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Current Vascular Pharmacology
ISSN: 1570-1611
Current Vascular Pharmacology
Volume 4, Number 1, January 2006
Contents
The Effects of Olprinone, a Phosphodiesterase 3 Inhibitor,
on Systemic and Cerebral Circulation Pp. 1-7
Takashi Ueda and Katsufumi Mizushige
[Abstract]
The Influence of Sex Hormones on Pulmonary Vascular
Reactivity: Possible Vasodilator Therapies for the Treatment
of Pulmonary Hypertension Pp. 9-15
A.M. Smith, R.D. Jones and K.S. Channer
[Abstract]
Hydrogen Sulfide as a New Endogenous Gaseous
Transmitter in the Cardiovascular System Pp. 17-22
Chaoshu Tang, Xiaohui Li and Junbao Du
[Abstract]
Chronic Inhibition of Na+/H+-Exchanger
in the Heart Pp. 23-29
Antonius Baartscheer
[Abstract]
Thrombolytic Therapy in Acute Ischemic Stroke –
Basic Concepts Pp. 31-44
Atte Meretoja and Turgut Tatlisumak
[Abstract]
Towards Newer Molecular Targets for Chronic Diabetic
Complications Pp. 45-57
Zia A. Khan, Hana Farhangkhoee and Subrata Chakrabarti
[Abstract]
Therapeutic Potential of Endothelial Progenitor Cells
for Cardiovascular Diseases Pp. 59-65
Lijing Jia, Masafumi Takahashi, Toru Yoshioka, Hajime
Morimoto, Hirohiko Ise and Uichi Ikeda
[Abstract]
Angiotensin II Regulates Vascular and Endothelial
Dysfunction: Recent Topics of Angiotensin II Type-1 Receptor
Signaling in the Vasculature Pp. 67-78
Hidekatsu Nakashima, Hiroyuki Suzuki, Haruhiko Ohtsu,
James Y. Chao, Hirotoshi Utsunomiya, Gerald D. Frank and Satoru
Eguchi
[Abstract]
The Effects of Obesity-Related Peptides on the Vasculature
Pp. 79-85
Michael R. Skilton and David S. Celermajer
[Abstract]
Abstracts
[Back to top]
The Effects of Olprinone, a Phosphodiesterase 3 Inhibitor,
on Systemic and Cerebral Circulation
Takashi Ueda and Katsufumi Mizushige
Olprinone, a phosphodiesterase (PDE) 3 inhibitor, is used
to treat heart failure due to its positive inotropic and vasodilative
effects. Selective inhibition of the PDE 3 isozyme increases
intracellular adenosine 3`5`-cyclic mono-phosphate and enhances
Ca2+ influx into cardiac muscle cells. The most
significant advantage of PDE 3 inhibitors is their ability
not only to enhance myocardial contraction, but to reduce,
through vasodilatory action, the stress to which the heart
is subjected. In peripheral vessels, the decrease of cytosolic
free Ca2+ induces the vasorelaxation of vascular
smooth muscle cells. In this way, olprinone reduces mean aortic
and pulmonary artery pressures. Additionally, olprinone exerts
differential vasodilatory effects on peripheral vessels in
each organ, based on the differences in the distribution of
PDE 3 among the organs. With respect to the cerebral circulation,
olprinone augments blood flow in the cerebral cortex through
direct vasodilatory effects on small cerebral arteries or
arterioles. Olprinone increases hepatosplanchnic blood flow
and improves oxygen supply. While long-term therapy with PDE
3 inhibitors in patients with chronic heart failure may accelerate
the progress of the underlying disease and provoke serious
ventricular arrhythmia, olprinone shows good potential for
short-term treatment in patients who have experienced severe
heart failure or patients who have undergone cardiac surgery.
[Back to top]
The Influence of Sex Hormones on Pulmonary Vascular
Reactivity: Possible Vasodilator Therapies for the Treatment
of Pulmonary Hypertension
A.M. Smith, R.D. Jones and K.S. Channer
Pulmonary hypertension is a rare disease of the pulmonary
vasculature defined as a mean pulmonary artery pressure >25
mmHg at rest or 30 mmHg with exercise. Recent therapies such
as epoprostenol, bosentan and sildenafil are directed at the
arterial vascular bed, causing vasodilatation and reducing
pulmonary vascular resistance. However idiopathic pulmonary
artery hypertension (IPAH) occurs predominantly in women,
with three times the incidence compared to men and this suggests
that sex hormones may be involved in the pathogenesis. 17β
-oestradiol is a pulmonary vasodilator, proposed to act via
an endothelium-dependant pathway, involving nitric oxide
(NO) and has also been shown to alter responses to hypoxia.
Progesterone is also a pulmonary vasodilator but differs from
17β-oestradiol
in having endothelial-dependant and independent processes
implicated. Interestingly testosterone has been shown to be
a vasodilator in both the coronary and pulmonary circulation
with a mechanism of action involving calcium channel block-ade
of the vascular smooth muscle and without endothelial involvement.
In clinical trials testosterone confers symptomatic benefits
in patients with coronary heart disease and heart failure,
acting as a vasodilator. These observations lend support to
the notion that testosterone could be a potential treatment
for patients with PAH as vasodilator therapy re-mains the
mainstay of treatment. Other potential beneficial effects
of testosterone in the pulmonary circulation include immuno-modulation,
altering expression of cytokines and an anti-thrombotic action.
In this review the influence of sex hormones on the pulmonary
vasculature will be discussed, with specific focus on pulmonary
hypertension and the poten-tial treatment of this condition.
[Back to top]
Hydrogen Sulfide as a New Endogenous Gaseous Transmitter
in the Cardiovascular System
Chaoshu Tang, Xiaohui Li and Junbao Du
Hydrogen sulfide (H2S) is a well-known toxic
gas with the smell of rotten eggs. Recent studies have shown
that H2S is generated in vivo in human
and animal organisms and that it participates in many pathophysiological
processes. H2S is produced endogenously in mammalian
tissues from L-cysteine metabolism mainly by 3 enzymes: cystathionine
β-synthetase
(CBS), cystathionine γ-lyase
(CSE) and 3-mercaptosulfurtransferase (MST). H2S
may not only function as a neuromodulator in the central nervous
system but it also relaxes gastrointestinal smooth muscles.
More importantly, present evidence shows that H2S
exerts regulatory effects on the pathogenesis of various cardiovascular
diseases such as hypertension, pulmonary hypertension, shock
and myocardial injury. The genomic basis of cystathioninuria
in humans is 2 nonsense and 2 sense mutations in CSE. This
review reveals that H2S is a new endogenous gaseous
transmitter in the cardiovascular system.
[Back to top]
Chronic Inhibition of Na+/H+-Exchanger
in the Heart
Antonius Baartscheer
The incidence and prevalence of heart failure (HF) has increased
over the last decades. The main reasons for this increase
are the ageing population and an increase in survival rate
after myocardial infarction and other cardiovascular diseases.
Although, pharmacotherapy has significantly improved survival,
the prognosis of HF is still rather poor. Total mortality
is high and approximately half of the deaths are sudden and
unexpected. Angiotensin-converting-enzyme (ACE)-inhibitors
generally given with diuretic and digoxin are the standard
treatment for patients with HF. Despite the established benefits
of ACE-inhibitors there is a need for new pharmacological
tools for the treatment of HF.
Recent experimental evidence has shown that activity of the
Na+/H+-exchanger in the heart (NHE-1)
is increased in HF. Because NHE-1 exchanges intracellular
H+ for extracellular Na+ in a one by
one stoichiometry, the intracellular ionic changes resulting
from increased activity, will be a increased pHi
and intracellular sodium ([Na+]i). Activation
of NHE-1 results only in a small increase in pHi,
under physiological conditions where bicarbonate-dependent
mechanisms are active. However, a considerable increase in
[Na+]i was always present. The elevation
of [Na+]i might be responsible for the
increase of intracellular calcium ([Ca2+]i)
levels mediated by the Na+/Ca2+-exchanger
(NCX). Increases in [Na+]i, pHi and
[Ca2+]i, features of cardiac myocytes
isolated from failing hearts, are recognized as a cell growth
signal And thus may play a role in the hypertrophic response,
cellular remodeling and finally the development of HF.
Acute application of cariporide, an inhibitor of NHE-1, on
failing myocytes not only normalized [Na+]i
but also cyto-plasmic and sarcoplasmic reticulum calcium handling
and the propensity to develop delayed after depolarizations
(DAD’s). In several animal models of HF it has been
shown the chronic inhibition of NHE-1 attenuates the development
of hypertrophy and whole heart remodeling. Recently, in a
volume and pressure overload model of HF in rabbits it has
been demonstrated that chronic treatment also prevents the
development of HF and cellular ionic and electrophysiological
remodeling. Therefore, chronic treatment with an inhibitor
of NHE-1 might prove beneficial in patients at risk of developing
HF, especially when given at an early stage.
[Back to top]
Thrombolytic Therapy in Acute Ischemic Stroke –
Basic Concepts
Atte Meretoja and Turgut Tatlisumak
Thrombolytic therapy with alteplase in acute ischemic stroke
is currently established within 3 h from symptom onset in
carefully selected patients. Expansion of the time window
is being assessed in trials with alteplase and desmoteplase.
Also, tenecteplase, reteplase and staphylokinase are being
evaluated in stroke patients. A better understanding of the
coagulation and fibrinolytic systems may provide insight into
drug development, interactions, complications, and may ultimately
improve patient triage and treatment regimens. Future adjuvant
and additional therapies could prove useful for patients who
do not benefit from standard thrombolytic treatment or may
augment the overall gain.
[Back to top]
Towards Newer Molecular Targets for Chronic Diabetic
Complications
Zia A. Khan, Hana Farhangkhoee and Subrata Chakrabarti
Prior to the discovery of insulin, the major cause of death
in the diabetic population was ketoacidosis. Although insulin
and improved glycemic control have improved the longevity
of diabetic patients, they still suffer from significant morbidity
and mortality due to chronic secondary complications. Long
standing diabetes leads to structural and functional alterations
in both the micro- and macrovasculature. These complications,
involving the retina, kidney, and peripheral nerves, as well
as cardiovascular system, severely compromise the quality
and expectancy of life. Large scale clinical trials have identified
hyperglycemia as the key determinant for the development of
such complications. Therapeutic modalities have been developed
to target glucose-induced alterations, such as protein kinase
C activation, augmented polyol pathway activity, non-enzymatic
glycation and oxidative stress to ameliorate chronic complications.
However, clinical trials targeting these biochemical alterations
have failed to show significant beneficial effects. The plethora
of biochemical anomalies that govern the development of chronic
diabetic complications may therefore be subject to cross-interaction
and complex interplays. Studies in both animal and human diabetes
have, however, showed alteration of several vasoactive effector
molecules such as endothelins. These molecules may be instrumental
in mediating diabetes-induced structural and functional deficits
at both the early and late stages of the disease. This review
will discuss the current mechanistic understanding of chronic
diabetic complications and will explore the potential novel
therapeutic interventions.
[Back to top]
Therapeutic Potential of Endothelial Progenitor Cells
for Cardiovascular Diseases
Lijing Jia, Masafumi Takahashi, Toru Yoshioka, Hajime
Morimoto, Hirohiko Ise and Uichi Ikeda
In the past decade, researchers have defined committed stem
or progenitor cells from various tissues, including bone marrow,
peripheral blood, brain, liver and reproductive organs, in
both adult animals and humans. Recently, endothelial progenitor
cells (EPCs) were isolated from peripheral blood mononuclear
cells and were shown to be incorporated into foci of neovascularization.
This finding that circulating EPCs may home into sites of
neovascularization and differentiate into mature endothelial
cells in situ is consistent with the concept of ’vasculogenesis’
and suggests that vasculogenesis and angiogenesis might constitute
complementary mechanisms for postnatal neovascularization.
Furthermore, experimental and clinical studies on ischemic
cardiovascular diseases suggest a therapeutic potential for
EPC transplantation. In this review, we summarize the biological
features of EPCs and discuss their therapeutic potential for
the treatment of cardiovascular diseases.
[Back to top]
Angiotensin II Regulates Vascular and Endothelial
Dysfunction: Recent Topics of Angiotensin II Type-1 Receptor
Signaling in the Vasculature
Hidekatsu Nakashima, Hiroyuki Suzuki, Haruhiko Ohtsu,
James Y. Chao, Hirotoshi Utsunomiya, Gerald D. Frank and Satoru
Eguchi
Accumulating evidence strongly implicates angiotensin II
(AngII) intracellular signaling in mediating cardiovascular
diseases such as hypertension, atherosclerosis and restenosis
after vascular injury. In vascular smooth muscle cells (VSMCs),
through its G-protein-coupled AngII Type 1 receptor (AT1),
AngII activates various intracellular protein kinases, such
as receptor or non-receptor tyrosine kinases, which includes
epidermal growth factor receptor (EGFR), platelet-derived
growth factor receptor (PDGFR), c-Src, PYK2, FAK, JAK2. In
addition, AngII activates ser-ine/threonine kinases such as
mitogen-activated protein kinase (MAPK) family, p70 S6 kinase,
Akt/protein kinase B and various protein kinase C isoforms.
In VSMCs, AngII also induces the generation of intracellular
reactive oxygen species (ROS), which play critical roles in
activation and modulation of above signal transduction. Less
is known about endothelial cell (EC) AngII signaling than
VSMCs, however, recent studies suggest that endothelial AngII
signaling negatively regulates the nitric oxide (NO) signaling
pathway and thereby induces endothelial dysfunction. Moreover,
in both VSMCs and ECs, AngII signaling cross-talk with insulin
signaling might be involved in insulin resistance, an im-portant
risk factor in the development of cardiovascular diseases.
In fact, clinical and pharmacological studies showed that
AngII infusion induces insulin resistance and AngII converting
enzyme inhibitors and AT1 receptor blockers im-prove
insulin sensitivity.
In this review, we focus on the recent findings that suggest
the existence of novel signaling mechanisms whereby AngII
mediates processes, such as activation of receptor or non-receptor
tyrosine kinases and ROS, as well as cross-talk be-tween insulin
and NO signal transduction in VSMCs and ECs.
[Back to top]
The Effects of Obesity-Related Peptides on the Vasculature
Michael R. Skilton and David S. Celermajer
Obesity and its related metabolic diseases, including type
2 diabetes, are associated with alterations in the circulating
levels of various peptides. These include the adipocytokines
(peptides released by adipocytes which circulate, such as
leptin, adiponectin and resistin), and other peptides whose
levels are altered in association with obesity (such as ghrelin,
neuropeptide Y, interleukin-1β
and tumour necrosis factor-α).
While the primary action of these peptides is linked with
the regulation and maintenance of energy balance and metabolism,
many of them have also been shown to possess vasoactive, inflammatory
and other properties that influence vascular biology, vascular
physiology and atherogenesis. As such, they may form an important
mechanistic link between obesity and cardiovascular disease.
In this review, we will outline the vasoactive properties
of adipocytokines and other obesity-related peptides. In particu-lar,
as pharmacotherapies suggested to achieve weight loss will
alter the pathways associated with these peptides, such treatments
might have either beneficial or deleterious effects on the
incidence and progression of cardiovascular disease.
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