Calcium channel blockers suppress cytokine-induced activation of human neutrophils.
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.
Shima
Etsuko
E
Department of Physiology, Osaka City University Medical School, Asahi-machi, Abeno-ku, Osaka, Japan.
Katsube
Masataka
M
Kato
Takayuki
T
Kitagawa
Maki
M
Hato
Fumihiko
F
Hino
Masayuki
M
Takahashi
Tatsuji
T
Fujita
Hisakazu
H
Kitagawa
Seiichi
S
D000959:Antihypertensive Agents / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D006801:Humans; D018375:Neutrophil Activation / Q000187:drug effects*; D009504:Neutrophils / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011994:Recombinant Proteins; D015398:Signal Transduction / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases