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Introduction
Penile erection is a neurovascular event modulated by psychological and hormonal factors. This brief review will
describe the functional response for erection with special emphasis on neural components. The topic of erectile dysfunction
will be considered and finally, the recent advances in the treatment of erectile dysfunction will be discussed.
Physiology of penile erection Penile erection involves
a complex interaction between the central nervous system and local factors. The penis is innervated by autonomic
(sympathetic and parasympathetic nerves) and somatic nerve fibers. Overall, erection is a neurovascular event modulated by
psychological and hormonal factors. Upon sexual stimulation, neurotransmitters are released from the cavernous nerve
terminals and also vasoactive relaxing factors from the endothelial cells of the penis, which relax arteries and arterioles
supplying the erectile tissue, increasing the penile blood flow. Concomitantly, relaxation of the trabecular smooth muscle
increases the compliance of the sinusoids, resulting in an
engorgement of the penis with blood. Therefore, penile
erection takes place when both dilation of the penile arteries and
relaxation of the erectile tissue occur. Because the erectile
tissue is surrounded by the tunica albuginea, a tissue that
does not distend easily, the increased blood flow to the
penis increases not only the penile volume but also intrapenile
pressure. This distension causes mechanical compression
of the emissary veins, which impedes their ability to drain
blood and thereby results in penile rigidity. Detumescence
is the result of a cessation of neurotransmitter release, the
breakdown of second messengers or sympathetic discharge
during ejaculation. Contraction of the trabecular smooth
muscle restores the venous outflow, the trapped blood is
expelled, and flaccidity returns[1].
Peripheral regulation of penile erection
The nerves and endothelium of sinusoids and vessels in the penis
produce and release transmitters and modulators, which
interact in their control of the contractile state of the penile smooth
muscles. The different structures of the penis are
functionally regulated by efferent sympathetic and parasympathetic
nerves, and the major neurotransmitters in postganglionic
fibers are norepinephrine and acetyl-choline, respectively.
Sympathetic input is antierectile, whereas parasympathetic
and somatic input are proerectile. Both sympathetic and
parasympathetic fibers reach the pelvic or inferior hypogastric
plexus where autonomic input to the penis is integrated; the
cavernous nerves originate from this plexus, and innervate
the helicine arteries and erectile tissue. Intracavernous
nerves are encased in fibrous tissue, which prevents their
compression during an erection. The dorsal penile nerves,
branches of the pudendal nerves, and the ilioinguinal nerve
also innervate the penis. These nerves provide sensory
input from the glans penis and skin, and penile
root[2].
About a decade ago, several investigators provided
evidence for functional roles of nonadrenergic noncholinergic
(NANC) inhibitory and excitatory nerves, containing
transmitters and transmitter/modulator-generating enzymes, such
as nitric oxide synthase (NOS) and heme oxygenases (HO).
NANC transmitters/modulators may be found in adrenergic
and cholinergic nerves[3], which should make it more
meaningful to define nerve populations based on their transmitter
content. Although various polypeptides have been regarded
as inhibitory neurotransmitters[3-5], the discovery that nitric
oxide (NO) functions as a mediator synthesized in and
released from the vascular
endothelium[6,7] and as a neurotransmitter in inhibitory nerves innervating the penis
represented a breakthrough in the comprehension of the
neurophysiological basis of erection. Figure 1 demonstrates the
experimental protocols for establishing the role of NO as a
neurotransmitter in the erectile response of the rat penis.
Erectile function and nitric oxide
Synthesis of NO and the consequences of NO binding to
soluble guanylyl cyclase is essential for the erectile process.
Identification of NO to be a neurotransmitter has been
achieved by the use of NOS inhibitors in the corpus
cavernosum of the penis[8]. NO, an inorganic and labile
molecule, is liberated immediately upon synthesis by
neuronal NOS (nNOS) from substrate L-arginine. To date, it is
widely accepted that NO is the main neurotransmitter
mediating penile erection, which is released during NANC
neuro-transmission. Upon its release, NO diffuses locally into
adjacent smooth muscle cells of the corpus cavernosum and
binds with its physiologic receptor, soluble guanylyl
cyclase[9]. The enzyme becomes activated following this
interaction whereupon the enzyme catalyzes the conversion
of guanosine triphosphate (GTP) to 3',5'-cyclic guanosine
monophosphate (cGMP). This cyclic nucleotide then serves
as a second-messenger function by activating protein
kinase G, alternatively known as cGMP-dependent protein
kinase I (cGKI), which in turn exerts actions involving ion
channels and contractile regulatory proteins that regulate
the contractile state of corporal smooth muscle. The
consequence is the decay in cytosolic calcium concentration and
relaxation of the smooth muscle, resulting in dilation of
arterial vessels and increased blood flow into the sinuses of the
corpora cavernosa[1,10]. Thus, at the onset of sexual
stimula-tion, neuronal NO induced by neuronal depolarization and
endothelial NO largely generated in response to shear forces
brought on by increased blood flow in the penis serve,
respectively, as a neurotransmitter initiating the erectile
process and as a paracrine factor sustaining the full physiologic
response. On the other hand, phosphodiesterase-5 (PDE5)
operates in this signal transduction pathway to restrain
erectile effects. This enzyme is predominantly expressed in the
corpus cavernosum[11] and functions as a cGMP-specific
phosphodiesterase, which catalyzes the hydrolysis of cGMP
to GMP[12,13]. Accordingly, in the penis, the enzyme controls
cGMP accumulation caused by NO signaling and consequently limits its relaxant actions.
Erectile dysfunction
Erectile dysfunction (ED) is defined as the persistent
inability to achieve or maintain an erection sufficient for
satisfactory sexual performance[14]. ED is highly prevalent and
by current estimates, 30 million men in the US and 150 million
men worldwide are affected[15] and occurs in
19%-64% of men aged 40_80 years, both in developing and industrialized
countries. Emotional, physical, and medical factors
contribute to ED, and this condition may also be a symptom of
various chronic diseases. ED may affect total health,
rela-tionships, and overall quality of
life[16,17]. Organic causes are now understood to constitute more than 80% of clinical
presentations. Associations include diabetes mellitus,
cardiovascular disease, hyperlipidemia, cigarette smoking and
obesity, indicating their significance as a public health
problem. Furthermore, the disorder is correlated with anxiety,
depression, interpersonal relationship difficulties and even
violence[18].
The exact etiological mechanisms responsible for
abnormal erectile response have yet to be determined. However,
organic and psychogenic factors may cause alterations in
the NO/cGMP pathway and impair smooth muscle relaxation
and/or increase smooth muscle contraction, thereby
resulting in ED. Ultimately, the treatment of ED has been
revolutionized from only surgical options (penile prostheses or
revascularization) to intracavernosal and intraurethral
administered agents [eg, prostaglandin E1 (PGE1), papaverine,
phentolamine] that paved the way to an effective oral therapy
such as PDE5 inhibitors. The clinical efficacy of oral agents
such as apomorphine, phentolamine, sildenafil, tadalafil, and
vardenafil represent the beginnings of noninvasive
pharmacological treatment for ED.
It is widely known that ED is associated with diseases
reported to be related with decreased NO bioavailability such
as arterial hypertension, hypercholesterolemia and diabetes.
However, a recent study showed that ED appears in
spontaneously hypertensive rats before they become hypertensive,
suggesting that ED might be a marker for
hypertension[19]. Also, it was recently demonstrated an impairment in both
endothelium-dependent and -independent dilation in patients
with ED, who did not present diseases such as coronary
artery disease or diabetes mellitus. It was suggested that ED
is associated with an abnormal function in the NO-cGMP
pathway even in the absence of any apparent
cardiovascular or metabolic disease[20]. Besides its direct effects in the
cavernosal smooth muscle, NO also contributes to the
maintenance of the erectile state by inhibiting contractile
mechanisms involving noradrenaline release, reactive oxygen
species (ROS) formation and Rho-kinase activity, thus favoring
the corpus cavernosum relaxation.
Treatment of erectile dysfunction
In the last decade, even with the introduction of
orally-administrated PDE5 inhibitors, the search for new drugs for
the treatment of erectile dysfunction has been extensive.
Since the discovery of NO as the main neurotransmitter
mediating penile erection, several studies regarding the role of
NO/cGMP pathway in the erectile function have been
performed. Both the endothelium and the NANC nerves of
the corpus cavernosum serve as the source of NO, and thus,
more than one isoform of NOS is involved. Several
investigators have demonstrated the presence of nNOS in the
cavernous nerves and their terminal endings within the corpora
cavernosa, as well as in the branches of the dorsal penile
nerves and nerve plexuses in the adventitia of the deep
cavernous arteries[9,21_26]. In human corpus cavernosum, nNOS
is present in nerve fibers innervating the cavernous body
and cavernosal arteries whereas eNOS is largely found in
the endothelial cells covering the cavernous spaces and
helicine arteries but not in the trabecular smooth muscle
cells[27]. Given the importance of NOS in the generation of
NO, NOS activity and expression represents an important
factor to be investigated. It is known that the activity of
constitutive NOS is completely dependent on calcium,
calmodulin and NADPH and addition of tetrahydrobiopterin
(BH4) increases NOS activity by approximately
30%[28]. Furthermore, it was recently demonstrated that the
BH4,
applied systemi-cally, improves erectile
function[29], suggesting that cofactors for NOS also might be important targets in
the treatment of erectile dysfunction.
Similarly, several studies have shown that ROS
generation decreases NO bioavailability, impairing the erectile
function[30]. However, in the corpus cavernosum of
streptozoto-cin-induced diabetic mice, vitamin E and sodium selenate
partially reversed the endothelial dysfunction and the
impairment of neurogenic relaxation[31]. Similarly, ascorbic
acid also prevented the impaired relaxation of acetylcholine
observed in middle aged non-diabetic and diabetic
rats[32], suggesting that decreased oxidative stress increases NO
bio-availability improving the erectile function. Also, physical
training is shown to reduce ROS generation and to raise
NOS gene expression and activity. Indeed, neurogenic
relaxation elicited by electrical field stimulation as well as the
relaxant response evoked by exogenous NO were increased
in rats submitted to endurance training, demonstrating that
physical training improves the NO/cGMP signaling pathway,
and thus the erectile response[33,34]. Taken together, these
data show an improvement of erectile function likely related
to a decreased ROS generation.
Since the primary synthesis of cGMP, driven by NO
production and release during sexual arousal, is a key to the
mechanism for erection, other means to achieve an
enhancement of NO responses is represented by the use of PDE5
inhibitors, such as sildenafil, vardenafil and tadalafil. These
drugs target PDE5 and inhibit the hydrolysis of cGMP, thus
preserving cGMP and permitting the cyclic nucleotide to
activate cGKI to a greater extent than at baseline conditions
such that corporal smooth muscle relaxation is enhanced.
Their precise mode of action is to bind to the catalytic
domain of PDE5 blocking substrate degradation. However,
the efficacy of the PDE5 inhibitor, sildenafil, in the
relaxa-tion of the corpus cavernosum is decreased when NOS is
blocked[35]. Recently, a novel NO-donating derivative of
sildenafil, NCX 911, was developed and showed to improve
the relaxation induced by carbachol and decrease the
superoxide formation compared to sildenafil citrate, in the corpus
cavernosum of hypercholesterolemic
rabbits[36]. Also, it was demonstrated that the potency of this compound in the
corpus cavernosum is not altered when the synthesis of NO is
inhibited by L-NAME[35], suggesting that a combination of a
NO-releasing compound with a PDE5 inhibitor, might be a
more interesting tool for the treatment of ED.
Another pathway that has been associated to ED and
extensively investigated is the RhoA/Rho-kinase pathway,
which mediates Ca2+ sensitization in the penile circulation
and maintains the penis in the flaccid state. Indeed, it was
recently demonstrated that intraperitoneal administration of
H-1152, a Rho-kinase inhibitor, enhanced the erectile
response produced by stimulation of the cavernous
nerve[37]. Futhermore, the ED observed in aged rats or in the
vasculo-genic model of ED is likely associated to an increased
RhoA/Rho-kinase pathway activity[38_40]. Further, it was shown
that the chronic treatment with fasudil, a Rho-kinase
inhibitor administrated orally, prevented the impaired erectile
function by reversing the increased RhoA/Rho-kinase activity
seen in vasculogenic model of ED[40]. Similarly, the impaired
corpus cavernosum pressure observed in castrate model of
ED, was restored by inhibiting this
pathway[41]. Taken together, these data show that the RhoA/Rho-kinase
pathway interferes with the NO/cGMP pathway and also might
represent an important target in the treatment of the erectile
dysfunction.
All of these observations indicate that, although several
studies have been searching new approaches for the
treatment of ED, it seems that increase in NO bioavailability and
consequent improvement of the corpus cavernosum relaxation, still represents the main target for the treatment of
ED.
Concluding remarks
There is a broad range of evidence indicating that NANC
neurotransmission has a vital role in mediating penile
erection via a NO/cGMP mechanism. Continuous advances in
our understanding of the physiology of penile erection
should help to elucidate further the mechanisms involved in
the pathophysiology of ED, and ultimately define alternate
therapeutic strategies to preserve this signaling pathway.
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