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Current Vascular Pharmacology
ISSN: 1570-1611
Current Vascular Pharmacology
Volume 4, Number 4, October 2006
Contents
The Metabolic Syndrome: Revisiting the Concept, the
Diagnosis and the Treatment (Part-II)
Guest Editors: John H. McNeill and Vijay Sharma
Editorial Pp. 291
The Etiology of Hypertension in the Metabolic Syndrome Part
One: An Introduction to the History, the Concept and the Models
Pp. 293-304
Vijay Sharma and John H. McNeill
[Abstract]
The Etiology of Hypertension in the Metabolic
Syndrome Part Two: The Gene-Environment Interaction Pp.
305-320
Vijay Sharma and John H. McNeill
[Abstract]
The Etiology of Hypertension in the Metabolic
Syndrome Part Three: The Regulation and Dysregulation of Blood
Pressure Pp. 321-348
Vijay Sharma and John H. McNeill
[Abstract]
The Etiology of Hypertension in the Metabolic
Syndrome Part Four: The Systemic Perspective – The Role
of the Neuroendocrine and Immune Systems, and the Challenge
of Integration Pp. 349-381
Vijay Sharma and John H. McNeill
[Abstract]
Leptin and Vascular Smooth Muscle Pp.
383- 393
Asad Zeidan and Morris Karmazyn
[Abstract]
General Articles
Recent Insights into the Role of Prostanoids in Atherosclerotic
Vascular Disease Pp. 395-408
Allison B. Reiss and Sari D. Edelman
[Abstract]
Lipid Modulation of Intravascular and Cellular
Sodium Handling: Mechanistic Insights and Potential Clinical
Implications Pp. 409-416
Andre C.K.B. Amaral and Andrei C. Sposito
[Abstract]
Abstracts
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Editorial
Towards an Integrated Understanding
of Hypertension in The Metabolic Syndrome: How Close Are We?
The interrelationships of the Metabolic Syndrome (MetS) are
very complex. The list of factors, pathways and systems which
appear to be involved is intimidatingly long. How far have
we come in our quest to understand the MetS and what is the
future direction of this research?
In this special issue, we take a comprehensive look at how
the concept of the MetS has shaped our understanding of hypertension
in a series of reviews. In Part One of our review series,
we review the history of hypertension and the MetS, introduce
the main concepts and provide a brief overview of the experimental
models which are available. In Part Two, we provide a comprehensive
overview of the gene-environment interaction with a strong
focus on clinical and epidemiological studies. In Part Three,
we examine the regulation and dysregulation of blood volume
and vascular tone, the two critical determinants of blood
pressure. In Part Four, we take a systemic perspective, examining
the important roles played by the neuroendocrine and immune
systems. We also discuss the concepts of causality and temperospatial
organisation as they relate to this research. Finally, we
discuss strategies for integrating our vast array of data.
Zeidan and Karmazyn then provide a focus on leptin signalling
in vascular smooth muscle and its relevance to a wider range
of vascular diseases.
There is still a great deal of work to be done if we are to
fully understand the MetS. To this end, we identified several
concepts and approaches which require much more focus and
which are seldom addressed directly. The first is peripheral
vascular resistance. As we discuss in detail in Part Two of
our review series, peripheral vascular resistance is a much
more heterogeneous and elusive entity than is generally realised.
It is very difficult to establish whether an artery is a true
resistance artery in the conscious organism. Furthermore,
the arteries which determine peripheral vascular resistance
in the resting state may not be the same arteries which respond
to changes in blood supply demand. Indeed, there is evidence
to suggest that the pattern of vasoconstriction or vasodilation
which occurs depends on the provoking stimulus. How such-stimulus
specific effects are coordinated is poorly understood. Furthermore,
the mechanisms which regulate vascular tone in a particular
vessel depend on its location (e.g. cerebral, mesenteric,
pulmonary) and size. We do not yet have an integrated understanding
of the mechanisms by which peripheral vascular resistance
is generated and sustained. This should be an important goal
for future research, as it will better inform our efforts
to reduce peripheral vascular resistance.
The central nervous system neural network that links appetite
control stimuli (e.g. leptin, ghrelin, insulin) to blood pressure
control networks also requires much further study. A wide
range of hormones have been shown to activate the sympathetic
nervous system centrally and increase blood pressure. These
effects frequently counteract and override the peripheral
effects of the same hormones. Central activation of both the
sympathetic nervous system and hypothalamo-pituitary-adrenal
(HPA) axis has been invoked in a number of models of how the
MetS occurs. It is therefore vital that we identify and map
out the neural networks which mediate these effects.
Our review of the literature highlights the enormous range
of MetS-related factors which the reductionist approach has
identified. The reductionist approach has been and continues
to be a valuable one. However, it is important that we begin
the long, painstaking task of integrating the data we have
gathered. Computer simulations provide a valuable adjunct
tool for this task. These are not meant to replace ‘real’
experiments (a commonly held misconception). They are meant
to provoke new thoughts, to help us factor in more variables
than can be handled by a conventional experiment (or our own
minds), and, as representations of the real system, they are
meant to fail; valuable information is gleaned from how computer
simulations fail. It is highly unlikely that integration,
particularly of data pertaining to a phenomenon as complex
as the MetS, will succeed without the use of computer simulations.
Finally, we feel that it is important to address the concept
of cause and effect, and our methods for establishing cause-effect
relationships. Establishing cause and effect relationships
within the MetS in humans has proved to be exceptionally challenging.
Most of the data pertaining to the interrelationships of the
MetS is observational. Furthermore, as experimental studies
continue to reveal bi-directional cause-and-effect relationships
between factors, we have been forced to gather observational
data on the experimental models. It is therefore important
that we develop analytical tools that can be used to identify
cause and effect relationships in observational data. Such
tools would help us overcome what has proved to be a major
stumbling block in translating the basic research findings
to the clinical setting. In Part Four of our review series,
we discuss approaches that are being used to develop such
tools.
The major challenge for the future is not only to identify
all the pieces of this multi-layered puzzle, but to put them
together. This integration must succeed if translational research
is also to succeed.
John H. McNeill and Vijay Sharma
Division of Pharmacology and Toxicology
Faculty of Pharmaceutical Sciences
The University of British Columbia
2146 East Mall, Vancouver, V6T 1Z3
Canada
Tel (604) 822 6159
Fax: (604) 822 8001
E-mails: vijaysha@interchange.ubc.ca
jmcneill@interchange.ubc.ca
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The Etiology of Hypertension in the
Metabolic Syndrome Part One: An Introduction to the History,
the Concept and the Models
Vijay Sharma and John H. McNeill
Hypertension is a complex, multifactorial disorder
which is an important cause of morbidity and mortality in
the modern world. The study of hypertension in the context
of the metabolic syndrome has yielded some important insights
into the etiology of the condition. With the recent controversy
surrounding the existence of the metabolic syndrome and the
clear need for further research, we have undertaken a four
part review of the literature in this field to provide a comprehensive
overview of experimental and clinical research as it currently
stands. In Part One, we review the history of hypertension
and the metabolic syndrome, discuss the role of the metabolic
syndrome as a concept and a diagnosis, and provide an introduction
to insulin resistance and hyperinsulinemia. We also provide
a broad overview of the range of animal models which are used
to study these conditions.
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The Etiology of Hypertension in the Metabolic
Syndrome Part Two: The Gene-Environment Interaction
Vijay Sharma and John H. McNeill
The pathogenesis of obesity, insulin resistance
and hypertension begins with an interaction between genetic
factors and environmental factors. The search for the underlying
genetic basis of these conditions has yielded disappointing
results. It is possible that the importance of environmental
influences has been underestimated. In Part Two of our series
of reviews, we discuss the key genetic, environmental and
evolutionary influences which lead to the development of these
conditions, and provide a detailed account of the mechanisms
by which these influences produce their effects.
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The Etiology of Hypertension in the Metabolic
Syndrome Part Three: The Regulation and Dysregulation of Blood
Pressure
Vijay Sharma and John H. McNeill
To understand blood pressure is regulated, and how
this regulation is disturbed in hypertension, we need to understand
how blood volume is regulated and how the distribution of
that volume across the vascular tree is regulated. Here we
review the literature on blood volume regulation and how it
is disturbed in the pre-diabetic and diabetic state. We also
provide a comprehensive overview of vascular dysfunction,
discussing the key mechanisms, mediators and pathways which
are involved. In particular, we focus on the key concept of
endothelial dysfunction and how this has shaped our un-derstanding
of hypertension.
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The Etiology of Hypertension in the Metabolic
Syndrome Part Four: The Systemic Perspective – The Role
of the Neuroendocrine and Immune Systems, and the Challenge
of Integration
Vijay Sharma and John H. McNeill
Insulin resistance can be regarded to be a cause,
a consequence, a sustainer or a marker of the wider neuroendocrine
dysfunction within which it occurs. In the final part of our
series of reviews, we examine the systemic influences which
operate within the metabolic syndrome: the endocrine system,
the central nervous system and the immune system. We discuss
strategies for integrating the array of information that is
being gathered, in particular the need for computer simulation.
We also advocate the need to move beyond the linear paradigm
of ‘cause and effect’ and use causal networks
to think about this system. We also discuss the need to understand
the temperospatial organisation of the factors being studied.
Finally, we draw together the data, concepts and hypotheses
we have reviewed over the course of these four articles.
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Leptin and Vascular Smooth Muscle
Asad Zeidan and Morris Karmazyn
Leptin has received extensive attention as an endogenously
produced satiety factor. Although once considered to be solely
derived from adipose tissue, it is now apparent that leptin
can be produced by various tissues including those comprising
the cardiovascular system such as blood vessels and cardiomyocytes.
Moreover, leptin receptors (OBR) have been identified in cardiovascular
tissues. The increased cardiovascular risk associated with
obesity is well known and many of the effects of leptin appear
to be compatible with its potential role as a contributing
factor to increased cardiovascular morbidity associated with
obesity. Evidence from both animal and human studies implicated
leptin as a potential contributor to the increased incidence
of cardiovascular morbidity associated with hyperleptinemic
conditions. This review focuses on some of the complex vascular
actions of leptin and the emerging role of leptin as a cardiovascular
regulator in terms of normal homeostatic function, but particularly
in cardiovascular pathology.
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Recent Insights into the Role of Prostanoids
in Atherosclerotic Vascular Disease
Allison B. Reiss and Sari D. Edelman
Atherosclerosis is characterized by chronic inflammation
and enrichment of inflammatory cells in the vessel wall. Acute
inflammation can lead to damaged endothelium triggering the
coagulation cascade and thrombus formation. Likewise, the
clotting cascade may elicit an inflammatory response. The
vascular endothelium regulates vascular tone, permeability,
inflammation, thrombosis, and coagulation. Dysfunction of
the vascular endothelium can promote atherosclerotic disease
processes. Prostanoids (prostaglandins, thromboxane, and prostacyclin)
have been established as inflammatory mediators in vascular
endothelial function and there continues to be growing insights
into their role in atherosclerotic disease.
This review examines the role of prostanoids as paracrine
inflammatory mediators of atherosclerotic vascular disease,
highlighting the relevant physiology of eicosanoid production
and endothelial dysfunction. We consider the role of prostanoids
in systemic diseases associated with high cardiovascular morbidity
and mortality, including diabetes mellitus, coronary artery
disease, peripheral arterial disease, rheumatologic disorders,
and dyslipidemia. We present emerging evidence that cardio-protective
and lipid lowering medications, such as irbesartan and simvastatin
may exert their effects via prostanoid mediated pathways.
Both serum and urinary prostanoids may be utilized as diagnostic
predictors of disease; for example 8-iso-PGF2αin
the serum has recently been reported as an independent predictor
of symptomatic peripheral arterial disease. In addition, we
discuss current recommendations on established therapeutic
uses of prostanoids for atherosclerotic diseases, such as
the use of PGE1 for the treatment of peripheral
arterial disease. Finally, we investigate original therapeutic
modalities of various prostanoids involved in the aforementioned
diseases.
[Back to top]
Lipid Modulation of Intravascular and Cellular
Sodium Handling: Mechanistic Insights and Potential Clinical
Implications
Andre C.K.B. Amaral and Andrei C. Sposito
Lipid metabolism can modulate structural and functional
characteristics of the vascular system. Recent studies suggested
that dyslipidemia may also affect the hemodynamic response
to salt intake through the impairment of intravascular volume
regulation and cellular sodium handling. Indeed, dyslipidemia
may affect sodium homeostasis through several pathways, including
defective nitric oxide and eicosanoid production, enhanced
renin-angiotensin system activity and increased sympathetic
response. Moreover, dyslipidemia directly affects cellular
membrane viscosity and modifies membrane ion transport activity.
In line with this evidence, attenuation of the above mentioned
mechanisms has been demonstrated after lipid-lowering treatment.
From the clinical point of view, such interaction between
plasma lipids and sodium homeostasis may adversely affect
the clinical presentation of diseases such as salt-sensitive
hypertension, congestive heart failure, renal diseases with
proteinuria or sodium retention.
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