CARDIOVASCULAR JOURNAL OF AFRICA • Vol 23, No 1, February 2012
AFRICA
21
tory, antioxidative, anti-apoptotic, antithrombotic, vasodilatory
and anti-infectious properties, all of which potentially contribute
to its atheroprotective nature.
23
Accumulating evidence shows
that HDL-C protects LDL-C from oxidation.
Epidemiological and observational studies have demonstrated
that HDL-C level is a strong, independent predictor of risk of
coronary heart disease (CHD), and raising HDL-C levels may
afford clinical benefit.
24
Since decreased HDL-C levels are asso-
ciated with increased production of ROS, increases in HDL-C
levels by amlodipine treatment may be a consequence of reduc-
tion in oxidative stress.
25
MDA is one of the most reliable and widely used indices of
oxidative stress and, as a marker of oxidative damage, has been
studied extensively.
26
It is known that lipid peroxidation is the
co-operative event involved in the development of atherosclero-
sis.
27
Also a positive correlation has been found between MDA
levels and coronary artery calcification scores, and it is more
convincingly correlated with TG levels and inversely correlated
with HDL-C levels.
28
In our study, as the level of MDA significantly increased
in cholesterol-fed rabbits, amlodipine treatment reduced it in
the blood and heart muscle. It has been suggested that highly
lipophilic CCBs such as amlodipine, by inserting to a location
in the membrane near conjugated double bonds, are capable of
donating protons to lipid peroxide molecules, thereby blocking
the peroxidation process.
21
Since amlodipine is lipophylic, it
easily enters the cells and prevents lipid peroxidation.
29
In our
results, increased MDA levels may have been attributed to a high
production of free radicals by a high-cholesterol diet, and the
ability of amlodipine to diminish lipid perxidation in the rabbits
fed a high-cholesterol diet may have been non-calcium depend-
ent and more related to proton donation.
30
It has been proposed that a high-cholesterol diet induces
free radical production and may result in oxidative stress,
which plays an important role in hypercholesterolaemia-induced
atheroschelerosis.
31
Our data showed that a high-cholesterol diet
decreased antioxidant enzyme activity (SOD and GPX) in both
blood and heart tissue, and also confirmed that amlodipine could
decrease the activation of oxidative stress. Previous reports indi-
cate that markers of oxidative stress, such as superoxide produc-
tion, were increased in atherosclerotic lesions.
32
This antioxidant
activity of amlodipine has also been observed in various animal
models, including non-human primates, which reveals the
important anti-atherogenic effect of this compound.
33
Increased ROS production can initiate a cascade of signal
transduction, which leads to endothelial dysfunction, changes
in vascular tone, vascular remodelling and vascular inflamma-
tory responses.
34-36
Under normal conditions, the heart minimises
oxidative stress-induced injuries by the enhancement of SOD
and GPX activity. SOD converts superoxide radicals to H
2
O
2
and GPX eliminates H
2
O
2
.
1
Since hypercholesterolaemia signifi-
cantly decreased GPX activity in the present study, this probably
resulted in aggregation of H
2
O
2
and other reactive oxygen species
and may have caused lipid peroxidation. It has also been reported
that amlodipine reduced oxidative stress by restoring copper/
zinc-containing SOD activity in the heart in hypertensive rats.
34
Amlodipine with or without a high-cholesterol (2%) diet
significantly increased SOD and GPX activity in the heart and
blood, compared with control or high-cholesterol fed groups.
Surprisingly the activity of these antioxidant enzymes was
approximately equal in groups 3 and 4. This suggests that the
high-cholesterol diet could not decrease the antioxidant enzyme
activity in the presence of amlodipine. Reduction of oxidative
stress protects not only lipids, but also DNA, which is crucial to
eventual cell death.
37
Exactly how amlodipine exercises its antioxidant activ-
ity is unclear, although several possible mechanisms have been
proposed, including antithrombotic, anti-inflammatory and anti-
oxidant properties of HDL-C, and decrease in plasma LDL-C
levels. The anti-oxidative property of these L-type CCBs may
stem from their chemical structure; they contain an aromatic
ring, which attracts free radicals. Furthermore, the dihydropyri-
dine ring in these CCBs is able to donate a proton, which stabi-
lises the free electron.
38
Since CCBs primarily affect the cellular interaction of
endothelial cells, smooth muscle cells, monocytes and thrombo-
cytes, which play key roles in the early phases of the develop-
ment of atherosclerosis, the amlodipine effect of inhibiting calci-
um influx is the main mechanism for attenuation of oxidative
stress in atherosclerosis. Therefore one of the major pathways
by which amlodipine exerts its antioxidant effect is prevention
of calcium overload.
39
There are some conflicting results in the
literature that may be partly due to differences in
in vitro
models
or the interventional drugs.
40
Conclusion
The present study indicated that the CCB amlodipine decreased
oxidative stress in the heart and blood and improved lipid profiles
in cholesterol-fed rabbits. It may therefore be beneficial for the
reduction of oxidative stress and improvement of lipid profiles in
patients with diseases related to hyperlipidaemia. Further clinical
trials are needed to prove the importance of amlodipine and other
CCBs in patients with atherosclerosis and similar diseases.
This study was supported by funding from the Drug Applied Research
Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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