CARDIOVASCULAR JOURNAL OF AFRICA • Vol 24, No 3, April 2013
AFRICA
63
protection of the myocardium, which was achieved by treatment
with AT
1
receptor antagonists.
In our studies, we observed significant improvement in
endogenous antioxidant activity, as evidenced by the elevation
in serum SOD and catalase activity. This is in concurrence
with that reported by Khafer and Singal who also showed that
treatment with losartan reduced oxidative stress, as indicated by
an increase in the redox ratio and decreased lipid hydroperoxide
content in the myocardial infarction.
45
Numerous studies have
demonstrated reversal of left ventricular hypertrophy, reduced
fibrosis, and improvement in coronary flow and cardiac function
following losartan treatment.
46,47
Myocardial antioxidants are dynamic in nature and have been
reported to change in various physiological and pathological
conditions, including hypertrophy,
48
exercise
49
and adriamycin-
induced cardiomyopathy.
50
It is also known that different
enzymatic and non-enzymatic antioxidants respond uniquely in
a variety of oxidative stress conditions. For example, hypoxia
resulted in a reduction in MnSOD and glutathione peroxidase
(GPx) activities with no change in catalase activity.
51
In the
pressure overload-induced model of heart failure, only SOD
activity was significantly less, with no changes in the GPx and
catalase activities.
52
Studies have reported unique regional differences in
non-enzymatic antioxidants in hearts subjected to ischaemia–
reperfusion.
53
The exact stimulus for the altered activity of
these enzymes is not known; however, increased free radical
formation and/or lipid peroxidation during stress conditions
may act as a signal.
54
Using the rat coronary artery ligation
model, studies have reported depressed myocardial endogenous
antioxidant reserve and increased oxidative stress associated
with poor cardiac function.
55-57
It is important to protect target organs from damage induced
by hypertension. This study demonstrates the histological
damage caused by hypertension induced by AAB in rats. Mild
perivascular fibrosis, oedema and mild lymphocytic infiltration
observed in the hypertensive rats concurs with that reported
by Chen
et al
.,
58
along with defragmentation of cardiac fibres,
mild-to-moderate degrees of haemorrhage, congestion, mild
vacuolations and focal areas of necrosis in one or two areas. All
these changes indicate the extent of damage to the heart due to
hypertension in this model.
As described in the results, treatment with AT
1
receptor
antagonists reduced the intensity of cardiac damage, as shown
by the mild degree of haemorrhage, mild perivascular fibrosis,
defragmentation of cardiac fibres, congestion, oedema and mild
vacuolations. Studies by Kumiko and co-workers demonstrated
that early and transient treatment with AT
1
receptor antagonists
were effective in the prevention of hypertension-induced
end-organ damage.
59
Sections of liver in the untreated AABIH group showed
congestion, multifocal areas of necrosis, and dilation of the
central vein. There was also a moderate degree of degeneration
and vacuolations restricted to the border areas below the hepatic
capsule, indicating early stages of ischaemia. Histological
changes following inhibition of the AT
1
receptors were mild
haemorrhage and moderate vacuolations in the borders of the
hepatic parenchyma, indicating a decrease in the extent of liver
damage or limited ischaemia.
Suppression of D-galactosamine-induced liver injury by
the AT
1
receptor blocker losartan, reported by Chan and
co-workers, suggests the protective effect of the AT
1
receptor
blocker.
60
This is in line with our results, as there were mild-
to-moderate degrees of vacuolation and degeneration in the
hepatic parenchyma, indicating a moderate degree of ischaemia.
Therefore treatment with AT
1
receptor blockers has therapeutic
potential in preventing the histopathological changes observed in
target organs of the hypertensive group.
Sections of the kidneys in the untreated AABIH group
showed oedema, vacuolations in the tubules, moderate to severe
haemorrhage and congested vessels, all of which are signs of
renal damage, which is in agreement with an earlier study.
61
As
described in the results, treatment with AT
1
receptor antagonists
reduced the intensity of damage to the renal tissue, indicated
by mild vacuolations in the tubules, a moderate degree of
haemorrhage, and congested blood vessels.
Endothelial dysfunction is one of the most important
mechanisms involved in the development of atherosclerosis
and is present in patients with various cardiovascular risk
factors, including hypertension, hypercholesterolaemia and type
2 diabetes, as well as in patients with coronary artery disease.
Endothelial dysfunction has important prognostic implications in
these groups of patients.
62,63
Blocking the RAS with AT
1
receptor
antagonists clearly ameliorates endothelial dysfunction, an effect
that is not totally dependent on BP reduction.
In an elegant study,
64
resistance arteries obtained from
subcutaneous gluteus muscle biopsies from a small group of
hypertensive patients and normotensive controls were studied
by measuring the endothelium-dependent and independent
responses and the cross-sectional area.
64
Histological sections of
the thoracic aorta in the untreated AABIH group showed mild
accumulation of foam cells in between the fibres. Treatment with
AT
1
receptor antagonists resulted in protection from this, which
may be attributed to the protective effect on vascular endothelium
seen in hypertension-induced damage to the vasculature.
Conclusion
Our study demonstrates that inhibition of the AT
1
receptor with
AT
1
antagonists caused an improvement in the myocardial
antioxidant reserve and decreased oxidative stress, and prevented
pathophysiological alterations associated with hypertension in
rats, which was evident in the protection of histological changes
observed in the treatment groups. The study also emphasises that
modulation of the RAS by AT
1
receptor blockade is beneficial in
preventing target-organ damage in hypertension.
The authors thank the Al-Ameen College of Pharmacy for funding, support-
ing and providing the facilities needed.
References
1.
De Gasparo M, Catt KJ, Inagami T, Wright W, Unget TH. International
union of pharmacology. XXIII. The angiotensin II receptors.
Pharmacol
Rev
2000;
52
: 415–472.
2.
Morishita R, Higaki J, Miyazaki M, Ogihara T. Possible role of the
vascular renin-angiotensin system in hypertension and vascular hyper-
trophy.
Hypertension
1992;
19
(suppl II): 1162–1167.
3.
Itoh H, Muloyama M, Pratt RE, Gibbons GH, Dzau VJ. Multiple
autocrine growth factors modulate vascular smooth muscle cell growth
response to angiotensin II
. J Clin Invest
1993;
91
: 2268–2272.
4.
Wolf G, Zihadeh FN, Zahner G, Stahl RAK. Angiotensin II is mitogenic
for cultured rat glomerular endothelial cells.
Hypertension
1996;
27
:
