Cardiovascular
& Hematological Disorders - Drug Targets
ISSN: 1871-529X
Current Drug Targets - Cardiovascular
& Hematological Disorders
Volume 6, Number 2, June 2006
Contents
The Effects of Prostaglandin E-1 in Patients with
Intermittent Claudication Pp. 71-76
Glauco Milio, Giuseppe Coppola and Salvatore Novo
[Abstract]
Prevention of Myocardial Damage During Coronary Intervention
Pp. 77-83
Vincenzo Pasceri, Giuseppe Patti and Germano Di Sciascio
[Abstract]
Cyclooxygenase-2 Inhibitors: A Painful Lesson Pp.
85-100
Sandhya Sanghi, Eric J. MacLaughlin, Coty W. Jewell, Sheldon
Chaffer, Peter J. Naus, Linley E. Watson and David E. Dostal
[Abstract]
Regulatory Mechanisms of Cardiac Development and
Repair Pp. 101-112
Ana Chinchilla and Diego Franco
[Abstract]
Inhibition of sPLA2-IIA,
C-reactive Protein or Complement: New Therapy for Patients
with Acute Myocardial Infarction? Pp. 113-123
Paul A.J. Krijnen, Christof Meischl, Remco Nijmeijer, Cees
A. Visser, C. Erik Hack and Hans W.M. Niessen
[Abstract]
Physiological Significance and Therapeutic Potential
of Adrenomedullin in Pulmonary Hypertension Pp. 125-132
Shinsuke Murakami, Hiroshi Kimura, Kenji Kangawa and Noritoshi
Nagaya
[Abstract]
Uremia, Atherothrombosis and Malnutrition: The Role
of L arginine-Nitric Oxide Pathway Pp. 133-140
Tatiana M.C. Brunini, Clarissa Demézio da Silva,
Mariana A.S. Siqueira, Monique B. Moss, Sérgio F. F.
Santos and Antônio C. Mendes-Ribeiro
[Abstract]
Abstracts
[Back to top]
The Effects of Prostaglandin E-1
in Patients with Intermittent Claudication
Glauco Milio, Giuseppe Coppola and Salvatore Novo
Aim of the study is to evaluate the effects of Prostaglandin
E-1 (PGE-1) in patients with peripheral arterial disease (PAD)
at the 2nd b stage Fontaine’s classification.
The study, controlled, single blinded, enrolled 123 patients
with intermittent claudication that were randomised in two
groups; the first group received a treatment with PGE-1 while
the second one received a pentoxifylline-buflomedil association
by venous infusion. We evaluated: Pain Free Walking Distance
(PFWD), Maximum Walking Distance (MWD), Rest Flow (RF), Peak
Flow (PF), Basal (BVR) and Minimal Vascular Resistance (MVR)
with a strain gauge plethysmograph, Resting Flow (RF), Peak
Flow (PF), time to reach the Peak Flow (tPF) and time to recovery
of the base values (tRF) with laser Doppler flowmeter.
After a four weeks treatment, we observed an increase of 370%
about PFWD and of 260% in the MWD in patients treated with
PGE-1; the other group showed an increase of 110% and 118%
respectively. Moreover, the patients of the first group showed
a significant increase regarding the plethysmographic Peak
Flow (from 9.75±1.37 to 16.21±1.75, p<0.001),
greater than the one observed in the second group (from 9.53±1.41
to 13.47±1.53, p<0.05); also the laser
Doppler parameters showed a significant reduction, more evident
in the first group (tPF from 23.0±7.5 to 10.5±4.9,
p<0.001; tRF from 73.5±22.7 to 48.3±13.5,
p<0.001) than in the second one.
In conclusion, our study shows the efficacy of PGE-1 in patients
with 2nd b stage Fontaine PAD; PGE-1 improves the
microcirculation and the haemodynamics in peripheral districts
and determines an increase in the pain free walking distance
and in maximum walking distance.
[Back to top]
Prevention of Myocardial Damage During Coronary Intervention
Vincenzo Pasceri, Giuseppe Patti and Germano Di Sciascio
Myocardial injury during coronary intervention occurs in
10-40% of cases and is often characterized by a slight increase
of markers of myocardial necrosis, without symptoms, electrocardiographic
changes or impairment of cardiac function. However, even small
increases of creatine kinase-MB levels are expression of a
true and detectable infarction, and may be associated with
higher follow-up mortality. The cause of CK-MB elevation in
case of procedural complications (dissection, transient vessel
closure, no reflow, side branch occlusion etc.) is obvious;
however, most cases of minor CK-MB elevation occur in patients
with uncomplicated procedure with excellent final angiographic
results. It has been suggested that the main mechanism explaining
occurrence of myocardial necrosis during otherwise successful
coronary interventions may be distal microembolization of
plaque components, an enhanced inflammatory state or due to
total plaque burden and/or to plaque instability.
Different treatments have been proposed to prevent myocardial
injury during coronary intervention, including nitrate infusion,
intracoronary beta-blockers, adenosine, clopidogrel and IIb/IIIa
inhibitors, but none of those (apart from the use of IIb/IIIa
inhibitors) has been routinely introduced in clinical practice.
We performed the ARMYDA (Atorvastatin for Reduction of MYocardial
Damage during Angioplasty) trial, i.e. the first prospective,
randomised, placebo controlled study to evaluate effects of
7 days of pre-treatment with a fixed dose of atorvastatin
(40 mg/day) on post-procedural release of markers of myocardial
damage in patients with stable angina undergoing percutaneous
intervention. In this study therapy with atorvastatin has
been associated with 80% risk reduction on the occurrence
of peri-procedural myocardial infarction, as well as with
significant reduction of post-intervention peak levels of
all markers of myocardial damage. The mechanisms underlying
the beneficial effects of atorvastatin may be an inflammatory
action reducing myocardial necrosis due to microembolization,
an improvement of endothelial function on microcirculation,
and direct protection of myocardium.
[Back to top]
Cyclooxygenase-2 Inhibitors: A Painful Lesson
Sandhya Sanghi, Eric J. MacLaughlin, Coty W. Jewell, Sheldon
Chaffer, Peter J. Naus, Linley E. Watson and David E. Dostal
Non-steroidal anti-inflammatory drugs (NSAIDs) represent
a clinically important class of agents. NSAIDs are commonly
used in treatment of conditions such as headache, fever, inflammation
and joint pain. Complications often arise from chronic use
of NSAIDs. Gastrointestinal (GI) toxicity in the form of gastritis,
peptic erosions and ulcerations and GI bleeds limit usage
of NSAIDs. These toxicities are thought to be due to cyclooxygenase
(COX)-1 blockade. COX-1 generates cytoprotective prostanoids
such as prostaglandin (PG) E2
and prostacyclin (PGI2).
COX-2 inhibitors, commonly referred to as coxibs, were developed
to inhibit inflammatory prostanoids without interfering with
production of COX-1 prostanoids. Concerns over cardiovascular
safety, however, have evolved based on the concept of inhibition
of COX-2-derived endothelial prostanoids without inhibition
of platelet thromboxane A2,
leading to increased cardiovascular risk. The Celecoxib Long-Term
Arthritis Safety Study (CLASS) trial did not show a significant
increase in cardiovascular risk for celecoxib (Celebrex),
but results of the Vioxx Gastrointestinal Outcomes Research
(VIGOR) study showed an increased cardiovascular risk with
long-term daily usage of rofecoxib in patients with rheumatoid
arthritis. The Adenomatous Poly Prevention on Vioxx (APPROVe)
trial further evaluated cardiovascular effects of rofecoxib
and recently led to removal of this drug from the marketplace.
Coxibs affect renal function via blockade of normal
COX-2 functions. COX-2 expression increases in high renin
states and in response to a high-sodium diet or water deprivation.
PGI2
and PGE2
are the most important renal prostanoids. PGI2
inhibition results in hyperkalemia. PGE2
inhibition results in sodium retention, which leads to hypertension,
peripheral edema and potentially exacerbation of heart failure.
This review article discusses beneficial and deleterious effects
associated with prostanoids produced by COX-1 and COX-2 in
various organs and how blockade of these products translates
into clinical medicine.
[Back to top]
Regulatory Mechanisms of Cardiac Development and Repair
Ana Chinchilla and Diego Franco
The heart originates from bilateral primordia that eventually
fuse in the embryonic midline leading to a linear tube. Soon
after, the heart bends to the right and atrial and ventricular
chambers are formed. Progressively each embryonic compartment
initiates a process of septation that eventually leads to
a four chambered heart with a double circuitry and synchronous
contraction. During these developmental events, the growth
of the heart and in particular of its myocardial component
gradually increases. However, as the heart gets into its mature
stage, myocardial growth ceases and concomitantly the myocardium
looses its proliferative capacity.
In the adult human population, the most frequent cardiac pathologies
emanate from a decompensated lost of myocardial function.
Therapeutical approaches aiming to add or replace new myocytes
to the failing heart are thus highly desired. Embryonic stem
cells have a high capacity to give rise to multiple cell types,
including myocardial cells, opening new therapeutical possibilities.
Unexpectedly discrete adult cell populations have also shown
a greater cell plasticity than previously thought, earning
therefore much attention as therapeutic targets. These observations
have launched initial clinical trials with great hope of clinical
benefit. However, it is essential in this respect to initially
understand, and eventually control myogenic cell fate determination.
Developmental biology of the heart provides a very suitable
model for this end. Over the last decade there has been a
considerable advance in the understanding of the molecular
mechanisms that lead to the determination of the cardiomyocyte
lineage and the regulatory mechanisms by which morphogenesis
of the heart takes place. Growth factor signalling and transcriptional
events controlling cardiac myogenesis have been progressively
unravelled. In this review we aim to summarise current data
concerning the cardiomyogenic cell fate determination pathways
occurring during the natural process of cardiogenesis as compared
to the myogenic lineages obtained from embryonic and adult
stem cells. Identification of key elements provides important
resources to which drugs can be targeted and eventually can
result in promising tools to control and expand cardiomyocyte
determination.
[Back to top]
Inhibition of sPLA2-IIA,
C-reactive Protein or Complement: New Therapy for Patients
with Acute Myocardial Infarction?
Paul A.J. Krijnen, Christof Meischl, Remco Nijmeijer, Cees
A. Visser, C. Erik Hack and Hans W.M. Niessen
Reperfusion of ischemic myocardium after acute myocardial
infarction (AMI) induces a local activation of inflammatory
reactions that results in ischemia/reperfusion (I/R)-injury.
I/R-injury contributes considerably to the total cell damage
in the heart after AMI. Secretory phospolipase A2-IIA
(sPLA2-IIA),
C-reactive protein (CRP) and complement are inflammatory mediators
that have been demonstrated to play key roles in I/R injury.
From studies by us and others a mechanism emerged in which
sPLA2-IIA
binds to reversibly damaged cardiomyocytes and subsequently
induces cell death, partly by potentiating binding of CRP
and subsequent complement activation. Next to this, sPLA2-IIA
also has a direct toxic effect, independent of CRP or complement.
Therefore, these studies indicate a crucial role of inflammatory
mediators in ischemia/reperfusion injury. This review will
focus on the pathogenic effects of sPLA2-IIA,
CRP and complement and on the putative therapeutic effects
of inhibitors of these inflammatory mediators in acute myocardial
infarction.
[Back to top]
Physiological Significance and Therapeutic Potential
of Adrenomedullin in Pulmonary Hypertension
Shinsuke Murakami, Hiroshi Kimura, Kenji Kangawa and Noritoshi
Nagaya
Adrenomedullin (ADM) is a potent vasodilator peptide that
was originally isolated from human pheochromocytoma. Its vasodilatory
effect is mediated by cyclic adenosine 3’,5’-monophosphate-
and nitric oxide-dependent mechanisms. Earlier studies have
demonstrated that ADM is secreted from various tissues, including
vessels, heart, and lungs. In addition, there are specific
receptors for ADM in the lungs. Plasma ADM level is elevated
in proportion to the severity of pulmonary hypertension, and
circulating ADM is partially metabolized in the lungs. These
findings suggest that ADM plays an important role in the regulation
of pulmonary vascular tone. Administration of ADM by intravenous
or intratracheal delivery significantly decreased pulmonary
arterial pressure and pulmonary vascular resistance in patients
with pulmonary arterial hypertension. Furthermore, we have
recently developed a new therapeutic strategy using ADM gene-modified
endothelial progenitor cells (EPC). Intravenously administered
ADM gene-modified EPC were incorporated into lung tissues
and attenuated monocrotaline-induced pulmonary hypertension
in rats. In addition, ADM has angiogenic and anti-apoptotic
activities via activation of Akt and/or mitogen-activated
protein kinase. These findings suggest that ADM may act not
only as a vasodilator but also as a vasoprotective factor.
Thus, ADM may be a promising endogenous peptide for the treatment
of pulmonary hypertension.
[Back to top]
Uremia, Atherothrombosis and Malnutrition: The Role
of L arginine-Nitric Oxide Pathway
Tatiana M.C. Brunini, Clarissa Demézio da Silva,
Mariana A.S. Siqueira, Monique B. Moss, Sérgio F. F.
Santos and Antônio C. Mendes-Ribeiro
The uraemic syndrome is a complex condition that results from
an accumulation of multiple waste compounds, combined with
failure of the endocrine and homeostatic functions of the
kidney in end-stage chronic renal failure (CRF) patients.
Recently it has become clear that uraemia is a microinflammatory
condition with a significant increase in inflammation markers.
Malnutrition is a common pathological condition which exacerbates
cardiovascular mortality in uraemic patients. Inadequate diet
and a state of persistent catabolism play major roles in uraemic
malnutrition, yet the underlying mechanisms have not been
completely clarified. Malnourished patients present elevated
levels of circulating cytokines, further aggravating the oxidative
and inflammatory characteristics of uraemia. It has been suggested
that abnormalities in nitric oxide bioactivity, coupled with
malnutrition and inflammation, may contribute to increased
incidence of atherothrombotic events in uraemia. Amongst the
earliest indications of nutritional deficiency are low concentrations
of plasma amino acids, including L-arginine, the precursor
for nitric oxide (NO) synthesis. Atherosclerosis is an inflammatory
disorder and NO is an important mediator of inflammation.
There is a close association between thrombosis and platelet
aggregation, and NO is involved in all stages of platelet
activation. L-arginine inhibits platelet aggregation both
in vitro and in vivo, while L-NMMA (NG-monomethyl-L-arginine),
an endogenous L-arginine analogue and inhibitor of NO synthase
(NOS), increases platelet activation and adhesion. The majority
of studies in animal models and human patients indicate that
the systemic production of NO is increased in uraemia. CRF
patients show reduced plasma concentration of L-arginine,
and the enhancement of L-arginine transport is essential to
maintain increased NO synthesis in platelets taken from these
patients. The present review provides an overview of recent
advances in the understanding of the association among malnutrition,
chronic inflammation and the L-arginine-nitric oxide pathway
in uraemic patients, and related potential interventions that
could improve clinical outcome in chronic renal failure.
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