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PDE5 is a dimeric enzyme that is composed of two identical 100 kD proteins. There are four known isoforms of PDE5 ( PDE5A 1-4 ) ACC . No : NM _ 03343I : these isoforms are products of a single gene and are formed by alternative splicing of mRNA . The enzymatic characteris- tics of the PDE5A1-3 appear to be quite similar although there may be some selectivity in their tissue distributions ; PDE5A3 is largely expressed in smooth muscle. The enzymatic properties of PDE5A4 have not been character- ized . Each of the monomers in PDE5 is a chimeric protein that contains two major functional domains that are approximately equal in size , i . e ., a catalytic domain ( C domain ) located in the more C-terminal portion of the protein and a regulatory domain ( R domain ) located in the more N-terminal portion. The single catalytic site located in the C domain is the target for sildenafil. The R domain of PDE5 contains allosteric cGMP-binding sites that contribute importantly to regulation of enzyme functions and to potency of these PDE5 inhibitors . However , the allosteric cGMP-binding sites in PDE5 are evolutionarily and biochemically distinct from that of the catalytic site . These sites are highly specific for cGMP : and do not interact with sildenafil. The catalytic site binds cGMP in a shallow pocket along the sur- face of the enzyme . When cGMP occupies this site , the cyclic phosphate bond of cGMP is brought into proximity with the catalytic machinery of the enzyme , which involves an array of amino acids and divalent cations including Zn2 +. This arrangement provides for the rapid hydrolysis of the cyclic phosphate bond of cGMP to form 5 ‘ -GMP , which has low affinity for the enzyme and rapidly dissociates from PDE5 . 5 ‘ -GMP is inactive in the cellular cGMP-signaling pathway . Other cellular phosphohydrolases do not hydrolyze the novel cyclic phosphate bond of eGMP or cAMP . Because the structure of sildenafil resembles that of eGMP , it can occupy the PDE5 catalytic site , thus blocking access to eGMP . In addition , sildenafil is stable and is not inactivated by the catalytic machinery ; nor is it metabolized significantly in the smooth muscle cell . For these reasons , occupation of the PDE5 catalytic site by sildenafil competitively inhibits eGMP breakdown since eGMP cannot gain access to the catalytic machinery . In the face of ongoing synthesis of eGMP in any tissue containing PDE5 , this will cause eGMP to accumulate and to increase cGMP signaling through PKG . In the penile corpora cavernosa , this contributes to improved erectile function . Although the C domain of PDE5 is the direct target of PDE5 inhibitors, functions of the R domain enhance the PDE5 inhibitor actions on the enzyme . Allosteric cGMP-binding is provided by sites in the R domain ; whether one or two eGMP molecules are bound per subunit is still unclear . In addition , there is a single consensus phosphorylation site for PKG or PKA near the N-terminus . Phosphorylation of this site activates PDE5 catalytic function and thereby provides for negative feedback regulation of cGMP levels. Phosphorylation of this serine is tightly controlled by cGMP levels since occupation of the PDE5 allosteric cGMP-binding sites is required for phosphorylation to occur , and the site is preferentially phosphorylated by PKG compared to PKA . Therefore , it is likely that the site is only phosphorylated when cGMP is elevated in the cell . When cGMP binds to the allosteric sites , cGMP is not degraded as it is in the catalytic site , but PDE5 enzyme functions are altered . Cyclic GMP binding to the allosteric sites in the R domain pro- duces a conformational change that exposes the serine allowing it to be rapid- ly phosphorylated , thereby increasing PDE5 catalytic activity. Cyclic GMP occupation of the allosteric sites also increases the affinity of the catalytic site for cGMP , thereby further activating PDE5 catalytic site func- tions. However , in the presence of a PDE5 inhibitor and ongoing syn- thesis of cGMP , cellular cGMP is elevated , which fosters increased binding of cGMP to the allosteric sites and phosphorylation of the serine by activated PKG ; as a result , the affinity with which PDE5 inhibitors bind at the catalytic site is increased . Therefore , due to its molecular mechanism , the potency of sildenafil is actually greater than would occur in the absence of the R domain . This property of the enzyme translates into greater clinical efficacy and poten- cy of sildenafil and other PDE5 inhibitors . Following ingestion of a PDE5 inhibitor tablet , any elevation of cGMP in smooth muscle cells should increase the avidity with which the PDE5 catalytic site binds that inhibitor . That is , the PDE5 inhibitor , by fostering increased binding of cGMP to PDE5 allosteric sites , stimulates its own efficacy and potency.

Viagra is used for:

Treating erectile dysfunction (ED). It may also be used for other conditions as determined by your doctor.

Viagra is a phosphodiesterase inhibitor. It works by helping to increase blood flow into the penis during sexual stimulation. This helps you to achieve and maintain an erection.

Do NOT use Viagra if:

• you are allergic to any ingredient in Viagra
• you have been advised by your doctor to avoid sexual activity because of heart problems
• you are taking nitrates (eg, isosorbide, nitroglycerin) in any form (eg, tablet, capsule, patch, ointment) or nitroprusside
• you use certain recreational drugs called “poppers” (eg, amyl nitrate, butyl nitrate)

Contact your doctor or health care provider right away if any of these apply to you.

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From the beginning, Viagra was a joke. You must have heard them. Viagra has been a big boon to stand-up comedians. Did you hear about the guy who took Viagra and got it stuck in his throat? He got a stiff neck. New Viagra eye drops make you look hard. In nursing homes, Viagra keeps male patients from rolling out of bed. Did you hear about the first death from an overdose of Viagra? A man took twelve pills and his wife died. Viagra is now being compared to Disneyland—a one-hour wait for a two-minute ride. Most of us are familiar with these one-liners. In 1998, they were delivered by our favorite talk show hosts and comedians. They were repeated by our friends, our relatives, and even our doctors. And they circulated over e-mail for years, it seemed. In our puritanical culture, the availability of a new erection pill and the social ramifications of this were, shall we say, slightly uncomfortable to talk about. But the idea of men of all ages taking pills and having erections as a result was easy to laugh about. And so we did. Because just like the news of Clinton’s affair months earlier, the existence of such a pill seemed both ludicrous and deeply serious, both enabling and frightening. Unlike news of Clinton’s affair, the Viagra phenomenon “penetrated” people’s daily lives in bedrooms and boardrooms. Viagra humor was one way to cope with the newness and awkwardness of Viagra in our lives, and all that went with it—including acknowledgment of erectile difficulties, awareness of medical risk, the idea of seniors as sexual beings, and the acceptance of sex for pleasure’s sake.
Actually, whether we felt like it or not, by 1998 Americans had already begun to transition into a new era in sex, medicine, and technological innovation. Numerous social changes at the end of the twentieth century paved the way for the emergence of .1 product like Viagra. These changes made it possible for many of us to see ourselves and our sex lives as “dysfunctional.” And they began the chain reaction that has resulted in industries and institutions dedicated to what we now call “sexual medicine” and “male enhancement.”
How did we get here? I believe that Viagra’s emergence in the late twentieth century can be distilled down to five shifting sets of social circumstances: medical expansion, scientific and technological innovation,  pharmaceutical deregulation and expansion,  cultural and demographic shifts in gender and aging, and  increasing scientific and popular attention to sexuality and sexual dissatisfaction. Together the factors made the Viagra phenomenon possible

In 1998, Viagra was first introduced to the world, and it is fair to say
that the world has not been the same since. The impact of this medication has been enormous, not just in the narrow area of treating erectile dysfunction (ED) for which it was approved, but also in the way we think of sex and sexuality, and even in the realm of relationships between men and women.
Millions of men in the United States have tried Pfizer’s wonder drug, sildenafil, better known as Viagra, and there are thus millions of women who have also seen its effects on their husbands, boyfriends, and lovers. Many other millions of men and women wonder about whether Viagra can offer a solution lor their own sexual and emotional problems or tor the problems ot their partners. We human beings are sexual animals, after all. And unfortunately, our sex lives are not always the way we want them to be. So it’s no surprise that when sex goes sour, relationships suffer in other ways as well.
As a practicing urologist in Boston on the faculty of Harvard Medical School, 1 have treated many men with sexual problems and many couples who have sexual issues in their relationships. I knew about the development of Viagra before it was introduced CO the public and was involved in its clinical application as soon as the Food and Drug Administration approved the new drug. I had anticipated using Viagra primarily for older patients with well-established erectile dysfunction, but it didn’t take long before I realized that 1 had completely underestimated the huge extent of public interest in trying this new medication. For example, shortly after Viagra became available, an orthopedic surgeon came up to me in the surgeons’ lounge as I was having a cup of coffee between operations.”Tell me,” he said, “what shouIJ I know about prescribing Viagra? I have a patient who I think should try it.” (more…)

Yes, Viagra is new—and news—but impotence istn’t. In a society that places a high value on well-toned bodies, virility, robust health, and youth. the inability to perform sexually is a disorder to which very few Ameri­can men will admit. In fact, in the Catholic church an annulment—the dissolution of a marriage—is granted only in the rarest of circumstances; impotence is one. Across the country, in some states impotence is viewed with such disdain that it is considered grounds for divorce. Still, despite the havoc it wreaks, for centuries major medical research centers around the world have ignored impotence. Incredibly, in fact, impotence—more properly known as erectile dysfunction, or E.D.—is probably the last stigmatized condition to receive recognition and study, decades after menopause, alcoholism, depression, and obsessive-compulsive disorder saw the light of day. Why? Some say the belief that impotence is “all in your head” was enough to keep any serious medical investigation at bay; others believed it was the excruciatingly personal dimension of the dis­order that discouraged investigation; still others felt it wasn’t a signifi­cant problem. Not significant, you say? Well, try this on for size: Worldwide, it is estimated that approximately 100,000,000 men suffer from E.D.—and that’s just an estimate! But, unfortunately, even today, less than 10 percent of these men seek treatment. (more…)