Novel anti-inflammatory actions of amlodipine in a rat model of arteriosclerosis induced by long-term inhibition of nitric oxide synthesis.
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 the beneficial effects of amlodipine, 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 (NO) by administration of a NO synthase inhibitor, N(omega)-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 the anti-inflammatory effects of amlodipine in vivo. Treatment with amlodipine markedly inhibited the L-NAME-induced increase in vascular inflammation, oxidative stress, and local ACE and Rho activity and prevented arteriosclerosis. Interestingly, amlodipine prevented the L-NAME-induced increase in MCP-1 receptor CCR2 expression in circulating monocytes. Amlodipine markedly attenuated the high mortality rate at 8 wk 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.
Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Chu
C
Kataoka
Kensuke
K
Egashira
Minako
M
Ishibashi
Shujiro
S
Inoue
Weihua
W
Ni
Ken-ichi
K
Hiasa
Shiro
S
Kitamoto
Makoto
M
Usui
Akira
A
Takeshita
D017311:Amlodipine / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001161:Arteriosclerosis / Q000188:drug therapy / Q000503:physiopathology*; D001483:Base Sequence; D001794:Blood Pressure / Q000187:drug effects; D017931:DNA Primers; D004195:Disease Models, Animal; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors*; D009589:Nitrogen Oxides / Q000097:blood; D007703:Peptidyl-Dipeptidase A / Q000187:drug effects / Q000378:metabolism; D016133:Polymerase Chain Reaction; D051381:Rats; D011921:Rats, Inbred WKY; D013481:Superoxides / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology
D000893:Anti-Inflammatory Agents; D017931:DNA Primers; D009589:Nitrogen Oxides; D014665:Vasodilator Agents; D013481:Superoxides; D017311:Amlodipine; D009569:Nitric Oxide; D007703:Peptidyl-Dipeptidase A; D019331:NG-Nitroarginine Methyl Ester