Indian Journal of Pharmacology 2003; 35: 349-362

EDUCATIONAL FORUM

D.K. BADYAL et al.

ANIMAL MODELS OF HYPERTENSION AND EFFECT OF DRUGS

D.K. BADYAL, H. LATA*, A.P. DADHICH

Department of Pharmacology, Christian Medical College, Ludhiana-141 008. *Department of Physiology,
Dayanand Medical College, Ludhiana-141 001.
Manuscript Received: 9.12.2002

Revised: 13.6.2003

Accepted: 19.8.2003

ABSTRACT

Hypertension, the most common cardiovascular disease is the primary cause of stroke, coronary artery
disease and sudden cardiac death. Many factors are believed to be involved in the pathogenesis of
hypertension and its complications. Experimental models of human disease are used to study
pathophysiological factors involved in hypertension and assess antihypertensive agents. Today different
strains of rats with genetic hypertension are available and in most laboratories, therapeutic studies on
hypertension are carried out on these models. As new insights in to the pathogenesis of hypertension are
revealed, new models are being developed to produce hypertension in animals. This article reviews
experimental models of hypertension. Both conventional and genetic models of hypertension are discussed.

KEY WORDS

Experimental hypertension

blood pressure

Introduction
Hypertension is the most common cardiovascular
disease and is a major public health issue in developed
as well as developing countries. Although it is common
and readily detectable, it can often lead to lethal
complications if left untreated. Because of its high
incidence and morbidity, various classes of drugs and
regimens have been advocated for the control of
hypertension. Despite the large armamentaria of drugs
being available for the treatment of hypertension, the
last two decades have witnessed the introduction of a
number of new antihypertensive drugs. Recent
research during this period has also added
considerably to our knowledge of the mechanisms
involved in the pathogenesis of hypertension.
Human essential hypertension is a complex,
multifactorial, quantitative trait under polygenic
control. In order to understand the pathogenesis and
to study the treatment and prevention of a disease, it
is useful to develop animal models. Various models
of experimental hypertension have been primarily
developed to obtain information on the etiopathoCorrespondence: D.K. Badyal
E-mail: dineshbadyal@rediffmail.com

cardiovascular disease

genesis of hypertension. These models are also used

in the pharmacological screening of potential
antihypertensive agents. In the past, hypertensive
animal models have been used infrequently for testing
antihypertensive potential of drugs. As new molecules
are being synthesized in a large number, the use of
animal models is increasing for testing these
molecules. New animal models of hypertension are
being developed as new insights in to the
pathogenesis of hypertension are revealed.
The animal models of hypertension share many
features which are common to human hypertension.
Many of these models have been developed by
utilizing the etiological factors that are presumed to
be responsible for human hypertension such as
excessive salt intake, hyperactivity of reninangiotensin-aldosterone system (RAAS) and genetic
factors. Since regulation of blood pressure (BP) is
multifactorial, the effectiveness of an antihypertensive
agent in one model does not necessarily mean that
the mechanism of action of a given agent in a given
model is related to the pathogenesis of elevated blood
pressure.

ANIMAL MODELS OF HYPERTENSION

An ideal animal model of hypertension should fulfill

the following criteria:

350

It should be feasible in small animals.

causes release of aldosterone leading to salt and

water retention resulting in increased blood volume
and hypertension (Figure 1)3,4,6.

It should be simple to perform and uniformly

reproducible.

The various methods of inducing renovascular

hypertension are as follows:

It should be able to predict the potential

antihypertensive properties of an agent.

I.

It should consume minimal quantities of

compounds.
It should be comparable to some form of human
hypertension.
Animals used: Whereas in the past, most studies
on experimental hypertension were carried out on
dogs, currently rat is the preferred animal species.
Spontaneous hypertensive rat (SHR), the genetic
strain of hypertensive rat, is the animal of choice for
screening antihypertensive agents. SHR is the
cornerstone of medical research in experimental
hypertension1. Rabbits, monkeys, pigs and mice are
also used to produce experimental hypertension2.
The various types of animal models of hypertension
being used are:
1.

Renovascular hypertension

2.

Dietary hypertension

3.

Endocrine hypertension

4.

Neurogenic hypertension

5.

Psychogenic hypertension

6.

Genetic hypertension

7.

Other models

1. Renovascular hypertension:
This is a very commonly used model of hypertension.
In renovascular hypertension, the RAAS plays an
important role3,4. Experimentally, renal hypertension
is produced by renal artery constriction, which
activates peripheral RAAS and sympathetic nervous
system5. A number of factors like decreased blood
volume may lead to sympathetic stimulation in this
model. Renin is secreted by kidneys when
sympathetic activity is increased. Renin converts
angiotensinogen to angiotensin-I. Angiotensin-I is
converted to angiotensin-II by angiotensin converting
enzyme (ACE). Angiotensin-II is a potent vasoconstrictor and increases BP. Angiotensin-II also

Goldblatt method: Goldblatt et al (1934)

reported that a partial constriction of renal
arteries in dogs produced hypertension7. This
type of hypertension has also been induced in
rabbits, rats and monkeys8. In rabbits and rats,
a U-shaped silver ribbon clip is used to
constrict the renal arteries 9. Rats weighing from
120 to 200 g are anaesthetized with hexobarbitone sodium (40 mg/kg body weight) and
a silver clip of 0.2 mm internal diameter is
placed on the left renal artery close to the
aorta10. The renal artery in rats can also be
ligated with 4-0 silk suture11. Constriction of
renal artery should be more than 50%. The
animal is considered hypertensive if systolic
BP is more than 160 mm Hg for two
consecutive days after 4 weeks of ligation5.
In dogs and rabbits, retroperitoneal approach
can be used and the operation is carried out
through an oblique lateral abdominal incision,
just below and parallel to costal margin.
Muscles are split and peritoneum is stripped
away from the kidney. The kidney and the renal
artery are easily identifiable. The first part of
renal artery is cleaned for 1 cm or so from its
origin from the aorta9. In dogs, renal arteries
can also be constricted with a small adjustable
silver clamp or with silk sutures 12.
In rabbits, bilateral constriction of renal arteries
is achieved in two stages with an interval of
1-4 weeks between operations. Persistent
hypertension, which is moderate to severe, will
develop over a period of 12 months 9. The BP
has been reported to increase from normal
mean level of 106 to 160-190 mm Hg from 4
weeks to 9 months in 65% of rabbits8. The most
satisfactory method in rabbits is to perform a
right nephrectomy and two or more weeks later
to apply a clip to the left renal artery 13.

Three types of hypertension are produced by

Goldblatt method:

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D.K. BADYAL et al.

Figure 1.

Renin angiotensin system and Goldblatt hypertension.

(-)

a.

Two kidney one clip (2K1C) hypertension:

The renal artery is constricted on only one
side with the other artery (or kidney) left
untouched. This results in a sustained
increase in BP due to increased plasma renin
activity (PRA), which in turn increases
circulating angiotensin-II, a potent vasoconstrictor. However, there is no salt and
water retention because of the other normal
kidney being intact. Thus, the resultant
hypertension at this stage is renin-angiotensin
dependent. After about 6 weeks, the
increased angiotensin-II releases aldosterone from adrenal cortex leading to a
gradual retention of salt and water. Retention
of salt and water leads to decreased renin

b.

production (Figure 1). From this stage

onwards, hypertension is volume dependent4,6,9. Hence, salt and water balance is
critically involved in the pathogenesis of
renovascular hypertension. Increased BP and
increased renin activity returns to normal by
unclipping or removal of the affected kidney 6.
One kidney one clip (1K1C) hypertension:
Constriction of renal artery is done on one side
and the contralateral kidney is removed. There
is an increase in BP within a few hours. Since
there is no other kidney, there is no pressure
diuresis and natriuresis, so there is rapid salt
and water retention (Figure 1). Plasma renin
activity is usually normal. Hypertension soon
becomes volume dependent 4,6,9.

ANIMAL MODELS OF HYPERTENSION

c.

Two kidney two clip (2K2C) hypertension:

Constriction of aorta or both renal arteries is
done. There is a patchy ischaemic kidney
tissue, which secretes renin leading to
increased BP. The remaining kidney tissue
retains salt and water. Indeed, one of the most
common causes of renal hypertension in
human beings is such a patchy ischaemic
kidney disease4.

II.

Hypertension induced by external

compression of renal parenchyma: This
type of hypertension is produced in dogs,
rabbits and rats. The following methods are
used to produce this type of hypertension:

a.

Page hypertension: A sheet of cellophane is

placed around the kidney and held in place by
silk sutures tied loosely around the renal hilus.
Both kidneys are wrapped or one kidney is
wrapped and other is removed 14 . A
fibrocollagenous shell is formed around the
kidney in 3-5 days because of reaction of the
tissue to the foreign material. This shell
compresses renal parenchyma leading to
decreased renal vascular pressure. This
expands the extracellular volume leading to
increased peripheral resistance and hence
increased BP. In rabbits, chronic hypertension
with normal or decreased renin activity is
produced over a period of approximately 6
weeks 6,15 . However, a high proportion of
animals develops severe hypertension and
dies within 2 months 8.

b.

Grollman hypertension: In this method,

kidney tissue is compressed by securing a
'figure of 8' ligature around the kidney 16. The
ligature around the kidney forms a figure
resembling number 8. This type of hypertension can be produced in dogs, rabbits and
rats. It is of two types:

1.

Two kidney one ligature (2K1L): Ligature is

applied to one kidney and contralateral kidney
is left untouched.

2.

One kidney one ligature (1K1L): Ligature is

applied to one kidney and contralateral kidney
is removed.

III.

Coarctation of aorta: Renal blood flow can

352

be decreased by compressing the aorta.

Coarctation can be done just above the renal
arteries, between renal arteries and superior
mesenteric arteries or between two renal
arteries with the right artery above and the
left artery below the site of coarctation17. An
increase in BP similar to 2K1C model can be
produced by applying a rubber band to
abdominal aorta along with constriction of right
renal artery for 8 weeks18. Coarctation can be
followed by unilateral nephrectomy to produce
this type of hypertension6,19.
IV.

Reduced renal mass: Reducing renal tissue

to five-sixth (5/6th) by renal mass ablation
produces hypertension. In this method, the
right kidney is removed and 2 or 3 branches
of left renal artery are ligated to produce
infarction of approximately 2/3rd of the left
kidney 20 .

V.

Glomerular sclerosis secondary to microsphere embolisation is also used to produce

renal hypertension21 .
The mean arterial pressure in renal hypertensive rats produced by above methods
(231.643.1 mm Hg) is significantly higher than
the mean arterial pressure in normotensive
control rats (1602.84 mm Hg)22.

2. Dietary hypertension:
I.

Increased salt intake: Physiologically, normal

kidney has the ability to excrete easily the daily
salt load without allowing a marked rise in
extracellular volume. However, general
epidemiological data have shown that higher
the average sodium intake in a given
population, the greater will be the prevalence
of hypertension. Chronic ingestion of excess
salt produces hypertension in rats, which
mimics human hypertension morphologically23.
High salt intake hypertension has been
produced in rats, rabbits and chicks by
replacing drinking water with 1-2% sodium
chloride for 9-12 months 8,24.
High salt intake along with unilateral
nephrectomy produces accelerated hypertension within 3-4 weeks in dogs 25. Accelerated
renal hypertension in rats is produced by

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D.K. BADYAL et al.

applying a 'figure of eight' ligature to one kidney

and removing the other in a single stage
operation performed under strict aseptic
conditions using pentobarbitone sodium (20
mg/kg, i.p. ) and ether anaesthesia. The
drinking water is replaced with physiological
saline for three weeks and the animals are
used 4 to 5 weeks after the operation22.

All operated rats receive an injection of

ampicillin (10 mg/kg, i.m.) daily for 5 days and
local application of neosporin-H to prevent
infection. A week later, DOCA (25 mg/kg/wk,
s.c. for 5 wk) dissolved in cotton seed oil, is
injected into nephrectomised rats. Alternatively,
nephrecto-mised rats could receive DOCA
from silicon rubber implants (200 mg/rat)
implanted subcutaneously 32 . NaCl (1.0%)
solution is substituted for drinking water and
given ad libitum 24.

3. Endocrine hypertension:
I.

Mineralocorticoid induced hypertension:

Mineralocorticoids cause retention of sodium
and water in the body until escape diuresis
occurs due to increased pressure on the
kidneys. No further retention of sodium and
water occurs, but general level of body sodium
and water is slightly raised.
Selye et al was the first to demonstrate that
deoxycorticosterone acetate (DOCA)
produces hypertension in rats26 . There is
increased DOCA-induced reabsorption of salt
and water leading to increased blood volume
and hence increased BP. There is also
increased secretion of vasopressin leading to
water retention and vasoconstriction. In
addition, altered activity of RAAS leads to
increased sympathetic activity 23,27. Rats,
especially female and young, are prone to
DOCA-salt induced hypertension23,24. This type
of hypertension can also be produced in dogs
and pigs28 . Other mineralocorticoids (e.g. ,
aldosterone) and glucocorticoids can also
produce this type of hypertension26,29.
DOCA induced hypertension is salt dependent
since neither administration of DOCA nor
partial removal of renal mass is effective in
increasing BP when applied without salt
administration23. To produce hypertension, rats
weighing about 100 g are kept on a diet high
in sodium chloride and drinking water is
replaced by 2% sodium chloride solution
ad libitum. After they attain a weight of about
250 g, they are given DOCA dissolved in
sesame seed oil at a dose of 10 mg/kg, twice
weekly for 43 days24,30.
In another method, unilateral nephrectomy is
performed followed by DOCA administration31.

II.

Adrenal regeneration hypertension:

Hypertension is produced in rats by unilateral
nephrectomy followed by removal of right
adrenal gland and enucleation of left adrenal
gland. Enucleation is carried out by making a
small incision in the capsule of adrenal gland
through which the bulk of glandular tissue is
extruded by gentle application of pressure with
curved forceps. Drinking water is replaced with
1% saline. Hypertension develops during
regeneration of adrenal glands in about 2
weeks 8. Once hypertension has been
established, neither removal of the regenerated adrenal nor substitution of saline
with drinking water brings about a return of BP
to normal33.
This type of hypertension develops more
readily in female and young rats. This model
is used mainly to study the role of various
factors e.g., steroids, in the pathophysiology
of hypertension33,34.

4. Neurogenic hypertension:
One of the most important negative feedback in the
control of BP originates from baroreceptors located
in the carotid sinus and aortic arch. Afferents of
baroreceptors travel along 9th and 10th cranial
nerves. The first synapse is present in the nucleus
tractus solitarius (NTS) of the medulla oblongata. NTS
is not merely a relay center, it also contains complex
synaptic connections and innervation from many brain
areas and receives information from periphery.
Stimulation of baroreceptors causes inhibition of
vasomotor center leading to vasodilatation,
bradycardia and decrease in BP8. Sectioning of the
baroreceptor nerves leads to persistent rise in BP in
dogs, cats and rabbits35. Neurogenic hypertension
can be produced by the following methods:

ANIMAL MODELS OF HYPERTENSION

I.

Denervation of sinoaortic baroreceptors:

This is the most often used neurogenic model
of hypertension. In dogs, cardioaortic nerve is
located at the junction of superior laryngeal and
vagus nerve and runs in the form of several
fine strands. These strands unite and may be
traced back as a white band lying within the
vagal sheath alongside the cervical
sympathetic nerve 8 . Following bilateral
vagotomy and carotid sinus denervation, the
region is painted with 5% phenol and then
alcohol to ensure complete denervation of the
carotid sinus. There is sudden increase in BP22.
The dog is allowed to equilibrate for
approximately 30 min and a bolus of the test
compound can be given by intravenous
administration. BP returns to normal within
about 2 days because the response of
vasomotor center to the absent baroreceptor
signals fades away, which is called resetting
of baroreceptors. Thus, this is only an acute
type of hypertension4.
In rabbits, right carotid sinus can be removed
together with 2 cm segments of the right
cervical sympathetic and depressor nerves
while the left carotid sinus can be removed later
on36. In rats, sinoaortic denervation leads to
marked and sustained increase in BP, which is
comparable to renovascular hypertension or
DOCA-induced hypertension36 .
Some investigators found no increase in BP
in dogs with sinoaortic denervation as
compared to sham-operated dogs since BP
was very labile in sinoaortic denervated dogs 37.
They concluded that primary function of
baroreceptors is not in regulation of BP but in
minimising variations in BP caused by
excitement, postural changes and diurnal
rhythm35. Bilateral destruction of NTS, the site
of termination of the baroreceptor afferents, is
more specific and complete than baroreceptor
denervation and leads to severe hypertension
that could be fatal 4,36,37. Baroreceptor
denervation is not recommended as a model
for screening antihypertensive agents.

II.

Electrical or chemical stimulation of different

areas of the brain leads to development of
hypertension in rats e.g., electrical stimulation

354

of hypothalamus, glutamate injection into the

rostral ventrolateral medulla38,39.
5. Psychogenic hypertension:
It has been reported that elevation of BP resulting
from repeated exposure to stressful situation may
lead to a state of persistent hypertension40. Borderline
hypertensive rats (BHR) are useful for psychogenic
hypertension. BHRs that were exposed to daily
sessions of either short (20 min) or long (120 min)
duration air-jet stimulation developed hypertension
within 2 weeks in comparison to home cage controls.
Animals exposed to 120 min stress sessions had
significantly higher systolic BP relative to the 20
minute group40.
Other types of stress have been applied, such as
emotional stimuli, psychosocial stress, immobilization
stress and electric stimuli, but in all cases the results
were similar41,42. However, the degree and stability of
hypertension was not comparable to other types of
hypertension2. The stress-induced hypertension was
associated with either normal or suppressed PRA
values, suggesting that the hypertension in these
animals is not renin-dependent 42. As stress plays an
important part in development of human hypertension, this model is very frequently used to study
the pathophysiology of hypertension.
6. Genetic hypertension:
In 1963, Okamoto and Aoki43 introduced a new model
of experimental hypertension that required no
physiological, pharmacological or surgical
intervention. The so called spontaneous hypertensive
rat (SHR) was developed by meticulous genetic
inbreeding that uniformly resulted in 100% of the
progeny having naturally occurring hypertension.
Since then, several expert panels have reported that
SHR is an excellent model of experimental
hypertension that could serve as a counterpart for
clinical essential hypertension as well as model for
complications of hypertension. Estimates have
ranged from a single gene to as many as six major
genes that determine high blood pressure in these
rats44. In SHRs, BP gradually increases until it is
maintained at a markedly elevated level after
approximately 12 weeks of age. In unrestrained male
SHRs, mean arterial pressure is approximately 190200 mm Hg as compared to 115-130 mm Hg in
normal rats1. During the early stable stages and

355

D.K. BADYAL et al.

developmental phase of hypertension, elevated BP

is maintained in large part by enhanced central
sympathetic outflow45. In the later stages increased
total peripheral resistance with a normal cardiac
output and decreased permeability of the glomerular
membranes form the basis for the long term
maintenance of the hypertension. Comparison
between spontaneous and essential hypertension
reveal that both are caused by multifactorial
inheritance and have in common an increased
vascular resistance which is caused by neural
vasomotor tone and non-neural structural alterations.
Guidelines have been published for the maintenance
and use of SHRs 46.
Spontaneous hypertension has been observed in a
number of different strains of common laboratory
animals, at least 6 different strains of rats, and at
least one strain each of dogs and rabbits. The New
Zealand strain of Smirk seems to be most similar to
the Japanese SHR, though this has not been studied
as widely47. In contrast, the Milan strain developed
by Bianchi et al, seems to be different involving
primarily alterations in renal sodium and water
metabolism; therefore it may not be analogous to
essential hypertension48. A fourth strain developed
by Dahl shows a high sensitivity (S strain) to sodium
intake in comparison to its normotensive control (R
strain), which is sodium resistant 49. Furthermore, a
fifth strain of hypertensive rats the Sabra strain have
been bred recently in Israel, and a sixth strain in
France, the Lyon strain50,51.
Among these strains, SHRs develop not only
moderate to severe hypertension but also typical
complications of hypertension. Stroke prone SHRs
(SHRSP), which are selectively bred from among
SHRs, are extreme examples that develop
cerebrovascular lesions spontaneously in over 80%
of rats52. Because of high mortality rate of stroke in
man, the similarity of stroke in SHRSP is important
for further application of this model to studies of
stroke in man. Other variants derived from SHRs
are obese SHRs and arteriolipidosis-prone
SHRs53,54. Extreme environmental conditions such
as stress and excess salt accelerate the
development of hypertension and aggravate the
hypertensive complications 55,56.
Complications such as cerebral hemorrhage,
thrombosis, nephrosclerosis and myocardial lesions

in SHRs and especially cerebral lesions in SHRSPs,

are pathogenically, pathologically and epidemiologically similar to those observed in essential
hypertension in man2. Therefore, these models can
be used to study not only the pathogenesis and
therapy but also prophylaxis in essential hypertension
and its complications. Because of apparent
similarities of the SHR to essential hypertension, SHR
models are highly recommended for screening
potential drug candidates for hypertension 1 .
Experimental models of genetic hypertension have
also been developed in animals other than the rat.
Though it has been produced in one strain of rabbit
and dog they have not been studied extensively for
practical, financial and other reasons 1,4,6. Rats are
mainly used because of their small size, short lifespan and low cost.
7. Other models:
1. Obesity-related hypertension: Wistar fatty
rats (WFR) derived from cross between obese
Zucker and Wistar Kyoto rats show persistent
hyperinsulinemia and hypertension after 16
weeks of age and may be a good model to
elucidate the relationship between hyperinsulinemia and hypertension57.
2. Hypertension induced by cholinomimetic
agents: Physostigmine (10-80 g/kg, i.v.), a
cholinesterase inhibitor, and oxotremorine
(20-40 g/kg, i.v. ), a direct muscarinic
cholinergic agonist, cause a dose-dependent
increase in BP58. The cholinomimetic-induced
hypertension has been shown to be elicited
through activation of central cholinergic
mechanism and mediated peripherally through
sympathetic nervous system45. Pretreatment
with methyl scopolamine (1 mg/kg) 5-10
minutes before giving oxotremorine prevents
initial hypotension in this model59.
3. Angiotensin-II induced hypertension:
Subcutaneous infusion of angiotensin-II (0.7
mg/kg/day) using minipump elicits hypertension in 4-8 weeks60,61.
4. Hypertension induced by cadmium:
Hypertension is produced by the chronic
administration of CdCI (1 mg/kg/day, i.p. for
2 wk). CdCl-induced hypertension might be
due to the fact that the metal ion might mimic

ANIMAL MODELS OF HYPERTENSION

Ca2+ ion as a partial agonist and produce a

direct contractile effect on vascular smooth
muscle24.
5. Chronic nitric oxide inhibition-induced
hypertension: SHRs when given a nonselective nitric oxide synthase inhibitor, Nnitro-L-argininemethyl ester (L-NAME), for 4
weeks develop time and dose-dependent
hypertension62 .
6. Transgenic rat (TGR) models: Transgenic
models of hypertension have revolutionized the
experimental work on hypertension. Several
transgenic rat lines expressing candidate
genes for hypertension have been produced.
Introducing an additional renin gene, the
murine Ren-2 gene, into the germ line of rats
results in transgenic hypertensive rat strain,
TGR (mREN2) 27, with an overexpression of
renin. Genetic linkage studies have shown that
the components of RAAS are associated with
this type of hypertension. Linkage has been
described for the angiotensinogen gene in
human hypertension. TGR model may be
useful for studying the role of local RAAS
system in hypertension63.
7. Uterine ischaemia: As in preeclampsia,
uterine ischaemia can induce hypertension in
rats and monkeys8,64,65. In monkeys at 1167
days of gestation, lower aortic pressure was
reduced by 2411 mm Hg by a stricture on the
aorta just below the renal arteries and animals
developed sustained hypertension66 .
Comparison of animal models with human hypertension is shown in Table 1. SHRs have been
compared most extensively with essential hypertension in human beings.
Measurement of BP in animal models: Repeated
measurement of BP is needed in experiments on
animal models of hypertension. In acute experiments,
the animals are usually anesthetized and BP is
measured for the duration of the experiment by
exposing an accessible artery and inserting a cannula
connected to a mercury manometer or a pressure
transducer. Frequent repetition of the surgical arterial
exposure under anaesthesia is undesirable.
Anaesthesia is used only when immobilization of the
animal is required to measure BP. Anaesthesia makes

Table 1.

356

Comparable forms of experimental and clinical

hypertension.

Experimental Hypertension

Clinical Hypertension

Spontaneous hypertension

Essential hypertension

Renal artery stenosis

hypertension

Renal artery stenosis

Overdosage of glucocorticoids

Cushing syndrome

Overdosage of mineralocorticoids
Overdosage of salt

Primary aldosteronism
Chronic high salt intake

Obesity related hypertension

Uterine ischaemia

Obese hypertension
Preeclampsia

Reduced renal mass

Renal diseases

determination of BP easier and more accurate but

the use of anaesthesia introduces an additional
variable. Anaesthetic agents have been reported to
alter BP and cardiovascular reflexes 66. BP can be
recorded in unanaesthetised state. There should be
minimal stress to the animal. The balance of relative
disadvantages favours the use of unanaesthetised
state only for those methods not requiring rigid
restraint, for example, aortic intubated rats.
The BP in the following animal models are measured
either directly (intravascular) or indirectly (bloodless).
Direct methods:
In dogs:

a) In unanaesthetised condition a small

hypodermic needle is inserted into a
superficial artery (e.g., femoral artery)
and connected to a mercury manometer
or pressure transducer. The system is
filled with an anticoagulant solution8,67
b) Carotid artery can be exteriorized in
dogs. Dogs are trained to cooperate and
lie quiet on table. Artery is punctured with
a needle attached to direct writing
muitichannel recorder68 .
c) Intraaortic cannulation: A cannula or
catheter filled with heparin is advanced
from femoral artery to abdominal aorta in
anaesthetised animals. Cannula can also
be passed from proximal stump of a cut
left cranial thyroid branch through

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D.K. BADYAL et al.

common carotid artery down to

descending thoracic aorta and BP is
measured8 .
In rabbits: a) In an unanaesthetised animal, central
artery of ear is cannulated. The disadvantages of this method include development
of hematoma and arterial spasm until total
denervation of ear is carried out and
animal needs to be closely restrained8,57.
Alternatively, carotid artery can be
cannulated after infusion with 1%
lignocaine. Cannulas made from vinyl
tubing (outside diameter 1.52 mm and
internal diameter 0.86 mm) flushed with
heparinised (50 u/ml) 0.9% saline is
used16. An exteriorised arterial loop can
be used as in dogs 57.
In rats: a) A week before the experiment,
each rat is anaesthetised with 40 mg/kg
pentobarbital57. Left or right carotid artery
or femoral artery (for recording BP) is
cannulated under aseptic conditions with
polyethylene cannula filled with 1%
heparin in normal saline69 . Free end of
the cannula is passed under the skin and
allowed to protrude 3-4 cm from the skin
behind the ears of the rat. The skin
incisions are sutured and a plastic skin
dressing is applied5. After recovery from
anaesthesia (2-2.5 h) each rat is placed
in an individual cage for 24 h habituation
period70 .
On the day of the experiment, a pressure
tube filled with 200 U/ml heparin in saline
is tied to the implanted catheter and
connected to a pressure transducer and
then to the pre-amplifier and recorded
on the polygraph or physiograph 57,69.
Alternatively, Condons mercury manometer can also be used for recording BP
in rats22,67. Popovic et al (1960) used
animals for 40 days before cannula was
blocked69 .
b) Abdominal aorta is cannulated with a
small polyethylene tube and led beneath
the skin to an exit at the back of the neck
for recording arterial BP. But a large

operation like laparotomy is required. In

other methods, catheters are inserted into
the inferior vena cava via the left femoral
vein for intravenous injections and the
abdominal aorta via the left femoral artery
for the continuous recording of mean BP
and heart rate on a polygraph via a
pressure transducer71 .
Indirect methods: These following methods are
used in unanaesthetised animals.
In dogs:

a) Tibial artery is occluded with a cuff on

the anteromedial surface of hindlimb or
radial artery on forelimb and BP is
recorded by auscultation or condenser
microphone. The problem in this method
is inherent elasticity of tissue surrounding
the artery 8.
b) Exteriorised artery in a skin flap can
be used conveniently for long periods.
The problem in this model is carotid sinus
reflex. Femoral artery loop has been used
in dogs and cats8.

In rabbits: a) The central artery of ear is com-pressed

by a transparent membrane applied to
ear, which permits visualisation of the
central artery. The pneumatic pressure
required just to break the column of blood
in this portion of central artery is taken
as the systolic pressure. This is a cheap
and simple method. Disadvantage is that
BP in rabbits is highly labile, BP in central
artery is lower than carotid artery and
pressure varies with the tone of arterial
wall, which is affected by heat 9.
b) BP is recorded by a cuff around radial
artery in forelimb8,9.
In rats:

a) Tail cuff is a common and convenient

method to measure systolic pressure in
rats. Tail cuff is inflated and then deflated.
Pulsations disappear when cuff is inflated.
When cuff is deflated pulsations start
appearing when pressure in the cuff
equals systolic pressure. Various devices
are used. The cuff is attached to a tail
cuff sphygmomano-meter or more
commonly to pressure transducer and BP

ANIMAL MODELS OF HYPERTENSION

is recorded on a chart. Training the animal

and warming the tail are required for this
method 61,72,73. Computerised tail cuff
instrument can also be used61.
b) Tail swelling: Pressure is applied to
the tail with a cuff. This results in swelling
of the tail. When the pressure is lowered
swelling starts decreasing indicating
systolic pressure8.
c) Foot swelling: Pressure is applied on
the proximal part of the foot. Swelling
appears on the foot. Photocell is used to
measure the light obstructed by the foot.
Swelling decreases the light reaching the
photocell8 .
Effects of antihypertensive agents: Today, each
new antihypertensive drug will be studied in more
than one hypertension model before it undergoes
clinical trials. In the assessment of antihypertensive
activity, it is essential to make sure that the drug is
administered according to a fixed schedule, which
corresponds to its duration of action. The BP should
be measured at various intervals after administration
of the drug. It is necessary to prepare a protocol for
such a study, which should be strictly adhered to and
monitored. Usually the drug is given after
establishment of hypertension to obtain a therapeutic
effect. In SHRs drugs are administered at an early
stage to prevent an increase in BP. Complications of
hypertension can be abolished or delayed by effective
control of hypertension.
Antihypertensive drugs, according to their mode of
action, may affect the blood pressure in certain types
of experimental hypertension, and not in others.
Diuretics and -adrenergic blockers have no or little
effect in renal hypertension. In contrast, pharmacological agents that interrupt the functioning of the
RAAS to prevent angiotensin II production or binding
to target receptors are highly effective in these
models. These drugs e.g. , ACE inhibitors,
angiotensin-II type-I (AT-1) receptor antagonists and
renin inhibitors are effective in initial renin or
angiotensin dependant phase of 2K1C hypertension
model and other renovascular models4,6,60,74-76. ACE
inhibitors and AT-1 antagonists decrease BP in initial
phase of 2K1C hypertension. In 1K1C model, ACE
inhibitors and AT-1 antagonists are not effective

358

except in very early phase4,6. All known AT-1 receptor

antagonists and ACE inhibitors induce a marked and
sustained hypotension in high renin-dependent hypertensive models such as 2K1C renal hypertensive rats
and renal artery-ligated hypertensive rats77. They are
more effective in renal hypertensive rats than in
SHRs. Both ACE inhibitor and AT-1 antagonists have
negligible effect in DOCA-salt hypertensive rats, a
low-renin model of hypertension77,78. This indicates
that normal levels of plasma renin activity are
necessary to demonstrate the antihypertensive action
of these drugs. However, ACE inhibitors and AT-1
antagonists are effective in salt induced hypertension
in reduced renal mass rats and in transgenic rats,
TGR (mREN2) 2779,80. Furthermore, these drugs have
been reported to decrease complications and
mortality of the salt-loaded SHRSP81,82.
Vasodilators like minoxidil, hydralazine and diazoxide
are effective in renal hypertensive rats17,33,83. Calcium
channel blockers (CCB), ACE inhibitors and AT-1
antagonists decrease BP in 5/6 nephrectomised SHR
and are also effective at reducing renal injury in these
rats84,78. Diuretics, are active in mineralocorticoid or
salt induced hypertension4-6.
Endocrine hypertension is the preferred model for
screening antihypertensive activity of diuretics e.g.
chlorthiazide and hydrochlorthiazide8. Both endothelin
receptor antagonists and CCBs are effective in
endocrine hypertension 23,24. Drugs targeting
sympathetic nervous system like phenoxybenzamine,
guanethidine, -methyldopa and clonidine decrease
BP in both endocrine and neurogenic hypertension7,8.
-adrenergic blockers decrease BP neither in renal
nor in endocrine hypertension, but show some effect
in SHR at a later stage when sympathetic activity is
increased2. SHR shows inconsistent BP responses
to -blockers, diuretics and sodium restriction, which
are common and effective antihypertensive drug
classes in essential hypertension79,85,86.
In conclusion, it may be stated that the various animal
models of experimental hypertension are tools in the
study of the pathophysiology of sustained hypertension and its complications. These animal models
are increasingly being used for testing new chemical
entities. Similarity of SHR to essential hypertension
and its complications and its easy availability has
made SHR, the main animal model of hypertension.

359

D.K. BADYAL et al.

SHR is widely used because of its reliable

spontaneous development not only of hypertension
but also of hypertensive complications. Thus, until a
better experimental model is available, we feel
justified in taking the affirmative position that the SHR
is indeed an excellent laboratory counterpart of
essential hypertension. Development of new models
incorporating recent advances in pathophysiology of
hypertension can accelerate the research in
understanding the pathophysiology and development
of new therapeutic agents for hypertension.
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IPS-2003
XXXVI ANNUAL CONFERENCE OF
THE INDIAN PHARMACOLOGICAL SOCIETY
5 - 7 DECEMBER, 2003
PRE-CONFERENCE WORKSHOP
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362

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