Cardiovascular
& Hematological Agents in Medicinal Chemistry
ISSN: 1871-5257
Cardiovascular & Hematological
Agents in Medicinal Chemistry
Volume 4, Number 4, October 2006
Contents
Cellular Mechanisms of the Protective Effect
of Polyphenols on the Neurovascular Unit in Strokes Pp.
277-288
Y. Curin, M.F. Ritz and R. Andriantsitohaina
[Abstract]
The Role of Ceramide Trihexoside (Globotriaosylceramide)
in the Diagnosis and Follow-Up of the Efficacy of Treatment
of Fabry Disease: A Review of the Literature Pp.
289-297
S. Bekri, O. Lidove, R. Jaussaud, B. Knebelmann and F.
Barbey
[Abstract]
From the Oxygen to the Organ Protection: Erythropoietin
as Protagonist in Internal Medicine Pp. 299-311
M. Buemi, L. Nostro, A. Romeo, M.S. Giacobbe, C. Aloisi,
A. Sturiale, D. Bolignano, A. Allegra, G. Grasso and N. Frisina
[Abstract]
Heart Rate Lowering by Inhibition of the Pacemaker
Current: A New Therapeutic Perspective in Cardiovascular Disease
Pp. 313-318
P. Dilaveris, G. Giannopoulos, A. Synetos, K. Gatzoulis
and C. Stefanadis
[Abstract]
Novel Therapeutic Agents in the Management of
Hemorrhage and Thrombosis Pp. 319-334
C.L. Kempton, R.D. Harvey III and H.R. Roberts
[Abstract]
Retrometabolic Syntheses of Astaxanthin (3,3’–
dihydroxy–β,β–carotene–4,4’–dione)
Conjugates: A Novel Approach to Oral and Parenteral Cardio-protection
Pp. 335-349
S.F. Lockwood, H.L. Jackson and G.J. Gross
[Abstract]
Prostacyclin Analogues: Prevention of Cardiovascular
Diseases Pp. 351-359
T. Nakayama
[Abstract]
Selective Serotonin Re-Uptake Inhibitors for the Treatment
of Depression in Coronary Artery Disease and Chronic Heart
Failure: Evidence for Pleiotropic Effects Pp. 361-367
I. Paraskevaidis, J.T. Parissis, K. Fountoulaki, G. Filippatos
and D. Kremastinos
[Abstract]
A New Approach for Treatment of Hypertension:
Modifying D1 Dopamine Receptor Function Pp.
369-377
C. Zeng, R.A. Felder and P.A. Jose
[Abstract]
Abstracts
[Back to top]
Cellular Mechanisms of the Protective Effect of Polyphenols
on the Neurovascular Unit in Strokes
Y. Curin, M.F. Ritz and R. Andriantsitohaina
Increasing evidence has suggested that our view of stroke
should be integrative, and thus a concept of dynamic interaction
between cells belonging to the neurovascular unit, such as
endothelial cells, astrocytes and neurons, is emerging. The
functionality of this unit is altered by the complex series
of interconnected pathophysiological processes that damage
the brain tissue during this kind of attack. The new strategies
target both the preservation of endothelium integrity and
the deleterious effects induced by ionic imbalance, excitotoxicity,
and the generation of reactive oxygen species within the neurovascular
unit. Polyphenols exert numerous biological effects that might
participate in the protection of the neurovascular unit, including
anti-aggregatory platelet activity, antioxidant and free radical
scavenging properties. Moreover, polyphenols are powerful
vasodilators through the generation of NO, and can act on
the expression of genes protective of the cardiovascular system.
Also, polyphenols contribute to the preservation of the integrity
of cells belonging to the neurovascular unit, mainly the endothelium,
by acting on the signaling cascades implicated in endothelial
apoptosis. All these effects of polyphenols might interfere
with atherosclerotic plaque development and stability, vascular
thrombosis and occlusion and therefore might explain their
vascular- and neuroprotective properties. In this review,
we focus on the beneficial effects of polyphenols on the complex
pathophysiological events of stroke and helpful indications
for the design of an effective and well-tolerated therapy
will be discussed.
[Back to top]
The Role of Ceramide Trihexoside (Globotriaosylceramide)
in the Diagnosis and Follow-Up of the Efficacy of Treatment
of Fabry Disease: A Review of the Literature
S. Bekri, O. Lidove, R. Jaussaud, B. Knebelmann and
F. Barbey
Fabry disease is caused by a deficiency of a-galactosidase
A which leads to the progressive intra-lysosomal accumulation
of ceramide trihexoside (CTH), also known as globotriaosylceramide
(Gb3), in different cell types and body fluids. The clinical
manifestations are multisystemic and predominantly affect
the heart, kidney and central nervous system. The role of
CTH in the pathophysiological process of Fabry disease is
not established, and the link between the degree of accumulation
and disease manifestations is not systematic. The use of CTH
as a diagnostic tool has been proposed for several decades.
The recent introduction of a specific treatment for Fabry
disease in the form of enzyme replacement therapy (ERT) has
led to the need for a biological marker, in place of a clinical
sign, for evaluating the efficacy of treatment and also as
a tool for following the long term effects of treatment. The
ideal biomarker must adhere to strict criteria, and there
should be a correlation between the degree of clinical efficacy
of treatment and a change in its concentration.
This review of the literature assesses the utility of CTH
as a diagnostic tool and as a marker of the efficacy of ERT
in patients with Fabry disease. Several techniques have been
developed for measuring CTH; the principles and the sensitivity
thresholds of these methods and the units used to express
the results should be taken into consideration when interpreting
data. The use of CTH measurement in Fabry disease should be
re-evaluated in light of recent published data.
[Back to top]
From the Oxygen to the Organ Protection: Erythropoietin
as Protagonist in Internal Medicine
M. Buemi, L. Nostro, A. Romeo, M.S. Giacobbe, C. Aloisi,
A. Sturiale, D. Bolignano, A. Allegra, G. Grasso and N. Frisina
Erythropoietin (EPO), already known as the stimulating
hormone for erythropoiesis, has shown different and interesting
pleiotropic actions. It does not only affect erythroid cells,
but also myeloid cells, lymphocytes and megakaryocytes. This
hormone can also enhance phagocytic function of the polymorphonuclear
cells and reduce the activation of macrophages, thus modulating
the inflammatory process.Moreover, hematopoietic and endothelial
cells probably have the same cellular origin, and the discovery
of erythropoietin receptors (EPO-R) also on mesangial and
myocardial cells, smooth muscle fibrocells and neurons has
prompted the study of the non-erythropoietic functions of
this hormone.The interaction between EPO and VEGF may be of
particular importance in neovascularization and wound healing.Different
studies have demonstrated that EPO has an important direct
hemodynamic and vasoactive action, which does not depend exclusively
on any increase in hematocrit and viscosity. Moreover EPO
showed protective effects on myocardial cells against apoptosis
induced by ischemia/repefusion injury, but it could negatively
affect pulmonary hypertension in patient with chronic cor
pulmonale.This review aims to stress the importance of the
increasing interest in EPO applications and the necessity
of further studies to gain a deeper knowledge of this hormone
and its pleiotropic and complex actions.
[Back to top]
Heart Rate Lowering by Inhibition of the
Pacemaker Current: A New Therapeutic Perspective in Cardiovascular
Disease
P. Dilaveris, G. Giannopoulos, A. Synetos, K. Gatzoulis
and C. Stefanadis
Several studies have demonstrated that resting heart
rate is an important correlate of cardiovascular and all-cause
mortality and that the mortality benefit of some cardiovascular
drugs seems to be related in part to their heart rate-lowering
effects. Since the currently available classes of drugs with
heart-rate lowering effect (e.g. beta-blockers and calcium
channel antagonists) also exert multiple structural and functional
actions on the cardiovascular system, which may be in some
cases undesired, the introduction of a new class of agents
exclusively affecting the pacemaker activity of the sinus
node is of particular interest. The first molecule of this
class – sinus node modulators or If
-current inhibitors – to reach clinical application
is ivabradine. Cardiac pacemaker cells generate a spontaneous
slow diastolic depolarisation that drives the membrane voltage
away from a hyperpolarised level towards the threshold level
for initiating a subsequent action potential, generating rhythmic
action potentials that propagate through the heart and trigger
myocardial contraction. The If current
is an inward ionic current that determines the slope of diastolic
depolarisation, which in turn controls the heart beating rate.
Extensive work has amply demonstrated its involvement in the
generation of spontaneous activity. The molecular basis of
the generation of the pacemaker current was landmarked by
the cloning of hyperpolarization-activated, cyclic nucleotide-gated
(HCN) channels, which constitute the structural units of the
f-channels. This review addresses the major basic properties
of cardiac f-channels, with a focus on the mode of action
of If-current inhibitors and outlines
the therapeutic implications of the existing research data.
[Back to top]
Novel Therapeutic Agents in the Management
of Hemorrhage and Thrombosis
C.L. Kempton, R.D. Harvey III and H.R. Roberts
Abnormalities in the hemostatic system can lead to, on
one end of the spectrum, hemorrhage, and on the opposite end,
thrombosis. Over the past decade, important new agents for
the management of hemorrhagic and thrombotic disorders have
been developed and more are in development. The care of patients
with bleeding disorders has been advanced by the development
of techniques to manufacture recombinant factor products with
reduced or absent exposure to human or animal proteins, prolonged
half-life or with reduced immunogenicity. Though first developed
for use in hemophiliacs with inhibitors, recombinant factor
VIIa (rFVIIa) has now garnered experience in a variety of
settings of inherited and acquired bleeding disorders. Thrombosis
can occur in a variety of vascular beds and cause a spectrum
of clinical sequelae. Depending on whether the thrombosis
is venous or arterial, major therapeutic targets are platelets
and procoagulant clotting factors. Novel targets on the platelet
surface include the thrombin protease activated receptors
(PAR) and the collagen receptor, glycoprotein VI (GPVI). In
animal models, PAR1 and GPVI inhibition have both demonstrated
a protective effect against arterial thromboembolism. For
many years, the only agents available to inhibit procoagulant
clotting factors were heparin and warfarin. The recent development
of a pentasaccharide and other agents targeting factor Xa,
factor IX, and thrombin offer useful alternatives for the
management of arterial and venous thrombosis. These agents
and others will be discussed in detail with respect to mechanism
of action, clinical efficacy and safety.
[Back to top]
Retrometabolic Syntheses of Astaxanthin (3,3’–
dihydroxy–β,β–carotene–4,4’–dione)
Conjugates: A Novel Approach to Oral and Parenteral Cardio-protection
S.F. Lockwood, H.L. Jackson and G.J. Gross
Disodium disuccinate astaxanthin has potent cardioprotective
effects in animals, with demonstrated preclinical efficacy
in the rat, rabbit, and canine models of experimental infarction.
It has been effective in subchronic and acute dosing regimens
after parenteral administration, and recently published data
in rats demonstrate that oral cardioprotection is also readily
achieved. Myocardial salvage in the canine can reach 100%
with a 4-day subchronic dosing regimen; single-dose I.V. cardioprotection,
when given 2 hours before experimental coronary occlusion,
is on average two-thirds of that achieved with the subchronic
regimen in dogs. In conscious animals, no effects on hemodynamic
parameters have been observed. Recently, the beneficial properties
of this prototypical astaxanthin conjugate have been extended
to include second- and third-generation compounds with improved
pharmacokinetic and/or potency profiles. The primary mechanism
of cardioprotection appears to be antioxidant activity: potent
direct scavenging of the lynchpin radical in ischemia-reperfusion
injury, superoxide anion, has been documented in appropriate
model systems. In addition, modulation of serum complement
activity, reduction of the levels of deposition of C-reactive
protein (CRP) and the membrane attack complex (MAC) in infarcted
tissue, and reduction in oxidative stress markers from the
arachidonic acid and linoleic acid pathways also suggest a
significant anti-inflammatory component to the mechanism of
cardioprotection. Favorable plasma protein binding has been
demonstrated in vitro for several astaxanthin conjugates;
this binding capacity overcomes the supramolecular assembly
of the compounds that occurs in aqueous solution, which in
itself improves the stability and shelf-life of aqueous formulations.
Astaxanthin readily populates cardiac tissue after metabolic
hydrolysis of both oral and parenteral administration of the
astaxanthin ester derivates, providing a reservoir of cardioprotective
agent with a significant half-life due to favorable ADME in
mammals. Due to the well-documented safety profile of astaxanthin
in humans, disodium disuccinate astaxanthin may well find
clinical utility in cardiovascular applications in humans
following successful completion of preclinical and clinical
pharmacology and toxicology studies in animals and humans,
respectively.
[Back to top]
Prostacyclin Analogues: Prevention of Cardiovascular
Diseases
T. Nakayama
Prostacyclin (PGI2) inhibits platelet aggregation
and vasoconstriction. PGI2 synthase (PGIS), a catalyst
of PGI2 formation from prostaglandin H2, is widely
distributed and predominantly found in vascular endothelial
and smooth muscle cells. Vane et al. first discovered
PGI2 in 1976, for which they received the Nobel
Prize in medicine and physiology in 1982. However, the later
discovery of nitric oxide (NO), which also resulted in a Nobel
Prize for the scientists involved, led to less attention being
focused on PGI2. The reason for this is somewhat
perplexing and may have been due to the lack of information
on how to correctly use PGI2. Current findings
suggest that researchers concentrated too much effort on the
therapeutic effects of PGI2, while largely ignoring
the potential for preventative effects. In addition, PGI2
was shown to be effective against diseases in some studies
but was without effect in others. The present paper contains
a review of PGI2 and PGIS, in addition to an examination
of the relationship between PGIS gene mutations and cardiovascular
diseases. PGI2 analogues that can be used in the
prevention of cardiovascular diseases are also discussed.
[Back to top]
Selective Serotonin Re-Uptake Inhibitors for
the Treatment of Depression in Coronary Artery Disease and
Chronic Heart Failure: Evidence for Pleiotropic Effects
I. Paraskevaidis, J.T. Parissis, K. Fountoulaki, G.
Filippatos and D. Kremastinos
Depression is a common co-morbidity in patients with
cardiovascular diseases such as chronic coronary artery disease,
acute coronary syndromes, post by-pass surgery and chronic
heart failure. There is a significant body of evidence suggesting
that the presence of depression is independently associated
with a decline in health status and an increase in the risk
of hospitalization and death for patients with coronary artery
disease or congestive heart failure. Novel treatment modalities
such as selective serotonin re-uptake inhibitors (SSRIs) may
improve depressive symptoms and prognosis of post-myocardial
infarction and heart failure patients interacting with the
common pathophysiologic mechanisms of depression and cardiovascular
disease. This review summarizes current experimental and clinical
evidence regarding the pleiotropic effects of SSRIs on platelet
functions, immune and neurohormonal activation, and cardiac
rhythm disturbances in patients with cardiovascular disease.
These bio-modulatory properties of SSRIs may be translated
into improvement of patient clinical outcomes beyond their
anti-depressant action.
[Back to top]
A New Approach for Treatment of Hypertension:
Modifying D1 Dopamine Receptor Function
C. Zeng, R.A. Felder and P.A. Jose
Essential hypertension is a major factor for myocardial
infarction, heart failure and kidney failure. Dopamine plays
an important role in the pathogenesis of hypertension by regulating
epithelial sodium transport and vasodilatation directly or
indirectly with other hormones and humoral factors, such as
reactive oxygen species and the renin-angiotensin system.
Dopamine receptors are classified into five subtypes based
on their structure and pharmacology. Among those dopamine
receptor subtypes, D1 receptor is the most important
one, during conditions of moderate sodium intake, more than
50% of renal sodium excretion is regulated by D1-like
receptors. Decreased renal dopamine production and/or impaired
D1 receptor function have been reported in hypertension.
Disruption of D1 receptor results in hypertension.
In this paper, we review the mechanisms by which hypertension
develops when D1 receptor function is perturbed.
We also discuss possible new approaches developing anti-hypertensive
medicine by increasing renal dopamine production, enhancing
D1 receptor function, or modifying its interactions
with other blood pressure-regulating systems.
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