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Cardiovascular & Hematological
Agents in Medicinal Chemistry
ISSN: 1871-5257 - Volume 4, 4 Issues, 2006
Current Medicinal Chemistry
- Cardiovascular & Hematological Agents
Volume 3, Number 2, April 2005
Contents
Natriuretic Peptide Family: New Aspects Pp.87-98
Luis Bolanos Cea
[Abstract]
Recent Development of Peptides from Glycoproteins IIb
(αIIb)
and IIIa (β3)
that Inhibit Platelet Fibrinogen Binding Pp.99-103
T. M. Chiang
[Abstract]
Molecular Predictors of Drug-Induced Prolongation of the
QT Interval Pp.105-118
Polychronis E. Dilaveris and Christodoulos I. Stefanadis
[Abstract]
The Multifunctional Protein C System Pp.119-131
F. Ediva, P. Medina, S. Navarro, E. Zorio, A. Estelles
and J. Aznar
[Abstract]
Angiotensin II Type I Receptor Blocker and Endothelial
Function in Humans: Role of Nitric Oxide and Oxidative Stress
Pp.133-148
Yukihito Higashi, Kazuaki Chayama and Masao Yoshizumi
[Abstract]
Chronic Heart Failure- Potential for Pharmacological Intervention
Pp.149-155
F. De Lorenzo and V. V. Kakkar
[Abstract]
Prostacyclin Synthase Gene: Genetic Polymorphisms and Prevention
of Some Cardiovascular Diseases Pp.157-164
Tomohiro Nakayama
[Abstract]
Ethiopathogenesis, Diagnosis and Prevention of Vascular
Calcification in End Stage Renal Disease Pp.165-171
Emiliana Ferramosca, Antonio Bellasi, Carlo Ratti and Paolo
Raggi
[Abstract]
Abstracts
[Back to top]
Natriuretic Peptide Family: New Aspects
Luis Bolanos Cea
Thus far, five molecules comprise the natriuretic peptide
family (NPF): ANP, urodilatin, BNP, CNP and DNP. Precursor
hormones for ANP, BNP and CNP are encoded by a different gene.
Final peptides are ligands for A, B and C receptors, acting
the latter as a clearance receptor besides neutral endopeptidase
(EC 24.11). cGMP acts as a second messenger. Natriuretic peptides
(NP) have well-known functions such as natriuretic, antihypertensive
and reduction of plasma renin-aldosterone concentrations.
An antiinflammatory ANP potential and a pro-apoptotic action
in rats endothelial cells of different NP have been described.
Unlike adults, NP show a different distribution during ontogeny
and a different pattern of excretion under different stimuli.
Noncompetitive immunoassays have become more suitable than
competitive ones for routine measurement of NP with recent
advances in speed of measurement. BNP and pro-BNP are emerging
as useful tools in diagnosis, management and prognosis of
heart disease. Preliminary data support a role of NP in the
therapy of congestive heart failure. Finally, potential therapeutic
compounds of NP in different pathologies are updated with
an important focus on vasopeptidase inhibitors. These are
capable of strengthening NP and inhibiting renin-angiotensin
system at the same time, as potential useful molecules in
cardiovascular therapy.
[Back to top]
Recent Development of Peptides from Glycoproteins IIb (αIIb)
and IIIa (β3)
that Inhibit Platelet Fibrinogen Binding
T. M. Chiang
The glycoprotein (GP) IIb/IIIa (αIlbβ3)
found on platelets binds fibrinogen when platelets are activated,
thereby mediating the platelet aggregation process. Blockading
of αIlbβ3
has been proposed to prevent platelet aggregation independent
of the substance(s) responsible for activating the platelets.
This inhibition of platelet aggregation is thought to be an
effective therapeutic approach to various thromboembolic syndromes.
The development of various forms of αIlbβ3inhibitors
has resulted in the inhibition of platelet aggregation, although
studies of αIlbβ3
receptor function and various αIlbβ3
inhibitors have demonstrated the potential for these agents
to produce effects on other aspects of platelet function as
well as having non-platelet effects. This review describes
the newly derived peptides from 1) glycoprotein IIb (αIIb)
that interferes with platelet aggregation by inhibiting the
binding of fibrinogen to αIlbβ3
and from 2) GP IIIa (β3)
by blocking the αIlbβ3
complex formation. These peptides may become effective agents
to block the interaction of ADP, type I collagen, and type
III collagen (type I collagen and type
III collagen are present in abundant amounts in blood vessel
walls) with platelets.
[Back to top]
Molecular Predictors of Drug-Induced Prolongation of the
QT Interval
Polychronis E. Dilaveris and Christodoulos I. Stefanadis
One of the most common causes of drug withdrawal from the
market is the prolongation of the QT interval associated with
polymorphic ventricular tachycardia or torsade de pointes
(TdP) that can degenerate into ventricular fibrillation and
sudden cardiac death. Cardiac and non-cardiac drugs prolong
the QT interval and cause TdP by blocking cardiac K+
channels in general, and selectively blocking the rapidly
activating delayed rectifier channel IKr. Co-assembly
of HERG (human-ether-a-go-go-related gene) alpha-subunits
and MiRP1 (MinK-related peptide 1) beta-subunits recapitulate
the behavior of native human IKr, and the majority
of mutations of HERG and MiRP1 decrease the repolarizing current,
delay ventricular repolarization and prolong the QT. Thus,
drug-induced QT prolongation and TdP might represent an iatrogenic
reproduction of the congenital long-QT syndrome (LQTS). Current
evidence suggests that 5 to 10% of persons in whom TdP develops
on exposure to QT-interval prolonging drugs harbor mutations
associated with the LQTS and can therefore be viewed as having
a subclinical form of the congenital syndrome. This clinical
observation is entirely consistent with the concept of reduced
repolarization reserve arising from a mutation in an ion-channel
gene, which predisposes the carrier to drug-induced TdP. This
review centers on the possible molecular mechanisms underlying
drug-induced QT prolongation and TdP, the description of specific
drugs and risk factors facilitating the development of TdP,
and the recommendations for preventing and treating this potentially
fatal arrhythmia.
[Back to top]
The Multifunctional Protein C System
F. Ediva, P. Medina, S. Navarro, E. Zorio, A. Estelles
and J. Aznar
The protein C pathway is a major regulator of blood coagulation,
since it controls the conversion of prothrombin to thrombin
through a feedback inhibition mechanism. Protein C circulates
in plasma as an inactive zymogen and is activated on the surface
of endothelial cells by the thrombin-thrombomodulin complex,
a process that can be further enhanced when protein C binds
to its membrane receptor, the endothelial-cell protein C receptor.
Activated protein C (APC) is then released from the complex,
binds protein S and inhibits thrombin formation by inactivating
coagulation factors Va and VIIIa. The importance of the protein
C anticoagulant pathway is emphasized by the increased risk
of venous thromboembolism (VTE) associated with protein C
and protein S deficiencies, the factor V Leiden mutation,
and reduced circulating APC levels. The protein C pathway
also plays a significant role in inflammatory processes, since
it prevents the lethal effects of E. coli-associated
sepsis in animal models and improves the outcome of patients
with severe sepsis. APC seems to display anti-apoptotic and
neuroprotective activities. Thus, it reduces organ damage
in animal models of sepsis, ischemic injury, endothelial cell
injury, or stroke. Further research will hopefully widen the
current therapeutic perspectives in all these illnesses, where
these effects might play a crucial role in their treatment.
This review will summarize the mechanisms that contribute
to these biological activities of the protein C pathway.
[Back to top]
Angiotensin II Type I Receptor Blocker and Endothelial
Function in Humans: Role of Nitric Oxide and Oxidative Stress
Yukihito Higashi, Kazuaki Chayama and Masao Yoshizumi
Recent large clinical trials have shown that angiotensin
II type I receptor blockers (ARBs) reduce cardiovascular morbidity
and mortality in patients with heart failure, acute myocardial
infarction, and hypertension. However, the mechanism underlying
antiatherogenic effects of ARBs remains unclear. The vascular
endothelium is involved in the release of various vasodilators,
including nitric oxide (NO), prostacyclin, and endothelium-derived
hyperpolarizing factor as well as vasoconstrictors. NO plays
an important role in the regulation of vascular tone, the
inhibition of platelet aggregation, and the suppression of
smooth muscle cell proliferation. Several investigators have
reported impairment in endothelium-dependent vasodilation
in the forearm, coronary, and renal vasculature in cardiovascular
diseases, including hypertensive patients. Cardiovascular
diseases are associated with alteration in endothelial function.
Endothelial dysfunction is the initial step in the pathogenesis
of atherosclerosis. Anti-renin-angiotensin system agents,
angiotensin-converting enzyme (ACE) inhibitors improve endothelial
function in patients with hypertension, diabetes mellitus,
and coronary artery disease. It is well known that ACE inhibitors
augment endothelium-dependent vasodilation through an increase
in NO bioavailability, by an increase in NO production and
a decrease in NO inactivation. ARBs are also thought to prevent
cardiovascular complications through an augmentation of endothelial
function. In this review, we focus on recent findings and
putative mechanisms of the beneficial effects of ARBs on endothelial
function.
[Back to top]
Chronic Heart Failure- Potential for Pharmacological Intervention
F. De Lorenzo and V. V. Kakkar
Heart failure is commonly associated with vascular diseases
and a high rate of athero-thrombotic events, but the risks
and benefits of antithrombotic therapy are unknown. The incidence
of thromboembolism in heart failure patients (which may include
stroke, peripheral embolism, pulmonary embolism) seems to
be around 2%, based on the data available from several small
studies. However, the incidence of thromboembolism should
greatly depend upon what is being looked at in each of these
studies, as it will (generally) not be individually categorised.
There is very little true epidemiological data to base this
figure.
The pathophysiology of heart failure is complex. There are
many well- recognised factors, which are associated with thrombosis
in heart failure patients, such as vascular abnormalities,
increased coagulability and impaired blood flow.
In the past 50 years, many studies have been performed to
find out if oral anticoagulation is of benefit for the prevention
of thromboembolism in patients with heart failure. Expert
therapeutic guidelines in the Europe and North America agree
that there is insufficient evidence to recommend that antithrombotic
therapy should be given to patients with heart failure, unless
they have atrial fibrillation or, perhaps, a previous thrombo-embolic
episode.
There is a lack of evidence for any antithrombotic agent
that is effective in patients with heart failure; therefore,
randomised clinical trials need to be designed to test the
hypothesis that patients with chronic heart failure would
have benefit from anticoagulant therapy.
This review summarises the incidence, potential mechanism
and therapeutic approaches for the management of thromboembolism
in heart failure.
[Back to top]
Prostacyclin Synthase Gene: Genetic Polymorphisms and Prevention
of Some Cardiovascular Diseases
Tomohiro Nakayama
Prostacyclin (PGI2) inhibits platelet aggregation
and vasoconstriction. Prostacyclin synthase (PGIS), a catalyst
of PGI2 synthesis from prostaglandin H2,
is widely distributed and predominantly found in vascular
endothelial and smooth muscle cells. The PGIS gene is localized
to 20q13.11-13, and a candidate gene for cardiovascular disease.
We discovered mutations and polymorphisms in this gene and
reported that they were associated with essential hypertension,
myocardial infarction and cerebral infarction. These results
suggest that PGI2 function depends on the different
alleles of the PGIS gene and that they may influence the risk
of cardiovascular diseases. Thus, individualized management
strategies, such as administration of PGI2 analog,
could be selected for variants of this gene to help prevent
the development of cardiovascular diseases.
[Back to top]
Ethiopathogenesis, Diagnosis and Prevention of Vascular
Calcification in End Stage Renal Disease
Emiliana Ferramosca, Antonio Bellasi, Carlo Ratti and
Paolo Raggi
Extensive atherosclerosis and heavy vascular and valvular
calcifications are common complications of end stage renal
disease (ESRD) and are very likely related to the high incidence
of cardiovascular disease in these patients. The greatly increased
incidence of cardiovascular disease is only partly explained
by traditional risk factors for atherosclerosis. In ESRD,
vascular calcification occurs both in the vascular intima
layer and in the tunica media. Intimal calcification is disseminated
and is characteristically associated with damaged and abnormally
functioning endothelium, and macrophage and vascular smooth
muscle cell (VSMC) infiltration typical of atherosclerosis.
On the contrary, medial calcification occurs in patchy distribution
and the most frequent cell types found in its vicinity are
the VSMC and macrophage. The uremic state is associated with
numerous metabolic abnormalities and endocrine disturbances
primarily involving calcium and phosphorus metabolism. Furthermore,
chronic kidney disease and dialysis are considered states
of active and strong inflammatory response. These dysfunctions
occur early in the course of renal failure and likely contribute
to the development and progression of vascular calcification
and atherosclerosis. For many years, vascular calcification
was considered solely the result of a passive deposition of
hydroxyapatite crystals in the arterial wall due to elevated
calcium-phosphate ion product. However, a large body of evidence
has now shown that this is a highly regulated process governed
by factors that closely resemble calcium deposition in bone
tissue. In fact, vascular calcification requires changes in
the phenotype of VSMC and the expression of several proteins
normally involved in bone metabolism. This review is centered
on the etiopathogenesis of vascular calcification in ESRD,
its detection with modern imaging modalities and the therapeutic
approaches currently available to slow its progression.
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