JOURNAL ARTICLE

Calcium channel blockers suppress cytokine-induced activation of human neutrophils

Etsuko Shima, Masataka Katsube, Takayuki Kato, Maki Kitagawa, Fumihiko Hato, Masayuki Hino, Tatsuji Takahashi, Hisakazu Fujita, Seiichi Kitagawa
American Journal of Hypertension 2008, 21 (1): 78-84
18091748

BACKGROUND: Neutrophils, in concert with proinflammatory cytokines, play an important role in the progression of atherosclerosis. Calcium channel blockers are commonly used in the treatment of hypertension, and their pleiotropic effects, other than the lowering of blood pressure, have been recently recognized.

METHODS: We studied the effects of various calcium channel blockers (amlodipine, nicardipine, cilnidipine, benidipine, efonidipine, nifedipine, azelnidipine, verapamil, and diltiazem; each being used at 5 and 10 micromol/l) on superoxide (O(2)(-)) release, migration, and signaling pathways in human neutrophils stimulated by granulocyte-macrophage colony-stimulating factor (GM-CSF) or tumor necrosis factor-alpha (TNF-alpha).

RESULTS: GM-CSF-induced O(2)(-) release was suppressed by amlodipine, nicardipine, and cilnidipine, whereas TNF-alpha-induced O(2)(-) release was suppressed by amlodipine, nicardipine, cilnidipine, benidipine, efonidipine, nifedipine, and azelnidipine. TNF-alpha-induced phosphorylation of extracellular signal-regulated kinase (ERK) and Akt, but not p38 mitogen-activated protein kinase (MAPK), was attenuated by nicardipine, cilnidipine, benidipine, efonidipine, and azelnidipine. By contrast, GM-CSF-induced phosphorylation of ERK, p38, and Akt was affected by none of the blockers. GM-CSF-induced neutrophil migration was also suppressed by amlodipine and nicardipine, but not by azelnidipine, when these blockers were assessed for their effect on neutrophil migration.

CONCLUSIONS: These findings suggest that (i) some calcium channel blockers can suppress cytokine-induced neutrophil activation, leading to possible prevention of the progression of atherosclerosis; and (ii) that activation of the ERK and phosphatidylinositol 3-kinase (PI3K)/Akt pathways, induced by TNF-alpha but not by GM-CSF, is selectively affected by some blockers.

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