REVIEW ARTICLE

Animal models of hypertension: An overview

LILACH O. LERMAN, ALEJANDRO R. CHADE, VINCENZO SICA, and CLAUDIO NAPOLI
ROCHESTER, MINNESOTA; BOSTON, MASSACHUSETTS; and NAPLES, ITALY

Hypertension is a multifactorial disease involving complex interactions between genetic and environmental factors. Development of experimental models of hypertension
allowed dissection and isolation of various factors associated with regulation of blood
pressure, inheritance of hypertensive traits, and cellular responses to injury. The phenotype-driven approach is taking advantage of selective breeding of animals (primarily rats) that exhibit a desired phenotype, like the useful SHR. Genotype-driven models
include transgenic techniques, in which mice are the most successful for selective
deletion or overexpression of target genes. Notably, a combination of comparative
genomics strategies and phenotypic correlates enhances the utility of hypertension
models and their clinical relevance. Indeed, experimental models enabled development of targeted interventions aimed at decreasing not only blood pressure but also
target organ injury. Continued utilization of experimental models simulating human
hypertension, particularly those that combine other clinically relevant comorbidities
like obesity or hypercholesterolemia, may afford development of effective strategies to
address this common disease. Nevertheless, a cautious approach is mandatory when
experimental findings in these models are extrapolated to human hypertension. (J Lab
Clin Med 2005;146:160 173)
Abbreviations: 2K1C 2-kidneys, 1-clip; ACE angiotensin-converting enzyme; AngII
angiotensin II; ANP atrial natriuretic peptide; AR adrenergic receptors; AT1 angiotensin
II type 1 receptor; DOCA deoxycorticosterone-acetate; eNOS endothelial nitric oxide
synthase; ET endothelin; NO nitric oxide; PRA plasma renin activity; RAS reninangiotensin system; SHR spontaneously hypertensive rat

ypertension is a multifactorial, polygenic disease that involves complex interactions between genetically determined homeostatic control mechanisms and environmental factors,1 and its
exploration thus requires availability of experimentally
manipulable animal models. The ideal animal model
for hypertension research should have human-like car-

diovascular anatomy, hemodynamics, and physiology

and develop human disease characteristics and complications in a timely or even accelerated fashion.2 Inevitably, no species can consistently answer all of these
needs, and experimental design and other constraints
often dictate the choice of animal models for specific
research applications.

From the Division of Nephrology and Hypertension, Mayo Clinic

College of Medicine, Rochester, Minnesota; the Research Center of
Excellence in Cardiovascular Diseases and Departments of General
Pathology and Medicine, University of Naples, Naples, Italy; and the
Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University, Boston, Massachusetts.
Supported in part by NIH Grants HL-63282 and 77131, the American
Heart Association, and unrestricted research funds from Regione
Campania 2004 2005, Naples, Italy.

Submitted for publication April 8, 2005; accepted for publication

May 20, 2005.
Reprint requests: Lilach O. Lerman, Division of Nephrology and
Hypertension, Mayo Clinic College of Medicine, 200 First Street
SW, Rochester, MN 55905; e-mail: lerman.lilach@mayo.edu.
0022-2143/$ see front matter
2005 Mosby, Inc. All rights reserved.
doi:10.1016/j.lab.2005.05.005

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Fig 1. Schematic of the general categories of animal models of

hypertension, divided into genetic and nongenetic models. The genetic models include those that are phenotype-driven (eg, SHR) or
genotype-driven (eg, null mice). The nongenetic models include
those obtained by nongenetic interventions (eg, 2K,1C).

Several techniques for specifically altering the genome have been developed that allow single genes to be
altered. Expression of human genes and proteins in
transgenic animals beginning in fetal life allows characterization of species- and substance-specific lifelong
effects of drugs. Almost all of these studies have been
restricted to investigations of the mouse, of which
many well-characterized genetic strains are available,
much is known about its embryogenesis, and pluripotent embryonic stem cells have been isolated. The application of novel comparative genomics strategy combined with phenotypic correlates in rats and mice
support the importance of these models to human disease and enables predicting several chromosomal regions in the human genome that potentially harbor
hypertension genes.3 Thus, the purpose of this review is
to summarize the main nongenetic and genetic models
of hypertension (Fig 1) that allow new approaches to
study this disease and may facilitate development of
novel therapeutic strategies.
NONGENETIC MODELS

Secondary causes are responsible for some hypertension in humans. The underlying origin of secondary
hypertension is most often renovascular and less frequently endocrine and/or metabolic disorders (Fig 1).
Several experimental nongenetic approaches have resulted in development of extremely useful models that
allow studying the effects of induced hypertension on
end-organ damage in different species, including large
animals possibly comparable with humans.
Surgically induced hypertension. The pioneering
work of Goldblatt et al4 in 1934 introduced the first
animal model of hypertension in dogs evoked by unilateral constriction of the renal artery (2K1C model)

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161

and was followed by similar demonstrations in rats5

and rabbits6 in the same decade. Indeed, partial occlusion of the renal artery has subsequently been shown to
lead to development of hypertension in rats, rabbits,
dogs,7 pigs,8 monkeys,9 and mice.10. In rats11 or rabbits,12 2K1C leads to a gradual and chronic increase in
blood pressure, which plateaus after 2 weeks but may
subsequently decrease in 10 20% of animals. In general, rats develop hypertension more easily than rabbits,
but its pattern may be influenced by the clip type, diet,
and animal age. Renovascular hypertension can also be
achieved by placing a clip on the aorta (coarctation)
between the 2 renal arteries.13
End-organ damage in the 2K1C model depends on
the size and time of the clipping and usually includes
endothelial dysfunction, cardiac hypertrophy (a 20
50% increase in cardiac size), and hypertrophy of the
contralateral kidney exposed to hypertension.14,15 As in
most models of hypertension, many of these effects
derive from the increase in systemic pressure, change in
blood flow patterns (nonlaminar fluid mechanics), and
shear stress. Stretch- or diet-induced activation of oxidative enzymes such as NAD(P)H oxidase, altered nitric oxide availability, and consequently oxidative
stress and inflammation, may all contribute to endothelial dysfunction and vascular remodeling, as does activation of systemic or tissue AngII in angiotensin-dependent models.
In dogs, achieving a sustained increase in blood
pressure is more difficult because of their pronounced
renal autoregulatory capacity,16 but it can still be obtained by placing sutures17 or an inflatable occluder16
on the renal artery. Increase in blood pressure in dogs is
rapid and can be maintained for weeks,18 although
extensive collateral development within 23 months
can eventually reduce blood pressure.19 Conversely, in
2K1C cynomolgus monkeys (Macaca fascicularis), the
increase in mean arterial pressure is maximal by 4 6
weeks and sustained for over 24 weeks.9 The consequences of renal artery stenosis can also be exacerbated
by contralateral nephrectomy (1K1C model), as observed in rats,20 rabbits,21 and dogs.22 Although its
pattern may depend on dietary sodium20 or the timing
of nephrectomy, this model usually provides reliable
development of hypertension.
The 2K1C model shows some sensitivity to diet,
because changes in potassium intake can affect development of hypertension. Sodium balance depends on
the degree of hypertension and pressure natriuresis of
the contralateral kidney.23 Sodium restriction attenuates development of hypertension in young rats,24
whereas a high sodium diet increases blood pressure in
moderately hypertensive rabbits25 but not in rats.26
Contrarily, in rabbits with severe hypertension and con-

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sequent extracellular volume depletion, a high salt diet

decreases PRA and blood pressure.27
Hypertension in 2K1C may be influenced by renin
release from the stenotic kidney. Systemic PRA increases faster in rabbits28 but lasts longer in rats,29
whereas in dogs19and pigs,30 the increase may be more
rapid, but PRA returns to normal values if the hypertension is moderate. Systemic levels of AngII and aldosterone follow a similar pattern.7 There might be
several reasons for the subsequent decline in systemic
PRA.8,30 The immediate increase in blood pressure in
renal artery stenosis results from release of renin from
the stenotic kidney, and consequently AngII.
In 2K1C, the interplay between PRA and extracellular volume is complex, because the contralateral kidney
suppresses renin release3133 and increases sodium excretion, which tends to drive the blood pressure down.
This process decreases stenotic renal perfusion pressure
and resumes renin release, which in turn elevates blood
pressure, and so forth.34 36 If the increase in systemic
pressure restores the perfusion pressure of the stenotic
kidney, many humoral changes return to baseline.37,38
In high-grade renal artery stenosis, this cycle of events
may induce volume depletion and renal failure. In
contrast, in moderate and untreated experimental renal
artery stenosis, renovascular hypertension can be sustained with relatively low systemic levels of AngII, as
observed in several surgically induced hypertension
models.8,27,37,39 42 In chronic 1K1C in rats,43 rabbits,44
and dogs16, blood pressure seems to be less dependent
on the RAS45 and more on extracellular volume status,
and PRA is lower than in 2K1C.
We have recently developed a pig model of unilateral
renal artery stenosis, which was achieved by intravascular implantation of a local-irritant coil in the renal
artery that leads to a gradual proliferative neointimal
response and progressive luminal narrowing, and we
developed many pathophysiological characteristics of
human renovascular hypertension8,30 (Fig 2). The domestic pig is a good large animal model of hypertension
and end-organ injury46 because the anatomy and physiology of its renal47 and cardiovascular48 systems are
comparable with humans. We have shown that PRA
increased only transiently in this model if the stenosis is
moderate, whereas oxidative stress remains elevated
and may contribute to sustenance of hypertension.8,30
In contrast to the somewhat predictable patterns observed in different experimental models, humans with
renal artery stenosis show considerable variability in
PRA, because of a wide range in severity of stenosis,
coexistent morbidities, age, and sodium intake. PRA
may also rise because of posture or sodium restriction
during testing,49 total occlusion,50 or antihypertensive
treatment that reduces renal perfusion.51,52 Few data

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Fig 2. Renal angiography shows unilateral renal artery stenosis in a

pig model, including poststenotic arterial dilation. Its radiological
appearance resembles observations of renal artery stenosis in humans.

track PRA over time in patients with renal artery stenosis, but it seems to also show an early increase and
later normalize.53 Indeed, normal PRA can be found in
about 2537% of patients.50,53 PRA variability partly
explains the failure of measuring any single pathway to
predict blood pressure response to intervention in
humans.54
Less common surgical forms of renal hypertension
can be achieved by complete occlusion of both renal
arteries, which in dogs or rabbits leads to a fast and
severe increase in blood pressure, or by renal microembolization.55 In 1939, Page56 developed a model of
hypertension obtained by wrapping the kidney in cellophane or silk, which lead to perinephritis and renal
parenchymal compression,57 as applied in dogs, cats,
rabbits, and cynomolgus monkeys.58 This model seems
to be dependent on increased activity of the RAS and
ET-1.59,60 In humans, hypertension has been infrequently attributed to a process comparable with Page
kidney,61 63 and renal compression has been also suggested as a potential mechanism for obesity-induced
hypertension.64
Total or subtotal nephrectomy is also associated with
development of hypertension,65 the characteristics of
which are dependent on contributing factors such as
survival time, dietary protein, sodium and water intake,
and the presence of the adrenal gland. This procedure is

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often accompanied by diffuse vascular calcifications,

which are particularly prominent in rats.7 Generation of
renal parenchymal disease or inflammation by injection
of bacteria,66 foreign proteins, or antibodies67 have also
induced hypertension in rats, rabbits, and dogs. More
recently, administration of phenol in the lower pole of
1 kidney induced neurogenic hypertension in the rat, an
effect possibly mediated by AngII.68
Endocrine, metabolic, and diet-induced hypertension.

The most common endocrine method to induce hypertension introduced over 60 years ago is administration
of mineralocorticoid,69,70 particularly DOCA. In rats
and dogs,71 but not in pigs,72 generation of hypertension often additionally requires partial removal of a
renal mass and a high-salt diet. The hypertension that
develops is characterized by volume expansion and
increased cardiac output, which by about a 30% increase in cardiac mass (rarely heart failure), endothelial
dysfunction, proteinuria, and glomerulosclerosis.14
Glucocorticoids can also induce hypertension in rats
and mice,73 possibly via activation of the RAS, but they
are less effective than DOCA. Chronic infusion of
components of the RAS has also been successful in
inducing hypertension. The features of renin-induced
hypertension in rabbits or rats resemble renovascular
hypertension. McCubbin et al showed in 196574 that
chronic systemic infusion of AngII at subpressor doses
results in slowly progressive increases in arterial pressure, possibly because of increased oxidative
stress,30,75 and more recently, chronic intrarenal infusion of AngII has also been shown to result in preglomerular vascular remodeling and hypertension.76
Chronic inhibition of NO produces volume-dependent
elevation of blood pressure77 in most tested species
such as rats,78 dogs,79 and pigs.80 Its physiological and
pathologic characteristics resemble essential hypertension,81 and alterations in this pathway have been speculated to underlie development of many forms of
hypertension.
Inherited salt sensitivity has been implicated in essential hypertension,82 and different dietary interventions have thus induced experimental hypertension. A
high-sodium diet superimposed on the appropriate genetic background can indeed promote hypertension in
rats. Dahl83 isolated a strain of salt-sensitive rats, characterized by high blood pressure and low heart rate
even on a relatively low-sodium diet (0.5% NaCl),
increased sodium and water retention and plasma volume, renal parenchymal lesions, and increased activity
of the sympathetic nervous system.84 Interestingly, in
offspring of these rats blood pressure cosegregates with
alleles for ACE and the GC-A/ANP receptor.85 Similarly, a high-salt/high-cholesterol diet in Dahl rats accentuated glomerular injury.86

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A high-fructose diet induces both insulin resistance

and hypertension in SpragueDawley87 and Wistar
Kyoto88 rats, possibly because of downregulation of
insulin receptors89 and upregulation of AT1. However,
despite development of insulin resistance, this maneuver fails to elicit hypertension in normal dogs,90 which
reiterates the contribution of genetic background.
GENETIC MODELS

The most common cause of hypertension in humans

is essential hypertension, in which multiple genes contribute to the individual phenotype, each by diverse
allele effects, penetrance, and contributions. As a result,
no single genetic defect can explain development of
essential hypertension in humans. The decoding of the
human and mouse genomes allowed generation of
transgenic or gene-targeted models suitable for studying hypertension. The phenotype-driven experimental
approach takes advantage of the natural variation
among inbred strains and crosses to find quantitative
traits and determine which genes are responsible.91 In
contrast, in the genotype-driven approach, a known
gene is studied with genetics-based interventions (overexpression or ablation) (Fig 1).
Phenotype-driven models. The phenotype-driven rat
experimental model is the most abundant for hypertension research and has particular potential for exploration of polygenic hypertension. In general, development of homozygous hypertensive rat strains is
achieved by selective breeding of animals displaying
the desired phenotype over several generations, and
once the trait is fixed, sib mating is maintained for
about 20 generations to achieve genetic homogeneity.
This approach has been useful to develop, from the
Wistar strain, fundamental models such as the SHR92 or
stroke-prone SHR93 (Table I). However, the SHR is not
a strictly inbred strain and gives way to a wide variety
of genes to cosegregate and may mimic a subtype of
human primary hypertension that is inherited in a Mendelian fashion.14 The genetic mechanisms of hypertension in SHR have been attributed to both neural and
vascular alterations. Individual variations in the genetic
background of the SHR may influence evolution of
hypertension and end-organ compromise in this model,14 but at least 3 major genes are involved in early
development of hypertension, whereas an additional
gene identified on chromosome 10 contributes to development and maintenance of hypertension during aging in SHR.94 Androgens may modulate the hypertension and age-related renal injury in this model95 by
altering pressure natriuresis and tubulo-glomerular
feedback96 in a manner that potentially resembles human hypertension. This prominent role of androgens in

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SHR has consequently imitated postmenopausal hypertension as well.97

One of the first strains of inherited hypertension was
the genetically hypertensive rat (Table I) developed
from the New Zealand strain.98 In this model the RAS,
fluid and sodium retention, and salt-sensitivity do not
seem to play a major role in the mechanism of hypertension.99 Other important hypertensive rat strains include the salt-sensitive Dahl (see below) and the Sabra
model, which exhibits gender-specific quantitative trait
loci for salt susceptibility on chromosome 1 SS1a and
SS1b in men and SS1b in women.100 Other important
models that were obtained with similar techniques include the Lyon genetic hypertensive rat, a model of
low-renin hypertension that shows hypersensitivity of
preglomerular vessels to AngII,101 and Milan SHR,
which has a mutation in the gene coding for adducin, a
skeletal protein involved in transepithelial sodium
transport.102 Many of these models indeed mimic the
human form of low-renin hypertension.103
Particularly relevant are models associated with coexisting morbidities accompanying hypertension, as
frequently observed in clinical practice. Notably, elevated plasma cholesterol has been observed accompanying hypertension in the Lyon genetic rat model, as
often observed in human essential hypertension.104
Others may be accompanied by obesity (and often type
II diabetes), including the obesity prone SpragueDawley,105 obese Zucker106 and Wistar fatty107 rats, and the
rat model of visceral obesity and hypertension.108 Another inbred transgenic model of atherosclerosis and
polygenic hypertension is the Dahl salt-sensitive rat
model (Tg53), which exhibits coronary artery disease
and overexpresses the hepatic human cholesteryl ester
transfer protein.109 This enzyme is an important regulator of lipoprotein metabolism, and its upregulation
has been implicated in the pathogenesis of hypertension
and increased cardiovascular risk in clinical metabolic
syndrome.110
In general, in most phenotype-driven models, hypertension is associated with cardiac hypertrophy, endothelial dysfunction, and renal functional impairment
(proteinuria, decreased creatinine clearance), but cardiac insufficiency and end-stage renal disease are not
consistently observed.14 The outcomes seem to depend
on the underlying origin, genetic background, and possibly species differences, as well as on the degree of
hypertension. For example, the Dahl rats seem more
prone to develop severe cardiac and renal failure than
SHR, which may be from, on the one hand, their higher
blood pressures, but also from the different origin involved in this strain.14 In addition, the commercially
available diet in some of these studies differs in many
aspects from the average Western human diet, which

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may contribute to these outcomes. Indeed, rodent models of hypertension seldom develop severe human-like
complications like atherosclerosis, myocardial infarction, aneurysm formation, or heart failure,111 and stroke
occurs only in subsets, which may be from shorter
exposure to the increased blood pressure, lack of comorbid conditions, or compensatory mechanisms different than that of humans. Interestingly, in the fawnhooded rat model that does develop hypertension and
chronic renal failure, susceptibility to complications is
under genetic control independent from that to hypertension,112 which raises the intriguing possibility that
vulnerability to end-organ injury in humans is derived
from pathways separate from the hypertension per se.
Studies are needed to explore the existence of specific
human susceptibility and whether it could be medically
targeted.
Genotype-driven models. Research on the molecular
basis of hypertensive disorders has shown significant
progress, and disease susceptibility genes have been recognized. Mutations in several genes that cause Mendelian
forms of human hypertension have been recently identified,113 such as those affecting the circulating levels and
receptors for mineralocorticoid hormones, renal ion channels and transporters114, and others.115117 In addition to
human studies, investigation of engineered genotypedriven models has contributed to our understanding of the
possible genetic basis for hypertension. Indeed, disruption
of genes that control peptides or receptors related to the
regulation of blood pressure has helped to clarify the role
of specific mechanisms in the pathogenesis of hypertension. Transgenic techniques have been applied in several
species (eg, sheep, cows, goats, chickens, and fish), but
mice are the most successfully and widely used by
researchers.
Gene function in hypertension is most often studied
with gene overexpression (eg, transgenic) or deletion
(knockout), usually related to candidate systems involved in regulation of vascular tone, renal physiology,
and/or electrolyte and fluid homeostasis118 (Table 1),
and several mouse models have been developed.
RAS. Association of gene polymorphism of the AT1
receptor, angiotensinogen, or ACE with hypertension
has been controversial and likely interacts with comorbid conditions. Both transgenic and knockout mouse
models of various components of the RAS have been
constructed (Fig 3). Mice may have 2 subtypes of the
gene for AT1 (AT-1a and AT-1b) and the REN gene
(Ren-1d and Ren-2d). Overexpression of the rat angiotensinogen gene in mice, without119 or with120 concomitant overexpression of rat renin, leads to development
of high blood pressure. Indeed, blood pressures in mice
carrying various numbers of copies of the angiotensinogen gene are predictable and increase at approximately

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Table I. Various experimental models of hypertension

Secondary hypertension

Renovascular

Renal injury

Vasoactive intervention

Endocrine and dietary

Neurogenic

Genetic models

Two-kidneys, one-clip
One-kidney, one-clip
Aortic coarctation
Total occlusion
Microembolization
Page-kidney
Partial or total nephrectomy
Injection-induced inflammation
Irradiation
Renin-angiotensin-aldosterone
Nitric oxide inhibition
Noradrenaline
Pressor prostaglandins
DOCA-salt
Glucocoticoids
Adrenal regeneration
Sex-hormone induced
Dahl salt-sensitive
Pregnancy, pre-eclampsia
Psychological
Environmental
Central NS stimulation
Baroreceptor denervation

Phenotype-driven

Genotype-driven

SHR
SHR-stroke prone
Dahl salt-sensitive rat
Genetically hypertensive rat
Sabra model
Lyon hypertensive rat
Milan SHR
Obesity-related
Postmenopause-related
Renin-angiotensin system
Sympathetic NS
Atrial natriuretic peptide
Nitric oxide
Endothelin
Neuropeptide Y
Vasopressin
Prostaglandin
Kallikrein-kinin
Vasopressin
Ion transport systems

DOCA, deoxycorticosterone-acetate; NS, nervous system; SHR, spontaneously hypertensive rat.

Fig. 3. Genetic murine models constructed to exhibit an increase (A) or decrease (B) in blood pressure. This
manipulation has been achieved by overexpression (yellow) or knockout (orange) of various components of the
RAS.

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8 mm Hg per gene copy, whereas conversely mice

completely knocked-out for this gene are hypotensive.121 Similarly, ACE knockout mice are also hypotensive, especially males122 and mice selectively deficient of
the vascular rather than proximal tubular enzyme,123
which introduces the possibility for specific tissue-targeted inhibition of ACE. Of note, studies in humans have
also suggested a linkage between the ACE locus and
hypertension in men but not in women,124,125 which supports the possible influence of androgens in regulation of
ACE and, thereby, blood pressure. In contrast, because of
species-specific interaction between human angiotensinogen and renin, overexpression of both human genes in
double transgenic mice is required to obtain a sustained
increase in blood pressure,126 which may be mediated
through central activation of AT1 receptors.127 Interestingly, this combination is also accompanied by complications like atherosclerosis128 and in the salt-fed
Tsukuba hypertensive mice by aortic aneurysm and
rupture,129 which may imply that the human forms of
these genes are more detrimental than some rodent
genes, which may partly explain the distinct human
vulnerability to complications of hypertension. Nevertheless, introduction of the mouse Ren-2 renin gene
into the genome of the rat also causes severe hypertension and its complications,130 including prominent cardiac hypertrophy and endothelial dysfunction, which
raises the possibility that gene xeno-expression per se
may exacerbate the outcomes of hypertension.
Genetic polymorphism and AT1R has been reported
to have a role in essential hypertension and in modulating end-organ damage (eg, heart, kidney) in both
experimental models131 and humans.132,133 Indeed,
overexpression of AT1 induces cardiac remodeling134
and augments contractile response to AngII,135 whereas
experimental overexpression of AT2 receptor stimulates production of bradykinin, NO, and cyclic
guanosine monophosphate to promote vasodilation136
and attenuate cardiac remodeling.137 On the other hand,
mice deficient in the Ren-1d138 and -2d139 genes are
normotensive. Heterozygous and homozygous mutant
mice knocked-out for the AT1a receptor-gene have a
corresponding decreases in blood pressure140 and
abnormal tubuloglomerular feedback responses,141
whereas mice deficient in AT1b have normal phenotypes, which indicates that AT1a can take over the role
of AT1b receptors.142 Indeed, mice lacking both the
AT1a and the AT1b show marked hypotension as well
as reduced growth and abnormal kidney structure.143,144 On the other hand, deletion of AT2 increases blood pressure and sensitivity to DOCA salt145,
which indicates that it modulates the pressor effects of
AngII.

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Natriuretic peptides. The natriuretic peptide signaling

pathway has often been considered a sensor of changes
in blood volume, opposing the actions of the renin/
angiotensin/aldosterone axis. ANP is released from the
heart in response to atrial stretch and is thought to
mediate its natriuretic and vaso-relaxant effects through
the guanylyl-cyclase-A receptor. Allelic variants of natriuretic peptide receptor genes have been observed to
be associated with family history of hypertension.146
Targeted ANP gene intervention is not necessarily associated with essential hypertension or salt sensitivity,
but it may alter regulation of aldosterone production.
Indeed, mice lacking ANP develop hypertension when
fed a high salt diet,147 whereas ablation of the ANP
GC-A receptor results in salt-resistant hypertension148
and cardiac hypertrophy,149 which suggests that this
signaling pathway is involved at the level of peripheral
resistance independently of ANP. On the other hand,
mice lacking the brain and c-type natriuretic peptide
genes do not develop hypertension.91
ET. Increased levels of the potent vasoconstrictor ET
may accompany some forms of hypertension, and polymorphism of the ET-2 gene in hypertensive patients can
influence the severity of hypertension.150 The ET-1
gene Lys198Asn polymorphism is associated with
blood pressure in overweight people151 and may interact with other genes or environmental factors to promote preeclampsia.152 Similarly, ET receptors gene
polymorphisms has also been reported to be associated
with clinical essential hypertension.153155
Disruption of the ET genes has also been attempted.
Gene transfer of ET-1 in rats increases blood pressure,
but it downregulates the ET-A receptor.156 ET-1-/homozygous mice die at birth and have morphological
abnormalities, whereas heterozygous ET-1/- surprisingly develop elevated rather than decreased blood
pressure,157 which is likely from a disturbance in central cardiorespiratory regulation. Furthermore, blood
pressure is higher in ET-B than in ET-A knockout
mice158 possibly because of a decrease in salt excretion
that ET-B mediates, or in ET-1 clearance.
Nitric oxide. The linkage between genetic alterations
in the eNOS gene and hypertension has been controversial possibly because of specificity of polymorphism
effects on different facets of hypertension. For example, the Glu298Asp variant of eNOS may be a genetic
susceptibility factor for hypertension159 or resistance to
therapy,160 whereas G11T polymorphism is not associated with hypertension.161 Mice deficient in the 3 NOS
isoforms (neuronal, inducible, and endothelial) have
been produced. Polymorphism in the neuronal or inducible NOS genes is apparently not associated with
essential hypertension,162and only the latter (eNOS
knockout mice) are hypertensive163 because of a com-

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bination of reduced NO production and modulation of

the RAS, which is suggested by the abnormally elevated secretion of renin observed in this model.91 In
addition to the impaired vascular relaxation, eNOS
knockout mice often have abnormal vascular remodeling164 and microvascular density165 (alterations that
likely contribute to hypertension in this model), as well
as cardiac hypertrophy and dysfunction.166 Therefore,
experimental evidence supports the notion that genetic
variance in the eNOS gene may underlie at least some
forms of essential hypertension.
Catecholamines. Several genes involved in the synthesis and metabolism of catecholamines have been
identified, and targeted mutants for the genes encoding
the tyrosine hydroxylase and ARs have been constructed91. The 2-AR play a key role in regulating neurotransmitter release in the central and peripheral sympathetic nervous systems, and its deletion increases
sympathetic activity.167 The 2B subtype mediates the
hypertensive response to 2 agonists, whereas the
2A-AR subtype exerts a sympatho-inhibitory effect,
and its loss leads to hypertension and a hyperadrenergic
state.168 Adult 2 knockout mice have normal blood
pressure, but they exhibit an exaggerated hypertensive
response to exercise and epinephrine because of alterations in vascular tone and energy metabolism.169 Polymorphism of this receptor has also been implicated in
influencing blood pressure levels in humans,170 although the observation that it does not necessarily
cosegregate with hypertension171 argues against a clear
causal role for AR mutation in essential hypertension.
Intrarenal dopamine regulates sodium transport and
interacts with renal neurohumoral systems. Abnormal
renal dopamine production and/or receptor function
have been reported in salt-dependent and low-renin
forms of human hypertension as well as in genetic
animal models, including SHRs and Dahl salt-sensitive
rats. Defective transduction of the D1 receptor signal in
renal proximal tubules decreases the inhibition of sodium transport by dopamine and leads to sodium retention and hypertension,172 but it does not seem to be a
common mechanism for essential hypertension.
Other genetic models. Genetic hypertension in rats
may be accompanied by a defect in renal prostaglandin
catabolism.173 Nevertheless, gene-targeted mutants for either the PGI2 or the thromboxane-A2 receptors, and for
cyclooxygenase-1 and -2, have normal blood pressures.
On the other hand, mice with targeted disruption of the
PGE2 receptor display salt-sensitive hypertension, which
implies a role for PGE2 in salt excretion174, but regulation
of blood pressure by PGE2 is influenced by its receptor
expression, sex, and genetic background.91
Another key system in regulation of hypertension is
the vasodilator and natriuretic kallikrein-kinin system.

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Genetic variation in the promoter region of the B2

bradykinin receptor gene can also be associated with
essential hypertension in humans,175 and deficiency in
tissue kallikrein activity has been observed to be associated with arterial dysfunction and inward remodeling.176 Either by long-term blockade or genes disruption of the bradykinin B2 receptors in mice,
hypertension develops mainly by decreasing the NO
pathway and thereby amplifying vasoconstriction. In
addition, bradykinin B2 receptor knockout mice show
salt-sensitive hypertension177 and enhanced propensity
for renovascular178 and AngII-induced179 hypertension.
However, this may not occur consistently, because in
the absence of the B2 receptor, B1 can be upregulated
and assume some of its hemodynamic properties.180
Possibly, comparing littermates on a pure genetic background may provide for more rigorous assessment of
the phenotypic effect of this specific mutation.181
Additional proposed peptides to be involved in regulation of blood pressure are the neuropeptide Y and
vasopressin; yet both the Y2 receptor deficient mice
and the transgenic mice overexpressing the vasopressin
rat gene have normal blood pressure regulation182 and
normal water metabolism183. Lastly, altered activity of
the Na/H exchanger has been implicated in development of high blood pressure in subgroups of essential
hypertensive patients. Indeed, transgenic mice overexpressing Na/H exchanger ion transport show decreased urinary water and sodium excretion and develop salt-sensitive hypertension, as may occur in
hypertensive patients.184
Therefore, the genotype-driven approach has been
useful to physicians for elucidating many mechanisms
that may contribute to the development of hypertension
and target-organ injury. A potential limitation for this
approach is that the genetic defect has to be known or
suspected a priori (reverse engineering), and the genetic background upon which the abnormality is expressed, as well as the nongenomic environmental factors, can obscure or enhance any association. On the
other hand, this may contrarily constitute an advantage,
because genotype-driven models may in turn potentially uncover unexpected and novel interactions that
may generate hypertension.
CONCLUSIONS

Development of experimental models of hypertension allowed prolific investigation of factors associated

with regulation of blood pressure, genetic basis of
hypertension, inheritance of hypertensive traits, and
cellular responses to injury (Table I). Genetic models of
hypertension were especially successful in rodents and
have encouraged studies in human population with the
candidate gene approach, as well as the development of

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new classes of drugs to decrease blood pressure and

target organ injury. Importantly, nongenetic approaches
have complemented the investigation of the effects of
secondary hypertension on end-organ injury in a larger
variety of animal models, thereby enriching our understanding of the pathophysiology of this disease. In
addition, experimental models of hypertension associated with comorbidities common in clinical practice
that accentuate development of hypertension and/or
target organ injury may provide closer simulation of the
human disease.
Notably, obtaining reliable measurements of blood
pressure is a challenging task, especially in small experimental animal models. Indirect techniques, like the
tail-cuff method, permit sporadic measurements and
could be suitable for some purposes, but they may
impose a substantial amount of thermal and restrain
stress that is known to affect heart rate, stress hormones, and consequently, blood pressure.185 In contrast, the telemetry method for direct blood pressure
measurement is generally superior, because of its ability to monitor the dynamic nature of blood pressure.
Telemetry allows continuous monitoring of conscious,
freely moving animals, as well as evaluation of blood
pressure variability under basal condition and in response to different interventions or variables such as
drugs, diet, or genotype.185 Thus, despite higher costs
and potential limitations related to the size of the device, radiotelemetry is accepted as the most reliable
tool for monitoring blood pressure.185,186
The road ahead is long, and a cautious approach and
rigorous analysis of experimental data are mandatory
before extrapolating experimental findings to humans.
Investigating its causes, effects, and interaction with
other cardiovascular risk factors by virtue of these
experimental models may not only shed light on the
complex mechanisms triggered by hypertension, but it
may also assist in development of novel therapeutic
strategies to manage this common disease.
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