CGMP-specific phosphodiesterase type 5: Difference between revisions

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'''cGMP-specific phosphodiesterase type 5''' is an [[enzyme]] ({{EC number|3.1.4.17}}) from the [[phosphodiesterase]] class. It is found in various tissues, most prominently the [[corpus cavernosum penis|corpus cavernosum]] and the [[retina]]. It has also been recently discovered to play a vital role in the cardiovascular system.
'''cGMP-specific phosphodiesterase type 5''' is an [[enzyme]] ({{EC number|3.1.4.17}}) from the [[phosphodiesterase]] class. It is found in various tissues, most prominently the [[corpus cavernosum penis|corpus cavernosum]] and the [[retina]]. It has also been recently discovered to play a vital role in the cardiovascular system.


The ''phosphodiesterase (PDE)'' [[isozyme]]s, 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 [[cyclic guanosine monophosphate|cGMP]] hydrolysis.<ref name="pmid4342220">{{cite journal | vauthors = Uzunov P, Weiss B | title = Separation of multiple molecular forms of cyclic adenosine-3',5'-monophosphate phosphodiesterase in rat cerebellum by polyacrylamide gel electrophoresis | journal = Biochim. Biophys. Acta | volume = 284 | issue = 1 | pages = 220–6 | year = 1972 | pmid = 4342220 | doi =10.1016/0005-2744(72)90060-5 }}</ref><ref name="pmid165666">{{cite journal | author = Weiss B | title = Differential activation and inhibition of the multiple forms of cyclic nucleotide phosphodiesterase | journal = Adv Cyclic Nucleotide Res | volume = 5 | issue = | pages = 195–211 | year = 1975 | pmid = 165666 | doi =  }}</ref>
The ''phosphodiesterase (PDE)'' [[isozyme]]s, 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 [[cyclic guanosine monophosphate|cGMP]] hydrolysis.<ref name="pmid4342220">{{cite journal | vauthors = Uzunov P, Weiss B | title = Separation of multiple molecular forms of cyclic adenosine-3',5'-monophosphate phosphodiesterase in rat cerebellum by polyacrylamide gel electrophoresis | journal = Biochimica et Biophysica Acta | volume = 284 | issue = 1 | pages = 220–6 | date = September 1972 | pmid = 4342220 | doi = 10.1016/0005-2744(72)90060-5 }}</ref><ref name="pmid165666">{{cite journal | vauthors = Weiss B | title = Differential activation and inhibition of the multiple forms of cyclic nucleotide phosphodiesterase | journal = Advances in Cyclic Nucleotide Research | volume = 5 | issue = | pages = 195–211 | year = 1975 | pmid = 165666 | doi =  }}</ref>


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.<ref name="pmid183099">{{cite journal | vauthors = Fertel R, Weiss B | title = Properties and drug responsiveness of cyclic nucleotide phosphodiesterases of rat lung | journal = Mol. Pharmacol. | volume = 12 | issue = 4 | pages = 678–87 | year = 1976 | pmid = 183099 | doi = | url = http://molpharm.aspetjournals.org/cgi/content/abstract/12/4/678 | format = abstract }}</ref><ref name="pmid17360">{{cite journal | vauthors = Weiss B, Hait WN | title = Selective cyclic nucleotide phosphodiesterase inhibitors as potential therapeutic agents | journal = Annu. Rev. Pharmacol. Toxicol. | volume = 17 | issue = | pages = 441–77 | year = 1977 | pmid = 17360 | doi = 10.1146/annurev.pa.17.040177.002301 }}</ref>
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.<ref name="pmid183099">{{cite journal | vauthors = Fertel R, Weiss B | title = Properties and drug responsiveness of cyclic nucleotide phosphodiesterases of rat lung | journal = Molecular Pharmacology | volume = 12 | issue = 4 | pages = 678–87 | date = July 1976 | pmid = 183099 | doi = | url = http://molpharm.aspetjournals.org/cgi/content/abstract/12/4/678 | format = abstract }}</ref><ref name="pmid17360">{{cite journal | vauthors = Weiss B, Hait WN | title = Selective cyclic nucleotide phosphodiesterase inhibitors as potential therapeutic agents | journal = Annual Review of Pharmacology and Toxicology | volume = 17 | issue = | pages = 441–77 | year = 1977 | pmid = 17360 | doi = 10.1146/annurev.pa.17.040177.002301 }}</ref>


[[Sildenafil]], [[vardenafil]], [[tadalafil]], and [[avanafil]] are PDE5 inhibitors that are significantly more potent and selective than [[zaprinast]] and other early PDE5 inhibitors.
[[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 ==
== 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 [[conformer]]s, 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 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 [[conformational isomerism|conformer]]s, 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 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]].
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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.
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.<ref name="pmid18456872">{{cite journal | vauthors = Nagayama T, Zhang M, Hsu S, Takimoto E, Kass DA | title = Sustained soluble guanylate cyclase stimulation offsets nitric-oxide synthase inhibition to restore acute cardiac modulation by sildenafil. | journal = J Pharmacol Exp Ther | volume = 326 | issue = 2 | pages = 380–7 | year = 2008 | pmid = 18456872 | doi =10.1124/jpet.108.137422 }}</ref>  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.<ref name="pmid20308615">{{cite journal | vauthors = 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 | title = Oxidative stress regulates left ventricular PDE5 expression in the failing heart. | journal = Circulation | volume = 121 | issue = 13 | pages = 1474–83 | year = 2010 | pmid = 20308615 | doi =10.1161/CIRCULATIONAHA.109.906818 | pmc=3110701}}</ref>  In an experiment, PDE5 overexpression was found to contribute to worsened pathological remodeling after mouse cardiomyocytes experienced myocardial infarction.<ref name="pmid19139381">{{cite journal | author = Janssens SP. | title = Ventricular phosphodiesterase-5 expression is increased in patients with advanced heart failure and contributes to adverse ventricular remodeling after myocardial infarction in mice. | journal = Circulation | volume = 119 | issue = 3 | pages = 408–16 | year = 2009 | pmid = 19139381 | doi =10.1161/CIRCULATIONAHA.108.822072 | pmc=3791110}}</ref> 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.
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.<ref name="pmid18456872">{{cite journal | vauthors = Nagayama T, Zhang M, Hsu S, Takimoto E, Kass DA | title = Sustained soluble guanylate cyclase stimulation offsets nitric-oxide synthase inhibition to restore acute cardiac modulation by sildenafil | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 326 | issue = 2 | pages = 380–7 | date = August 2008 | pmid = 18456872 | doi = 10.1124/jpet.108.137422 }}</ref>  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.<ref name="pmid20308615">{{cite journal | vauthors = 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 | title = Oxidative stress regulates left ventricular PDE5 expression in the failing heart | journal = Circulation | volume = 121 | issue = 13 | pages = 1474–83 | date = April 2010 | pmid = 20308615 | pmc = 3110701 | doi = 10.1161/CIRCULATIONAHA.109.906818 }}</ref>  In an experiment, PDE5 overexpression was found to contribute to worsened pathological remodeling after mouse cardiomyocytes experienced myocardial infarction.<ref name="pmid19139381">{{cite journal | vauthors = 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 | title = Ventricular phosphodiesterase-5 expression is increased in patients with advanced heart failure and contributes to adverse ventricular remodeling after myocardial infarction in mice | journal = Circulation | volume = 119 | issue = 3 | pages = 408–16 | date = January 2009 | pmid = 19139381 | pmc = 3791110 | doi = 10.1161/CIRCULATIONAHA.108.822072 }}</ref> 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. <ref>{{cite journal | vauthors = Hutchings DC, Anderson SG, Caldwell JL, Trafford AW | title = Phosphodiesterase-5 inhibitors and the heart: compound cardioprotection? | journal = Heart | date = March 2018 | pmid = 29519873 | doi = 10.1136/heartjnl-2017-312865 }}</ref>


== PDE5-inhibiting drugs ==
== PDE5-inhibiting drugs ==
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Particular caution should be used when prescribing PDE5 inhibitors for erectile dysfunction for patients receiving [[Protease inhibitor (pharmacology)|protease inhibitor]]s, 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]].{{citation needed|date=December 2012}}
Particular caution should be used when prescribing PDE5 inhibitors for erectile dysfunction for patients receiving [[Protease inhibitor (pharmacology)|protease inhibitor]]s, 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]].{{citation needed|date=December 2012}}


PDE5-inhibiting drugs are very effective.{{peacock term|date=December 2012}} PDE5 inhibitor drugs appear to work in men regardless of why they have erectile dysfunction — including vascular [[disease]], nerve problems, and even [[psychological]] causes.{{citation needed|date=December 2012}} PDE5-inhibiting drugs can cause a number of minor [[Adverse drug reaction|side-effects]], including [[headache]], lightheadedness, [[dizziness]], flushing, nasal congestion, and changes in [[Visual perception|vision]].{{citation needed|date=December 2012}} In 2011, the [[Food and Drug Administration]] (FDA) issued additional guidance on regulations related to cGMP manufacture and packaging.<ref>{{cite web |title=FDA Issues Guidance on Dietary Supplement cGMP Regulations |url=http://www.natlawreview.com/article/fda-issues-guidance-dietary-supplement-cgmp-regulations|publisher=Duane Morris LLP|work=The [[National Law Review]]|date=2011-02-07|accessdate=2012-01-19}}</ref>
PDE5-inhibiting drugs are very effective.{{peacock term|date=December 2012}} PDE5 inhibitor drugs appear to work in men regardless of why they have erectile dysfunction — including vascular [[disease]], nerve problems, and even [[psychological]] causes.{{citation needed|date=December 2012}} PDE5-inhibiting drugs can cause a number of minor [[Adverse drug reaction|side-effects]], including [[headache]], lightheadedness, [[dizziness]], flushing, nasal congestion, and changes in [[Visual perception|vision]].{{citation needed|date=December 2012}} In 2011, the [[Food and Drug Administration]] (FDA) issued additional guidance on regulations related to cGMP manufacture and packaging.<ref>{{cite web |title=FDA Issues Guidance on Dietary Supplement cGMP Regulations |url=http://www.natlawreview.com/article/fda-issues-guidance-dietary-supplement-cgmp-regulations|publisher=Duane Morris LLP|work=The [[National Law Review]]|date=2011-02-07|access-date=2012-01-19}}</ref>


===Viagra (sildenafil)===
===Sildenafil===
{{Main article|Sildenafil}}
[[File:CBP with bag of seized counterfeit Viagra.jpg|right|thumb|upright|Bulk bag of counterfeit [[Viagra]]]]
[[File:CBP with bag of seized counterfeit Viagra.jpg|right|thumb|upright|Bulk bag of counterfeit [[Viagra]]]]
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.<ref>{{cite web | url = https://www.healthexpress.co.uk/erectile-dysfunction/treatment/pfizer-viagra | title = Viagra | publisher = Healthexpress.co.uk | accessdate = November 5, 2015}}</ref>  Viagra contains sildenafil citrate packaged as a [[Pill (pharmacy)|pill]]. 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 [[Human sexuality|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.
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.<ref>{{cite web | url = https://www.accessdata.fda.gov/drugsatfda_docs/NDA/98/viagra/viagra_toc.cfm | work = Drug Approval Package | title = Viagra | publisher = United States Food and Drug Administration | date = March 27, 1998}}</ref>  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 [[Human sexuality|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.<ref>{{cite web | url = https://www.medicines.org.uk/emc/medicine/30942 | title = Sildenafil 50 mg film-coated tablets | publisher = Medicines.org.uk | accessdate = November 4, 2015}}</ref> 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.<ref>{{cite web | url = http://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=4d60822d-1c9b-494d-adb3-20fe921d9c58&type=display | title = Viagra -sildenafil citrate tablet | publisher = Daily Med- U.S National Library of Medicine | accessdate=November 5, 2015}}</ref>
Studies in vitro have shown that sildenafil is selective for PDE5.<ref>{{cite web | url = https://www.medicines.org.uk/emc/medicine/30942 | title = Sildenafil 50 mg film-coated tablets | publisher = Medicines.org.uk | access-date = November 4, 2015}}</ref> 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.<ref>{{cite web | url = http://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=4d60822d-1c9b-494d-adb3-20fe921d9c58&type=display | title = Viagra -sildenafil citrate tablet | publisher = Daily Med- U.S National Library of Medicine | access-date=November 5, 2015}}</ref>


===Levitra (vardenafil)===
=== Vardenafil ===
[[Levitra]] was the second oral PDE-5 inhibitor for erectile dysfunction to be FDA approved in August 2003.{{Citation needed|date=June 2009}}
{{Main article|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|date=June 2009}}


===Cialis (tadalafil)===
===Tadalafil===
[[Cialis]] has an estimated effective duration of 36 hours; however, there are studies showing high efficacy up to 100 hours. {{Citation needed|date=March 2010}}
{{Main article|Tadalafil}}
Tadalafil (marketed as Cialis) is a PDE5 inhibitor commonly that, in addition to its use in erectile dysfunction <ref>{{cite journal | vauthors = Khera M, Goldstein I | title = Erectile dysfunction | journal = BMJ Clinical Evidence | volume = 2011 | date = June 2011 | pmid = 21711956 | pmc = 3217797 }}</ref> is also used to treat pulmonary arterial hypertension.<ref name=":0">{{cite journal | vauthors = Henrie AM, Nawarskas JJ, Anderson JR | title = Clinical utility of tadalafil in the treatment of pulmonary arterial hypertension: an evidence-based review | journal = Core Evidence | volume = 10 | pages = 99–109 | date = 2015 | pmid = 26587013 | pmc = 4636095 | doi = 10.2147/CE.S58457 }}</ref>  It has a longer half life than sildenafil of 17.5 hours, allowing it to be taken once a day. <ref name=":0" />  In patients with pulmonary arterial hypertension, tadalafil improves symptoms and also slows down the progressive deterioration in breathlessness seen in this condition. <ref name=":0" /> Studies have shown that tadalafil is more selective for PDE5 over PDE6 than sildenafil or vardenafil.<ref>{{cite journal | vauthors = Bischoff E | title = Potency, selectivity, and consequences of nonselectivity of PDE inhibition | journal = International Journal of Impotence Research | volume = 16 Suppl 1 | pages = S11-4 | date = June 2004 | pmid = 15224129 | doi = 10.1038/sj.ijir.3901208 }}</ref>


Studies have shown that tadalafil is more selective for PDE5 over PDE6 than sildenafil or vardenafil. {{Citation needed|date=March 2009}}
== See also ==
 
==See also==
* [[PDE5 drug design]]
* [[PDE5 drug design]]
* [[PDE5 inhibitor]]
* [[PDE5 inhibitor]]
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* [[Icariin]]
* [[Icariin]]


==References==
== References ==
{{reflist|30em}}
{{reflist|30em}}


==External links==
== External links ==
* [http://macromoleculeinsights.com/pde5.php The cGMP Specific Phosphodiesterase Type 5 Enzyme]
* [http://macromoleculeinsights.com/pde5.php The cGMP Specific Phosphodiesterase Type 5 Enzyme]
* [http://www.pfizer.com/download/uspi_viagra.pdf Pfizer Pharmaceutical]
* [http://www.pfizer.com/download/uspi_viagra.pdf Pfizer Pharmaceutical]
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{{Portal bar|Molecular and Cellular Biology|border=no}}


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[[Category:PDE5 inhibitors|*]]
[[Category:PDE5 inhibitors|*]]
[[Category:EC 3.1.4]]
[[Category:EC 3.1.4]]
[[Category:Enzymes of known structure]]
[[Category:Enzymes of known structure]]

Revision as of 20:34, 27 July 2018

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cGMP-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.[1][2]

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.[3][4]

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.[5] 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.[6] In an experiment, PDE5 overexpression was found to contribute to worsened pathological remodeling after mouse cardiomyocytes experienced myocardial infarction.[7] 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. [8]

PDE5-inhibiting drugs

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.[citation needed]

PDE5-inhibiting drugs are very effective.[peacock term] PDE5 inhibitor drugs appear to work 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 minor 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.[9]

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.[10] 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.[11] 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.[12]

Vardenafil

Main article: 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

Main article: Tadalafil

Tadalafil (marketed as Cialis) is a PDE5 inhibitor commonly that, in addition to its use in erectile dysfunction [13] is also used to treat pulmonary arterial hypertension.[14] It has a longer half life than sildenafil of 17.5 hours, allowing it to be taken once a day. [14] In patients with pulmonary arterial hypertension, tadalafil improves symptoms and also slows down the progressive deterioration in breathlessness seen in this condition. [14] Studies have shown that tadalafil is more selective for PDE5 over PDE6 than sildenafil or vardenafil.[15]

See also

References

  1. ↑ 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. 284 (1): 220–6. doi:10.1016/0005-2744(72)90060-5. PMID 4342220.
  2. ↑ 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.
  3. ↑ 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.
  4. ↑ 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.
  5. ↑ 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.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ Hutchings DC, Anderson SG, Caldwell JL, Trafford AW (March 2018). "Phosphodiesterase-5 inhibitors and the heart: compound cardioprotection?". Heart. doi:10.1136/heartjnl-2017-312865. PMID 29519873.
  9. ↑ "FDA Issues Guidance on Dietary Supplement cGMP Regulations". The National Law Review. Duane Morris LLP. 2011-02-07. Retrieved 2012-01-19.
  10. ↑ "Viagra". Drug Approval Package. United States Food and Drug Administration. March 27, 1998.
  11. ↑ "Sildenafil 50 mg film-coated tablets". Medicines.org.uk. Retrieved November 4, 2015.
  12. ↑ "Viagra -sildenafil citrate tablet". Daily Med- U.S National Library of Medicine. Retrieved November 5, 2015.
  13. ↑ Khera M, Goldstein I (June 2011). "Erectile dysfunction". BMJ Clinical Evidence. 2011. PMC 3217797. PMID 21711956.
  14. ↑ 14.0 14.1 14.2 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.
  15. ↑ 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.

External links

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