Immunology,
Endocrine & Metabolic Agents in Medicinal Chemistry
(Formerly 'Current Medicinal Chemistry - Immunology, Endocrine
and Metabolic Agents')
ISSN: 1871-5222
Immunology, Endocrine &
Metabolic Agents in Medicinal Chemistry
Volume 6, Number 4, August 2006
Contents
Pathophysiological Basis For New Frontiers
in Arterial Hypertension
Guest Editor: A. Nitenberg
Editorial Pp.
317
Hypertension, Prehypertension and Blood Pressure Related
Diseases Pp. 319-330
D. Chemla, I. Antony, K. Plamann, P. Abastado and A. Nitenberg
[Abstract]
Conductance and Resistance Vessels in Arterial
Hypertension Pp. 331-341
B.I. Levy, N. Kubis, R. Fressonnet and M.E. Safar
[Abstract]
Determinants of Left Ventricular Hypertrophy
Pp. 343-365
J.J. Mercadier
[Abstract]
The Coronary Circulation in Arterial Hypertension
Pp. 367-383
A. Nitenberg, I. Antony and D. Chemla
[Abstract]
High Blood Pressure and the Risk of Stroke
Pp. 385-394
P. Rossignol, A. Chedid, A. Bura-Rivière and P-F.
Plouin
[Abstract]
Arterial Hypertension and Kidney Circulation
Pp. 395-405
M. Beaufils
[Abstract]
Obesity, Metabolic Syndrome, Diabetes and Arterial
Hypertension Pp. 407-423
P. Valensi, B. Chanu and E. Cosson
[Abstract]
Abstracts
[Back to top]
Editorial
“Knowledge gains through experimentation, everything
else is only information”
Albert Einstein
Arterial hypertension is an important cause of morbidity
and mortality because arterial hypertension is not only an
abnormal increase of arterial pressure, it is also accompanied
by a number of concomitant disorders. More than a “silent
killer”, high blood pressure is a “time bomb”
because patients who can feel great and have high blood pressure
are exposed to stroke, myocardial infarction, heart failure
and kidney failure.
Prevalence of arterial hypertension in the world in adult
population was about 26.6% in men and 26.1% in women in 2000,
that corresponds to 1 million individuals with considerable
disparities between developed countries and other countries,
especially for the complications, due both to diagnostic failure
and absence of therapy. Projections estimate that this number
would increase by 60% in 2025, mainly due to the increase
in food intake that should dramatically increase the prevalence
of diabetes, metabolic syndrome and obesity, three important
causes of arterial hypertension in developed countries and
in emergent countries with an expected increase of respectively
25% and 80% of arterial hypertension in 2025.
Arterial hypertension is a frequent disease that induces an
important amount of research activity and a constant flow
of knowledge and findings. Although the understanding of the
factors involved in the pathophysiology of arterial hypertension
has increased, which include neuro-endocrine factors, vascular
and endothelial functions, autocrine and paracrine functions,
interrelationships between target organ functions, metabolic
disorders, genetic factors, primary (essential) hypertension
remains a blanket that recovers our ignorance.
Although important progress have been made in the treatment
in arterial hypertension these last years in western countries,
and although we have very efficient compounds to reach the
goals of pressure values, the best statistics show that only
about 50% of the known hypertensive are correctly treated.
Moreover, even in patients correctly treated, the risk of
complications remains higher than in normotensive patients
showing the reduction of arterial pressure is only a part
of the treatment. Thus, the challenge for the next years is
not only the improvement of our means to reach the goal of
“normal” pressure in hypertensive patients, it
is also the prevention of target organs from deterioration
due to the disease which does nor resume in an elevated pressure.
This important objective will be reached only if our knowledge
of pathophysiology of the disease(s) increases.
With the assistance of the writers who have helped to produce
this issue, it is possible to examine the most relevant aspects
of arterial hypertension in a detailed and, I hope, a clear
and accessible manner. The papers published in this issue
try to provide pathophysiological informations that may be
useful for the comprehension of arterial hypertension and
its complications, and that also could be useful for the development
of new therapeutic interventions that are not only pharmalogical.
Alain Nitenberg, M.D.
Professor of Physiology and Cardiology
Bondy, France, 2006
[Back to top]
Hypertension, Prehypertension and Blood Pressure Related
Diseases
D. Chemla, I. Antony, K. Plamann, P. Abastado and A. Nitenberg
Hypertension is defined as either an elevation of systolic
blood pressure (SBP) to ≥ 140 mmHg and/or elevation
of diastolic blood pressure (DBP) to ≥ 90 mmHg for adults.
Hypertension is a frequent, age-related disorder and a major
risk factor for stroke, coronary heart disease, heart failure
and renal failure. The relation between BP and cardiovascular
disease (CVD) mortality and morbidity is strong, direct and
continuous over a wide range such that BP values must be viewed
as a continuum in which a high BP means an increased cardiovascular
risk and worse prognosis. Thus, the paradigm has shifted from
hypertension to BP-related diseases. The magnitude of the
burden of hypertension and high BP in both developed and developing
countries contributes to prediction of worldwide epidemic
of CVD. Effective strategy emphasizes focusing on SBP, identifying
high-risk patients and targeting reductions in multiple risk
factors, including end-organ damages. Recent studies have
focused on six modifiable risk factors, namely cigarette smoking,
lipids abnormalities, diabetes, BP levels, obesity, and stress.
Three protective factors have also been individualized, namely
the Mediterranean regimen, regular physical activity and regular,
moderate alcohol consumption. Besides health promoting life-style
modifications, the major classes of antihypertensive agents,
namely diuretics, β-blockers,
calcium antagonists, angiotensin converting enzyme inhibitors,
angiotensin receptor antagonists, are suitable for the initiation
and maintenance of therapy, and there is a frequent need to
use at least two drugs in combination in order to achieve
optimal BP. It is important to point out the fact that most
clinical trials are of short duration and their significance
must be confirmed on long-term outcomes.
[Back to top]
Conductance and Resistance Vessels in Arterial
Hypertension
B.I. Levy, N. Kubis, R. Fressonnet and M.E. Safar
More than one-fourth of individuals in the Eastern populations
are hypertensive. Both large (conductance) arteries and small
(resistance) arterioles are involved in the physiopathology
of hypertension.
Large arteries from hypertensive subjects are stiffer and
thicker than in normotensive matched controls. Stiffer arterial
walls are responsible for higher pulse wave velocity and earlier
reflection wave in hypertensives leads to increased systolic
pressure and pulse pressure and finally to increased left
ventricular after-load. Evidence for these pathophysiological
mechanisms arises from studies of pulsatile arterial hemodynamics,
as highlighted recently by the role of PWV and wave reflections
as independent factors in cardiovascular risk in hypertension.
Resistance arterioles (200-30 µm) are characterized
by the presence of a myogenic tone able to protect the capillary
bed against abnormally high blood pressure and to control
the local tissue blood flow. Several types of alterations
of resistance vessels are characteristics of chronic hypertension.
– reduced lumen diameter in relation with exaggerated
vasoconstriction,
– hypertrophy of the vascular wall resulting in decreased
lumen size and increased wall-to-lumen ratio,
– rarefaction of microvessels i.e. arterioles and capillaries.
Experimental and clinical results allowed to evidence that
antihypertensive drugs might reverse the structural changes
of the large and resistance arteries. Through modification
in the timing of wave reflections, it is also possible to
reduce the disproportionate increase in systolic blood pressure
and the associated cardiovascular risk. Some recent trials
are aiming to reduce or reverse microvascular network rarefaction.
This could be a promising way not only to normalize arterial
blood pressure but also to reduce target organs complications.
[Back to top]
Determinants of Left Ventricular Hypertrophy
J.J. Mercadier
Left ventricular hypertrophy (LVH), defined as an increase
in left ventricular mass, is one the aspect of the cardiac
phenotype observed during hypertension and other conditions
associated with a chronic increase in LV afterload. Since
myocardial hypertrophy helps to normalize LV wall stress and
the load of the constituting myocytes, LVH has long been considered
to be a beneficial adaptive mechanism. However, LVH is also
an independent risk factor for the occurrence of clinical
events, including death. During the past 25 years, basic cardiac
research has allowed to better understand the reasons for
such a negative outcome. During the eighties, the other phenotypic
characteristics of the hypertrophied LV have been established,
showing a number of tissular, cellular and molecular alterations,
the adaptive nature of which was clearly questionable. Since
the beginning of the nineties, research has moved to the field
of the mechanisms responsible for such changes and has allowed
to identify a large number of triggers, initiators, signal
transduction pathways and networks, effectors and counter-effectors
responsible for LVH and the other phenotypic aspects of LV
remodeling. Some of them referred to as “adaptive”
are beneficial and participate to LV adaptation to the chronically
increased afterload. However, in the context of hypertension
most of them referred to as “maladaptive” are
clearly detrimental and can be regarded, as at least in part,
as responsible for the poor prognosis. The goal of the present
article is to summarize the main actors of this hypertension-associated
LV remodeling putting emphasis on those constituting potential
targets for the development of new therapies aimed at preventing
detrimental LV remodeling resulting from chronic hypertension.
[Back to top]
The Coronary Circulation in Arterial Hypertension
A. Nitenberg, I. Antony and D. Chemla
Arterial hypertension is a major coronary risk factor due
to an increase prevalence of coronary atherosclerosis. On
the other hand, many arguments are suggestive of symptomatic
or silent episodes of “myocardial ischemia” in
hypertensive patients without coronary artery stenosis. Several
pathophysiological processes that are implicated in coronary
vascular changes are detrimental for the oxygen demand/supply
equilibrium and adaptation of coronary circulation and coronary
blood flow to an increase in myocardial oxygen demand. First,
apart from coronary atherosclerosis, epicardial vessels are
altered by vessel wall remodelling and structure changes.
Second, structural alterations of the coronary arterioles
due to medial hypertrophy and perivascular fibrosis limit
the functional area of the vessels which are also compressed
by a higher intramyocardial pressure, resulting in a reduction
of coronary flow reserve. Third, the increase in intercapillary
distance due to myocardial hypertrophy increases the distance
of oxygen diffusion to cardiac myocyte mitochondria, the site
of ATP synthesis. Fourth, the endothelium-dependent nitric-oxide
dilation of coronary vessels is depressed, thus impairing
the adaptation of coronary circulation to changes in myocardial
oxygen demand. All these changes do not depend on myocardial
hypertrophy, although myocardial hypertrophy aggravates the
disorders. Antihypertensive therapy may have beneficial effects
by reducing myocardial mass and arterial pressure, by restoring
a normal vascular structure and architecture, and by improving
coronary vasomotion.
[Back to top]
High Blood Pressure and the Risk of Stroke
P. Rossignol, A. Chedid, A. Bura-Rivière and P-F.
Plouin
High blood pressure is the most prevalent modifiable risk
factor for stroke. Observational and interventional studies
have shown that lowering blood pressure with drugs, even in
normotensive high-risk patients, may achieve effective primary
stroke prevention. Uncertainties remain concerning the optimal
blood pressure target, especially in older people with low
diastolic blood pressures. Data from The Perindopril Protection
Against Recurrent Stroke Study and other placebo-controlled
trials showed that secondary prevention of stroke can also
be provided by blood pressure lowering medication, even in
normotensive subjects. Possible differences in the preventive
potential of the various available antihypertensive agents
remain to be documented, both for the primary and secondary
prevention of stroke. Much uncertainty remains concerning
the optimal blood pressure management in the context of acute
stroke. Some trials currently evaluate the effect of lowering
blood pressure on subsequent outcome, such as mortality and
dependence, whereas others assess the effect of increasing
blood pressure. Conflicting results have been obtained from
small trials. These are possibly explained by differences
in inclusion criteria or follow-up duration, or by a U-shaped
relationship between systolic blood pressure at admission
and outcome. This review focuses on the preventive trials
that led to implement the current guidelines concerning blood
pressure management in relation to the risk of stroke. It
briefly describes ongoing trials that test new strategies
to improve the management of acute stroke.
[Back to top]
Arterial Hypertension and Kidney Circulation
M. Beaufils
Hypertension may cause renal vascular lesions and glomerular
damage, constituting hypertensive nephrosclerosis. This ultimately
may lead to end-stage renal failure, mainly in African-American
subjects. Such a situation is exceedingly rare in Caucasian
patients with non-malignant hypertension. The direct effect
of pressure is well evidenced experimentally in the 2 kidneys-one
clip Goldblatt model: only in the unclipped kidney which is
exposed to high blood pressure, vascular lesions develop in
interlobular arteries and afferent arterioles, followed by
glomerular sclerosis. The pressure-induced glomerular damage
is limited by an autoregulation based on vasoconstriction
of the afferent arteriole. The efficiency of this autoregulation
is largely under genetic influence. A deficient autoregulation
with vasodilated afferent arterioles leads to more early and
severe glomerular damage.
Conversely, afferent arteriolar vasodilatation, with glomerular
hyperfiltration, may precede any increase in blood pressure.
This occurs mainly when sodium excretion is limited, due to
any congenital functional defect, or a reduced number of nephrons.
Hypertension occurs secondarily, and appears as the hemodynamic
counterpart necessary to maintain the sodium balance. In this
case, the same primary renal abnormality causes both hypertension
and glomerulosclerosis. This is believed to be a frequent
cause of hypertension-associated glomerulosclerosis.
Whatever the sequence of events, reducing blood pressure is
the best way to limit kidney damage. Antihypertensive drugs
have, however some actions on renal circulation independent
of blood pressure. Calcium channel blockers blunt the auto-regulation
of afferent arterioles. On the contrary, drugs which inhibit
the renin angiotensin system reduce glomerular capillary pressure,
and have a beneficial effect on the progression of renal failure.
[Back to top]
Obesity, Metabolic Syndrome, Diabetes and Arterial
Hypertension
P. Valensi, B. Chanu and E. Cosson
Hypertension is a frequent condition in obese subjects and
in subjects with diabetes and other components of the metabolic
syndrome. The pathophysiology of the increase in blood pressure
(BP) is multifactorial. Three targets, heart, vessels and
the kidneys, are involved in BP regulation. Insulin, leptin
and some adipocytokins, whose plasma levels are often increased
in these subjects, are likely to play a major role. They act
through various mechanisms, some of them contributing to rise
BP and others to lower BP. An imbalance between these opposite
effects, as evidenced in insulin resistance state, may account
for elevated BP. Because hypertension is a major determinant
for cardiovascular complications and also for microangiopathic
complications in patients with diabetes, tight BP control
is mandatory to prevent these complications. Weight loss and
lifestyle changes are the cornerstone of hypertensive management,
but pharmacological anti-hypertensive treatments are often
required to achieve this goal. Drugs with favourable metabolic
effects, including for some of them a demonstrated effect
in diabetes prevention, should be preferably chosen.
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