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Hypertension is the prevalent cause of cardiovascular disease that
leads to heart failure, stroke, renal failure, and, ultimately,
to death. In the USA, approximately 50 million people have hypertension,
according to Phase I estimates of the National Health and Nutrition
Examination Survey III (NHANES III), from 1988 to 1991[1].
The prevalence is about 20%. According to a report[2],
about 40% of white people and more than 50% of black people aged
65 or older suffer from some form of high blood pressure in the
USA. Epidemiological surveys have demonstrated an increasing prevalence
of hypertension in China, from 5.11% in 1958 to 7.73% in 1980 and
11.89% in 1991[3,4]. Although this incidence is lower
than that in many developed countries such as the USA (20%)[1]
and Canada[5], it represents 50 million people in 1980
and 90 million people in 1991 due to the size of the Chinese population.
According to relevant reports[4,6], cardiovascular diseases
are the leading causes of death in Chinese society.
The syndrome of hypertension is more than just an elevation of
arterial pressure, although it is this aspect that the general public
is most familiar with. Hypertension when fully developed is characterized
by an increase in vascular resistance to blood flow, cardiac hypertrophy,
often an increase in cardiac output, an increased output of sympathetic
nervous system (SNS), changes within the vascular smooth muscles,
often atherosclerosis, and abnormalities in renal function. Increased
vascular resistance is due to constriction of the vascular smooth
muscle, primarily in the high resistance vessels. The etiology of
essential hypertension is not known and the causes of it may be
multifactorial. It is generally believed that both genetic and environmental
factors and their interactions play a critical role in the pathogenesis
of hypertension and other cardiovascular diseases. Since hypertension
and associated cardiovascular diseases are the leading causes of
death of human beings, medical scientists are dedicated to elucidate
the mechanism of and explore the treatment for hypertension.
It is noticed that animal models of human disease have been widely
used to study etiology and pathogenesis of human disease, to prevent
disease or to find a therapy and identify risk factors contributing
to the disease. This literature reviews briefly advances in the
most widely used rodent models of hypertension, including advantages
and limitations. Hopefully, this will be useful to those in choosing
appropriate animal models of hypertension for their researches.
This comprehensive review may help physicians and scientists understand
the pathogenesis of hypertension and therefore optimize therapeutic
approaches. It is our expectation that the creation and utilization
of novel animal models of hypertension will fundamentally advance
the fields of cardiovascular medicine and physiology.
The major animal models of hypertension
Basically, animal models of hypertension comprise primary and secondary
hypertension according to hypertension etiology (Figure 1). The
primary hypertension includes genetically-induced and environmentally-induced
hypertension and the secondary hypertension includes pharmacologically-induced
and renal-induced hypertension by the way of induction.
Genetically-induced hypertension Animals that have undergone
artificial genetic manipulation are predestined to become hypertensive.
Some investigators believe that genetically hypertensive rats comprise
the most popular mo-dels to study essential hypertension[7].
One example is the spontaneously hypertensive rat (SHR), originally
inbred from Wistar stock by Okamoto and Aoki, and their WKY inbred
nonhypertensive controls. These rats develop hypertension at about
4-6 weeks of age, largely independent of die-tary levels of either
Na+ or Cl-. Another model is the Dahl salt-sensitive
rats, originally derived from Sprague-Dawley stock by Dahl on the
basis of developing hypertension with high NaCl diet. When fed with
normal salt diets, these rats become hypertensive, indicating that
this is a genetic model of hypertension with the feature of salt
sensitivity. O'Dowd and Rapp[8] have refined the genetic
background of the original Dahl stock, and their salt-sensitive/Jr
line is now preferred (along with their salt-resistant/Jr controls).
Genetic analysis revealed linkage with loci close to the angiotensin
converting enzyme (ACE) and guanylyl cyclase A (GCA)/atrial natriuretic
factor (ANF) receptor genes in Dahl salt-sensitive rats[9].
It was found that certain alleles at the GCA and ACE loci (or at
loci closely linked to them) had a significant impact on blood pressure
response to high salt in Dahl salt-sensitive rats.
The SHR was generated by inbreeding Wistar rats with the highest
blood pressure[7]. The SHR develop many features of hypertensive
end-organ damages including cardiac hypertrophy, heart failure,
and renal dysfunction. According to relevant reports[11,12],
the SHR is the most commonly used genetic model although the mechanisms
for producing the hypertension are not clear. Overactivity of the
brain renin-angiotensin system (RAS) appears to be involved in initiating
the development of spontaneous hypertension based on the finding
that central injections of angiotensin II (AngII) receptor antagonists
cause greater reductions in systolic blood pressure in SHR than
in normotensives[13,14]. However, DePasquale and colleagues[15]
reported that central administration of AT1 receptor
blocker losartan (DuP 537) did not lower blood pressure in SHR.
Thus, the above hypothesis needs further confirmation. Interestingly,
some hemodynamic alterations which occur during the development
of the disease are similar to human essential hypertension (ie,
a high cardiac output early, and in the adult, a normal cardiac
output and an increased vascular resistance)[16]. In
this model, there is also an increase in the activity of the sympathetic
nervous system as evidenced by increased renal sympathetic activity[16].
The renal blood flow and glomerular filtration rate are normal[17]
and renal vascular resistance is increased[22]. The SHR
stroke prone (SHR-SP) is a further developed sub-strain with even
higher levels of blood pressure and a strong tendency to die from
stroke[18]. The SHR has been used to evaluate genetic
factors involved in hypertension. Although a wide variety of genes
seems to cosegregate in various crosses[12], neither
of these genes is confirmed to be the etiological gene for hypertension.
The advantage of this model is that its pathophysiological changes
are similar to those found in human essential hypertension[16,19].
A major drawback of this model is the lack of an appropriate control,
which has been genetically altered yet is free from the disease
and the complexity of the genetic mutations which have affected
not only blood pressure but many other regulatory systems as well.
Transgenic hypertension models can be generated by over-expressing
a specific gene. This type of genetic model usually has a relatively
good normotensive control, the same strain of animals without genetic
alteration. It is an excellent model to study the role of a specific
gene in the pathogenesis of hypertension. However, the transgenic
model may not mimic human essential hypertension as well as the
SHR does in terms of pathophysiology. A representative of this type
of hypertension is the TGR (mREN2)27 transgenic rats[10].
In this genetic model, the introduction and overexpression of the
mouse Ren-2 gene in Sprague-Dawley rats leads to severe hypertension[10].
The appropriate control is the age-, body weight-, and sex-matched
normotensive Sprague-Dawley rats without renin transgene.
Environmentally-induced hypertension In recent years, the
important role of environmental factors in the disease process has
received great attention from scientists and physicians. The primary
interest is focused on the area of cardiovascular disorders, particularly
hypertension. To understand better the ways in which the environmental
factors affect the cardiovascular functions, researchers have tried
to produce experimental hypertension in animals by exposing them
to different experimental paradigms.
Stress-induced hypertension Epidemiologists and clinicians have
long suspected that stressful life events can be a sufficient trigger
for the expression of hypertension in some individuals[20].
Attempts to induce hypertension in animals using sensory stimulation
have generally employed loud noises, flashing lights, and oscillating
cages, either separately or together. For example, in one early
study rats were subjected to 20 weeks of randomized flashing lights,
motion, and loud noises[21]. After 12 weeks on this schedule,
systolic blood pressure (SBP) values reached approximately 150-160
mmHg. Perhaps a better example of this type of experiment is found
in a study by Lin and Li[22]. Stressed rats developed
hypertension within two weeks after irregular foot electric-shocks
combined with buzzing noise. It is accepted that activation of sympathetic
nervous system[23] and the RAS[24] play a
role in the initiation of stress-induced hypertension. Li[25]
found that increased activity of the cholinergic system in the rostral
ventrolateral medulla (rVLM) was also involved in the development
of stress-induced hypertension. Plasma catecholamine, corticosterone,
angiotensin II, glucose, and lipids were found to be increased during
stress. In this model, about 40%-50% of stressed rats failed to
develop hypertension[26].
Diet-induced hypertension It is known that long-term exposure to
a special diet (high salt, fat, or sugar) results in dietary hypertension
in some animals or humans. For example, chronic fructose treatment
in rats repeatedly has been shown to elevate blood pressure associated
with insulin resistance and hyperinsulinemia[27,28].
Hyperactivity of the SNS and the RAS, vascular hypertrophy, and
sodium retention by the kidney tubules have been proposed to be
some of the mechanisms by which fructose induces hypertension. By
degeneration of capsaicin-sensitive nerves, Wang and colleagues[29,30]
developed a salt-sensitive model of hypertension. In this model,
the increased salt sensitivity is mediated by the enhancement of
the SNS[29].
Cold-induced hypertension: Fregly[31] and Sun[32-36]
found that chronic exposure of rats to mild cold (41 °F or
5 °C) induced hypertension including cardiac hypertrophy within
3 weeks. This is presently the only "naturally-occurring"
form of experimentally-induced hypertension that is induced without
surgical intervention, administration of excessive doses of drugs
or hormones, or genetic manipulation. It is interesting that the
elevated blood pressure of rats after 7 weeks of exposure to cold
does not return to pre-cold exposure level during the 4 weeks after
removal from cold. Thus, an elevation of blood pressure induced
by a longer period of cold exposure might not be reversible after
return to thermoneutral temperature. Intermittent exposure of rats
to cold also induces hypertension, with a sigmoid relationship between
the hours per day exposed to cold and systolic blood pressure.
Cold-induced hypertension (CIH) is also demonstrable in humans.
Epidemiological surveys and clinical observations have established
that people who live and work in cold areas have a high incidence
of hypertension and related cardiovascular diseases[37-39].
Cold temperature (weather) makes hypertension more severe in hypertensive
patients[39,40]. The cold winter season has the highest
mortality and morbidity of cardiovascular diseases in a year[39-42].
Donaldson[38], after studying the relationship between
outdoor temperature and blood pressure in men in central London
between 1986 and 1992, reported that cold exposure of normal life
in winter is sufficient to induce significant and prolonged hypertension
in the general population.
It was originally assumed that cold-induced elevation of blood
pressure was a direct vasoconstrictive effect of sympathetic nervous
system (SNS). Indeed, the SNS is activated by chronic cold exposure
and the plasma and urine levels of catecholamines are increased
significantly in cold-exposed rats[32-34,43]. However,
the in vitro vascular contractile response to ¦Á1-adrenoceptor
agonist, phenylephrine, is decreased significantly in cold-exposed
rats[44]. The in vivo pressor response to phenylephrine
is significantly reduced by chronic cold exposure[45].
Thus, the vascular ¦Á1-adreno-ceptors are down-regulated
during cold exposure. Several studies[32,34,36,46] have
shown that blockade of the RAS at different sites could attenuate
or prevent the cold-induced elevation of blood pressure. Antisense
oligodeoxynucleo-tides to angiotensinogen mRNA or AT1-receptor
mRNA reduce elevated blood pressure of cold-exposed rats[47].
Angio-tensinogen gene knockout delays and attenuates CIH[48].
It has been therefore suggested elsewhere[32-34,36,48]
that the hyperactivity of the SNS initiates CIH probably via activation
of the RAS. Indeed, plasma renin activity (PRA) is increased during
exposure to cold and abolishment of the rise in PRA by renal denervation
prevents the development of CIH[32]. Cold-exposed rats
had an elevation of blood pressure that was proportional to the
concentration of NaCl in the diet[49], suggesting that
CIH is sodium-dependent hypertension.
CIH is a prototypic model of environmentally-induced hypertension,
which is similar in many ways to human hypertension. Induction of
CIH requires a climate-controlled chamber, with a strict requirement
of temperature and humidity. Perhaps, this is the limitation of
this model.
Pharmacologically-induced hypertension The DOCA-salt-induced
model of hypertension is a typical representative of pharmacologically-induced
hypertension. A very high dose of deoxycorticosterone acetate (DOCA)
ranging from about 300 to 1000 mg×kg-1×d-1
(sc) is required to induce hypertension in rats. Isotonic saline
is the sole drinking fluid. This is an important co-factor because
it expedites the deve-lopment of hypertension and makes it more
severe. Thus, this model is salt-dependent in its initiation. It
often needs surgical reduction of renal mass or unilateral nephrectomy.
The combination of DOCA-salt and unilateral nephrectomy results
in hypertension, cardiac and renal hypertrophy, and nephrosclerosis[50].
DOCA-salt hypertension is a low renin and volume overloaded form
of hypertension. There is evidence that arginine vasopressin (AVP)
plays a role in both the development and maintenance of DOCA-salt
hypertension[51,52]. It is believed that AVP is involved
as a vasopressor hormone in the pathogenesis of malignant DOCA-salt
hypertension[53]. The SNS also appears to be involved
in the development of DOCA-salt hypertension[54]. The
increased activity of the SNS may affect renal function through
the renal nerve, as denervation of the kidneys delays the onset
and decreases the severity of the disease[54,55]. Further
studies[56] indicated that AngII receptor binding sites
were increased in the brain, suggesting an up-regulation of AngII
receptors. However, AngI converting enzyme inhibitors and AngII
receptor blocker are ineffective in reducing blood pressure in low-renin,
DOCA-salt hypertension[57,58]. In contrast, aldosterone
receptor blockers and diuretics are effective in reducing blood
pressure in this model[59]. Most recent studies indicate
that the endothelin system plays an important role in the pathogenesis
of DOCA-salt hypertension[60-65]. Oxidative stress may
also be involved in DOCA-salt hypertension[65,66]. The
major limitations of the DOCA-salt model are: 1) the pharmacological
(large) doses of drug required; 2) requirement for surgical reduction
of renal mass; and 3) ingestion of a large amount of NaCl required.
The major advantage of this model is the potential to investigate
the role of sodium in the developmental stages of hyperten-sion.
Renal-induced hypertension The physiological function of
the kidney includes maintenance of electrolyte and fluid balance
and secretion of renin, an important component of the RAS. Thus,
its involvement in the regulation of blood pressure and its important
role in the development of hypertension are well accepted. Since
1934, when Goldblatt and his co-workers[67] induced an
elevation of blood pressure by partial constriction of the renal
artery of the dog, many renal-induced models of hypertension have
been successfully established in rats, rabbits, sheep, and cats[68].
Generally, renal-induced experimental hypertension includes two-kidney
Goldblatt hypertension (constriction of one renal artery while the
contralateral kidney is left intact) and one-kidney Goldblatt hypertension
(one renal artery is constricted and the contralateral kidney is
removed).
In the rat, by clipping one renal artery (leaving the contralateral
kidney untouched) with a clip which induced a severe hypertension,
a biphasic course in the plasma renin activity was found. In the
initial phase, sodium retention occurred and was associated with
a transient increase in plasma renin activity returning to control
levels within a week[69,70]. Thus, it has been suggested
that the RAS plays a role in the development of two-kidney Goldblatt
hypertension[69-71]. The sustained elevation of blood
pressure may still be AngII-dependent since a sub-pressor dose of
AngII would result in an elevation of blood pressure due to a shift
in the dose-response curve of AngII[72]. This suggests,
but does not prove, that AngII receptors are upregulated in this
model of hypertension. The initial elevation of blood pressure in
the one-kidney Goldblatt model is also AngII-mediated[73].
Due to the absence of the other normal kidney, no compensatory increase
in sodium and water excretion can occur, and hence, fluid volume
is retained[74]. This model is thus a sodium-fluid volume-dependent
model. This would be an ideal model for studying the role of volume
expansion in the development of hypertension.
During the early developmental stage of these two renal-dependent
models, when the clip is removed, arterial blood pressure returns
to normal[70,75]. Thus, renal-induced hypertension is
reversible and reproducible. Furthermore, these models provide a
unique opportunity to investigate the changes which occur specifically
at the level of the kidney, as well as the role of the kidney in
the long-term blood pressure control. If the reversal of hypertension
is time-depen-dent, it would suggest that relevant changes, perhaps
structural, have developed.
Clinical implications of animal models of hypertension
It should be mentioned that each of the above models of experimental
hypertension studies a specific aspect of hypertension. Neither
of them encompasses all traits of human essential hypertension.
Due to the unknown etiologies of hypertension, the use of various
research models, each of which induces the disease by a different
mechanism yet with the same end result, is advantageous. By using
different types of experimental hypertension, scientists could identify
and evaluate potential risk factors contributing to hypertension
and related cardiovascular diseases. This would allow new and effective
measures to be adopted for preventions and therapies. Usually, animal
studies are essential to the success of clinical trials. It is noted
that remarkable advances in cardiovascular medicine have been originated
from experimental hypertension. Therefore, animal models of hypertension
are very important approaches to the study of human hypertension.
Physicians and scientists could learn the developmental process
and pathogenesis of hypertension from these animal models that are
designed to mimic those of human hypertension. The induction of
hypertension in animals could help understand the etiological factors
that may be involved in essential hypertension. For example, hypertension
and cardiovascular diseases (CVD) may have genetic predeter-minants.
There is a predisposition to hypertension and CVD in those patients
with a positive family history. The notion of genetic predisposition
for the development of hypertension has been strengthened by the
development of genetic or spontaneous models of hypertension. The
pathophysiological changes of spontaneous hypertension in animals
are very similar to those of human essential hypertension. Also,
transgenic models of hypertension induced by targeting different
genes are excellent tools to study genes relevant to hypertension.
An animal model of DOCA-induced hypertension is an ideal model for
evaluating the role of sodium in hypertension. Studies from DOCA-induced
hypertension have provided a strong basis for using spironolactone
(aldosterone receptor blocker) to treat clinical hypertension. Because
some special diets (high salt, fat, or sugar) could result in dietary
hypertension, restriction of these diets has been suggested by clinicians
for preventive and therapeutic purposes. The cause of hypertension
varies with hypertensive patients. Thus, it is important to identify
the potential cause of hypertension prior to treatment; which guarantees
appropriate and effective treatment. For example, stenosis of the
renal artery could cause hypertension as learned from an animal
model of renal-induced hypertension. In this case, surgical correction
of the stenosis of the renal artery may be more important than treatment
with antihypertensive drugs. In addition, research findings from
experimental hypertension may have clinical implications. For example,
the RAS has been found to play a critical role in the pathogenesis
of CIH in rats. This has led to a clinical trial which proves that
the ACE inhibitor (captopril) or AT1 receptor blocker
(losartan) can control hypertension appropriately and effectively
in hypertensive patients in winter. This also could help to control
the high incidence of myocardial infarction and stroke during the
cold season. In contrast, the use of animal models of hypertension
would allow scientists to test new pharmacological treatments and
gene therapy for hypertension and related CVD. Thus, what is learned
from animal hypertension may reveal new insights into both preventive
strategies and optimization of therapeutic approaches. It should
be emphasized that any experimental data from animal models of hypertension
must be tested and further validated in humans before they can be
applied in hypertensive patients.
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