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.
||brain, testis, sperm, coronary artery,
lung, heart, pancreas
||brain, adrenal gland, heart
||T lymphocytes, macrophages, platelets,
smooth muscle, heart, adipose tissue
||monocytes, leukocytes, central nervous
||lung, smooth muscle, platelets,
||retina of eye
||high affinity, cAMP specific
Because of the way in which sildenafil acts, it has no effect in the absence
of sexual stimulation when used at the recommended doses.
The enzyme with which sildenafil interacts, phosphodiesterase type 5, is represented
below, along with cGMP which is hydrolysed by PDE5.