New Insights into Hypertension-Associated Erectile Dysfunction

Abstract

Erectile dysfunction is recognized as a quality-of-life disorder that needs to be treated. Currently, it is estimated to affect as many as 30 million American men. Thirty percent of hypertensive patients complain of erectile dysfunction. The understanding of common mechanisms involved in the cause of erectile dysfunction associated with hypertension, and the investigation of antihypertensive drugs that impact erectile dysfunction, will provide important tools toward identifying new therapeutic targets that will improve the quality of life for patients in these conditions.
Hypertension and erectile dysfunction are closely intertwined diseases, which have endothelial dysfunction as a common base. During hypertension and/or erectile dysfunction, disturbance of endothelium-derived factors can lead to an increase in vascular smooth muscle (VSM) contraction. Hypertension can lead to erectile dysfunction as a consequence of high blood pressure (BP) or due to antihypertensive treatment. However, growing evidence suggests erectile dysfunction is an early sign for hypertension. Also, some phosphodiesterase-5 inhibitors used to treat erectile dysfunction can improve BP, but the link between these conditions has not been totally understood.
This review will discuss the interplay between hypertension and erectile dysfunction, exploring newest insights regarding hypertension-associated erectile dysfunction, as well as the effect of antihypertensive drugs in erectile dysfunction patients.

Full text

New Insights into Hypertension-Associated Erectile Dysfunction
Kenia Pedrosa Nunes*, Hicham Labazi*, and R. Clinton Webb
Department of Physiology, Georgia Health Sciences University, Augusta, USA
Abstract
Purpose of review—Erectile dysfunction (ED) is recognized as a quality of life disorder that
needs to be treated. Currently, it is estimated to affect as many as 30 million American men.
Thirty percent of hypertensive patients complain of ED. The understanding of common
mechanisms involved in the etiology of ED associated with hypertension, and the investigation of
antihypertensive drugs that impact ED, will provide important tools toward indentifying new
therapeutic targets that will improve the quality of life for patients in these conditions.
Recent findings—Hypertension and ED are closely intertwined diseases which have
endothelium dysfunction as a common base. During hypertension and/or ED, disturbance of
endothelium derived factors can lead to an increase in vascular smooth muscle (VSM) contraction.
Hypertension can also lead to ED as a consequence of high blood pressure (BP) or due to
antihypertensive treatment. However, growing evidence suggests ED as an early sign for
hypertension. Also, some PDE-5 inhibitors used to treat ED can improve BP, but the link between
these conditions has not been totally understood.
Summary—This review will discuss the interplay between hypertension and ED, exploring
newest insights regarding hypertension-associated ED, as well as the effect of antihypertensive
drugs in ED patients.
Keywords
Erectile dysfunction; hypertension; endothelial dysfunction; antihypertensive drugs
A-Introduction
Erectile dysfunction (ED) is a condition of increasing prevalence worldwide which has been
estimated to affect 150 million individuals and is supposed to impact up to 50% of men
between the ages of 40 and 70 (1). Also, it is expected that 322 million men will be suffering
from ED by the year 2025 (2). ED and hypertension, a major factor for cardiovascular
disease (CVD), are common conditions that possibly share pathophysiologic pathways.
Compared to the general population, hypertensive patients have a higher prevalence of ED
(3–4). However, an important point has been raised as to whether the higher prevalence of
ED in those patients is the result of hypertension per se, of antihypertensive treatment, or as
Corresponding author: R. Clinton Webb, Ph.D. Georgia Health Sciences University, Department of Physiology, 1120 15th Street,
CA 3135 Augusta, GA 30912, U.S.A. Phone: +1 (706) 721-7814 Fax: +1(706) 721-6299 cwebb@georgiahealth.edu.
*Both authors contributed equally to this manuscript.
The authors declare no conflict of interest.
NIH Public Access
Author Manuscript
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Published in final edited form as:
Curr Opin Nephrol Hypertens. 2012 March ; 21(2): 163–170. doi:10.1097/MNH.0b013e32835021bd.
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a combination of both. Also, studies in models of pre-clinical hypertension have suggested
that high BP causes morphological modifications in the penile vascular bed, contributing to
ED. Furthermore, much evidence suggests that vascular abnormalities such as endothelial
dysfunction and atherosclerosis play a critical role in both conditions (3, 5). Importantly, the
concept that ED is a prior indicator of CVD is growing stronger (6)*.
ED is often a disease of vascular origin. The penile endothelial bed is considered a
specialized extension of the peripheral vascular system, responding similarly to various
stimuli in order to maintain homeostasis, playing a particular regulatory role in the
modulation of VSM tone which is crucial for normal erectile function (7)*. The small
diameter of the cavernosal arteries plus the high content of endothelium and VSM may
make the penile vascular bed a sensitive indicator of systemic vascular disease (8). Thus, the
penis is a vascular organ that is sensitive to changes in oxidative stress and systemic NO
levels. It is also sensitive to local modifications in the vasculature, making the penis an
organ supposed to precede vascular systemic alterations. Therefore, ED has a higher
incidence in patients with hypertension, a disease which it often precedes. In addition,
atherosclerotic disease associated with hypertension can interrupt normal erectile
physiology, and it has been proposed that ED is not only significantly correlated with but is
also strongly predictive of subsequent atherosclerosis (9)*. Atherosclerosis is characterized
by the cross-talk between excessive inflammation and lipid accumulation. Development of
atherosclerosis and vascular inflammation involves Rho-kinase pathway, which the main
function is the regulation of VSM tone (10)*. Also, Rho-kinase signaling is desregulated in
hypertension, as well as ED. Finally, both conditions are interconnected by many common
agents, such as endothelin (ET-1), angiotensin II (AngII) and reactive oxygen species
(ROS), and its pathways.
B- Mechanisms of erection
ED is defined as the regular inability to reach or maintain a penile erection of sufficient
quality to perform satisfactory sexual intercourse; it has been progressively associated with
many comorbities. There are two main intracellular mechanisms for relaxing the cavernosal
VSM leading to normal erectile function: the guanylate cyclase (GS)/cGMP and adenylate
cyclase (AC)/cAMP pathways. Both pathways results in NO release, which is the main
factor initiating erection. NO is produced by endothelial (eNOS) or neuronal (nNOS) nitric
oxide synthase via acetylcholine or neuronal stimulation. Upon its release, NO diffuses
locally into adjacent VSMC of the corpus cavernosum and binds to GC, which catalyzes the
conversion of guanosine trisphosphate (GTP) to cGMP. Consequently, protein kinase G
(PKG) is activated, leading to a decrease in cytosolic Ca2+ by various mechanisms. cGMP
also blocks Rho-kinase activation. The decay in cytosolic Ca2+ concentration induces
relaxation of the VSMC in the penis, leading to dilation of arterial vessels, increased blood
flow into the corpora cavernosa, allowing penile erection. Contributing to penile relaxation
and reduction of intracellular Ca2+, other substances activate the enzyme AC, leading to
cAMP production, which in turn activates protein kinase A (PKA) (7). The erectile process
is completely dependent on relaxation and intact endothelium function, which is also true for
vascular homeostasis and normal BP maintenance. cGMP and cAMP levels are modulated
by phosphodiesterase (PDE) enzymes, which cleave these signaling molecules to 5’GMP
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and 5’AMP, respectively. Phosphodisterase-5 (PDE-5) is a key enzyme in the NO/cGMP
signal transduction pathway and functions to restrain VSM relaxation and thus the erectile
process. Another mechanism involved in maintenance of the erectile process is the
phosphatidylinositol 3-kinase (PI3-kinase) pathway that activates the serine/threonine
protein kinase Akt (also known as PKB). PKB causes direct phosphorylation of eNOS,
reducing the enzyme's Ca+2 requirement and causing increased production of NO. It has
been suggested that rapid, brief activation of nNOS initiates the erectile process, whereas
PI3-kinase/Akt-dependent phosphorylation and activation of eNOS by augmented blood
flow and endothelial shear stress lead to sustained NO production and maximal erection (7).
C- ED in hypertension
In the vasculature, as well in the penile tissue, circulating neurotransmitters, hormones and
endothelium derived factors play a critical role in modulating the VSM tone (Figure 1).
During hypertension, disturbance of these factors can lead to an increase in VSM tone which
favors contraction.
1-Vasoconstrictors in hypertension and erectile function
Angiotensin II (AngII)—the predominate bioactive component of the renin-angiotensin
system (RAS) plays a role in the maintenance of systemic BP through various mechanisms
in the cardiovascular and renal systems. AngII also plays an important role in penile
erection. However, an increase in circulating levels of AngII can lead to an increase vascular
smooth muscle contraction and sodium retention, which contributes to the pathogenesis of
hypertension. Some studies have shown that excessive production of AngII is associated
with ED. AngII levels were also shown to be increased in the cavernous blood of men with
ED as compared to healthy subjects (11–12). AngII exerts its biologic effect via activation
of either one of its receptors: AT1 or AT2. While the AT2 receptor has been shown to
modulate vasodilation (13), AT1 receptor activation is known to modulate vasoconstriction,
induce VSM cell proliferation, inflammation, activation of sympathetic nervous system and
aldosterone secretion. This is in addition to its effects on salt and water retention. In the
penis, AngII modulates the tone of human penile arteries and trabecular VSM (14–15) *.
AT1 receptor blockade was shown to improve erectile function (16). Jin et al. has shown that
AngII infusion in rats caused ED through the activation of the NADPH oxidase, resulting in
increased ROS (17). ROS are known to be detrimental to the endothelium and smooth
muscle due to the direct scavenging of available NO necessary for vasorelaxation. ROS can
also stimulate the RhoA/Rho-kinase pathway (11). Stimulation of the RhoA/Rho kinase
pathway results in phosphorylation of the myosin-binding subunit of MLC phosphatase and
inhibits its activity, thus promoting the phosphorylated state of MLC that leads to
contraction and penile flaccidity.
Endothelin 1(ET-1)—ET-1 is an endothelium-derived peptide and one of the most potent
endogenous vasoconstrictors. ET-1 cellular signaling in the vasculature is similar to that of
AngII. In mammalian cells, ET-1 exerts its biologic effect through the activation of its
receptors: ET-A and ET-B. The typical receptor found in the smooth muscle cells is ET-A
receptor which mediates a vasoconstrictor effect. Penile VSM cells are able to synthesize
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ET-1 as well as respond to stimulation with ET-1(18). In addition, both ET-A and ET-B
have been reported to be expressed in cavernosal tissue (19–22). In the penis, ET-1 induces
corpus cavernosum vasoconstriction through the ETA receptor and subsequent activation of
the inositol triphosphate (IP3) / Ca2+ signaling pathway (Ca2+sensitive) and the RhoA/Rho-
kinase signaling pathway (Ca2+ independent) (23). On the other hand, ETB receptor
activation was shown to induce vasodilation by means of NO release from the cavernosal
endothelial cells (24).
In some forms of hypertension, ET-1 has been demonstrated to contribute to its pathogenesis
i.e. mineralocorticoid hypertension. It was shown that salt-sensitive hypertensive animals
display abnormal vascular responses to ET-1 as well as increased tissue ET-1 expression. As
mentioned previously, ROS are produced during hypertension; these ROS have been shown
to also stimulate ET-1 production by endothelial cells, producing a cycle leading to further
increases in vasoconstriction. Concurrently, ET-1 was shown to increase ROS generation via
NADPH oxidase activation. Data from our laboratory has shown that ET-1 mediates not
only penile vasoconstriction, but also contraction of the internal pudendal artery, the major
artery providing blood flow to the penis (22, 25). We have also revealed that the corpora
cavernosum from DOCA-salt hypertensive rats exhibit increased contractile responses to
ET-1when compared with their normotensive counterpart controls (22).
2-Morphological changes in hypertension and erectile dysfunction
As blood vessels undergo remodeling during hypertension, the penile tissue also undergoes
morphological changes (26–27). During hypertension, increases in wall thickness and
collagen deposition, with a decrease in lumen diameter are common structural changes
which can affect the vasculature. Studies have shown that hypertension was associated with
ED which might have resulted from a decrease in elastic fibers, increase of collagen fiber of
the sinusoid, and a thinning of the tunica albugina in the penis of hypertensive animals.
Hypertension was associated also with endothelial cells and VSM cells damage and
degenerated Schwann cells (26). Also shown, an association of hypertension with increase
vascular smooth muscle and cavernous VSM proliferation and fibrosis, moreover,
hypertensive animals exhibited increase in surrounding connective tissue in the amyelinated
nerves, suggesting that the increase in extracellular matrix seems to affect not only the
interstitium but also the neural structure of the penis resulting in ED (28). In addition, the
vascular changes in hypertension may affect the penile vasculature as well as the pudendal
arteries resulting in a decrease in blood supply to the penis (29).
3-Vasodilators in hypertension and erectile dysfunction
ED can result from either an increase in the production of or an abnormal response to
contractile stimuli such as AngII and ET-1, or from a decrease in production or response to
stimuli that favor penile VSM relaxation. These are similar hallmarks of endothelial
dysfunction, which is defined as a decreased responsiveness to vasodilatory mediators and
an increased sensitivity to vasoconstrictor molecules. These abnormal responses to
mediators can affect the normal regulatory role of peripheral vascular endothelium,
including the cavernosal arterial and venous systems.
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Nitric Oxide (NO)—During hypertension, there is a decrease in NO bioavailability, which
may be due to decreased eNOS expression or uncoupling, as well as a decrease or
impairment of the NO signaling pathway (30). The decrease in NO bioavailability can result
from NO scavenging by ROS, of which is increased as result of NADPH activation and an
alteration of intracellular antioxidant enzymes, including SOD (5, 17, 31). Other studies
using hypertensive animal models also showed an impairment of relaxation mediated by
neurogenic NO (32).
During hypertension, there is an imbalance between pro-oxidant and anti-oxidant
mechanisms in the endothelial cells resulting in an increase in ROS generation. ROS are
known to be very important in the pathophysiology of vascular disease. An interaction
between ROS and NO has been implicated in many vascular diseases, such as atherogenesis
and has been suggested to play an important role in ED (33). One of the most detrimental
ROS is superoxide (O2−·), which interacts with NO decreasing NO bioavailability and
resulting in the formation of peroxynitrite (ONOO−). In turn ONOO− was shown to cause
damage to the mitochondria which may contribute to apoptotic and necrotic cell death (34).
Although ONOO− was shown to mediate relaxation of rabbit corpus cavernosum, the
relaxation to NO was short lived with the contractile tension returning to its original level,
whereas relaxation to ONOO− was less potent, of a slower onset and more prolonged with
tissues unable to recover tension (35). These will result in an ineffective relaxation in
cavernosal tissue and may contribute to the pathogenesis of ED.
Hydrogen sulfide (H2S)—H2S deficiency contributes to hypertension. H2S is produced
from L-cysteine through cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE).
CBS is mainly expressed in the brain, peripheral nervous system, liver and kidney, whereas
CSE is mostly found in liver, vascular and nonvascular smooth cells. Pharmacological
inhibition or genetic deletion of the gene responsible for H2S synthesis, CSE, resulted in
hypertension and a decrease in endothelium- mediated relaxation (36). Recent studies have
also shown that H2S can facilitate erectile function (37). Interestingly, a recent study
revealed that human penile tissue possesses both CBS and CSE. Both enzymes were found
to be localized in the muscular trabeculae and the smooth muscle component of penile
artery. They also showed that human corpus cavernosum relaxes to exogenous H2S as well
as L-cysteine in dose-dependent manner (38). Pharmacological inhibition of the H2S
producing enzymes was shown to decrease intracavernosal pressure in non-human primates,
as well as increase electric field stimulation-mediated contraction in human corpus
cavernusom (38–39). The mechanisms through which H2S may mediate erection and penile
smooth muscle relaxation are still not well understood and further investigation will be
necessary to elucidate the role that H2S may play in erectile function and/or dysfunction
(40–41)*. H2S represent a potential and promising therapeutic aimed for the treatment of
ED.
D- Antihypertensive pharmacology
Despite the availability of more than 75 antihypertensive agents, blood pressure control in
the general population is, at best, inadequate, making hypertension a public health problem
with estimated direct and indirect costs of more than $93.5 billion per year (42). In addition,
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combination pharmacotherapy is often required in order to reach the currently recommended
BP goals in the majority of hypertensive patients. Drugs used to treat hypertension are
classified as: diuretics, sympathoplegic agents, direct vasodilators, angiotensin-converting
enzyme (ACE) inhibitors and angiotensin II receptors antagonists (ARB). ED is considered
a common side effect of various antihypertensive, such as central-acting, β blockers and
diuretics (43). However, newer-generation antihypertensive drugs, for example calcium
antagonists and ACE inhibitors, seem to have neutral effects (44). The first line of drugs for
hypertension is β-blockers and diuretics. β-Blockers are a complex class of drugs involving
several compounds that differ from each other by pharmacological characteristics, such as
β1/β2 selectivity, intrinsic sympathomimetic activity and vasodilatory capacity. In general,
they lower blood pressure by reducing cardiac output, inhibiting renin release, Ang II and
aldosterone production, and decreasing adrenergic outflow from central nervous system
(CNS) (45)*. β-Blockers are indicated as a treatment for hypertensive patients with some
specific organ damage, but they have been outlined as one of the leading causes of drug-
related ED (46). Diuretics act by depleting body sodium stores, which in the beginning
causes a reduction in total blood volume, and consequently cardiac output. In turn, this
initially causes an increase in peripheral vascular resistance, which is normalized after 6–8
weeks.
Direct vasodilators act by relaxing smooth muscle of arterioles and sometimes veins,
reducing systemic vascular resistance. Some of them, such as hydralazine and minoxidil
have rarely been reported to cause ED. Calcium channels blockers, which dilate arteries by
reducing calcium influx into cells, effectively lower BP. The currently available ones inhibit
L-type channels in humans and seem to have a neutral effect on erectile function (47).
Possibly this is because this channel is linked with nNOS activation from cholinergic nerve
endings into the penis, which is important for NO release and consequently erection.
However, although this channel is inhibited, nNOS from nitrergic nerves will be activated,
allowing the erectile process to begin. Another class of antihypertensive drugs is the ACE
inhibitors. They act by mimicking the structure of the ACE substrate, directly blocking Ang
II formation and at the same time increasing bradykinin levels. The net results are reduced
vasoconstriction, decreased sodium and water retention, and increased vasodilation through
bradykinin.
As a future antihypertensive treatment, there is theoretical evidence that gene therapy may
produce long-lasting antihypertensive effects by influencing the genes associated with
hypertension. Nevertheless, the treatment of human essential hypertension requires sustained
over-expression of genes and identification of target genes can be a challenging task, which
is necessary for successful results. Also, many other problems are encountered to reach the
promising gene therapy. Among them is low efficiency for gene transfer into vascular cells,
difficulties in determining how to prolong and control transgenic expression or antisense
inhibition, lack of selectivity and minimization of adverse effects of viral vectors. Despite
these concerns, animal studies showed that gene therapy may be feasible to treat human
hypertension. Another possibility is the utilization of vaccines as a treatment, albeit not in
the near future (48).
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E- Treatment of ED in hypertensive patients
Although ED is often a result of hypertension, some studies have suggested that ED can also
result from hypertension treatment. Whereas some studies did not find a significant
influence, other suggested that anti-hypertension drugs, in particular, diuretics and β-
blockers are associated with ED. Given that AngII plays an important role in the etiology of
ED during hypertension, the use of ARB and ACE inhibitors were studied for their effects
on erectile function. Animal studies showed that treatment with ARBs improves endothelial
function in the cavernosal tissue. In humans, ARBs were shown to increase cavernosal
relaxation mediated by NANC stimulation and sodium nitroprusside (15). Other studies
have shown that treatment of hypertensive patients with ARBs resulted in improved sexual
activity and erectile function. Whereas the use of ACE inhibitors in hypertensive animals
showed improvement of erectile function, studies conducted in human showed neutral to
negative effects on sexual activity (44).
Since it was shown that ET-1 is a potent vasoconstrictor of corporal SMCs, some studies
have focused on ET-A antagonism and its effect on erectile function. Current studies did
show a significant alteration of the erectile response despite inhibition of contraction to
exogenous ET-1 using ET-1 receptor antagonists. ET-1 plays an important role in
mineralocorticoid hypertension and is directly involved in end-organ damage, so ET-1
receptor blockade may provide a therapeutic approach to this hypertensive condition, or
other clinical condition where ET-1 levels are increased such as in diabetes and systemic
sclerosis (49)*.
The phosphodiesterase type 5 inhibitors (PDE5I) are approved treatment for ED. PDE5I act
by inhibiting PDE5, the enzyme that catalyses the breakdown of the second messenger
cGMP. cGMP is the downstream effector in the NO signaling pathway, so, PDE5I are
dependent upon the integrity of the NO generating system. In patients where the NO
pathway is compromised, the benefits of such drugs will be lower when compared to others.
The PDE5I are used also for the treatment of pulmonary hypertension (PAH). However,
patients treated with nitrates or nitrate-donors or vasodilators such as α-blockers should not
take PDE5I, otherwise, combining these drugs will result in hypotension (50).
Treatment with β-blockers is considered to cause ED. In fact, studies have shown that
treatment of hypertensive patients with β-blockers is associated with sexual dysfunction and
impotence. However, the new generation β-blocker nebivolol may have positive effects on
erectile function. Recent studies showed that nebivolol treatment improves endothelial
function and reverses ED in animals through the activation of the NO/cGMP pathway (51).
In humans, nebivolol was shown to dilate penile arteries and treatment of hypertensive
patients with nebivolol significantly improved erectile function (44). More studies of the
new generation of the β-blockers are necessary to elucidate their effects on the erectile
function. Another treatment that was shown to be associated with ED is diuretic therapy.
Treatment of patients with diuretics alone or with diuretics added to their therapy was shown
to worsen sexual dysfunction (44).
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Conclusion
A common denominator in hypertension-associated ED is endothelial dysfunction. Even
though ED and hypertension are both vascular diseases, various aspects regarding the
disruption and modifications in the pathways (Figure 1) leading to hypertension and ED
remain to be elucidated. However, it is undeniable that many of the factors leading to
hypertension also have contributed significantly to the ED process, and the opposite is also
true. Also, ED can be a condition prior to hypertension or antihypertensive drug associated.
It is expected that pathophysiological modifications resulting in ED can be more useful in
the future to predict systemic vascular disorders such as hypertension.
Acknowledgments
This work was supported by NIH and Dr. Nunes is supported by AHA.
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Key Points
•Is ED an early sign for hypertension?
•Hypertension and ED are related diseases with a common etiology: endothelium
dysfunction
•Are antihypertensive drugs a solution for hypertension and yet a problem for
sexual function?
•Could ED be used to predict systemic vascular disorders such as hypertension?
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Figure 1. Pathways involved in erectile function
On the right, signaling pathways involved in mediating cavernosal smooth muscle cell (CSMC) relaxation. On the left, signaling
pathway involved in mediating CSMC contraction. During normal conditions, there is a balance between pro-erectile and pro-
relaxation signaling pathways resulting in a normal erectile function. During hypertension, there is an increase in pro-contractile
signaling and/or decrease in pro-relaxation signaling resulting in increased contractility and decrease relaxation of CSMC,
therefore, resulting in ED. Treatment with hypertensive drugs resulting in either increasing CSMC relaxation (i.e. PDEi), or
decreasing CSMC contractility (i.e. ACEi), which will result in improvement of CSMC function and improving or restoring
erectile function. Ach: acetylcholine, ACE: angiotensin converting enzyme, ACEi: ACE inhibitors, CBS: cystathionine-β-
synthase, CSE: cystathionine gamma-lyase, DAG: diacylglycerol, H2S: hydrogen sulfide, IP3: inositol 1,4,5-trisphosphate,
PIP2: phosphatidylinositol 4,5-bisphosphate, MLC: myosin light chain, MLCK: myosin light chain kinase, NO: nitric oxide,
PLC: phospholipase C, PDE: phosphodiesterase, PDEi: PDE inhibitors.
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