CGMP-specific phosphodiesterase type 5

Last updated

PDE5A
Phosphodiesterase-5.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases PDE5A , CGB-PDE, CN5A, PDE5, phosphodiesterase 5A
External IDs OMIM: 603310; MGI: 2651499; HomoloGene: 842; GeneCards: PDE5A; OMA:PDE5A - orthologs
EC number 3.1.4.35
Orthologs
SpeciesHumanMouse
Entrez

8654

242202

Ensembl

ENSG00000138735

ENSMUSG00000053965

UniProt

O76074

Q8CG03

RefSeq (mRNA)

NM_033437
NM_001083
NM_033430

NM_153422

RefSeq (protein)

NP_001074
NP_236914
NP_246273

NP_700471

Location (UCSC) Chr 4: 119.49 – 119.63 Mb Chr 3: 122.52 – 122.65 Mb
PubMed search [3] [4]
Wikidata
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 of the clitoris and of the penis as well as the retina. [5] 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. [6] [7]

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. [8] [9]

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 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.

Tissue distribution of PDE5

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. [10] 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. [11] In an experiment, PDE5 overexpression was found to contribute to worsened pathological remodeling after mouse cardiomyocytes experienced myocardial infarction. [12] 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. [13]

PDE5-inhibiting drugs

The most commonly available PDE5 inhibitors are sildenafil (Viagra), [14] vardenafil (Levitra), [15] tadalafil (Cialis), [16] and avanafil (Stendra). [17]

PDE5 inhibitors are not routinely prescribed as first line treatment for erectile dysfunction. This is as they cause unwanted side effects like hair loss, headache, and nausea (among others). Often, erectile dysfunction can instead be treated non-pharmacologically, by identifying and addressing a psychogenic cause of the disease. [18]

Particular caution should be used when prescribing PDE5 inhibitors for erectile dysfunction for patients receiving protease inhibitors, like Atazanavir, which are used to treat HIV. 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.[ citation needed ]

PDE5 inhibitor drugs are effective in men regardless of why they have erectile dysfunction — including vascular disease, nerve problems, and even psychological causes.[ citation needed ] PDE5-inhibiting drugs can cause a number of side-effects, including headache, lightheadedness, dizziness, flushing, nasal congestion, and changes in vision.[ citation needed ] In 2011, the Food and Drug Administration (FDA) issued additional guidance on regulations related to cGMP manufacture and packaging. [19]

Sildenafil

Bulk bag of counterfeit Viagra CBP with bag of seized counterfeit Viagra.jpg
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. [20] 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. [21] 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. [22]

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 [23] and pulmonary arterial hypertension. [24] It has a longer half life than sildenafil of 17.5 hours, allowing it to be taken once a day. [24] Tadalafil "daily" (5 mg) is also used for treatment of benign prostate hyperplasia. [25]

In patients with pulmonary arterial hypertension, tadalafil improves symptoms and also slows down the progressive deterioration in breathlessness seen in this condition. [24] Studies have shown that tadalafil is more selective for PDE5 over PDE6 than sildenafil or vardenafil. [26]

See also

Related Research Articles

<span class="mw-page-title-main">Phosphodiesterase inhibitor</span> Drug

A phosphodiesterase inhibitor is a drug that blocks one or more of the five subtypes of the enzyme phosphodiesterase (PDE), thereby preventing the inactivation of the intracellular second messengers, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) by the respective PDE subtype(s). The ubiquitous presence of this enzyme means that non-specific inhibitors have a wide range of actions, the actions in the heart, and lungs being some of the first to find a therapeutic use.

<span class="mw-page-title-main">Sildenafil</span> Drug for erectile dysfunction and hypertension

Sildenafil, sold under the brand name Viagra among others, is a medication used to treat erectile dysfunction and pulmonary arterial hypertension. It is also sometimes used off-label for the treatment of certain symptoms in secondary Raynaud's phenomenon. It is unclear if it is effective for treating sexual dysfunction in females. It can be taken orally, intravenously, or through the sublingual route. Onset when taken orally is typically within twenty minutes and lasts for about two hours.

<span class="mw-page-title-main">Phosphodiesterase</span> Class of enzymes

A phosphodiesterase (PDE) is an enzyme that breaks a phosphodiester bond. Usually, phosphodiesterase refers to cyclic nucleotide phosphodiesterases, which have great clinical significance and are described below. However, there are many other families of phosphodiesterases, including phospholipases C and D, autotaxin, sphingomyelin phosphodiesterase, DNases, RNases, and restriction endonucleases, as well as numerous less-well-characterized small-molecule phosphodiesterases.

<span class="mw-page-title-main">Tadalafil</span> Medication used to treat erectile dysfunction

Tadalafil, sold under the brand name Cialis among others, is a PDE5 inhibitor medication used to treat erectile dysfunction, benign prostatic hyperplasia, and pulmonary arterial hypertension. It is taken by mouth. Onset is typically within half an hour and the duration is up to 36 hours.

<span class="mw-page-title-main">Cyclic guanosine monophosphate</span> Chemical compound

Cyclic guanosine monophosphate (cGMP) is a cyclic nucleotide derived from guanosine triphosphate (GTP). cGMP acts as a second messenger much like cyclic AMP. Its most likely mechanism of action is activation of intracellular protein kinases in response to the binding of membrane-impermeable peptide hormones to the external cell surface. Through protein kinases activation, cGMP can relax smooth muscle. cGMP concentration in urine can be measured for kidney function and diabetes detection.

<span class="mw-page-title-main">Vardenafil</span> Chemical compound

Vardenafil, sold under the brand name Levitra among others, is a medication that is used for treating erectile dysfunction. It is a PDE5 inhibitor. It is taken by mouth.

<span class="mw-page-title-main">PDE5 inhibitor</span> Vasodilating drug

A phosphodiesterase type 5 inhibitor is a vasodilating drug that works by blocking the degradative action of cGMP-specific phosphodiesterase type 5 (PDE5) on cyclic GMP in the smooth muscle cells lining the blood vessels supplying various tissues. These drugs dilate the corpora cavernosa of the penis, facilitating erection with sexual stimulation, and are used in the treatment of erectile dysfunction (ED). Sildenafil was the first effective oral treatment available for ED. Because PDE5 is also present in the smooth muscle of the walls of the arterioles within the lungs, two PDE5 inhibitors, sildenafil and tadalafil, are FDA-approved for the treatment of pulmonary hypertension. As of 2019, the wider cardiovascular benefits of PDE5 inhibitors are being appreciated.

<span class="mw-page-title-main">Cyclic nucleotide phosphodiesterase</span> Class of enzymes

3′,5′-cyclic-nucleotide phosphodiesterases (EC 3.1.4.17) are a family of phosphodiesterases. Generally, these enzymes hydrolyze a nucleoside 3′,5′-cyclic phosphate to a nucleoside 5′-phosphate:

<span class="mw-page-title-main">Phosphodiesterase 3</span> Class of enzymes

PDE3 is a phosphodiesterase. The PDEs belong to at least eleven related gene families, which are different in their primary structure, substrate affinity, responses to effectors, and regulation mechanism. Most of the PDE families are composed of more than one gene. PDE3 is clinically significant because of its role in regulating heart muscle, vascular smooth muscle and platelet aggregation. PDE3 inhibitors have been developed as pharmaceuticals, but their use is limited by arrhythmic effects and they can increase mortality in some applications.

Phosphodiesterase 1, PDE1, EC 3.1.4.1, systematic name oligonucleotide 5′-nucleotidohydrolase) is a phosphodiesterase enzyme also known as calcium- and calmodulin-dependent phosphodiesterase. It is one of the 11 families of phosphodiesterase (PDE1-PDE11). Phosphodiesterase 1 has three subtypes, PDE1A, PDE1B and PDE1C which divide further into various isoforms. The various isoforms exhibit different affinities for cAMP and cGMP.

<span class="mw-page-title-main">Phosphodiesterase 2</span> Class of enzymes

The PDE2 enzyme is one of 21 different phosphodiesterases (PDE) found in mammals. These different PDEs can be subdivided to 11 families. The different PDEs of the same family are functionally related despite the fact that their amino acid sequences show considerable divergence. The PDEs have different substrate specificities. Some are cAMP selective hydrolases, others are cGMP selective hydrolases and the rest can hydrolyse both cAMP and cGMP.

<span class="mw-page-title-main">Udenafil</span> Chemical compound

The drug udenafil is marketed under the trade name Zydena. It is within the PDE5 inhibitor class (which also includes avanafil, sildenafil, tadalafil, and vardenafil). Like other PDE5 inhibitors, it is used to treat erectile dysfunction. Udenafil was developed by Dong-A Pharmaceutical. It has fairly rapid onset of action (peak plasma concentration after 1 to 1.5 hours), and has long duration of action (plasma half-life of 11 to 13 hours). Udenafil's pharmacokinetics allows once-daily dosage (in addition to on-demand use). Typical doses are 100 and 200 mg. Udenafil is available in Korea, Russia, and the Philippines. It has not yet been approved for use in the United States by the U.S. Food and Drug Administration.

<span class="mw-page-title-main">Avanafil</span> Chemical compound

Avanafil is a PDE5 inhibitor approved for erectile dysfunction by the FDA on April 27, 2012 and by EMA on June 21, 2013. Avanafil is sold under the brand names Stendra and Spedra. It was invented at Mitsubishi Tanabe Pharma, formerly known as Tanabe Seiyaku Co., and licensed to Vivus Inc., which partnered with Menarini Group to commercialise Spedra in over forty European countries, Australia, and New Zealand. Metuchen Pharmaceuticals obtained exclusive rights within the United States.

<span class="mw-page-title-main">PDE11A</span> Protein-coding gene in the species Homo sapiens

Dual 3',5'-cyclic-AMP and -GMP phosphodiesterase 11A is an enzyme that in humans is encoded by the PDE11A gene.

<span class="mw-page-title-main">Acetildenafil</span> Chemical compound

Acetildenafil (hongdenafil) is a synthetic drug which acts as a phosphodiesterase inhibitor. It is an analog of sildenafil (Viagra) which has been detected in numerous different brands of "herbal aphrodisiac" products sold in convenience stores that claim to boost libido and alleviate erectile dysfunction.

<span class="mw-page-title-main">Lodenafil</span> Chemical compound

Lodenafil is a drug belonging to a class of drugs called PDE5 inhibitor, which many other erectile dysfunction drugs such as sildenafil, tadalafil, and vardenafil also belong to. Like udenafil and avanafil it belongs to a new generation of PDE5 inhibitors.

<span class="mw-page-title-main">Sulfoaildenafil</span> Chemical compound

Sulfoaildenafil (thioaildenafil) is a synthetic drug that is a structural analog of sildenafil (Viagra). It was first reported in 2005, and it is not approved by any health regulation agency. Like sildenafil, sulfoaildenafil is a phosphodiesterase type 5 inhibitor.

<span class="mw-page-title-main">Zaprinast</span> Chemical compound

Zaprinast was an unsuccessful clinical drug candidate that was a precursor to the chemically related PDE5 inhibitors, such as sildenafil (Viagra), which successfully reached the market. It is a phosphodiesterase inhibitor, selective for the subtypes PDE5, PDE6, PDE9 and PDE11. IC50 values are 0.76, 0.15, 29.0, and 12.0 μM, respectively.

Phosphodiesterases (PDEs) are a superfamily of enzymes. This superfamily is further classified into 11 families, PDE1 - PDE11, on the basis of regulatory properties, amino acid sequences, substrate specificities, pharmacological properties and tissue distribution. Their function is to degrade intracellular second messengers such as cyclic adenine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) which leads to several biological processes like effect on intracellular calcium level by the Ca2+ pathway.

<span class="mw-page-title-main">Homosildenafil</span> Chemical compound

Homosildenafil is a synthetic drug which acts as a phosphodiesterase inhibitor. It is an analog of sildenafil and vardenafil. Homosildenafil was first identified as an adulterant in sex enhancement products in 2003 and was more recently detected in dietary supplements.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000138735 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000053965 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ d'Amati G, Di Gioia CR, Bologna M, Giordano D, Giorgi M, Dolci S, Jannini EA (2002). "Type 5 phosphodiesterase expression in the human vagina". Urology. 60 (1): 191–195. doi:10.1016/s0090-4295(02)01663-1. PMID   12100961.
  6. ↑ Uzunov P, Weiss B (September 1972). "Separation of multiple molecular forms of cyclic adenosine-3′,5′-monophosphate phosphodiesterase in rat cerebellum by polyacrylamide gel electrophoresis". Biochimica et Biophysica Acta (BBA) - Enzymology. 284 (1): 220–6. doi:10.1016/0005-2744(72)90060-5. PMID   4342220.
  7. ↑ Weiss B (1975). "Differential activation and inhibition of the multiple forms of cyclic nucleotide phosphodiesterase". Advances in Cyclic Nucleotide Research. 5: 195–211. PMID   165666.
  8. ↑ Fertel R, Weiss B (July 1976). "Properties and drug responsiveness of cyclic nucleotide phosphodiesterases of rat lung" (abstract). Molecular Pharmacology. 12 (4): 678–87. PMID   183099.
  9. ↑ Weiss B, Hait WN (1977). "Selective cyclic nucleotide phosphodiesterase inhibitors as potential therapeutic agents". Annual Review of Pharmacology and Toxicology. 17: 441–77. doi:10.1146/annurev.pa.17.040177.002301. PMID   17360.
  10. ↑ Nagayama T, Zhang M, Hsu S, Takimoto E, Kass DA (August 2008). "Sustained soluble guanylate cyclase stimulation offsets nitric-oxide synthase inhibition to restore acute cardiac modulation by sildenafil". The Journal of Pharmacology and Experimental Therapeutics. 326 (2): 380–7. doi:10.1124/jpet.108.137422. PMID   18456872. S2CID   10202683.
  11. ↑ Lu Z, Xu X, Hu X, Lee S, Traverse JH, Zhu G, Fassett J, Tao Y, Zhang P, dos Remedios C, Pritzker M, Hall JL, Garry DJ, Chen Y (April 2010). "Oxidative stress regulates left ventricular PDE5 expression in the failing heart". Circulation. 121 (13): 1474–83. doi:10.1161/CIRCULATIONAHA.109.906818. PMC   3110701 . PMID   20308615.
  12. ↑ Pokreisz P, Vandenwijngaert S, Bito V, Van den Bergh A, Lenaerts I, Busch C, Marsboom G, Gheysens O, Vermeersch P, Biesmans L, Liu X, Gillijns H, Pellens M, Van Lommel A, Buys E, Schoonjans L, Vanhaecke J, Verbeken E, Sipido K, Herijgers P, Bloch KD, Janssens SP (January 2009). "Ventricular phosphodiesterase-5 expression is increased in patients with advanced heart failure and contributes to adverse ventricular remodeling after myocardial infarction in mice". Circulation. 119 (3): 408–16. doi:10.1161/CIRCULATIONAHA.108.822072. PMC   3791110 . PMID   19139381.
  13. ↑ Hutchings DC, Anderson SG, Caldwell JL, Trafford AW (March 2018). "Phosphodiesterase-5 inhibitors and the heart: compound cardioprotection?". Heart. 104 (15): 1244–1250. doi:10.1136/heartjnl-2017-312865. PMC   6204975 . PMID   29519873.
  14. ↑ "Sildenafil". National Institute for Health and Care Excellence. 2018-08-07. Retrieved 2024-05-18.
  15. ↑ "Vardenafil". National Institute for Health and Care Excellence. 2011-10-15. Retrieved 2024-05-18.
  16. ↑ "Tadalafil". National Institute for Health and Care Excellence. 2012-07-15. Retrieved 2024-05-18.
  17. ↑ "Avanafil". National Institute for Health and Care Excellence. 2017-08-24. Retrieved 2024-05-18.
  18. ↑ "Erectile dysfunction: Phosphodiesterase-5 (PDE-5) inhibitors". National Institute for Health and Care Excellence. 2023-04-04. Retrieved 2024-05-18.
  19. ↑ "FDA Issues Guidance on Dietary Supplement cGMP Regulations". The National Law Review . Duane Morris LLP. 2011-02-07. Retrieved 2012-01-19.
  20. ↑ "Viagra". Drug Approval Package. United States Food and Drug Administration. March 27, 1998.
  21. ↑ "Sildenafil 50 mg film-coated tablets". Medicines.org.uk. Retrieved November 4, 2015.
  22. ↑ "Viagra -sildenafil citrate tablet". Daily Med- U.S National Library of Medicine. Retrieved November 5, 2015.
  23. ↑ Khera M, Goldstein I (June 2011). "Erectile dysfunction". BMJ Clinical Evidence. 2011. PMC   3217797 . PMID   21711956.
  24. 1 2 3 Henrie AM, Nawarskas JJ, Anderson JR (2015). "Clinical utility of tadalafil in the treatment of pulmonary arterial hypertension: an evidence-based review". Core Evidence. 10: 99–109. doi: 10.2147/CE.S58457 . PMC   4636095 . PMID   26587013.
  25. ↑ Hatzimouratidis K (August 2014). "A review of the use of tadalafil in the treatment of benign prostatic hyperplasia in men with and without erectile dysfunction". Therapeutic Advances in Urology. 6 (4): 135–47. doi:10.1177/1756287214531639. PMC   4054509 . PMID   25083163.
  26. ↑ Bischoff E (June 2004). "Potency, selectivity, and consequences of nonselectivity of PDE inhibition". International Journal of Impotence Research. 16 (Suppl 1): S11-4. doi:10.1038/sj.ijir.3901208. PMID   15224129. S2CID   22178197.
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