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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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