4.17) from the phosphodiesterase class. It is found in various tissues, most prominently the corpus cavernosum and the retina. It has also been recently discovered to play a vital role in the cardiovascular system.
The phosphodiesterase (PDE) isozymes, found in several tissues including the rod and cone photoreceptor cells of the retina, belong to a large family of cyclic nucleotide PDEs that catalyze cAMP and cGMP hydrolysis.[5][6]
The interest in PDEs as molecular targets of drug action has grown with the development of isozyme-selective PDE inhibitors that offer potent inhibition of selected isozymes without the side-effects attributed to nonselective inhibitors such as theophylline.[7][8]
Sildenafil, vardenafil, tadalafil, and avanafil are PDE5 inhibitors that are significantly more potent and selective than zaprinast and other early PDE5 inhibitors.
Action of PDE5
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
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.
Tissue distribution of PDE5
PDE5 is expressed in human
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]
PDE5-inhibiting drugs
There are now four oral erectile dysfunction (ED) drugs: Viagra (
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
PDE5-inhibiting drugs are very effective.[
Sildenafil
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]
Vardenafil
Vardenafil (marketed as Levitra, Staxyn and Vivanza) was the second oral PDE-5 inhibitor for erectile dysfunction to be FDA approved in August 2003.[citation needed]
Tadalafil
Tadalafil (marketed as Cialis) is a PDE5 inhibitor used to treat erectile dysfunction[17] and pulmonary arterial hypertension.[18] It has a longer half life than sildenafil of 17.5 hours, allowing it to be taken once a day.[18] Tadalafil "daily" (5 mg) is also used for treatment of benign prostate hyperplasia.[19]
In patients with pulmonary arterial hypertension, tadalafil improves symptoms and also slows down the progressive deterioration in breathlessness seen in this condition.[18] Studies have shown that tadalafil is more selective for PDE5 over PDE6 than sildenafil or vardenafil.[20]
See also
- PDE5 drug design
- PDE5 inhibitor
- Phosphodiesterase
- Icariin
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000138735 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000053965 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- PMID 4342220.
- PMID 165666.
- PMID 183099.
- PMID 17360.
- S2CID 10202683.
- PMID 20308615.
- PMID 19139381.
- PMID 29519873.
- National Law Review. Duane Morris LLP. 2011-02-07. Retrieved 2012-01-19.
- ^ "Viagra". Drug Approval Package. United States Food and Drug Administration. March 27, 1998.
- ^ "Sildenafil 50 mg film-coated tablets". Medicines.org.uk. Retrieved November 4, 2015.
- ^ "Viagra -sildenafil citrate tablet". Daily Med- U.S National Library of Medicine. Retrieved November 5, 2015.
- PMID 21711956.
- ^ PMID 26587013.
- PMID 25083163.
- S2CID 22178197.
External links
- 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.