CGMP specific phosphodiesterase type 5
Encyclopedia
cGMP-specific phosphodiesterase type 5 is an enzyme
from the phosphodiesterase
class. It is found in various tissues, most prominently the corpus cavernosum
and the retina
.
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 cGMP
hydrolysis.
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.
Sildenafil
, vardenafil
, and tadalafil
are PDE5 inhibitors that are significantly more potent and selective than zaprinast
and other early PDE5 inhibitors.
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 colon
ic 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.
) by Pfizer
, Levitra (vardenafil
) by Bayer
Pharmaceutical and Glaxo-Smith-Kline-Beecham
/Schering Plough, and Cialis (tadalafil
) by Lilly
-ICOS
.
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 etiology of their erectile dysfunction before instituting treatment since the disease process may be more serious than the symptoms, i.e., the ED itself. In some cases, treatment of the primary disease may in fact resolve the sexual dysfunction
. However, most men have a cause for their ED as noted by the history and physical examination and the laboratory tests and PDE-5 inhibitors are the first line of choice.
Particular caution should be used when prescribing PDE5 inhibitors for erectile dysfunction for patients receiving 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
.
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
.
(FDA) approved Viagra on March 27, 1998. 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. 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.
Studies have shown that tadalafil is more selective for PDE5 over PDE6 than sildenafil or vardenafil.
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
from the phosphodiesterase
Phosphodiesterase
A phosphodiesterase is any enzyme that breaks a phosphodiester bond. Usually, people speaking of phosphodiesterase are referring to cyclic nucleotide phosphodiesterases, which have great clinical significance and are described below...
class. It is found in various tissues, most prominently the corpus cavernosum
Corpus cavernosum penis
The corpus cavernosum penis is one of a pair of sponge-like regions of erectile tissue which contain most of the blood in the penis during penile erection...
and the retina
Retina
The vertebrate retina is a light-sensitive tissue lining the inner surface of the eye. The optics of the eye create an image of the visual world on the retina, which serves much the same function as the film in a camera. Light striking the retina initiates a cascade of chemical and electrical...
.
The phosphodiesterase (PDE) isozyme
Isozyme
Isozymes are enzymes that differ in amino acid sequence but catalyze the same chemical reaction. These enzymes usually display different kinetic parameters Isozymes (also known as isoenzymes) are enzymes that differ in amino acid sequence but catalyze the same chemical reaction. These enzymes...
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 cGMP
Cyclic guanosine monophosphate
Cyclic guanosine monophosphate is a cyclic nucleotide derived from guanosine triphosphate . cGMP acts as a second messenger much like cyclic AMP...
hydrolysis.
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.
Sildenafil
Sildenafil
Sildenafil citrate, sold as Viagra, Revatio and under various other trade names, is a drug used to treat erectile dysfunction and pulmonary arterial hypertension . It was originally developed by British scientists and then brought to market by the US-based pharmaceutical company Pfizer...
, vardenafil
Vardenafil
Vardenafil is a PDE5 inhibitor used for treating erectile dysfunction that is sold under the trade names Levitra and Staxyn.-History:...
, and tadalafil
Tadalafil
Tadalafil is a PDE5 inhibitor, currently marketed in pill form for treating erectile dysfunction under the name Cialis; and under the name Adcirca for the treatment of pulmonary arterial hypertension...
are PDE5 inhibitors that are significantly more potent and selective than zaprinast
Zaprinast
Zaprinast was an unsuccessful clinical drug candidate that was a precursor to the chemically-related PDE5 inhibitors, such as sildenafil , 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,...
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 catalysisCatalysis
Catalysis is the change in rate of a chemical reaction due to the participation of a substance called a catalyst. Unlike other reagents that participate in the chemical reaction, a catalyst is not consumed by the reaction itself. A catalyst may participate in multiple chemical transformations....
imply the existence of two PDE5 conformers, and results of native gel electrophoresis
Gel electrophoresis
Gel electrophoresis is a method used in clinical chemistry to separate proteins by charge and or size and in biochemistry and molecular biology to separate a mixed population of DNA and RNA fragments by length, to estimate the size of DNA and RNA fragments or to separate proteins by charge...
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
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
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 colon
Colon (anatomy)
The colon is the last part of the digestive system in most vertebrates; it extracts water and salt from solid wastes before they are eliminated from the body, and is the site in which flora-aided fermentation of unabsorbed material occurs. Unlike the small intestine, the colon does not play a...
ic 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
Muscle
Muscle is a contractile tissue of animals and is derived from the mesodermal layer of embryonic germ cells. Muscle cells contain contractile filaments that move past each other and change the size of the cell. They are classified as skeletal, cardiac, or smooth muscles. Their function is to...
. 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.
PDE5-inhibiting drugs
There are now three oral erectile dysfunction (ED) drugs: Viagra (sildenafilSildenafil
Sildenafil citrate, sold as Viagra, Revatio and under various other trade names, is a drug used to treat erectile dysfunction and pulmonary arterial hypertension . It was originally developed by British scientists and then brought to market by the US-based pharmaceutical company Pfizer...
) by Pfizer
Pfizer
Pfizer, Inc. is an American multinational pharmaceutical corporation. The company is based in New York City, New York with its research headquarters in Groton, Connecticut, United States...
, Levitra (vardenafil
Vardenafil
Vardenafil is a PDE5 inhibitor used for treating erectile dysfunction that is sold under the trade names Levitra and Staxyn.-History:...
) by Bayer
Bayer
Bayer AG is a chemical and pharmaceutical company founded in Barmen , Germany in 1863. It is headquartered in Leverkusen, North Rhine-Westphalia, Germany and well known for its original brand of aspirin.-History:...
Pharmaceutical and Glaxo-Smith-Kline-Beecham
GlaxoSmithKline
GlaxoSmithKline plc is a global pharmaceutical, biologics, vaccines and consumer healthcare company headquartered in London, United Kingdom...
/Schering Plough, and Cialis (tadalafil
Tadalafil
Tadalafil is a PDE5 inhibitor, currently marketed in pill form for treating erectile dysfunction under the name Cialis; and under the name Adcirca for the treatment of pulmonary arterial hypertension...
) by Lilly
Eli Lilly and Company
Eli Lilly and Company is a global pharmaceutical company. Eli Lilly's global headquarters is located in Indianapolis, Indiana, in the United States...
-ICOS
ICOS
Icos Corporation was the largest biotechnology company in the U.S. state of Washington before it was sold to Eli Lilly and Company in 2007. Co-founded in 1989 by George B. Rathmann, a pioneer in the industry and Chief Executive Officer and co-founder of Amgen, Icos focused on the development of...
.
For all practical purposes, these drugs including Viagra, Levitra, and Cialis are the first line of oral treatment
Pharmacotherapy
Pharmacotherapy is the treatment of disease through the administration of drugs. As such, it is considered part of the larger category of therapy....
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 etiology of their erectile dysfunction before instituting treatment since the disease process may be more serious than the symptoms, i.e., the ED itself. In some cases, treatment of the primary disease may in fact resolve the sexual dysfunction
Sexual dysfunction
Sexual dysfunction or sexual malfunction refers to a difficulty experienced by an individual or a couple during any stage of a normal sexual activity, including desire, arousal or orgasm....
. However, most men have a cause for their ED as noted by the history and physical examination and the laboratory tests and PDE-5 inhibitors are the first line of choice.
Particular caution should be used when prescribing PDE5 inhibitors for erectile dysfunction for patients receiving protease inhibitor
Protease inhibitor
Protease inhibitor can refer to:* Protease inhibitor : a class of medication that inhibits viral protease* Protease inhibitor : molecules that inhibit proteases...
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
Hypotension
In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...
, visual changes, and priapism
Priapism
Priapism is a potentially harmful and painful medical condition in which the erect penis or clitoris does not return to its flaccid state, despite the absence of both physical and psychological stimulation, within four hours. There are two types of priapism: low-flow and high-flow. Low-flow...
.
PDE5-inhibiting drugs are very effective. PDE5 inhibitor drugs appear to work in men regardless of why they have erectile dysfunction — including vascular disease
Disease
A disease is an abnormal condition affecting the body of an organism. It is often construed to be a medical condition associated with specific symptoms and signs. It may be caused by external factors, such as infectious disease, or it may be caused by internal dysfunctions, such as autoimmune...
, nerve problems, and even psychological causes. PDE5-inhibiting drugs can cause a number of minor side-effects
Adverse drug reaction
An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...
, including headache
Headache
A headache or cephalalgia is pain anywhere in the region of the head or neck. It can be a symptom of a number of different conditions of the head and neck. The brain tissue itself is not sensitive to pain because it lacks pain receptors. Rather, the pain is caused by disturbance of the...
, lightheadedness, dizziness
Dizziness
Dizziness refers to an impairment in spatial perception and stability. The term is somewhat imprecise. It can be used to mean vertigo, presyncope, disequilibrium, or a non-specific feeling such as giddiness or foolishness....
, flushing, nasal congestion, and changes in vision
Visual perception
Visual perception is the ability to interpret information and surroundings from the effects of visible light reaching the eye. The resulting perception is also known as eyesight, sight, or vision...
.
Viagra (sildenafil)
Viagra was the first PDE5 inhibitor on the market. The Food and Drug AdministrationFood and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA) approved Viagra on March 27, 1998. Viagra contains sildenafil citrate packaged as a pill
Pill
Pill or The Pill may refer to:* Pill , referring to anything small and round for a specific dose of medicine. The term is used colloquially in several ways:** A tablet or capsule which replaced dosing via pill...
. Discovered by Pfizer
Pfizer
Pfizer, Inc. is an American multinational pharmaceutical corporation. The company is based in New York City, New York with its research headquarters in Groton, Connecticut, United States...
, 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
Human sexuality
Human sexuality is the awareness of gender differences, and the capacity to have erotic experiences and responses. Human sexuality can also be described as the way someone is sexually attracted to another person whether it is to opposite sexes , to the same sex , to either sexes , or not being...
stimulation leads to increased levels of cGMP in the corpus cavernosum, which leads to better erections. Without sexual stimulation
Sexual stimulation
Sexual stimulation is any stimulus that leads to, enhances and maintains sexual arousal, and may lead to ejaculation and/or orgasm...
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. 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
Retina
The vertebrate retina is a light-sensitive tissue lining the inner surface of the eye. The optics of the eye create an image of the visual world on the retina, which serves much the same function as the film in a camera. Light striking the retina initiates a cascade of chemical and electrical...
. This lower selectivity is thought to be the basis for abnormalities related to color vision observed with higher doses or plasma levels.
Levitra (vardenafil)
Levitra was the second oral PDE-5 inhibitor for erectile dysfunction to be FDA approved in August 2003.Cialis (tadalafil)
Cialis has an estimated effective duration of 36 hours; however, there are studies showing high efficacy up to 100 hours.Studies have shown that tadalafil is more selective for PDE5 over PDE6 than sildenafil or vardenafil.