title: Calcium channel blockers suppress cytokine-induced activation of human neutrophils.
abstract: 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.
authors: Department of Physiology, Osaka City University Medical School, Asahi-machi, Abeno-ku, Osaka, Japan.
authors: Etsuko
authors: E
authors: Shima
authors: Masataka
authors: M
authors: Katsube
authors: Takayuki
authors: T
authors: Kato
authors: Maki
authors: M
authors: Kitagawa
authors: Fumihiko
authors: F
authors: Hato
authors: Masayuki
authors: M
authors: Hino
authors: Tatsuji
authors: T
authors: Takahashi
authors: Hisakazu
authors: H
authors: Fujita
authors: Seiichi
authors: S
authors: Kitagawa
mesh_terms: 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
chemical_list: 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