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Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical Design
Volume 14, Number 35, 2008
Contents
Drugs Targeted to Improve Endothelial
Function: Clinical Correlates Between Sexual and Internal
Medicine
Executive Editor: Antonio Aversa
Editorial: Pp.
3698-3699
The Triad: Erectile Dysfunction - Endothelial Dysfunction-
Cardiovascular Disease Pp. 3700-3714
C. Vlachopoulos, N. Ioakeimidis, D. Terentes-Printzios
and C. Stefanadis
[Abstract] [Purchase
Article] [PMID: 19128223 PubMed - indexed for MEDLINE]
Non-Invasive Diagnostic Tools for Investigating
Endothelial Dysfunction Pp. 3715-3722
L. Ghiadoni, D. Versari, C. Giannarelli,
F. Faita and S. Taddei
[Abstract] [Purchase
Article] [PMID: 19128224 PubMed - indexed for MEDLINE]
The Brain, the Penis and Steroid Hormones:
Clinical Correlates with Endothelial Dysfunction Pp.
3723-3736
A.M. Traish, H. Abu-Zahra and A.T.
Guay
[Abstract] [Purchase
Article] [PMID: 19128225 PubMed - indexed for MEDLINE]
Abnormal Insulin Signaling: Early Detection
of Silent Coronary Artery Disease-Erectile Dysfunction?
Pp. 3737-3748
M.A. Potenza and M. Montagnani
[Abstract] [Purchase
Article] [PMID: 19128226 PubMed - indexed for MEDLINE]
The Mineralocorticoid Receptor in Endothelial
Physiology and Disease: Novel Concepts in the Understanding
of Erectile Dysfunction Pp. 3749-3757
M. Caprio, C. Mammi, I.Z. Jaffe, M.-C. Zennaro, A. Aversa,
M.E. Mendelsohn, A. Fabbri and G.M.C. Rosano
[Abstract] [Purchase
Article] [PMID: 19128227 PubMed - indexed for MEDLINE]
Drugs Designed to Improve Endothelial
Function: Effects on Erectile Dysfunction Pp.
3758-3767
A.W. Shindel, S. Kishore and T.F.
Lue
[Abstract] [Purchase
Article] [PMID: 19128228 PubMed - indexed for MEDLINE]
Endothelial Effects of Drugs Designed
to Treat Erectile Dysfunction Pp. 3768-3778
A. Aversa, M. Caprio, G.M.C. Rosano and
G. Spera
[Abstract] [Purchase
Article] [PMID: 19128229 PubMed - indexed for MEDLINE]
Abstracts
[Back to top]
Editorial: Drugs Targeted to Improve Endothelial Function:
Clinical Correlates Between Sexual and Internal Medicine
Advances in genomics and proteomics have uncovered
an expansive array of site-specific properties of the endothelium.
Amongst the physiological role of endothelium, it mediates
vasomotor tone, regulates cellular and nutrient trafficking,
maintains blood fluidity, contributes to the local balance
between pro- and anti-inflammatory mediators as well as procoagulant
and anticoagulant activity, participates in generation of
new blood vessels, and undergoes programmed cell death. Such
heterogeneity provides the endothelium with remarkable flexibility
and the capacity to respond to the unique needs of the underlying
tissue.
Endothelial dysfunction occurs in a variety of pathological
conditions in internal medicine, such as atherosclerosis,
hypercholesterolemia, type2-diabetes/metabolic syndrome, hypertension,
heart failure, cigarette smoking, recreational drugs abuse;
the incidence of sexual dysfunctions in such conditions is
much increased. The reciprocal relationship between endothelial
dysfunction and sexual medicine is based on the scientific
agreement that erectile dysfunction (ED), benign prostatic
hyperplasia and Peyronie’s disease are believed to be
vascular diseases in which endothelial dysfunction represents
one of the common etiological factors. Despite this, drugs
improving endothelial function, i.e. anti-hypertensives, statins,
antioxidants etc. are able to prevent the progression of atherosclerosis
but mildly improve erectile function per se since
they lack specificity of action at the level of the penile
vasculature and smooth muscle cells. Phosphodiesterase type-5
inhibitors (PDE5-i) are a class of new on-demand drugs that
have revolutionized the treatment of male ED [1]. Sildenafil
began as a potential alternative agent to oral nitrates for
the treatment of stable angina pectoris, but its short half-life
and modest nitrate-like hemodynamic effects were not seen
as a clinical advance. During chronic dosing studies, improved
erections were reported, and this led to sildenafil development
as a treatment for ED over ten years ago. Soon further, research
has focused on more potent (vardenafil) and long-acting (tadalafil)
drugs belonging to the same pharmacologic class, in order
to accomplish different patients’ requests. Their oral
acceptability and success rate rapidly moved them into the
treatment of first choice for most men with ED. Evidence-based
medicine regarding alternative PDE5-i dosing e.g. once-a-day
is now growing.
This issue of Current Pharmaceutical Design focuses on the
most recent knowledge regarding clinical correlates between
sexual and internal medicine. Vlachopoulos et al.
[2] report about the frequent association between endothelial
dysfunction, atherosclerosis and ED, suggesting that this
latter condition carries an incremental risk for future cardiovascular
events; symptoms of ED may precede clinical cardiac manifestations
usually by 3-4 years. They conclude that ED symptoms should
prompt cardiac risk assessment. Ghiadoni et al. [3]
remind us that no available test to assess endothelial function
has sufficient sensitivity and specificity to be used yet
in clinical practice. They conclude that only once a specific
and affordable test has been validated, and definite evidence
becomes available to demonstrate that endothelial dysfunction
must be a target of pharmacological treatment, the evaluation
of endothelium-dependent vasodilation would be included in
the list of clinical examinations for assessing early vascular
alterations also in patients at risk for developing ED.
The cerebral and peripheral vasculatures are a target tissue
for sex steroid hormones which play an important role in maintaining
endothelial health; sex steroid deficiency is associated with
endothelial dysfunction, vascular disease and ED. Traish et
al. [4] suggest that clinical conditions such as metabolic
syndrome, obesity or type-2 diabetes mellitus are associated
with sexual steroid hormone insufficiency, and this may determine
a dysregulation of endothelial function thus contributing
to the pathogenesis of ED. Whether adipose tissue accumulation
is able to inhibit testosterone production or decreasing testosterone
levels with ageing may contribute to visceral obesity and
increased CVD incidence is not known yet. The role of adipose
tissue deposition and increased waist circumference in men
seems to be the predominant mechanism that predisposes to
metabolic disorders in which insulin resistance plays a central
role. To this purpose, Potenza and Montagnani [5] discuss
on the role of insulin physiology in determining correct endothelial
functioning. Interestingly, they demonstrate that derangement
of the insulin signaling into the cell leads to insulin resistance/endothelial
dysfunction which precedes structural changes and clinical
appearance of cardiovascular complications. Also, they propose
ED as a sentinel symptom in patients with insulin resistance
conditions.
Aldosterone is recognized as an important player in cardiovascular
disease. The prevalence of primary hyperaldosteronism is approximately
6% in the general population, raising up to 20% in patients
with resistant hypertension. Emerging data suggest that aldosterone
up-regulates the rho-kinase calcium sensitizing pathway and
this might therefore cause a deterioration of cardiac function
[6]. Animal models suggested the involvement of this pathway
in the development of vasculogenic ED [7]. Caprio et al.
[8] herein suggest that an excess of mineralocorticoid receptor
activation may have a negative impact on endothelial function
hence playing a role in the pathogenesis of vasculogenic ED.
The use of newest and more tissue-selective mineralocorticoid
receptor antagonists might be hypothesized to be beneficial
in treating hypertensive patients with concomitant ED. Other
cardiovascular medications have mechanisms of action that
involve the endothelium (statins, ACEI, ARB, β-blockers),
and some of them have been found to improve penile erection,
although an endothelium-dependent mechanism has not been conclusively
demonstrated. After a critical revision of the literature,
Shindel et al. [9] conclude that no endothelial active
drugs can be recommended as mono-therapy for the treatment
of ED.
The role of PDE5-i beyond the treatment of ED is still controversial.
A great debate against or in favor once-daily administration
of PDE5-i for endothelial rehabilitation exists, since it
has been demonstrated that these drugs do not produce sustained
clinical benefits on erection beyond cessation of treatment
above those observed with on-demand administration. Aversa
et al. [10] discuss these critical issues, suggesting
that PDE5-i have the potential to improve both ED and endothelial
dysfunction during continuous assumption especially in patients
in whom endothelial function is impaired, without negative
impact regarding safety. Unlike pulmonary hypertension, for
which sildenafil may provide a net cost savings compared with
inhaled or intravenous medications, daily PDE5-i use may be
actually limited by high costs, given the average intercourse
frequency of five to six times per month. Should lower-dose
daily administration confirm attractive efficacy and safety
profiles compared with on-demand use, and equivalent net monthly
cost approach, once-a-day PDE5-i use will become an important
treatment option especially in the internal medicine patients
in whom endothelial dysfunction is present.
This issue is dedicated to my wife Emanuela, and to my sons
Elena and Alessandro.
References
[1] Barbaro G. Phosphodiesterase 5 inhibitors: Pharmacology
and therapeutic perspectives. Curr Pharm Des 2006; 12: 3437.
[2] Vlachopoulos C, Ioakeimidis N, Terentes-Printzios D, Stefanadis
C. The triad: erectile dysfunction - endothelial dysfunction-cardiovascular
disease. Curr Pharm Des 2008; 14(35): 3700-3714.
[3] Ghiadoni L, Versari D, Giannarelli C, Faita F, Taddei
S. Non-invasive diagnostic tools for investigating endothelial
dysfunction. Curr Pharm Des 2008; 14(35): 3715-3722.
[4] Traish AM, Abuzahra H, Guay AT. The brain, the penis and
steroid hormones: clinical correlates with endothelial dysfunction.
Curr Pharm Des 2008; 14(35): 3723-3736.
[5] Potenza MA, Montagnani M. Abnormal insulin signaling:
early detection of silent coronary artery disease-erectile
dysfunction? Curr Pharm Des 2008; 14(35): 3737-3748.
[6] Doi T, Sakoda T, Akagami T, Naka T, Mori Y, Tsujino T,
et al. Aldosterone induces interleukin-18 through
endothelin-1, angiotensin II, Rho/Rho-kinase, and PPARs in
cardiomyocytes. Am J Physiol Heart Circ Physiol 2008; 295(3):
H1279-87.
[7] Park K, Kim SW, Rhu KS, Paick JS. Chronic administration
of an oral Rho kinase inhibitor prevents the development of
vasculogenic erectile dysfunction in a rat model. J Sex Med
2006; 3: 996-1003.
[8] Caprio M, Mammi C, Jaffe IZ, Zennaro MC, Aversa A, Mendelsshon
M, et al. The mineralocorticoid receptor in endothelial
physiology and disease: novel concepts in the understanding
of erectile dysfunction. Curr Pharm Des 2008; 14(35): 3749-3757.
[9] Shindel AW, Kishore S, Lue TF. Drugs designed to improve
endothelial function: effects on erectile dysfunction. Curr
Pharm Des 2008; 14(35): 3758-3767.
[10] Aversa A, Caprio M, Rosano GMC, Spera G. Endothelial
effects of drugs designed to treat erectile dysfunction. Curr
Pharm Des 2008; 14(35): 3768-3778.
Antonio Aversa MD, PhD
Chair of Internal Medicine
Dept. of Medical Pathophysiology
Sapienza University of Rome
Rome
Italy
[Back to top]
[Purchase
Article] [PMID: 19128223 PubMed - indexed for MEDLINE]
The Triad: Erectile Dysfunction - Endothelial Dysfunction-
Cardiovascular Disease
C. Vlachopoulos, N. Ioakeimidis, D. Terentes-Printzios
and C. Stefanadis
Endothelial dysfunction is an important process in the
development of atherosclerotic cardiovascular disease, while
it is also a major pathophysiological mechanism underlying
vasculogenic erectile dysfunction (ED). Expectedly, these
two prevalent disorders are linked also at the clinical level:
ED is common in patients with overt and silent coronary artery
disease, while ED is increasingly being regarded as the early
clinical manifestation of a generalized vascular disease and
carries an independent risk for future cardiovascular events.
The emerging awareness of ED as a barometer for cardiovascular
disease offers a unique opportunity to enhance preventive
vascular health in men. Lifestyle and risk factor modification,
as well as pharmacologic therapy (both phosphodiesterase type-5
inhibitors and non-ED-targeting drugs), appear to confer additional
benefit both in terms of ED treatment and overall cardiovascular
risk; this benefit may be related, at least partly, to the
improvement of endothelial function and anti-inflammatory
effects. The present review identifies pathophysiologic links
between endothelial dysfunction, ED and coronary artery disease,
presents methodological aspects regarding penile and systemic
endothelial function, and discusses the clinical implications
in terms of diagnosis of ED, assessment of patient risk, and
treatment.
[Back to top]
[Purchase
Article] [PMID: 19128224 PubMed - indexed for MEDLINE]
Non-Invasive Diagnostic Tools for Investigating Endothelial
Dysfunction
L. Ghiadoni, D. Versari, C. Giannarelli,
F. Faita and S. Taddei
The endothelium is not merely a barrier but it plays
a key role in the maintenance of vascular homeostasis.
A dysfunctional endothelium is an early marker of the development
of atherosclerotic changes and can also contribute to cardiovascular
events. Vascular reactivity tests represent the most widely
used methods in the clinical assessment of endothelial function
and in the last two decades, several methodologies were developed
to study it non invasively in the peripheral macrocirculation
(conduit arteries) and microcirculation (resistance arteries
and arterioles). This review will centre on the most relevant
available non-invasive techniques in the research on endothelial
function, their advantages and limitations.
Flow mediated dilation (FMD) of the brachial artery by ultrasounds
is the most widely used vascular test to assess endothelium-dependent
vasodilation. Other approaches include measurement of microcirculatory
reactive hyperaemia by forearm venous pletysmography or digital
pulse amplitude tonometry, response to β2
agonist by applanation tonometry or digital photoplethysmography
and several test by skin laser doppler. It appears that FMD
is the most reproducible test when an appropriate and accurate
methodology is applied.
Recently, post-ischemic vasodilation in the cavernous arteries
was also suggested to study endothelial function in patients
with erectile dysfunction. Systemic markers proposed as measures
of NO biology, inflammatory cytokines, adhesion molecules,
or markers of endothelial damage and repair have only a very
limited role as a result of biological and assay availability
and variability, these factors currently have a limited role
in the assessment of individual patients. The optimal methodology
for investigating the multifaceted aspects of endothelial
dysfunction is still under debate. Therefore, no available
test to assess endothelial function has sufficient sensitivity
and specificity to be used yet in clinical practice. Only
the growing concordant results from different reproducible
and reliable non-invasive methods exploring endothelial function
with different stimuli will support and strengthen experimental
findings, thus providing conclusive answers in this area of
research.
[Back to top]
[Purchase
Article] [PMID: 19128225 PubMed - indexed for MEDLINE]
The Brain, the Penis and Steroid Hormones: Clinical Correlates
with Endothelial Dysfunction
A.M. Traish, H. Abu-Zahra and A.T.
Guay
Erectile function is a complex neurovascular process
that depends on the health of the central and peripheral nervous
systems and the vasculature. Thus, signaling from the central
nervous system (brain) to the peripheral nervous system (penis)
is critical and is modulated by a set of complex interactions
that depend on cerebral and vascular circulation. The cerebral
and peripheral vasculatures are target tissues for sex steroid
hormones. Gonadal, adrenal and neurosteroids regulate the
function and physiology of the endothelium and modulate vascular
and cerebral circulation by genomic and non-genomic dependent
mechanisms. Recent advances in cell and molecular biology
have defined a critical role of endothelium in vascular function.
A host of biochemical and clinical markers of endothelium
function and dysfunction have been identified to assess vascular
pathology. Emerging evidence suggests that sex steroid hormones
play an important role in maintaining endothelial health and
sex steroid deficiency is associated with endothelial dysfunction,
vascular disease and erectile dysfunction. Such information
has important clinical implications in patient management
with sex steroid hormone insufficiency, diabetes, metabolic
syndrome, vascular disease and erectile dysfunction. In this
review, we discuss the role of sex steroid hormones in modulation
of the biochemical and clinical markers associated with endothelial
dysfunction. Specifically the regulation of endothelial nitric
oxide synthase, assymetric dimethylarginine, reactive oxygen
species, endothelin-1, inflammatory cytokines, tumor necrosis
factor-α,
markers of cell adhesion, dysregulation of fibrinolytic factors
and the inability to regenerate from endothelial progenitor
cells concomitant with increased endothelial apoptosis, increased
cellular permeability and increased vascular tone.
[Back to top]
[Purchase
Article] [PMID: 19128226 PubMed - indexed for MEDLINE]
Abnormal Insulin Signaling: Early Detection of Silent Coronary
Artery Disease-Erectile Dysfunction?
M.A. Potenza and M. Montagnani
Coronary Artery Disease (CAD) and erectile dysfunction
(ED) are cardiovascular complications frequently occurring
in patients with diabetes, obesity, and dyslipidemia. All
these metabolic disorders are characterized by insulin resistance,
defined as decreased sensitivity and/or responsiveness to
metabolic actions of insulin promoting glucose disposal. Insulin
resistance is not only a hallmark of metabolic abnormalities,
but also a prominent feature of haemodynamic disorders. Indeed,
insulin-stimulated release of endothelial factors takes part
into the physiological regulation of vascular function, and
altered insulin actions may profoundly affect cardiovascular
homeostasis under metabolic derangement.
The signpost of impaired vascular reactivity is endothelial
dysfunction, a condition in which the endothelium loses its
physiological ability to produce the vasodilator nitric oxide
(NO). A number of molecular, cellular, physiological, and
clinical studies have indicated that insulin resistance may
impair NO release and damage endothelial function through
several patho-physiological mechanisms reciprocally interconnected.
Although considered the earliest marker of impaired vascular
health, endothelial dysfunction is initially asymptomatic;
additional changes in the vessel structure are usually required
before vascular complications manifest. Nevertheless, endothelial
dysfunction may become clinically evident when endothelial-mediated
relaxation is necessary and sufficient to exert a specific
effect. ED may be the first expression of endothelial dysfunction,
and therefore represents a sentinel event in the clinical
appearance of silent CAD.
Thus, insulin resistance triggers endothelial dysfunction,
and endothelial dysfunction may manifest as ED long before
CAD or other vascular complications become clinically evident.
This review briefly outlines the main characteristics of endothelial
function and dysfunction, and describes the signaling pathways
involved in cardiovascular actions of insulin under physiological
and pathological conditions. Moreover, potential cellular
and molecular mechanisms linking insulin resistance to early
CAD-ED detection are also illustrated.
[Back to top]
[Purchase
Article] [PMID: 19128227 PubMed - indexed for MEDLINE]
The Mineralocorticoid Receptor in Endothelial Physiology and
Disease: Novel Concepts in the Understanding of Erectile Dysfunction
M. Caprio, C. Mammi, I.Z. Jaffe, M.-C. Zennaro, A. Aversa,
M.E. Mendelsohn, A. Fabbri and G.M.C. Rosano
Aldosterone is a steroid hormone that controls blood
pressure by binding to the mineralocorticoid receptor (MR),
a ligand-activated transcription factor, and regulating genes
that play a role in salt and water homeostasis in the kidney.
Dysregulation of the mineralocorticoid system reveals its
crucial role in various human diseases including hypertension,
atherosclerosis, cardiac failure, mineralocorticoid resistance,
and disorders of the nervous system. Recently, experimental
animal models of mineralocorticoid/salt-induced hypertension
and atherosclerosis have revealed an epithelial, pro-inflammatory
role for MR activation. Extensive investigation has begun
to elucidate the mechanisms underlying the vascular effects
of MR activation which involve its direct role in cardiomyocytes,
vascular smooth muscle cells, and endothelial cells. More
specifically, in patients with cardiovascular risk factors
and disease, including diabetes, hypertension, and/or congestive
heart failure, an excess of MR activation has been shown to
have a negative impact on endothelial function hence disrupting
the physiological balance between vasoconstriction and vasodilation.
Such a mechanism may play a role in the pathogenesis of erectile
dysfunction (ED), a condition that occurs frequently in patients
with increased cardiovascular risk and involves endothelial
dysregulation of vascular relaxation.
The aim of this review is to summarize the latest concepts
in MR signaling, with particular attention to the endothelium,
and to discuss the potential benefits of tissue-selective
MR blockade in treating subsets of ED patients, such as those
with congestive heart failure and hypertension, in which the
MR system may be over activated.
[Back to top]
[Purchase
Article] [PMID: 19128228 PubMed - indexed for MEDLINE]
Drugs Designed to Improve Endothelial Function: Effects on
Erectile Dysfunction
A.W. Shindel, S. Kishore and T.F.
Lue
Endothelial dysfunction (EtD) has emerged as a critical
master pathway in the pathogenesis of both vascular disease
and erectile dysfunction (ED). Drugs that have been developed
for vascular diseases and/or found to have beneficial endothelial
effects may be helpful in the management of ED. In this manuscript
we summarize the current state of the art with respect to
endothelial active drugs and discuss the evidence supporting
their use in the management of ED. Pubmed query for the terms
Endothelial dysfunction, erectile dysfunction, pharmaceuticals,
“endothelium”, “function”, “pharmaceutical”,
“eNOS”, “erectile dysfunction” and
“erectile function” was conducted. Relevant articles
were reviewed and summarized. A variety of cardiovascular
medications have mechanisms of action that involve the endothelium.
Examples include HMG-CoA Reductase inhibitors (“statins”),
Angiotensin Converting Enzyme Inhibitors (ACEI), Angiotensin
Receptor blockers (ARB), Endothelin Receptor Antagonists (ERA),
certain beta blockers, and some oral hypoglycemics. Some of
these drugs have been found to improve penile erection, although
an endothelium dependent mechanism has not been conclusively
demonstrated in all studies.
Drugs that improve endothelial function in the cavernous arteries
and the erectile tissues of the corpora cavernosa hold great
promise in treating or at least minimizing the vascular damage
that contributes to ED. ACEI and ARB appear to hold great
promise in this regard, while statins and oral hypoglycemics
may play a potentially useful role as adjunctive therapy for
ED. Improvements in endothelial function may help reverse
ED in some cases, which would be a marked improvement over
management with currently available “on demand”
ED therapies.
[Back to top]
[Purchase
Article] [PMID: 19128229 PubMed - indexed for MEDLINE]
Endothelial Effects of Drugs Designed to Treat Erectile Dysfunction
A. Aversa, M. Caprio, G.M.C. Rosano and
G. Spera
Erectile dysfunction (ED) and endothelial dysfunction
are common in individuals with multiple cardiovascular risk
factors (CRFs) and are longitudinal predictors of cardiovascular
events. ED is associated with systemic endothelial cell activation/dysfunction
independent from CRFs or from diffuse, unrecognized vascular
damage. The pathogenesis of endothelial dysfunction and ED
is intimately linked through decreased expression and activation
of endothelial nitric oxide (NO) synthase and the subsequent
physiologic actions of NO. Furthermore, reduced biologic activity
of endothelium-derived NO links atherosclerosis to ED and
underscores the role of altered endothelium in the pathogenesis
of both conditions. Evidence-based data suggest that daily
use of phosphodiesterase type-5 inhibitors (PDE5-i) improves
endothelial and erectile functions and that this benefit is
lost upon drug withdrawal. Daily PDE5-i may also improve lower
tract urinary symptoms related to benign prostatic hyperplasia
through a reduction of adrenergic overtone. The relevance
for these drugs in the prevention of complications in internal
medicine diseases, i.e. cardiovascular disease, clotting disorders
and autoimmune disease is uncertain. Finally, endothelial
dysfunction is present in testosterone deficiency syndromes
and replacement therapy is able to revert ED and to improve
endothelial function.
Aim of the present review is to discuss the systemic effects
of drugs designed to treat ED, such as testosterone and PDE5-i,
with regard to safety, unwanted effects and efficacy in improving
endothelial function; finally, a goal-oriented approach to
rehabilitation using daily vs. on-demand PDE5-i in difficult
patients is discussed.
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