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New Insights into Hypertension-Associated Erectile Dysfunction


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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.
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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
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.
Erectile dysfunction; hypertension; endothelial dysfunction; antihypertensive drugs
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
*Both authors contributed equally to this manuscript.
The authors declare no conflict of interest.
NIH Public Access
Author Manuscript
Curr Opin Nephrol Hypertens. Author manuscript; available in PMC 2014 April 29.
Published in final edited form as:
Curr Opin Nephrol Hypertens. 2012 March ; 21(2): 163–170. doi:10.1097/MNH.0b013e32835021bd.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
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
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
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
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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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.
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
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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... Erectile dysfunction (ED) is a quality of life disorder and a potential warning sign of cardiovascular [1][2][3] disease that needs to be treated. It is defined as consistent or recurrent inability to achieve or maintain penile erection for satisfactory sexual 4 intercourse. ...
... It has been reported to have affected up to one third of men at one point of their lives. 5 Approximately 30 million men suffer from erectile 1,8 dysfunction in United States of America. ...
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Background: Erectile dysfunction(ED) among adult hypertensives is common, yet it is under-reported, under-diagnosed and under-treated in primary care. Screening and early diagnosis of erectile dysfunction will reduce its negative effects on the quality of life among hypertensive patients. This study was done at the Family Medicine Department of UITH, Ilorin, Kwara State. The aim was to assess the prevalence, severity pattern and physician enquiry of ED among adult hypertensives. Methods: This study is a descriptive cross-sectional hospital based study. Data was collected from 228 adult hypertensive male patients from June through August 2016 using the International Index of Erectile Function (IIEF-5), and semi-structured questionnaire and was analyzed with Statistical Package for Social Sciences (SPSS 20). Results: The prevalence of ED among respondents was 85.1%, mild in 22.4%, mild to moderate in 28.5%, moderate in 21.5 % and severe in 12.7%. Overwhelming percentage of the respondents (86.8%) had not been asked question related to ED by their physicians. Conclusion: This study showed that ED is a major problem and physician enquiry of ED among hypertensives is very poor.
... Erectile Dysfunction (ED), is defi ned as persistent inability to attain and/or maintain suffi cient erection for satisfactory sexual intercourse [1]. It appears to be an important problem among men over the age of 50 years [2]. Various cardiovascular risk factors including hypertension and diabetes induce alteration of erectile function through generalized endothelial dysfunction [3][4][5]. ...
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Objective: We assessed the frequency of erectile dysfunction and associated risk factors among diabetic patients attending Kinshasa hospitals. Methods: We enrolled 205 male diabetic patients (mean age: 53 ± 11 years) from three public hospitals at Kinshasa to assess erectile dysfunction defined by a score of 6 to 20 on International Index of Erectile Function (IIEF-5). Logistic regression model was applied to identify determinants of erectile dysfunction. A p-value ≤ 0.05 was considered significant. Results: Erectile dysfunction was observed in 59% (95% CI: 52.2 - 66%) of diabetic patients; it was mild, moderate and severe in respectively 68.6%, 25.6% and 7.5%. It commonly affected older patients (55 ± 11 years vs. 51 ± 12 years, p = 0.004) with a longer duration of diabetes (11 ± 6 years vs. 9 ± 6years, p = 0.045), abdominal obesity (p < 0.001) and diabetic retinopathy (p < 0.001). In the logistic model the odds for erectile dysfunction increased with abdominal obesity (OR: 12.9 and 95%CI [5.39-30.91]; p < 0.001), age (For age > 50 ans: 7.9 [2.62-23.74]; p < 0.001), uncontrolled diabetes (7.1 [2.43-20.62]; p < 0.001), hypertension (2.8 [1.13-6.87]; p = 0.027) and chronic kidney disease (2.5 [1.05-5.93]; p = 0.038). Conclusion: The magnitude of erectile dysfunction among diabetic patients requires early detection and precocious prevention through control of diabetes, hypertension and underlying obesity.
... Hypertension and erectile dysfunction (ED) are related diseases with a common denominator, i.e. endothelial dysfunction. Changes in the endothelium-derived factors can lead to an increase in vascular smooth muscle (VSM) contraction [58]. Hypertension induces vascular changes that affect pudendal arteries and penile vasculature leading to reduced blood circulation to the penis [59]. ...
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Hypertension and diabetes mellitus (DM) are two of the leading lifestyle diseases in the Indian and South Asian populations that often co-exist due to overlapping pathophysiological factors. Obesity, insulin resistance, inflammation, and oxidative stress are thought to be some common pathways. Up to 50% of hypertensive cases in India are diagnosed with type 2 diabetes mellitus (T2DM), which defines the need for a comprehensive guideline for managing hypertension in diabetic patients. These RSSDI guidelines have been formulated based on consultation with expert endocrinologists in India and Southeast Asia, acknowledging the needs of the Indian population. Ambulatory blood pressure monitoring and office and home-based blood pressure (BP) monitoring are recommended for the early analysis of risks. Cardiovascular risks, end-organ damage, and renal disorders are the primary complications associated with diabetic hypertension that needs to be managed with the help of non-pharmacological and pharmacological interventions. The non-pharmacological interventions include the nutrition education of the patient to reduce the intake of salt, sodium, and trans fats and increase the consumption of nuts, fresh fruits, vegetables, and potassium-rich foods. It is also recommended to initiate 50 to 60 min of exercise three to four times a week since physical activity has shown to be more beneficial for hypertension control in Indian patients than dietary modulation. For the pharmacological management of hypertension in patients with T2DM, angiotensin II receptor blockers (ARBs) are recommended as the first line of therapy, demonstrating their superiority over other antihypertensive agents such as ACEi. However, most of the global hypertension guidelines recommend initiation with combination therapy to achieve better BP control in most patients and to reduce the risk of adverse events. For combination therapy, calcium channel blockers (CCBs) are recommended to be administered along with ARBs instead of beta-blockers or diuretics to avoid the risk of cardiovascular events and hyperglycaemia. Among the CCBs, novel molecules (e.g. cilnidipine) are recommended in combination with ARBs for better cardiovascular and reno-protection in diabetic hypertensive patients.
... Low testosterone and elevated oestradiol increase the incidence of erectile dysfunction independently of each other [42] but other, non-endocrine causes include neurogenic, vascular and iatrogenic [48]. Various estimates indicate around 1:3 men are affected by ED [49,50], 30 million men to be affected by ED in United States [51] and a global ED prevalence of 3-76.5% [52]. Common to all studies, the incidence of ED increases with male age. ...
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Compared to women, increasing male age is not accompanied by such marked changes in reproductive function but changes certainly do happen. These include alterations to the hypothalamo-pituitary-testicular axis, with resultant implications for testosterone production and bioavailability as well as spermatogenesis. There is a decline in sexual function as men age, with a dramatic increase in the prevalence of erectile dysfunction after the age of 40, which is a marker for both clinically evident as well as covert coronary artery disease. Despite a quantitative decline in spermatogenesis and reduced fecundability, the male potential for fertility persists throughout adult life, however there are also increasingly recognised alterations in sperm quality and function with significant implications for offspring health. These changes are relevant to both natural and medically assisted conception.
... It has also been reported that angiotensin II (Ang II) has a crucial role in erection. Ang II levels were determined to be higher in the cavernous blood of patients with ED (Nunes et al., 2012). According to the literature, sympathetic activation and RAS have a place in the pathophysiology of non-dipper HT (White, 2007 F I G U R E 2 ROC curve analysis of international index of erectile function-5 score to predict the dipper status Carey, 2010). ...
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By the beginning of this study in 2019, it was known that hypertension is a risk factor for erectile dysfunction, and also, there are circadian changes that occur in blood pressure. Further, non-dipping hypertension is known to be linked to poor cardiac outcomes and erectile functions, so the research described in this article was initiated with an aim to explore the potential relationship between erectile dysfunction and circadian patterns of newly diagnosed hypertension. Between April 2019 and May 2022, 583 patients aged 30-70 years were diagnosed with erectile dysfunction (ED) in our outpatient clinic. Applying our exclusion criteria to 583 patients, a group of 371 patients left with us; these patients were referred to the cardiology clinic for hypertension evaluation with consecutive ambulatory blood pressure monitoring (ABPM). Data were collected for the study prospectively. Of the 371 patients evaluated with ABPM, 125 had newly diagnosed hypertension (mean BP ≥135/85 mmHg in ABPM). These patients were divided into two groups according to the pattern of hypertension identified in ABPM: dippers (Group D) and non-dippers (Group ND). They were then compared using clinical and laboratory findings, including erectile function scores. While the number of patients in the ND group was 83, the number in the D group was 42. In the ND group, the mean age was higher (59 ± 10 vs. 54 ± 12, p = 0.0024). IIEF-5 (international index of erectile function) scores were determined to be significantly lower in the ND group (14.4 ± 4.9 vs. 11.5 ± 4.6, p = 0.001). Also, serum creatinine levels were higher in Group ND than in D (0.96 ± 0.12 vs. 1 ± 0.15, p = 0.001). In our multivariate analysis, IIEF-5 scores (OR: 0.880, 95% CI: 0.811-0.955; p = 0.002) and serum creatinine levels (OR: 1027, 95% CI: 1003-1052; p = 0.025) were found to be independent risk factors of non-dipper HT. The cutoff value of the IIEF-5 score for non-dipper HT in a ROC curve analysis was 13.5 with 64.3% sensitivity and 66.1% specificity (area under curve value: 0.673 [95% CI: 0.573-0.772, p < 0.001]). This study showed that, in patients with ED, the non-dipper pattern was associated with poorer erectile function when HT was newly diagnosed. We also found that the severity of erectile dysfunction is an independent marker for non-dipper HT.
... Erectile dysfunction is the most common form of male sexual dysfunction, which affects about 30 million men in the United States [1] and is expected to impact over 300 million men worldwide by the year 2025 [2]. Prostate Cancer is one of the leading causes of cancer death in men in the US. ...
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Background Inclusion of ethnic/racial minorities in clinical trials is essential to fully assess therapeutic efficacy. It is well-known that populations respond dissimilarly to interventions. Our objective is to analyze the inclusion of minority men in clinical trials for erectile dysfunction (ED). Methods We searched for the disease keyword: “Erectile Dysfunction (ED)” and used “Prostate Cancer” for comparison. Completed trials which reported demographic data were included for analysis. Literature was reviewed to determine the prevalence of ED and prostate cancer (PC) among Hispanic, Black, White, and Asian men. The proportion of individuals of each group that participated in trials is divided by the proportion of each group in the disease population to calculate the “Participation to Prevalence Ratio” (PPR). PPRs between 0.8-1.2 indicates adequate representation, <0.8 is under-representation and >1.2 is over-representation. Results A total of 312 trials were assessed: 289 for prostate cancer and 23 for ED. Hispanic men comprised 11.8% of ED trial participants and 4.61% of prostate cancer trial participants, yet represented 18% of ED patients and 7.3% of PC patients. Black/African-American (AA) men accounted for 10.2% of ED trial participants and 9.4% of PC trial participants, but comprise 16% of ED patients, and 16.3% of PC patients. Hispanic and AA men are under-represented in trials for ED and Prostate Cancer (Hispanic ED PPR = 0.66; Hispanic PC PPR = 0.63; AA ED PPR = 0.42; AA PC PPR = 0.58). Conclusion Our analysis shows that both Hispanic and AA men are underrepresented in both ED and PC clinical trials.
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Chronic liver diseases (CLDs) are characterized by progressive necrosis of hepatocytes, which leads to liver fibrosis and cirrhosis, and ultimately liver dysfunction. The statistics of 2020 shows that the number of patients with CLDs, including chronic hepatitis, fatty liver, and cirrhosis, may exceed 447 million in China. The liver is a crucial organ for the metabolism of various substances, including sex hormones and lipids. CLDs frequently result in abnormalities in the metabolism of sex hormones, glucose, and lipids, as well as mental and psychological illnesses, all of which are significant risk factors for erectile dysfunction (ED). It has been reported that the prevalence of ED in male patients with CLDs ranges from 24.6 to 85.0%. According to a survey of Caucasians, liver transplantation may improve the erectile function of CLDs patients with ED. This finding supports the link between CLDs and ED. In addition, ED is often a precursor to a variety of chronic diseases. Given this correlation and the significant prevalence of CLDs, it is important to evaluate the epidemiology, risk factors, etiology, and treatment outcomes of ED in male patients with CLDs, expecting to attract widespread attention.
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Erectile dysfunction (ED) is considered a public health problem with numerous risk factors, such as hypertension. Besides the existing oral treatment for ED, there are individuals that do not respond to or present numerous side effects to this therapy. Changes in the TRP channels can lead to several clinical complications, such as hypertension. More specifically, the cooling-sensing TRPM8 channel could be a novel target for the development of new drugs. In this line, menthol, a natural product TRPM8 channel agonist may be a molecule for use to treat erectile dysfunction. Then, we conducted a patent review to evaluate the application of menthol focusing on the treatment of erectile dysfunction. The search was conducted on Espacenet® associating A61K31/045 and A61K36/534 codes or using keywords, "erectile dysfunction AND menthol". We analyzed 1,331 patents, which fourteen patents were found with the use of menthol in the genitourinary system. Although the patents had menthol in their formulations, none went directly to the development of pharmaceutical applications to treat erectile dysfunction. Taking these data into account, the use of menthol in the treatment of erectile dysfunction has been underexplored and is an opportunity for research and technological development based on a high innovation potential.
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Sexual dysfunction (SD) is a prevalent but very commonly ignored aspect in the treatment of liver diseases and cirrhosis. The etiology of SD is multifactorial and therefore treatment strategies are complex, especially in females. Phosphodi- esterase inhibitors are useful and effective in erectile dysfunction in males but in females, no single drug is available for SD, therefore multimodal treatment is required depending upon the cause. The foremost and fundamental requirement in both genders is to be stress-free and have adequate control of liver diseases. Improved quality of life is helpful in improving SD and vice versa is also true. Therefore, patients suffering from liver diseases should come forward and ask for treatment for SD, and physicians should actively enquire about SD while history taking and evaluating these patients. SD results in deterioration of quality of life, and both are modifiable and treatable aspects of liver diseases, which are never addressed actively, due to social taboos and fears of SD treatment in the presence of liver diseases. The diagnosis of SD does not require costly investigations, as the diagnosis can be established based on validated questionnaires available for both genders, therefore detailed targeted history taking using questionnaires is essential. Data are emerging in this area but is still at an early stage. More studies should be dedicated to SD in liver diseases.
Sildenafil (SIL) is widely used to treat erectile dysfunction. Information on its consumption and the factors influencing its use is limited in China. In this study, we sampled composite influent wastewater samples from 33 Chinese cities and analyzed SIL using liquid chromatography-tandem mass spectrometry. SIL consumption was estimated using wastewater-based epidemiology (WBE) and ranged from 10.6 mg/d/1000 people to 132 mg/d/1000 people, with a mean of 53 mg/d/1000 people. Prescription sales (3570 kg) accounted for 13.3% of the estimated SIL use (26842 kg) in 2018, thereby implying that SIL illicit use was greater than prescription use in China. Some regional differences were observed in SIL use, which was significantly higher in North China than South China (p<0.05), thereby reflecting that the prevalence of SIL was affected by differences in lifestyle and socioeconomic factors. We found significant positive correlations between SIL use and consumption of allopurinol, hydrochlorothiazide, nicotine, and alcohol, thereby suggesting that the prevalence of SIL was associated with the prevalence of gout, hypertension, smoking, and drinking. Moreover, age structures, internet use, and marriage rates were positively correlated with SIL use, whereas the unemployment rate was negatively correlated with SIL use. Our study demonstrates that WBE is valuable for medical research to investigate licit and illicit drug use and to assess the underlying associations of different chemical uses.
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Hydrogen sulfide (H(2)S) is a gaseous transmitter involved in the control of vascular homeostasis. H(2)S is formed endogenously from L-cysteine or L-methionine by two enzymes, cystathionine beta-synthase (CBS) and cystathionine gamma-lyase (CSE), and normally circulates in blood. Studies from the past few years have demonstrated the involvement of H(2)S in erectile mechanisms in animal and human tissues. Exogenous H(2)S relaxes human and animal tissues in vitro and increases intracavernous pressure in experimental animal models. Electrical field stimulation studies on animal and human tissues have demonstrated that endogenous H(2)S is involved in the physiological control of penile tone. In humans, both CBS and CSE are widely expressed on trabecular muscle, implying that the smooth muscle component is the major source of H(2)S. Thus, the L-cysteine-H(2)S pathway may represent a promising target for development of new therapeutics for erectile dysfunction.
KEY POINTS AND PRACTICAL RECOMMENDATIONS: •  Calcium channel blockers, which dilate arteries by reducing calcium flux into cells, effectively lower blood pressure, especially in combination with other drugs, and some formulations of agents of this class are approved for treating angina or cardiac dysrhythmias. •  Calcium channel blockers reduce blood pressure across all patient groups, regardless of sex, race/ethnicity, age, and dietary sodium intake. •  Nondihydropyridine calcium channel blockers are more negatively chronotropic and inotropic than the dihydropyridine subclass, which is important for patients with cardiac dysrhythmias or who need β-blockers. •  Extensive experience in comparative randomized trials indicates that an initial calcium antagonist can prevent all major types of cardiovascular disease, except heart failure (for which a diuretic is superior). Initial dihydropyridine calcium channel blockers have not reduced the rate of progression of renal disease as well as inhibitors of the renin-angiotensin system, although members of the nondihydropyridine subclass can reduce albuminuria. •  High doses of dihydropyridine calcium channel blockers often cause edema, headache, flushing and tachycardia; high doses of verapamil can cause constipation. Diltiazem and verapamil have important drug interaction with digoxin and cyclosporine, among others.
To our knowledge the interaction between angiotensin II and nitric oxide in the control of human corpus cavernous function has not been assessed previously. We determined the presence and role of angiotensin II and its receptors in human penile function. Corpus cavernous tissue was obtained from 35 patients undergoing gender reassignment surgery. Immunohistochemical analysis was done to determine angiotensin II peptide tissue distribution. Organ bath studies were done to determine the angiotensin II/nitric oxide interaction on corpus cavernous smooth muscle function. The role of oxidative stress in the angiotensin II response was also examined using the nicotinamide adenine dinucleotide phosphate oxidase inhibitor apocynin. Angiotensin II was distributed in arteriolar endothelium, endothelium lining sinusoids and smooth muscle cells, and caused dose dependent contraction of human corpus cavernous smooth muscle strips that was inhibited by the angiotensin type 1 receptor antagonist losartan. Relaxation of corpus cavernous smooth muscle induced by the nitric oxide donor sodium nitroprusside or electrical field stimulation was potentiated by losartan. Apocynin decreased angiotensin II induced corpus cavernous contraction. Angiotensin II and nitric oxide interact to modulate human cavernous function since losartan potentiated sodium nitroprusside and electrical field stimulation mediated corpus cavernous smooth muscle relaxation. The angiotensin II response involves the production of superoxide and the development of oxidative stress. These findings support the role of angiotensin II in the regulation of human penile smooth muscle tone and suggest that angiotensin type 1 receptor inhibition may be a therapeutic approach to erectile dysfunction.
The current pharmacotherapy for erectile dysfunction (ED) relies significantly on the use of phosphodiesterase type 5 (PDE5) inhibitors, but quite a proportion of ED patients are resistant to this therapy, necessitating a search for an alternative treatment. We reviewed available published data to analyze current evidence of hydrogen sulfide (H(2) S) as a novel pharmacotherapeutic agent with supportive role in sexual function. To discuss the role of H(2) S in erectile function, its possible mechanism of action, and how this knowledge may be exploited for therapeutic use. Pubmed and Medline search was conducted to identify original articles and reviews. Data from peer-reviewed publications. Animal studies using different species, including in vitro study done in humans, show evidence of H(2) S's pro-erectile effects. The mechanism behind is still unclear, but evidence in literature points out the involvement of K(+) (ATP) channel, modulation of protein with anti-erectile effects, as well as involvement of the nitrergic pathway through a complex cross-talk. A new drug called H(2) S-donating sildenafil (ACS6), which incorporated an H(2) S-donating moiety in sildenafil, has been developed. While more studies are still needed, this heralded a new pharmacotherapeutical approach, which is multipronged in nature. Given the mounting evidence of H(2) S's role in erectile function and how it appears to achieve its pro-erectile effects through different mechanisms, H(2) S represents a potentially important treatment alternative or adjunct to PDE5 inhibitors.
National and international guidelines still recommend β-blockers (BBs) as first-line agents in uncomplicated prevention of hypertension. However, it has been shown that BBs reduce blood pressure less than other drugs, specifically with regard to central aortic pressure. More importantly, recent meta-analyses have highlighted that in primary prevention BBs are associated with a relatively weak effect in reducing stroke compared to placebo or no treatment and, compared with other drugs, show evidence of a worse cardiovascular outcome. Several reasons might explain their mild cardioprotective effect, such as their unfavorable metabolic properties, a lack of efficacy on left ventricular hypertrophy regression and endothelial dysfunction, and reduced patient compliance. Thus, the available evidence does not support the use of BBs as first-line drugs in the treatment of uncomplicated hypertension. It remains to be determined whether newer BBs, such as nebivolol and carvedilol, will be more effective than older compounds in improving cardiovascular prognosis.
Erectile dysfunction (ED) is common and a significant contributor to poor quality of life and psychosocial morbidity in men. Normal erectile function requires effective co-ordination between a number of complex neural pathways. Penile tumescence occurs in response to rapid arterial inflow to the corpora cavernosa with simultaneous venous outflow restriction due to expansion of the lacunar spaces. This process is under both central and local neuromediation. Endothelins are potent vasoconstrictor peptides that cause strong, slowly developing but sustained contraction of trabecular smooth muscles cells of the corpora cavernosa. Multiple mechanisms of action are proposed, including transmembrane calcium flux, mobilisation of inositol triphosphate sensitive intracellular calcium stores and calcium sensitisation through the Rho-Rho kinase pathway. The exact role of endothelins in the pathogenesis of ED currently remains unclear. Elevated endothelin-1 levels are found in patients with diabetes mellitus and this alone may be sufficient to cause ED. However, this is not borne out in clinical studies. The resultant elevated intracellular calcium may, however, modulate gene expression sufficiently to cause smooth muscle proliferation. Alternatively, alterations in endothelin receptor sensitivity in conditions such as diabetes and hypertension may enhance vasoconstrictor processes. Currently there is contradictory evidence for the role of endothelin receptor antagonists in ED. Animals studies suggest they inhibit corporal vasoconstriction, improve erectile function and protect against diabetes-induced smooth muscle apoptosis. However, the results of clinical studies in ED have been less promising. Uncertainty regarding the exact role of endothelin in penile erection hampers progress in this area. It is possible that the endothelin system may only be relevant to ED in certain conditions where global endothelial dysfunction exists (e.g. diabetes mellitus, systemic sclerosis) and the use of endothelin antagonists in these patient groups may yield improved outcomes.
Previous studies have shown an increased incidence of erectile dysfunction (ED) among patients diagnosed with cardiovascular disease (CVD). Both conditions, which may be a consequence of underlying endothelial dysfunction, share many risk factors such as hypertension, dyslipidemia, diabetes, depression, obesity, and cigarette smoking. Because vascular disturbance of the penile endothelium leads to ED, the possibility arises that ED may be an early indicator for systemic endothelial dysfunction and subsequent CVD. Recognizing ED as a disease marker for CVD may help to identify individuals at risk for having a premature cardiovascular event.
RhoA/Rho-kinase pathway plays an important role in many pathological conditions. RhoA participates in the regulation of smooth muscle tone and activates many downstream kinases. The best characterized are the serine/threonine kinase isoforms (Rho-kinase or ROCK), ROCKα/ROCK2 and ROCKβ/ROCK1. ROCK is necessary for diverse functions such as local blood flow, arterial/pulmonary blood pressure, airway resistance and intestinal peristalsis. ROCK activation permits actin/myosin interactions and smooth muscle cells contraction by maintaining the activity of myosin light-chain kinase, independently of the free cytosolic calcium level. The sensitization of smooth muscle myofilaments to calcium has been implicated in many pathological states, such as hypertension, diabetes, heart attack, stroke, pulmonary hypertension, erectile dysfunction, and cancer. The focus of this review is on the involvement of RhoA/Rho-kinase in diseases. We will briefly describe the ROCK isoforms and the role of RhoA/Rho-kinase in the vasculature, before exploring the most recent findings regarding this pathway and various diseases.