title: Dual mechanism of action of amlodipine in human vascular smooth muscle cells.
abstract: OBJECTIVE
  It has been recently shown that calcium channel blockers (CCBs) could also control smooth muscle cell (SMC) growth/reactivity through mechanisms that were unrelated to their CCB property. Here, we investigated the effects of amlodipine and isradipine on Ca2+ movements and p42/p44 mitogen-activated protein kinase (ERK 1/2) activities, which are two early signalling events triggered by growth factors such as thrombin and basic fibroblast growth factor (bFGF).
  
  
  METHODS
  In cultured human SMCs isolated from internal mammary arteries, Ca2+ movements and ERK 1/2 activation were studied by measurement of the intracellular Ca2+ concentration in Fura 2-labelled SMCs and by Western blots, respectively.
  
  
  RESULTS
  In thrombin- and thapsigargin-stimulated SMCs, amlodipine and not isradipine dose-dependently reduced Ca2+ mobilization (i.e. Ca2+ release from internal stores); these dihydropyridines did not affect either Ca2+ influx or ERK 1/2 activation. In bFGF-stimulated SMCs, amlodipine and isradipine reduced both Ca2+ influx and ERK 1/2 activation without affecting Ca2+ mobilization. ERK 1/2 activation could also be directly stimulated by the l-type channel agonist Bay K 8644, demonstrating the involvement of voltage-gated Ca2+ influx in this process. Most of the observed effects described were obtained with approximately 10 nmol/l amlodipine/isradipine (i.e. concentrations close to the peak plasma level in treated patients).
  
  
  CONCLUSIONS
  In human SMCs, amlodipine can (i) specifically alter Ca2+ mobilization, likely by interacting with the sarcoplasmic reticulum and (ii) inhibit voltage-dependent Ca2+ influx and the resulting ERK 1/2 activation. It is likely that amlodipine exerts its growth-inhibitory potency by interfering with multiple branches of mitogenic signalling pathways.
authors.affiliation: Department of Pharmacology, CNRS UMR 8604 and University René Descartes, Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Stepien
authors.forename: Yuzhen
authors.initials: Y
authors.lastname: Zhang
authors.forename: Dingliang
authors.initials: D
authors.lastname: Zhu
authors.forename: Pierre
authors.initials: P
authors.lastname: Marche
mesh_terms: D017311:Amlodipine / Q000494:pharmacology*; D000959:Antihypertensive Agents / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D005346:Fibroblast Growth Factors / Q000494:pharmacology; D006490:Hemostatics / Q000494:pharmacology; D006801:Humans; D008323:Mammary Arteries / Q000737:chemistry / Q000166:cytology; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D013917:Thrombin / Q000494:pharmacology
chemical_list: D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D006490:Hemostatics; D017311:Amlodipine; D005346:Fibroblast Growth Factors; D020928:Mitogen-Activated Protein Kinases; D013917:Thrombin