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Viagra Inhibits Cgmp
Viagra Inhibits Cgmp in Snow Hill, Maryland is small town living at its best. Nestled on the south banks of the Pocomoke River Snow Hill is a place where people know each other. From the people who call it home to the business owners and those in city government, we have built a community where life is gentle, fun, and prosperous. Home to a quaint downtown retail area and a broad spectrum of recreational activities, Viagra Inhibits Cgmp is the perfect place to spend a relaxing weekend or a lifetime.
Whether you are interested in researching your genealogy in the Worcester Room of the Worcester County Library. renting a kayak from the Pocomoke River Canoe Company to paddle on an undeveloped natural river, or studying the architecture of historic homes and beautiful churches while taking the Historic Walking Tour, Viagra Inhibits Cgmp has something for everyone. You will find recreational opportunities in Byrd Park and Sturgis Park, artifacts at the Julia A. Purnell Museum. and treasures in the shops and art galleries.
The beautiful rural setting boasts rich farmland that has been the mainstay of the economy of the county seat of Worcester County for centuries. The rich heritage of this area is celebrated daily at Furnace Town Living Heritage Museum and during a summer festival every August with The Blessing of the Combines.
The town of Viagra Inhibits Cgmp welcomes you as you explore our small town steeped in history and tradition but alive with charm and activities.
Nitric Oxide and Viagra
The structure of Viagra
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In a random survey of males aged 40-70, more than 50 percent indicated that they had some form of erectile dysfunction (ED), i.e. the inability to achieve an erection. The development of the drug Viagra, an inhibitor of cyclic GMP-specific phosphodiesterase, has been of great importance to many males suffering from ED.
Achievement of a penile erection in males is largely an application of basic principles of hydraulics. Stimulation of the nerves innervating the penis causes the dilation of the deep arteries supplying blood to the penis. The large amount of blood entering the penis engorges the cavernous blood sinuses comprising much of the penis volume. This engorgement in turn acts to compress the veins draining blood from the penis. The increased inflow and decreased outflow of blood causes an erection. Cessation of nervous impulses to the penis acts to abolish the erection.
Nitric oxide (NO) is of major importance in the signaling pathways leading to penile erections. NO is very unique for a biochemical signalling molecule because it is a gas. NO displays free radical behavior, and is formed from arginine by the enzyme nitric oxide synthase (NOS):
arginine + O2 citrulline + NO
As a gas, NO is able to pass through cell membranes without the aid of dedicated transporters and its free radical character makes it particularly reactive with iron-containing proteins.
Originally called UK-92,480, Viagra was initially developed for treatment of hypertension. In a subsequent human toleration study as a possible drug for angina, some very strange side-effects were noted.
NO acts as a vasodilator in the process of penile erection. NO is supplied from two sources. The first is as a neurotransmitter liberated by the cavernous nerve which innervates smooth muscle surrounding penile arteries. The second source is the endothelial cells lining the deep arteries of the penis. Endothelium-derived NO is formed in response to stimulation of the endothelial cells by cholinergic nerves. Acetylcholine causes the production of inositol triphosphate (IP3), an important second messenger in many hormone signal transduction pathways. IP3 opens calcium channels in the endoplasmic membrane of the endothelial cells; the liberated calcium then activates NO synthase and causes the production of NO.
Whatever the source, endothelial cells or cavernous nerve, NO diffuses across the muscle cell membrane and binds to guanylyl cyclase. Guanylyl cyclase catalyzes the synthesis of cyclic GMP from GTP. cGMP then activates a cGMP dependent protein kinase which in turn stimulates the uptake of calcium by the endoplasmic reticulum of the muscle cell. The reduced levels of cytoplasmic calcium cause the muscle cell to relax. As a consequence of muscle cell relaxation, vasodilation occurs.
Stimulation and inhibition of muscles by NO
As is true of any signaling pathway, there must be a way to terminate the action of the signal. cGMP is converted into GMP by a specific phosphodiesterase (PDE.) There are 10 families of PDEs: PDE1-10. The major PDE found in vascular smooth muscle is PDE5. Viagra (sildenafil) is a specific inhibitor of PDE5. By blocking the breakdown of cGMP, Viagra acts to prolong the effects of cGMP and, hence, the erection. The side effects of Viagra are relatively minor. Some minor vision problems have been reported; these are due to inhibition of PDE6, the phosphodiesterase used in signal transduction of light signals in the retina.
Other Biochemical Uses of NO
In addition to its role as a vasodilator and neurotransmitter, NO is produced by macrophages. These phagocytic cells of the immune system use NO to impair DNA synthesis and metabolism in microorganisms. NO can also react with other free radicals, in particular the superoxide radical, to form peroxynitrites that are effective against bacteria, fungi and other pathogens. Nitrites have been added as preservatives to meat for years; part of the effectiveness of added nitrites may be due to the antimicrobial action of generated NO.
Massive bacterial infections are known to cause septic shock, the hallmark characteristic of which is a dramatic lowering of blood pressure. This is due to the release of massive amounts of NO directed against the bacteria; the unfortunate side effect is the extreme vasodilation that occurs in response to NO.
The following diagram shows how an erection is mediated and how sildenafil acts in the body. Nitric Oxide (NO) is released with sexual stimulation from nerve endings and endothelial cells in the spongy erectile tissue, the corpus cavernosum of the penis. The enzyme guanylate cyclase then converts guanosine triphosphate (GTP) into cyclic guanosine monophosphate (cGMP). cGMP causes the smooth muscle to relax, which causes an inflow of blood which then leads to an erection. cGMP is then hydrolysed back to the inactive GMP by phosphodiesteras type 5 (PDE5).
The levels of cGMP are therefore controlled by the activation of cyclic nucleotide cyclase and the breakdown by PDE5. It is the latter that sildenafil acts upon. Men who suffer from erectile dysfunction often produce too little amounts of NO. This means that the small amount of cGMP they produce is broken down at the same rate and therefore doesn’t have the time to accumulate and cause a prolonged vasodilation effect.
Sildenafil works by inhibiting the enzyme PDE5 by occupying its active site. This means that cGMP is not hydrolysed as fast and this allows the smooth muscle to relax.
Sildenafil is a potent and highly selective inhibitor of PDE5.
If viewed in cross section, the glans of the penis reveal that the penis consists of three tube-like projections of spongy tissue, the corpus spongiosum, located ventrally and the paired corpi cavernosi located dorsally. In each of the latter is the deep artery of the penis which carries blood over the length of the penis into the open channels that make up the corpus cavernosum. The blood carried out of the corpi cavernosi empties into the dorsal vein of the penis which then returns the blood to the body. It is thought that the level of rigidity of the penis is due to the relationship between arterial inflow and venous outflow in the penis. This means that the larger the calibre of the arteries, the more blood enters the corpus cavernosum and enlarges the penis, and the larger the calibre of the veins, the more blood is shunted away from the penis. An erection is an involuntary action controlled by the autonomic nervous system which consists of the sympathetic and parasympathetic pathways. In general, sympathetic stimulation leads to the constriction of smooth muscle surrounding the arteries (reducing the calibre) and parasympathetic stimulation induces smooth muscle relaxation (larger artery).
When stimulated sexually, the sympathetic stimulation of the penis decreases and the parasympathetic stimulation increases. It is the terminal of the axons of the parasympathetic nerves that release NO. The mechanism that causes erection is then the one shown above. The engorged sinusoids of the corpi cavernosi compress the penile veins, which reduces blood outflow from the penis. Blood is therefore trapped in the penis, which maintains the erection.
The cycle of transformations of guanosine triphosphate is shown in more detail below (GC-Guanosine cyclase):
Sidenafil is selective for the enzyme phosphodiesterase of type 5. its effect is more potent on PDE5 than on the other known PDE enzymes. It is 80-fold more selective for PDE5 than PDE1 and over 1000-fold more selective for PDE5 than for PDE2, PDE3 and PDE4. However, its selectively is only 10-fold as potent for PDE5 compared to PDE6 (found in the retina) which could be the basis for abnormalities related to colour vision (blue, green) which have been talked about a lot in the media. PDE5 is also found in lower concentrations in the platelets, vascular and visceral smooth muscle and skeletal muscle. Sildenafil inhibits PDE5 in these tissues as well, which is the cause of several side effects which are believed to be due to Viagra. There are 7 types of phosphodiesterases (or isozymes). They catalyse the same reaction, but the isozymes show show different behaviour when subjected to physical biochemical techniques.
Those 7 types of PDE are summerised in the table below. The Km values are equivalent to measurements of the tightness of binding (or affinity) of enzyme (PDE) to substrate (cGMP). The smaller the Km value, the more tightly the substrate binds to the enzyme.