eau-ebu update series 4 (2006) 96–108

available at www.sciencedirect.com
journal homepage: www.europeanurology.com

Physiology of Erectile Function: An Update on Intracellular

Molecular Processes§

Annamaria Morelli a,*, Sandra Filippi b, Linda Vignozzi a, Rosa Mancina a, Mario Maggi a
a
Andrology Unit, Department of Clinical Physiopathology, University of Florence, Florence, Italy
b
Interdepartmental Laboratory of Functional and Cellular Pharmacology of Reproduction, Departments of Pharmacology and
Clinical Physiopathology, University of Florence, Florence, Italy

Article info Abstract

Keywords: Objectives: To provide a comprehensive update of current knowledge con-

Erectile function cerning the molecular mechanisms underlying the erectile physiology.
Penile smooth muscle tone Methods: Results from numerous investigations, including both basic and
NO/cGMP signalling clinical studies, have been considered. In particular, we pointed out the
RhoA/ROK pathway advances concerning the peripheral control of erection that ultimately
PDE5 influence the functional state of the penis.
Androgens Results: Numerous neurotransmitters and endothelial factors modulate
Erectile dysfunction the penile vasculature and smooth muscle tone of corpora cavernosa in
the penis. The regulation of adequate intracellular calcium levels repre-
sents the key determinant of the smooth muscle tone. Following the sexual
stimulation, the activation of smooth muscle relaxation in the penis is
mainly mediated by nitric oxide (NO), which acts via cyclic guanosine
monophosphate (cGMP)-mediated intracellular signalling. The pro-erectile
NO/cGMP pathway is coupled to the anti-erectile RhoA/Rho-kinase calcium-
sensitizing pathway, which was recently highlighted as another important
regulator of the erectile function. In the last decade, the enzyme phospho-
diesterase 5 (PDE5), critically involved in the degradation of cGMP and thereby
in the maintenance of penile detumescence, has gained attention as target
enzyme of the most used drugs (PDE5 inhibitors) for the treatment of erectile
dysfunction. Moreover, androgens play an important role in peripheral
regulation of erection, acting positively either on the enzyme which synthe-
sizes NO (NOS), and on that involved in the degradation of cGMP (PDE5).
Conclusion: The recent advances added to new insights into our knowledge
of erectile physiology and leaded to the improvement in the clinical man-
agement of men affected by erectile dysfunction.
# 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved.

§
In this article, we review the physiological mechanisms that regulate penile erection.
Particular emphasis is given to those intracellular molecular processes involved in regula-
tion of penile smooth muscle tone, including signaling pathways leading to contraction and
relaxation of erectile tissue.
* Corresponding author. Andrology Unit, Department of Clinical Physiopathology, Univer-
sity of Florence, V.le G. Pieraccini, 6, 50139 Florence, Italy. Tel. +39 0554271487;
Fax: +39 0554271371.
E-mail address: a.morelli@dfc.unifi.it (A. Morelli).

1871-2592/$ – see front matter # 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.eeus.2006.03.003
 eau-ebu update series 4 (2006) 96–108
1. Introduction
Penile erection is a complex neurovascular event
involving the interaction between different systems:
the nervous system (central and peripheral) and the
penile (arterial and trabecular) smooth muscle
system. The tone of penile smooth muscle is a key
determinant of the hemodynamic events that
maintain penile flaccidity or allow erection. The
cavernosal arteries supply blood to the corpora
cavernosa of the penis (through the pudendal
artery), while the emissary veins running through
the tunica albuginea allow blood to flow out of the
penis. In the flaccid penis, smooth muscle cells of
corpora cavernosa are contracted and penile blood
inflow is low. During erection, relaxation of trabe-
cular smooth muscle results in an increased blood
flow and pressure in the corpora cavernosa and an
expansion of sinusoidal spaces. The expanded
corpora cavernosa cause mechanical compression
of the emissary veins, restricting the venous outflow
from the cavernosal spaces and facilitating an
entrapment of blood in the cavernosal sinusoids.
This blood engorgement finally results in penile
rigidity [1].
Several neurotransmitters and endothelial fac-
tors have been shown to control erectile function by
modulating the penile vasculature and smooth
muscle tone of corpora cavernosa [2]. The correct
balance between relaxant and contractile factors is
required to determine the functional state of the
penis, finally resulting in a normal erectile function.
In this article, we review the physiological
mechanisms that regulate penile erection with
particular focusing on those intracellular molecular
processes involved in regulation of penile smooth
muscle tone.
2. Neurophysiological control of erection
The nervous system is considered to be the primary
regulatory site affording the control of penile
erection. Multiple levels of the neuroaxis, from the
brain and spinal cord to nerves terminating within
the penis, release several neurotransmitters that
induce penile response. The neurophysiological
control of erections occurs both at central and
peripheral level (Fig. 1).
2.1. Central mechanisms
Central mechanisms regulating erection are com-
plex and only partially elucidated, at least in
humans. They are essentially not revised here,
97
because beyond the main purpose of this article.
Briefly, the central nervous system coordinates
sensory stimuli from a variety of sources (visual,
auditory, imaginative, tactile, and olfactory). Strong
evidences from animal models support an impor-
tant involvement of the hypothalamic neurons
within the medial preoptic area (MPOA) and para-
ventricular nuclei (PVN), including oxytocinergic
neurons, whose activation by dopamine and by
oxytocin itself, leads to penile erection in male rats
[3,4]. The release of OT is secondary to production of
nitric oxide (NO) by nitric oxide synthase (NOS) in
the PVN. The interaction between nitric NO and
paraventricular oxytocinergic neurons seems to be
the crucial mechanism of the central regulation of
erection [4]. Dopamine is the most important
neurotransmitter which exerts at central level a
facilitatory effect on penile erection. A second
putative excitatory pathway, within both hypotha-
lamic and spinal loci, is the melanocortin system.
Preliminary data in animal models and even in
humans indicate that melanocortin receptors play
an important role in the control of sexual beavior
and therefore may represent a new pharmacological
target for the treatment of ED [5].
2.2. Peripheral mechanisms
The pro-erectile and anti-erectile messages deriving
from the integration and processing of sexual
stimuli in the brain, descend in the spinal cord
and activate nervous peripheral systems (Fig. 1).
Peripheral control of erection depends on both
neuronal and local factors that ultimately influence
the vascular events in the penis. The different
structures of the penis receive autonomic (sympa-
thetic and parasympathetic) and somatosensory
innervations [6]. They are innervated mainly by
pudendal nerves, which originate from the sacral
tract of the spinal cord (S2–S4) and contain the
primary afferent sensory and motor pathways, and
by cavernosal nerves, which originate in the pelvic
plexuses containing the primary efferent sympa-
thetic (hypogastric nerves from the thoracic-lumbar
tract, T11-L2, of the spinal cord) and parasympa-
thetic (pelvic nerves from the sacral tract, S2–S4, of
the spinal cord) pathways.
The nerve populations have been categorized as
adrenergic, cholinergic and nonadrenergic noncho-
linergic (NANC), which release transmitters acting
on vascular endothelium and smooth muscle
components of corpora cavernosa and thereby
modulate the functional state of the penis. Erections
are inhibited by basal sympathetic tone, mainly
mediated by noradrenaline (NA), whereas pro-
98 eau-ebu update series 4 (2006) 96–108

Fig. 1 – Schematic representation of neurophysiological control of erection. NO, nitric oxide; T11-L2, thoraco-lumbar tract of
the spinal cord; S2-S4, sacral tract of the spinal cord.

erectile dopamine-activated oxytocinergic neurons predominance [1,8]. a1-adrenoceptors subtypes

stimulate the parasympathetic system and promote
the release of neuronal relaxing factors, mainly
acetylcholine and nitric oxide (NO). Sexual arousal is
the result of both increased parasympathetic activ-
ity and decreased sympathetic activity. Fig. 2 sum-
marizes contraction/relaxation mediating trans-
mitters or modulators in the penis.
(a1A, a1B, a1D and a1L) as well as a2-adrenoceptors
subtypes (a2A, a2B, and a2C) have all been demon-
strated in human corporal smooth muscle and it
seems that a1A-, a1L- and a2A-adrenoceptors are
predominant [9]. In the penile vasculature, both a1-
and a2-adrenoceptors can contribute to contraction,

2.3. Factors leading to smooth muscle contraction

A tonic sympathetic neural input is the main

mechanism leading to smooth muscle contraction
in the penis. NA and endothelins (ETs) are the main
neurotransmitters that contribute to contraction in
penile tissue [7]. Released NA from simpathetic
adrenergic nerves stimulates post-junctional recep-
tors (adrenoceptors) in the penile vasculature and
trabecular smooth muscle of the corpora cavernosa
to induce contraction [1]. The pharmacological
characterization of such receptors indicates that
the a subtype is 10-times more abundant than b Fig. 2 – Summary of the contraction/relaxation mediating
subtype and that both a1 and a2 are present in penile transmitters in the penis. NPY, neuropeptide Y; PGF2a,
tissue, although they are differentially expressed, prostanoid F2a; TXA2, tromboxane A2; VIP, vasointestinal
with the a1 adrenoceptors having the functional peptide; PGE1 and PGE2, prostaglandin E1 and E2.
 eau-ebu update series 4 (2006) 96–108
but the a2 subtype may have a more important role
than in corpus cavernosum. Moreover, while post-
junctional a-adrenoceptors mediate penile smooth
muscle contractility and detumescence, prejunc-
tional a2-adrenoceptors are usually involved in a
negative regulation of NA transmission [10]. In
addition, stimulation of prejunctional a2-adreno-
ceptors in horse penile resistance arteries was
shown also to inhibit NANC nitrergic transmission,
suggesting that this might be one of the mechan-
isms by which NA maintains detumescence [11].
Experiments in rabbits indicate that blocking a2-
adrenoceptors with yohimbine resulted in an andro-
gen-dependent increase in NO signaling [12].
Administration of a-adrenoceptor agonists cause
detumescence, further confirming the role of a-
adrenoceptor in the regulation of smooth muscle
tone, whereas the employment of a adrenoceptors
antagonists has been shown to be efficacious for
induction and/or maintanance of penile erection
[13].
ET-1 is the most potent contractile agent respon-
sible for long-lasting contractions in the corpora
cavernosa and penile vessels and contributes to the
maintenance of the cavernosal smooth muscle tone
[1,14]. ET-2 and ET-3 are less potent than ET-1 to
induce contractions in penile tissue [15].
Other important contractile factors in erectile
physiology inducing penile detumescence are neu-
ropeptide Y (NPY) released by the nerve endings,
prostanoids (PGF2a) and tromboxane A2 (TXA2)
released from vascular endothelium, and angioten-
sin II synthesized by penile tissue, although their
roles have not yet been fully established [16].
2.4. Factors leading to smooth muscle relaxation
Smooth muscle relaxation in the penis is dependent
on the parasympathetic system, in which the most
important neurotransmitter is NO. The other neu-
rotransmitter released from parasympathetic nerve
endings is acetylcholine which exerts an indirect
smooth muscle relaxing action: (1) it stimulates the
release of NO from the vascular endothelium of
corpora cavernosa; (2) it reduces stimulation of the
receptors on sympathetic endings, leading to
decreased release of NA [16].
Thus, there are two major sources of NO in the
penis: parasympathetic nerve endings and endothe-
lium of corporal blood vessels and sinuses stimu-
lated by acetylcholine. Synthesis of NO is catalyzed
by the action of the enzyme nitric oxide synthase
(NOS) that convert L-arginine an O2 to L-citrulline
and NO both in endothelial cells and in nerve
endings. Three distinct isoforms of NOS have been
99
identified and functionally they are grouped as:
constitutive calcium-dependent NOS, including
neuronal (nNOS) and endothelial (eNOS), and indu-
cible calcium-independent NOS (iNOS). All three
NOS isoforms have been identified in the corpora
cavernosa, with nNOS and eNOS being preferen-
tially expressed in the autonomic nerves and
endothelium of the penis, respectively, and iNOS
in virtually all cell types [17,18]. Postganglionic
parasympathetic nerves whose transmitter function
depends on the release of NO are now termed
nitrergic nerves [19]. Both NANC and cholinergic
nerves contain nNOS [20]. The expression of penile
variants of nNOS (PnNOS) has been identified in
nNOS knock-out mice, which are fertile and have
intact neurogenic NO production [21]. A recent
publication documented that the alternatively
spliced forms of nNOS are major mediators of penile
erection and that the b splice variant (nNOSb) has
unique structural properties that may explain the
robust production of NO and the preserved erectile
function in nNOS knock-out mice [22].
Besides the action of acetylcholine for the
activation of eNOS, also the shear stress induced
by the increased blood flow in the penile vessels
could contribute to activate the eNOS to produce
continuously NO by a process involving PI3 kinase/
Akt pathway. Therefore, it has been hypothesized
that NO derived from nNOS is responsible for the
initiation of erection, whereas NO from shear-
stress-activated eNOS contributes to the mainte-
nance of penile rigidity during erection [16].
Vasoactive intestinal polypeptide (VIP) and calci-
tonin gene related peptide (CGRP) are other sub-
stances released by parasympathetic nerve endings
that contribute to cavernous smooth muscle relaxa-
tion. Prostanoids, such as prostaglandin E1 and E2
(PGE1, PGE2), released by the endothelium also have
an important smooth muscle relaxing action [2].
PGE1 not only exerts a direct relaxant effect on the
cavernous smooth muscle, but it also exerts a pro-
erectile activity through the inhibition of NA release
from adrenergic nerves [23]. For self-injection
therapy, PGE1 (alprostadil) represents one of the
most effective and safest vasoactive drug in the
treatment of ED [24].
3. Regulation of penile smooth muscle tone
In combination, all the neural pathways regulate the
effectors sites of action within the penis which
responds to the appropriate neuronal stimulus by
generating a degree of smooth muscle tone and
thereby the functional state of the penis. Therefore,
100 eau-ebu update series 4 (2006) 96–108
the regulation of penile smooth muscle tone con-
sists of molecular mechanisms that essentially
depend on adequate levels of agonists (neurotrans-
mitters, hormones, and endothelium-derived fac-
tors), integrity of intracellular transduction
signalling, and interactions between effectors (con-
tractile/relaxant) proteins. In particular, adequate
intracellular levels of calcium and the sensitivity of
the contractile machinery to calcium are required
for the regulation of the smooth muscle tone.
Smooth muscle cells contract when intracellular
calcium concentration increases and relax when it
falls. Moreover, though the nerve endings do not
innervate each smooth muscle fiber, all cells
contract and relax at the same time in the corpora
cavernosa. This coordination process is allowed by
intercellular communication channels called ‘‘gap
junctions’’ which make possible the transfer of
chemicals between the cytoplasm of adjacent cells
and thereby is responsible for the synchronized
erectile response [25].
3.1. Intracellular molecular process of smooth muscle cell
contractility
As shown in Fig. 3, the binding of NA, ETs and
prostanoids with their receptors on the surface of
smooth muscle cells increases the intracellular
activity of the membrane-bound enzyme phospho-
lipase C (PLC) which converts phosphatidylinositol
Fig. 3 – Intracellular signalling leading to smooth muscle
cell contraction in corpora cavernosa and determining the
flaccid state of the penis. NA, noradrenaline; ET-1,
endothelin-1; PLC, phospholipase C; PIP,
phosphatidylinositol biphosphate; IP3, inositol-3-
phosphate; DAG, diacylglycerol; PKC, protein kinase C;
CaM, calmodulin; MLC, myosin light chain; MLCK, MLC
kinase; SR, sarcoplasmic reticulum.
biphosphate (PIP) to inositol triphosphate (IP3) and
diacylglycerol (DAG). IP3 liberates calcium ions from
intracellular stores (such as sarcoplasmic reticu-
lum), while DAG stimulates protein kinase C (PKC)
which opens the calcium channels on the smooth
muscle cell membrane leading to calcium influx
from extracellular space into the cell. This results in
a transient rise in the cytoplasmic free calcium
concentration, which induces smooth muscle con-
traction [26]. In details, calcium ions at elevated
levels binds to calmodulin which changes its
conformation and interacts with myosin light-chain
kinase (MLCK). The resultant activation of MLCK
determines phosphorylation of myosin light chains
(MLC) and triggers the cycling of myosin cross-
bridges along actin filaments and the development
of force. In addition, phosphorylation of the MLC
also activates myosin ATPase providing energy for
the muscle contraction.
Although the increase of intracellular calcium is
transitory, the smooth muscle cell is able to
maintain the contracted status also after that the
cytoplasmic calcium returns to the basal level. In
fact, the so-called calcium-sensitizing pathways
take over and consist of activation of receptors
coupled to G-proteins that can also cause contrac-
tion by increasing calcium sensitivity without
changing the intracellular calcium level. The most
representative of such mechanisms involves the
RhoA/Rho-kinase pathway, which is depicted in
Fig. 4. RhoA is a member of the small monomeric
GTPase family, including five subfamilies: Rho-like
(RhoA, B, and C); Rac-like (Rac1, 2, and 3 and RhoG);
Cdc42-like; RhoBTB-like and Rnd-like (Rnd 1, 2, and
3) [27]. In addition to its role in mediating smooth
muscle contraction, RhoA is involved in the regula-
tion of several cellular processes, such as stress fiber
formation and cell migration. When inactive RhoA is
GDP-bound and localizes within the cytoplasm.
When NA and ETs bind to their excitatory receptors,
RhoA is converted from the inactive GDP complex
into an active GTP-bound complex that translocates
to the plasma membrane where it binds through
geranylgeranylation, initiating signaling transduc-
tion. The activity of RhoA is regulated by three
proteins: RhoGDI (GDP dissociation inhibitor) which
binds to RhoA-GDP to form the inactive cytoplasmic
complex; RhoGEF (guanine nucleotide exchange
factor) which facilitates the dissociation of RhoA-
GDP from RhoGDI and thereby the traslocation of the
active form RhoA-GTP to the plasma membrane;
RhoGAP (GTPase-activating protein) which acceler-
ates the intrinsic GTPase activity of RhoA with the
subsequent re-association of RhoA-GDP/RhoGDI
and re-localization in the cytoplasm [28]. The best
 eau-ebu update series 4 (2006) 96–108 101

Fig. 4 – Intracellular molecular mechanism of smooth muscle cell contraction via RhoA/ROK mediated calcium-sensitizing
pathway. NA, noradrenaline; ET-1, endothelin-1; GPCR, G protein coupled receptor; PLC, phospholipase C; GTP, guanosine
triphosphate; GDP, guanosine diphosphate; GEF, guanine nucleotide exchange factor; GAP, GTPase-activating protein; GDI,
GDP dissociation inhibitor; MLC, myosin light chain; MLCK, MLC kinase; MLCP, MLC phosphatase; ATP, adenosine
triphosphate; SR, sarcoplasmic reticulum.

characterized downstream effector of RhoA is Rho-
kinase (ROK) which is directly involved in smooth
muscle contraction. ROK is a serine-threonine
kinase that phosphorylates and thereby inhibits
the regulatory subunit of MLC phosphatase. Conse-
quently MLCs remain phosphorylated and sensi-
tized to intracellular calcium. Alternatively, ROK
prevents dephosphorylation of myofilaments
through an indirect mechanism consisting of the
phosphorylation/activation of a specific inhibitor of
MLC phosphatase, CPI-17, or it directly phosphor-
ylates MLC, thus maintaining contractile tone [14].
RhoA and ROK have been shown to be expressed in
penile smooth muscle and, accordingly, a selective
inhibitor of ROK (Y27632) has been shown to cause
relaxation of human corpora cavernosa in vitro and
to induce penile erection in animal models [29].
Moreover, it has been found that the transfection of
dominant negative of RhoA enhanced erectile
function in rats [30].
It has been proposed that the phasic contraction
of penile smooth muscle is regulated by an increase
in cytoplasmic calcium, while the tonic contraction
is governed by the calcium-sensitizing pathway [16].
It is noteworthy that contractile mechanisms that
take place in penile tissue are responsible for the
predominant physiological condition of the penis
which resides in the contracted/flaccid status for the
majority of time. The predominant contracted
status of the penis is associated to a low oxygenation
of the penile tissue that is physiologically inter-
rupted by the erectile episodes related and not
related (nocturnal erections) to sexual activity. Thus
the normal erectile function is important to allow
the oxygenation of penile tissue to preserve tissue
composition and the erectile function itself. Hypoxia
is potentially dangerous in the penis, in fact, when
protracted (more than 24 hours) it may damage
penile tissue and compromise its erectile capacity
[31]. It has been demonstrated in human and animal
models that hypoxic condition in penile tissue
induced the activation of compensatory and pro-
erectile mechanisms in order to re-oxygenate the
tissue, such as the increasing of vasorelaxant
receptor subtype of ET-1 (ETB) and the reduction
of RhoA/ROK expression [32].
3.2. Intracellular molecular process of smooth muscle cell
relaxation
Although several vasodilators have been implicated
in the erectile response, including VIP an prosta-
glandins, as well as acetylcholine, NO is considered
the pivotal physiological stimulus for penile smooth
muscle relaxation. Individual neurotransmitters act
via different pathways, but the intracellular
mechanism in every case is essentially based on
the changing in the cytoplasmic calcium concentra-
tions (Fig. 5).
In response to sexual stimuli NO released from
parasympathetic nerves and endothelial cells
crosses the smooth muscle cell membrane and
102 eau-ebu update series 4 (2006) 96–108

Fig. 5 – cGMP-mediated intracellular signalling leading to smooth muscle cell relaxation in corpora cavernosa and
determining the erection state of the penis. NANC, nonadrenergic noncholinergic; NO, nitric oxide; sGC, soluble guanylate
cyclase; GTP, guanosine triphosphate; GMP, guanosine monophosphate; cGMP, cyclic GMP; PKG, cGMP-dependent protein
kinase; PDE5, phosphodiesterase type 5; MLC, myosin light chain; MLCK, MLC kinase; MLCP, MLC phosphatase; SR,
sarcoplasmic reticulum.

binds to the soluble guanylate cyclase (sGC) in the
cytoplasm. Binding of NO to sGC activates this
enzyme, which converts guanosine triphosphate
(GTP) into cyclic guanosine monophosphate (cGMP),
the active second messenger which triggers a
biochemical cascade of events culminating in
smooth muscle relaxation [1]. These events include
the activation of a cGMP-dependent protein kinase
(PKG or cGKI) which in turn phosphorylates several
key target proteins, including ion channels, ion
pumps, and enzymes all involved in the control of
intracellular calcium level. Phosphorylation of these
target proteins reduces the intracellular availability
of calcium through the following mechanisms: (1)
inhibition of cell membrane Ca2+-channel activity, by
a direct mechanism or indirectly through the activa-
tion of K+ channels that act hyperpolarizing cell
membrane and inhibiting calcium influx; (2) activa-
tion of the plasma membrane Ca2+/ATPase pump
with the extrusion of calcium across the membrane
(this is thought to be the main mechanism mediating
smooth muscle relaxation via intracellular calcium
reduction); (3) activation of the sarcoplasmic reticu-
lum Ca2+/ATPase pump responsible for the uptake of
calcium from cytoplasm; (4) inhibition of IP3-
mediated pathway by phosphorylation of an IP3
regulatory protein associated with the receptor,
leading to a decreased IP3-induced calcium release
from intracellular stores [33]. Overall these mechan-
isms lead to a reduction of the Ca2+-/calmodulin
complex which results in a decreased MLC kinase
activity, reduced levels of phosphorilated MLC,
breakdown of actin/myosin crossbridges and relaxa-
tion of the cavernosal smooth muscle.
The other vasorelaxant factors, VIP and prosta-
noids (PGE1, PGE2) act via a different pathway that
concomitantly to that mediated by cGMP takes place
in penile smooth muscle tissue. Following the
interaction with their specific receptors, these
vasorelaxant factors act by activating adenylate
cyclase, the enzyme which converts adenosine
triphosphate (ATP) into cyclic adenosine monopho-
sphate (cAMP), another intracellular second mes-
senger which lowers cytosolic calcium levels. cAMP
through the activation of the related protein kinase
(PKA) leads to the opening of the K+ channels
causing plasma membrane hyperpolarization
resulting in the inhibition of the voltage-gated
Ca2+-channels and reduction of calcium influx into
the cell. Moreover, activation of PKA may leads to
the induction of transcriptional factors. Therefore,
PGE1 and other vasoactive agents which increase
 eau-ebu update series 4 (2006) 96–108
intracellular cAMP, may regulate mRNA expression
of a1- and a2-adrenoceptors [34]. On the other hand,
an interaction between PGE1 and the NO/cGMP
signalling has been suggested by the observation
that PGE1 up regulates eNOS and nNOS improving
erectile response in rats [35] and that a synergistic
interaction of PGE1 and NO is involved in relaxation
of human corpus cavernosum [36].
However, the cAMP-mediated smooth muscle
relaxation has only a marginal role in the erectile
physiology, with the NO-activated cGMP-mediated
pathway representing the most important.
Besides calcium mobilization and calcium sensi-
tization mechanisms, hyperpolarization of smooth
muscle cells through the opening of K+ channels
represents one of the salient mechanisms known to
be important in the regulation of penile smooth
muscle tone. Corporal smooth muscle cells express
distinct K+ channels subtype, including the best
characterized ATP-sensitive (KATP) and large-con-
ductance Ca2+-activated K+ channels, also termed
maxi-K, whose activation may occur by different
mechanisms. The opening of K+ channels may be
stimulated by PKA, PKG, or by cGMP itself. In
addition it has been proposed that NO can directly
stimulate K+-channels opening as well as Na+/K+-
ATPase in the arteries and trabecular muscle [37].
Pharmacological or genetic manipulation of K+
channels as therapy for ED provides a useful tool
to regulate penile smooth muscle tone [38,39].
Given that the intracellular levels of both cAMP
and cGMP second messengers are determinant to
regulate the availability of cytoplasmic free calcium
and thereby to trigger the contraction or relaxation
of penile smooth muscle cells, a key role in the
regulation of erectile function is played by the class
of enzymes phosphodiesterases (PDEs) which con-
verts cAMP and cGMP into their inactive metabo-
lites, adenosine monophosphate (AMP) and
guanosine monophosphate (GMP), respectively. This
enzymatic degradation represents the crucial event
terminating the above described cascade.
3.3. Phosphodiesterases
PDEs are enzymes critically involved in regulation of
cellular cAMP and/or cGMP levels by many stimuli.
Eleven families of PDEs with varying selectivities for
cAMP or cGMP have been identified in mammalian
tissues [40]. Each PDE family includes multiple
isoforms either as products of different genes or of
the same gene through alternative splicing. PDE type
5 (PDE5) is the predominant PDE in the penis [41],
responsible for the regulation of penile smooth
muscle tone. The human PDE5 gene has been
103
identified by three independent groups [42–44], it
has been mapped to chromosome 4q26, and consists
of 21 exons. Alternative splicing of this gene results in
three transcript variants encoding distinct isoforms
and it has been found that two alternate promoters
regulate transcription of three PDE5 isoforms [45].
This enzyme contains a catalytic domain that
specifically hydrolyzes cGMP and a regulatory
domain that binds cGMP itself. Moreover cGMP
transcriptionally regulates PDE5 gene. PDE5 is widely
distributed, especially in those tissues with large
smooth muscle component (visceral and vascular),
with the corpora cavernosa being the tissue quanti-
tatively expressing the highest level of PDE5 mRNA,
as demonstrated both in human and rat tissues
[46,47]. The quantitative PDE5 tissue distribution may
explain the selectivity of action of PDE5 inhibitor
(PDE5i) drugs in the penis, representing the first line
therapy for the oral treatment in patients affected by
erectile dysfunction (ED). In Fig. 6 is shown the PDE5
activity in human corpora cavernosa extracts, as
measured by inhibition efficacy of the most used
PDE5i (sildenafil, tadalafil, vardenafil).
Because PDE5 is the predominant enzyme
responsible for cGMP degradation in penile smooth
muscle, the activation of this enzyme terminates the
NO-induced cGMP-mediated vasorelaxation, restor-
ing the basal smooth muscle tone and penile
Fig. 6 – Inhibition curves of cGMP-hydrolysing activity
induced by PDE5 inhibitors (vardenafil, sildenafil, tadalafil)
in corpora cavernosa extracts from human penile biopsies.
Aliquots of tissue homogenates (0.1 mg protein/ml) were
incubated with 0.5 mM cGMP and 0.1 mM [3H]cGMP in
absence or in presence of vardenfil (10S13–10S6 M),
sildenafil (10S11–10S6 M) and tadalafil (10S11–10S6 M).
Ordinate: cGMP hydrolysing activity expressed as
conversion percentage; Conversion (%) = [products count/
(substrate + products counts)]  100. Abscissa: inhibitor
concentration. Inhibition curves obtained in three different
experiments were fitted simultaneously with the program
ALLFIT using the four-parameter logistic equation.
104 eau-ebu update series 4 (2006) 96–108
flaccidity. In response to sexual stimulation, PDE5i
act to potentiate the NO-mediated vasorelaxation in
the erectile tissue by maintaining increased intra-
cellular cGMP levels in vascular and corporal smooth
muscle cells, thus improving penile erection in ED
patients. It seems clear that the correct tight
regulation of every enzyme involved in the NO-
mediated pathway, especially NOS and PDE5
responsible for cGMP formation and degradation,
respectively, is required to assure a normal erectile
function.
Recent publications showed that dysregulation of
PDE5 expression/activity is involved in etiology of
priapism, a condition in which abnormally pro-
longed penile erection occurs, unassociated with
sexual interest [48,49]. As a result of PDE5 down-
regulation, the penile tissue may become hypersen-
sitive to cGMP signalling causing unrestrained
erectile tissue relaxation after an episode of sexual
stimulation.
3.4. Androgens and erectile function
The role of androgens in the molecular mechanisms
underlying the erectile function has become clearer
during the past decade (Fig. 7). Besides the well
known role that androgens play at the central
nervous system level as important modulators of
male sexual behaviour, including libido [50], recent
advances about the relationship between androgens
and erectile function at peripheral level have also
Fig. 7 – Mechanisms of action of testosterone on erectile
function. By maintaining the correct balance between
NOS and PDE5 expression/activity, T regulates
intracellular cGMP levels in penile tissue and thereby
smooth muscle relaxation for erectile function. On the
other hand, T exerts a trophic and differentiating action
for cavernous smooth muscle cells to maintain integrity of
erectile structures. NOS, nitric oxide synthase; PDE5,
phosphodiesterase type 5.
been gained [51]. Although studies showed that not
all castrated men become impotent [52] and that a
high percentage (20–45%) of prostatic cancer
patients preserved erectile function after medical
or surgical castration [53,54], it has been demon-
strated that androgen manipulation affects erectile
function.
A number of different studies on experimental
animal models have shown that testosterone (T)
regulate both formation and degradation of cGMP
in the penis by acting on NOS and PDE5 expression.
It has been demonstrated in the rat that androgen
deprivation associated to several conditions,
including ageing, and pathologies such as diabetes
mellitus type I and II, adrenalectomy, hypophys-
ectomy and castration, induced a reduction of
penile NOS expression with decreased erectile
function, that was reversed by androgen replace-
ment therapy [50]. Moreover, a trophic effect of T on
penile architecture has been demonstrated in
different animal species [55]. Androgen deprivation
in the animal model by surgical and medical
castration resulted in loss of trabecular smooth
muscle and increase in deposition of extracellular
matrix, producing diffuse fibrosis and ED [56–58].
The androgen-dependent loss of erectile response
was restored by androgen administration [56]. In
addition, it has also been shown that T is involved
in the maturation of penile tissue composition by
promoting the commitment of pluripotent stem
cells into the myogenic lineage and inhibiting their
differentiation in adipogenic lineage [59–61]. Traish
et al. [62] have demonstrated a similar mechanism
in the rabbit with an accumulation of adipocytes in
the subtunical region of the corpus cavernosum,
thus impairing the veno-occlusive mechanism, if
T levels are low. This study also confirmed that
androgen deprivation leads to loss of trabecular
smooth muscle and increase of connective tissue
fibers.
Hence, androgens play an important role not only
in the formation of the main relaxing factor, cGMP
by regulating NOS activity, but also in the integrity of
erectile apparatus.
Recently, it has been demonstrated that, in
several species including human, rabbit and rat,
androgens are also important for the regulation of
cGMP degradation by modulating PDE5 expression
and activity [46,47]. This dual and antithetic role of
androgens in promoting both the increase and the
decrease of cGMP intracellular concentration in
penile smooth muscle underlies the mechanism
by which the erections are finalized to sexual act
and thereby synchronized to sexual desire. More-
over, the androgen-dependent PDE5 expression
 eau-ebu update series 4 (2006) 96–108
might explain the occurrence of erections in pre-
sence of low T levels and in absence of sexual
interest, as it occurs in children and in eunuchs, as
well as in hypogonadal subjects when adequately
stimulated (hard erotic movies). In fact, because of
androgen deficiency, a reduced PDE5 activity
favours an enhancement of cGMP signalling allow-
ing penile smooth muscle relaxation and erection.
Clinical studies recently evidenced a marginal effect
of T on penile erections, suggesting that the
decreased sexual activity in hypogonadal subjects
is due to a decreased libido rather than to a direct
effect of reduced T on erectile process [63,64].
This important role played by T in regulating both
expression and activity of the main cGMP-catalys-
ing enzyme in the penis (PDE5), reflects another
important evidence concerning the responsiveness
of patients with ED to PDE5i. In fact, in animal
models, low levels of T severely hampered the PDE5i
effectiveness, that was completely restored by T
replacement [46,47]. The explanation is that the
drug efficacy depends on the availability of the
target enzyme. Accordingly, clinical studies
demonstrated that in ED patients with low T levels
who do not respond to PDE5i, T replacement was
able to rescue therapy [65–67]. Hypogonadism is
often associated with diabetes and both conditions
represent major risk factors for ED [68]. Moreover,
response to PDE5i is resulted less satisfactory in
diabetic patients than in other subjects with ED [69].
A recent publication demonstrated in two different
animal models of chemical diabetes that T defi-
ciency underlies biochemical alteration, including
nNOS and PDE5 down-regulation, leading to ED and
is responsible of unresponsiveness to sildenafil [70].
Indeed, T replacement was able to reinstate dia-
betes-associated ED and reduced responsiveness to
sildenafil, suggesting the importance to test T
plasma levels in the clinical management of
diabetic patients.
4. Concluding remarks
Penile erection is a complex neurovascular phenom-
enon that depends upon a tight regulation of several
factors involved at multiple levels, from the neural
control of sexual stimulation to the peripheral
response occurring at penile tissue level. The
coordinated functions of neurotransmitters and
factors locally released in penile tissue are funda-
mental to regulate the degree of penile smooth
muscle tone and allow normal erectile processes.
The elucidation of the NO/cGMP/PDE5 pathway has
provided a significant advancement not only in the
105
comprehension of intracellular mechanisms basi-
cally involved in erectile functions, but also in the
identification of those alterations responsible for
ED, promoting the development of the most effica-
cious drugs (PDE5i) currently used for ED treatment.
NO released by nerves and endothelium in the penis
plays a crucial role in the initiation and maintenance
of increased intracavernous pressure and penile
erection, but the normal erectile function is war-
ranted by a tight balance between relaxant and
contractile factors. Conditions associated with
reduced function of nerves and endothelium that
alter a such balance (i.e., aging, hypertension,
smoking and diabetes) cause changing in penile
tissue resulting in impaired smooth muscle relaxa-
tion and erection. In addition, given the crucial role
of testosterone in maintaining normal erectile
function, at central level (sexual desire), as well as
at peripheral level (trophic effect for penile tissue
and important regulator of both NOS and PDE5
activity), the hypogonadal condition has to be
accurately considered in the clinical management
of ED patients. Besides the NO/cGMP signalling the
opposite mechanism mediated by the RhoA/ROK
contractile pathway has just emerged recently.
Overactive RhoA/ROK signalling results in ED con-
dition, suggesting that improved understanding of
the upstream regulation of this anti-erectile intra-
cellular mechanism will probably lead to the
development in the near future of therapeutic
interventions for ED, especially in those cases of
reduced PDE5i efficacy.
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108 eau-ebu update series 4 (2006) 96–108

CME questions C. activation of phospholipase C-mediated path-

Please visit www.uroweb.org/updateseries to
answer these CME questions on-line. The CME
credits will then be attributed automatically.
1. One of the neurotransmitters involved in penile
detumescence is:
A. Neuropeptide Y (NPY)
B. Acetylcholine
C. Vasointestinal peptide (VIP)
D. Nitric oxide (NO)
2. The most important neurotransmitter involved
in penile smooth muscle relaxation is:
A. Noradrenaline (NA)
B. Endothelin-1 (ET-1)
C. Nitric oxide (NO)
D. Tromboxane A2
3. During erection intracellular transduction sig-
nalling cause penile smooth muscle relaxation
through:
A. cGMP-mediated decreasing of cytoplasmic
calcium concentration
B. cGMP-mediated increasing of cytoplasmic
calcium concentration
way
D. induction of myosin/actin crossbridges
4. In the penis, the calcium-sensitizing RhoA/
Rho-kinase pathway mediates:
A. penile smooth muscle relaxation and erection
B. maintainance of penile smooth muscle tone
and flaccidity
C. detaches of myosin heads from actin
D. decreasing of intracellular calcium levels
5. PDE5 inhibitors, the most used drugs for the
treatment of erectile dysfunction, act by:
A. the reduction of intracellular cGMP levels
B. the increase of free calcium concentration
C. the inhibition of cGMP degradation
D. the induction of nitric oxide synthesis
6. The role of androgens in the erectile physiology is
exerted:
A. at central level, exclusively on sexual desire
B. both at central and peripheral level
C. exclusively at peripheral level
D. only marginally