title: Impaired mechanisms of leukocyte adhesion in vitro by the calcium channel antagonist mibefradil.
abstract: OBJECTIVE
  Enhanced adhesion to the vascular endothelium and excessive trafficking to extravascular locations can lead to serious tissue injury and destruction. Therefore, interfering with molecular mechanisms of leukocyte adhesion to the vascular endothelium is an important goal to block diseases like chronic inflammations and atherosclerosis.
  
  
  METHODS
  We studied the influence of the calcium antagonists mibefradil (T-type channel blocker), amlodipine and verapamil (both L-type channel blockers) on mechanisms related to leukocyte adhesion using isolated peripheral human blood leukocytes.
  
  
  RESULTS
  Mibefradil but not amlodipine and verapamil attenuated leukocyte adhesion in vitro. Regarding the mechanisms we found that mibefradil reduced the surface expression of beta2 integrins and L-selectin. The immobilization of the beta2 integrin subunit to the cytoskeleton that was inducible by receptor cross linking was impaired. Mibefradil was able to significantly inhibit the formyl-methionyl-leucyl-phenylalanine (fMLP) induced calcium rise, which suggests that mibefradil interfered with integrin signaling through blocking the intracellular calcium rise. SK&F 96365, a blocker of the capacitative calcium entry had no effect on cell adhesion and was less effective to influence integrin mediated mechanisms than mibefradil.
  
  
  CONCLUSIONS
  Our data suggest that mibefradil or chemically related substances are promising to serve as potent drugs to prevent excessive adhesion of leukocytes.
authors.affiliation: Department of Internal Medicine, University of Rostock, Ernst-Heydemann-Strasse 6, 18055 Rostock, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Nebe
authors.forename: Christian
authors.initials: C
authors.lastname: Holzhausen
authors.forename: Joachim
authors.initials: J
authors.lastname: Rychly
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Urbaszek
mesh_terms: D000328:Adult; D017311:Amlodipine / Q000494:pharmacology; D018821:CD18 Antigens / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000187:drug effects; D020747:Calcium Channels, T-Type / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006098:Granulocytes / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D006801:Humans; D019041:L-Selectin / Q000378:metabolism; D007962:Leukocytes / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D008297:Male; D020748:Mibefradil / Q000494:pharmacology*; D018613:Microscopy, Confocal; D014700:Verapamil / Q000494:pharmacology
chemical_list: D018821:CD18 Antigens; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D020747:Calcium Channels, T-Type; D019041:L-Selectin; D017311:Amlodipine; D020748:Mibefradil; D014700:Verapamil; D002118:Calcium