関: PDE5、type 5 cyclic nucleotide phosphodiesterase

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/06/22 15:04:06」(JST)

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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, and tadalafil 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.

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.^[8]

Viagra (sildenafil)

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.^[9] Viagra contains sildenafil citrate packaged as a 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 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.^[10] 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.^[11]

Levitra (vardenafil)

Levitra was the second oral PDE-5 inhibitor for erectile dysfunction to be FDA approved in August 2003.^{[citation needed]}

Cialis (tadalafil)

Cialis has an estimated effective duration of 36 hours; however, there are studies showing high efficacy up to 100 hours.^{[citation needed]}

Studies have shown that tadalafil is more selective for PDE5 over PDE6 than sildenafil or vardenafil.^{[citation needed]}

References

^ Uzunov P, Weiss B (1972). "Separation of multiple molecular forms of cyclic adenosine-3',5'-monophosphate phosphodiesterase in rat cerebellum by polyacrylamide gel electrophoresis". Biochim. Biophys. Acta 284 (1): 220–6. doi:10.1016/0005-2744(72)90060-5. PMID 4342220.
^ Weiss B (1975). "Differential activation and inhibition of the multiple forms of cyclic nucleotide phosphodiesterase". Adv Cyclic Nucleotide Res 5: 195–211. PMID 165666.
^ Fertel R, Weiss B (1976). "Properties and drug responsiveness of cyclic nucleotide phosphodiesterases of rat lung" (abstract). Mol. Pharmacol. 12 (4): 678–87. PMID 183099.
^ Weiss B, Hait WN (1977). "Selective cyclic nucleotide phosphodiesterase inhibitors as potential therapeutic agents". Annu. Rev. Pharmacol. Toxicol. 17: 441–77. doi:10.1146/annurev.pa.17.040177.002301. PMID 17360.
^ Nagayama T, Zhang M, Hsu S, Takimoto E, Kass DA (2008). "Sustained soluble guanylate cyclase stimulation offsets nitric-oxide synthase inhibition to restore acute cardiac modulation by sildenafil.". J Pharmacol Exp Ther. 326 (2): 380–7. doi:10.1124/jpet.108.137422. PMID 18456872.
^ 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 (2010). "Oxidative stress regulates left ventricular PDE5 expression in the failing heart.". Circulation 121 (13): 1474–83. doi:10.1161/CIRCULATIONAHA.109.906818. PMID 20308615.
^ Janssens SP. (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. PMID 19139381.
^ "FDA Issues Guidance on Dietary Supplement cGMP Regulations". The National Law Review. Duane Morris LLP. 2011-02-07. Retrieved 2012-01-19.
^ "Viagra". Healthexpress.co.uk. Retrieved November 5, 2015.
^ "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.

External links

The cGMP Specific Phosphodiesterase Type 5 Enzyme
Pfizer Pharmaceutical
New Scientist article on Viagra and the female 'G spot'

Molecular and Cellular Biology portal

UpToDate Contents

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1. 収縮能障害による心不全における強心剤 inotropic agents in heart failure due to systolic dysfunction
2. 男性性機能不全の治療 treatment of male sexual dysfunction
3. 下肢末梢動脈疾患の症状を治療するための試験的治療 investigational therapies for treating symptoms of lower extremity peripheral artery disease
4. Investigational and emerging therapies for heart failure
5. 心血管疾患患者における性的活動 sexual activity in patients with cardiovascular disease

English Journal

Effect of repeated prostate biopsies on erectile function in men on active surveillance for prostate cancer.

Braun K1, Ahallal Y2, Sjoberg DD3, Ghoneim T2, Dominguez Esteban M2, Mulhall J4, Vickers A3, Eastham J4, Scardino PT4, Touijer KA5.Author information 1Urology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York; Department of Urology, University Hospital Ruhr University Bochum, Marienhospital Herne, Herne, Germany.2Urology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York.3Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York.4Urology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York; Department of Urology, Weill Medical College of Cornell University, New York, New York.5Urology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York; Department of Urology, Weill Medical College of Cornell University, New York, New York. Electronic address: touijera@mskcc.org.AbstractPURPOSE: Active surveillance is becoming an increasingly common management strategy for low grade prostate cancer and involves repeat prostate biopsies over time. It has been hypothesized that serial biopsies can lead to reduced erectile function in patients on active surveillance and we explored this hypothesis in a longitudinally followed cohort.
The Journal of urology.J Urol.2014 Mar;191(3):744-9. doi: 10.1016/j.juro.2013.08.054. Epub 2013 Sep 5.
PURPOSE: Active surveillance is becoming an increasingly common management strategy for low grade prostate cancer and involves repeat prostate biopsies over time. It has been hypothesized that serial biopsies can lead to reduced erectile function in patients on active surveillance and we explored th
PMID 24012535

Phosphodiesterase 5 inhibitors enhance chemotherapy killing in gastrointestinal/genitourinary cancer cells.

Booth L1, Roberts JL, Cruickshanks N, Conley A, Durrant DE, Das A, Fisher PB, Kukreja RC, Grant S, Poklepovic A, Dent P.Author information 1Departments of Biochemistry and Molecular Biology (L.B., J.L.R., N.C., A.C., P.D.), Cardiology (D.E.D., A.D., R.C.K.), Medicine (S.G., A.P.), Human and Molecular Genetics (P.B.F.), Virginia Commonwealth University, Richmond, Virginia.AbstractThe present studies determined whether clinically relevant phosphodiesterase 5 (PDE5) inhibitors interacted with clinically relevant chemotherapies to kill gastrointestinal/genitourinary cancer cells. In bladder cancer cells, regardless of H-RAS mutational status, at clinically achievable doses, PDE5 inhibitors interacted in a greater than additive fashion with doxorubicin/mitomycin C/gemcitabine/cisplatin/paclitaxel to cause cell death. In pancreatic tumor cells expressing mutant active K-RAS, PDE5 inhibitors interacted in a greater than additive fashion with doxorubicin/gemcitabine/paclitaxel to cause cell death. The most potent PDE5 inhibitor was sildenafil. Knock down of PDE5 expression recapitulated the combination effects of PDE5 inhibitor drugs with chemotherapy drugs. Expression of cellular FLICE-like inhibitory protein-short did not significantly inhibit chemotherapy lethality but did significantly reduce enhanced killing in combination with sildenafil. Overexpression of B-cell lymphoma-extra large suppressed individual and combination drug toxicities. Knock down of CD95 or Fas-associated death domain protein suppressed drug combination toxicity. Combination toxicity was also abolished by necrostatin or receptor interacting protein 1 knock down. Treatment with PDE5 inhibitors and chemotherapy drugs promoted autophagy, which was maximal at ∼24 hour posttreatment, and 3-methyl adenine or knock down of Beclin1 suppressed drug combination lethality by ∼50%. PDE5 inhibitors enhanced and prolonged the induction of DNA damage as judged by Comet assays and γhistone 2AX (γH2AX) and checkpoint kinase 2 (CHK2) phosphorylation. Knock down of ataxia telangiectasia mutated suppressed γH2AX and CHK2 phosphorylation and enhanced drug combination lethality. Collectively our data demonstrate that the combination of PDE5 inhibitors with standard of care chemotherapy agents for gastrointestinal/genitourinary cancers represents a novel modality.
Molecular pharmacology.Mol Pharmacol.2014 Mar;85(3):408-19. doi: 10.1124/mol.113.090043. Epub 2013 Dec 18.
The present studies determined whether clinically relevant phosphodiesterase 5 (PDE5) inhibitors interacted with clinically relevant chemotherapies to kill gastrointestinal/genitourinary cancer cells. In bladder cancer cells, regardless of H-RAS mutational status, at clinically achievable doses, PDE
PMID 24353313

Effect of phosphodiesterase-5 inhibition on apoptosis and beta amyloid load in aged mice.

Puzzo D1, Loreto C, Giunta S, Musumeci G, Frasca G, Podda MV, Arancio O, Palmeri A.Author information 1Department of Bio-Medical Sciences, Section of Physiology, University of Catania, Catania, Italy.AbstractAge-related cognitive decline is accompanied by an increase of neuronal apoptosis and a dysregulation of neuroplasticity-related molecules such as brain-derived neurotrophic factor and neurotoxic factors including beta amyloid (Aβ) peptide. Because it has been previously demonstrated that phosphodiesterase-5 inhibitors (PDE5-Is) protect against hippocampal synaptic dysfunction and memory deficits in mouse models of Alzheimer's disease and physiological aging, we investigated the effect of a treatment with the PDE5-I, sildenafil, on cell death, pro- and antiapoptotic molecules, and Aβ production. We demonstrated that chronic intraperitoneal injection of sildenafil (3 mg/kg for 3 weeks) decreased terminal deoxyuridine triphosphate nick end labeling-positive cells in the CA1 hippocampal area of 26-30-month-old mice, downregulating the proapoptotic proteins, caspase-3 and B-cell lymphoma 2-associated X, and increasing antiapoptotic molecules such as B-cell lymphoma protein-2 and brain-derived neurotrophic factor. Also, sildenafil reverted the shifting of amyloid precursor protein processing toward Aβ42 production and the increase of the Aβ42:Aβ40 ratio in aged mice. Our data suggest that PDE5-I might be beneficial to treat age-related detrimental features in a physiological mouse model of aging.
Neurobiology of aging.Neurobiol Aging.2014 Mar;35(3):520-31. doi: 10.1016/j.neurobiolaging.2013.09.002. Epub 2013 Oct 7.
Age-related cognitive decline is accompanied by an increase of neuronal apoptosis and a dysregulation of neuroplasticity-related molecules such as brain-derived neurotrophic factor and neurotoxic factors including beta amyloid (Aβ) peptide. Because it has been previously demonstrated that phosphodi
PMID 24112792

Japanese Journal

造精機能障害に対するPDE5阻害薬の効果

日本薬理学雑誌 147(1), 35-39, 2016
NAID 130005118579

可溶性グアニル酸シクラーゼ刺激薬の肺高血圧治療における多面性 (新規薬剤の考え方)

循環器内科 = Cardioangiology 78(6), 630-636, 2015-12
NAID 40020691413

IPFに合併する二次性肺高血圧症の管理 (特集特発性肺線維症の併存症・合併症とどう向き合うか)

呼吸器内科 = Respiratory medicine 28(5), 358-364, 2015-11
NAID 40020665078

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★リンクテーブル★

リンク元	「ホスホジエステラーゼ5」「PDE5」「type 5 cyclic nucleotide phosphodiesterase」
拡張検索	「phosphodiesterase-5 inhibitor」
関連記事	「phosphodiesterase」「phosphodiesterases」

「ホスホジエステラーゼ5」

PDE5A
Available structures
PDB	Ortholog search: PDBe RCSB
List of PDB id codes
	4OEX, 1RKP, 1T9R, 1T9S, 1TBF, 1UDT, 1UDU, 1UHO, 1XOZ, 1XP0, 2CHM, 2H40, 2H42, 2H44, 2XSS, 3B2R, 3BJC, 3HC8, 3HDZ, 3JWQ, 3JWR, 3LFV, 3MF0, 3SHY, 3SHZ, 3SIE, 3TGE, 3TGG, 4G2W, 4G2Y, 4I9Z, 4IA0, 4MD6, 4OEW
Identifiers
Aliases	PDE5A, CGB-PDE, CN5A, PDE5, phosphodiesterase 5A
External IDs	OMIM: 603310 MGI: 2651499 HomoloGene: 842 GeneCards: 8654
Gene ontology
Molecular function	• nucleotide binding; • 3',5'-cyclic-nucleotide phosphodiesterase activity; • 3',5'-cyclic-GMP phosphodiesterase activity; • cGMP binding; • metal ion binding; • cyclic-nucleotide phosphodiesterase activity; • catalytic activity; • phosphoric diester hydrolase activity; • hydrolase activity;
Cellular component	• cytosol; • cellular_component;
Biological process	• regulation of cGMP metabolic process; • positive regulation of MAP kinase activity; • cGMP metabolic process; • blood coagulation; • positive regulation of cardiac muscle hypertrophy; • cGMP catabolic process; • negative regulation of T cell proliferation; • positive regulation of oocyte development; • metabolic process; • relaxation of cardiac muscle; • signal transduction; • negative regulation of cardiac muscle contraction;
	Sources:Amigo / QuickGO
RNA expression pattern
	More reference expression data
Orthologs
	8654
	242202
	ENSG00000138735
	ENSMUSG00000053965
	O76074
	Q8CG03
	NM_033437; NM_001083; NM_033430
	NM_153422
	NP_001074.2; NP_236914.2; NP_246273.2
	NP_700471.2
	Wikidata
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