Atherosclerosis is a common disease in
which the artery wall thickens as a result of a
build-up
of fatty materials. The narrowing of arteries caused by atherosclerosis can significantly
reduce the blood supply to vital organs. The complications of advanced atherosclerosis
include heart attack and stroke, which are the major killers in modern society. While many
clinicians consider the use of lipid-lowering agents like statins as the main
strategy to prevent atherosclerosis, the combination
of dihydropyridine-type calcium channel blockers (DHP) (a blood vessel dilator used
in the treatment of patients with angina and
hypertension) and statins has been shown
to produce an additional 60% reduction of
atherosclerosis compared with that observed with statins alone. Therefore, the effects of
DHP on atherosclerosis are promising.
The inflammation of endothelial cell layers
is regarded as an initial and the most critical
step in the development of atherosclerosis.
Biochemical assays show that nimodipine,
a DHP which is more commonly used in the prevention/treatment of cerebral
vasospasm, can reduce the release of proinflammatory
cytokines and chemokines from endothelial cells. These results indicate that
nimodipine exerts anti-inflammatory effect on endothelial cells. Among the DHP, the
anti-inflammatory effect of nimodipine is the most potent. Most of the DHP are known to
reduce reactive oxygen species formation. However, nimodipine exerts no antioxidant
effect. We measured the adenosine transport into endothelial cells by using radioactive
adenosine as a tracer. Our data shows that
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nimodipine can inhibit the equilibrative nucleoside transporter type-1 (ENT-1) ,
thereby increasing the local concentration
of adenosine in the vicinity of adenosine
receptors on endothelial cells. The
increased stimulation of adenosine receptors may be a
mechanism underlying the anti-inflammatory effect of nimodipine. The mechanism by which
nimodipine inhibits ENT-1 has been further investigated. The study of structure-activity
relationship reveals that the inhibitory potency of nimodipine is closely associated with the
presence of the 4-aryl ring, as well as the bulkiness of ester groups at the C-3 and C-5
positions. Nimodipine is a non-competitive
inhibitor of ENT-1, probably working through
the reversible interactions with allosteric
sites of ENT-1. The nimodipine binding site
is probably located in the transmembrane
domains 3-6 on ENT-1.
It is hoped that the findings in this study
can add new knowledge on treatment of
atherosclerosis. The anti-inflammatory
properties of nimodipine on endothelial cells
may provide extra benefit in preventing the
atherosclerotic type of stroke.
Understanding the structural determinants involved in the
interaction between ENT-1 (which is the major adenosine transporter in
endothelial cells)
and nimodipine may facilitate the design and development of
novel cardiovascular protective drugs.
Dr George Pak-Heng Leung
Department of Pharmacology and
Pharmacy
The University of Hong Kong
gphleung@hkucc.hku.hk
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