CARDIOVASCULAR JOURNAL OF AFRICA • Vol 24, No 3, April 2013
62
AFRICA
areas below the hepatic capsule, indicating the initial stages of
ischaemia (lack of blood supply).
Compared to the untreated AABIH group, the losartan-treated
group showed congestion, and dilation of the central vein.
There was also a moderate degree of vacuolations in the hepatic
parenchyma. The candesartan-treated group showed congestion,
multifocal areas of necrosis, and dilation of the central vein. There
was also a moderate degree of degeneration and vacuolations in
the hepatic parenchyma (hydropic degeneration), indicating a
moderate degree of ischaemia. The tissue also showed a mild-
to-moderate degree of neutrophil and lymphocytic infiltration.
The irbesartan-treated group showed congestion, dilation of the
central vein, mild haemorrhage and moderate vacuolations in the
borders of the hepatic parenchyma, indicating limited ischaemia
(Fig. 1F–J).
The sections of normal control, sham-operated rat kidneys
showed normal structure and architecture. The kidney section of
the untreated AABIH rats showed oedema, vacuolations in the
tubules, moderate to severe haemorrhage and congested vessels.
Compared to the untreated AABIH group, the kidney sections
of the losartan-treated group showed oedema, vacuolations in
the tubules, a moderate degree of haemorrhage, congested blood
vessels, and dilatation of vessels and hypertrophy of the tubules.
The sections of the candesartan-treated group showed mild
oedema, vacuolations in the tubules, a mild-to-moderate degree
of haemorrhage, and congested blood vessels. The sections of
the irbesartan-treated group showed mild oedema, vacuolations
in the tubules, a mild-to-moderate degree of haemorrhage, and
congested blood vessels (Fig. 2A–E).
The sections of normal control, sham-operated rat thoracic
aorta showed normal structure and architecture. The thoracic
aorta section of the untreated AABIH rats showed mild
accumulation of foam cells in between the fibres. Compared to
the untreated AABIH group, the sections of the losartan-treated
group showed no changes. The sections of the candesartan-
treated group showed one to two foam cells. The sections of the
irbesartan-treated group showed no changes (Fig. 2F–J).
From the results of the histopathological evaluation, it
is evident that angiotensin receptor antagonists significantly
reduced the histological changes in the target organs such
as heart, liver, kidneys and thoracic aorta, compared to the
untreated AABIH group. Therefore the AT
1
receptor blockers
have the potential to protect end organs. They were shown in this
study to have beneficial effects in the treatment of hypertension,
both by decreasing blood pressure and protecting the target
organs.
Discussion
The results of this study demonstrate that blockade ofAT
1
receptors
with AT
1
antagonists reduced the systolic BP significantly,
caused an improvement in the myocardial antioxidant reserve
(serum catalase and SOD enzyme activity), decreased oxidative
stress and reduced the histopathological changes induced in the
pressure-overload rat model of AABIH and cardiac hypertrophy.
In our study, abdominal aortic banding was found to have
increased systolic BP in a consistent manner, which was
sustainable throughout the study period. Constriction of the
thoracic or abdominal aorta provides an experimental model
of what has been previously described as pressure-overload
cardiac hypertrophy. The increased blood pressure proximal to
the constriction has been postulated to provide a stimulus for the
development of cardiac hypertrophy.
16
Bardy and co-workers
21
reported that increased transmural
pressure in the aorta might be causing the local generation of
Ang-II, which acts synergistically with the transmural pressure
to enhance vascular fibronectin expression via the AT
1
receptor.
Furthermore, Bonnet and co-workers
22
later demonstrated that
the AT
2
receptor mRNA was up-regulated in rat mesenteric
arteries after a pressure dose of Ang-II infusion for two weeks,
suggesting the involvement of AT
1
receptor mediation in this
Ang-II effect, because AT
1
receptor antagonists inhibited the
Ang-II-induced up-regulation of the AT
2
receptor.
In the aortic banding model, the decreased blood pressure
distal to the banding stimulates the kidney to release renin,
resulting in increased circulating levels of Ang-II. However, as
shown by investigators,
17,23
the fact that the elevation of plasma
renin is observed only within a few days of aortic banding does
not account for the increased levels of AT
2
receptor mRNA over
three weeks. Because Ang-II binds to the AT
1
and AT
2
receptor
subtypes with similar affinity,
24
the contractile response of the
aorta to Ang-II seems to be dependent on the relative expression
level and/or responsiveness of both receptors. Therefore it seems
that the decreased response to Ang-II in the pressure-overloaded
aorta is likely to depend on, at least in part, the up-regulation of
the AT
2
receptor.
AT
1
receptor antagonists dose-dependently attenuated the
pressor response to intravenous angiotensin-II
25-30
and reduced
blood pressure in animal models of hypertension. They also
reduced cardiac hypertrophy and improved haemodynamics
in animal models of heart failure.
25,31-33
They increased sodium
excretion and diuresis, lowered blood pressure and proteinuria,
and reduced glomerulosclerosis in rats with chronic renal
failure.
34,35
Ang-II receptor antagonists have been thoroughly evaluated
for their efficacy in mild, moderate and severe hypertension, and
lower BP more effectively than placebo without affecting heart
rate.
25,27-31
They do so regardless of gender, race or age. Long-
term studies have demonstrated that angiotensin II antagonists
have comparable efficacy in terms of blood pressure reduction
at trough.
28,36-40
In the present study, we observed a reduction
in systolic BP in the AABIH rats treated with an AT
1
receptor
antagonist, which is in agreement with previously reported
studies.
Free radical-scavenging antioxidants such as SOD and
catalase are the first line of cellular defense against oxidative
injury.
41
The observed decrease in levels of these antioxidants in
the heart following ischaemia–reperfusion in our study confirms
the excessive generation of reactive oxygen species, such as
superoxide and hydrogen peroxide, which in turns leads to
consumption of these endogenous antioxidants.
It has been well documented that AABIH causes increased
oxidative stress in rats, as evidenced by reduction in serum SOD
and catalase activities.
42,43
In the present study, we observed
that the decreased activities of SOD and catalase in AABIH
in the rats were significantly ameliorated by treatment with
AT
1
receptor antagonists. These finding are in accordance with
studies reporting that telmisartan had an antioxidant effect in a
mouse model of atherosclerosis.
44
The increase in endogenous
antioxidant activities is an indication of structural integrity and
