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1 Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyushu University, Fukuoka, Fukuoka, Japan
* To whom correspondence should be addressed. E-mail: egashira{at}cardiol.med.kyushu-u.ac.jp.
Amlodipine (a new class of calcium channel antagonist) has been shown to limit the progression of arteriosclerosis and decrease the incidence of cardiovascular events. The
mechanisms underlying amlodipine's beneficial effects however remain unclear. Therefore, we hypothesized that amlodipine attenuates the development of arteriosclerosis through the inhibition of inflammation in vivo.
Long-term inhibition of nitric oxide by administering a nitric oxide synthase inhibitor
N
-nitro-L-arginine methyl ester (L-NAME) to rats induces coronary vascular inflammation
{monocyte infiltration, monocyte chemoattractant protein-1 (MCP-1) expression, increased activity of angiotensin-converting enzyme (ACE)} and arteriosclerosis. Here, we used the rat model to investigate anti-inflammatory effects of amlodipine in vivo. Treatment with amlodipine markedly inhibited the L-NAME-induced increase in vascular inflammation, oxidative stress, local ACE and Rho activity, and prevented arteriosclerosis. Interestingly, amlodipine prevented the L-NAME-induced increase in the MCP-1 receptor CCR2 expression in circulating monocytes. Amlodipine markedly attenuated high mortality rate at 8 week of treatment.
These data suggest that amlodipine attenuated arteriosclerosis through inhibiting inflammatory disorders in the rat model of long-term inhibition of NO synthesis. The anti- inflammatory effects of amlodipine seem to be mediated not only by the inhibition of local factors such as MCP-1 but also by the decrease in CCR2 in circulating monocytes. Inhibition of the MCP-1 to CCR2 pathway may represent novel anti-inflammatory actions of amlodipine beyond blood pressure lowering.
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