title: Action of dihydropyridine calcium antagonists on early growth response gene expression and cell growth in vascular smooth muscle cells.
abstract: OBJECTIVE
  Evidence suggests that calcium antagonists may suppress vascular smooth muscle cell (VSMC) growth and proliferation, which may be a crucial step in the pathogenesis of hypertension and atherosclerosis.
  
  
  METHODS
  The effects of the dihydropyridine calcium antagonists nifedipine, nitrendipine, nisoldipine, nimodipine and isradipine on cell growth induced by platelet-derived growth factor (PDGF)-AB and angiotensin II (Ang II), and expression of the transcription factors c-fos and early-growth response gene 1 (egr-1) were investigated.
  
  
  METHODS
  Proliferation of VSMC in culture was measured by [3H]-thymidine incorporation into cell DNA and by cell count. Expression of c-fos and egr-1 messenger RNA (mRNA) was determined by the Northern blot technique.
  
  
  RESULTS
  All of the calcium antagonists blunted the PDGF-induced rise in VSMC DNA synthesis. The inhibitory potency of isradipine on PDGF-stimulated DNA synthesis was approximately 10-fold that of the other calcium antagonists used, isradipine having a half-maximal inhibitory concentration (IC50) of (4.2 +/- 0.16) x 10(-7) mol/l. The calcium antagonists investigated also inhibited Ang II-induced DNA synthesis. Isradipine (10(-6) mol/l) completely abolished the PDGF-induced cell proliferation. Both PDGF (50 ng/ml) and Ang II (10(-7) mol/l) induced c-fos and egr-1 mRNA expression, having maximum effect after 30 min. In the case of c-fos, pre-incubation with 5 x 10(-6) mol/l isradipine led to a decrease in both Ang II- and PDGF-induced expression of this immediate-early gene. The expression of egr-1 was not affected by pre-incubation with 5 x 10(-6) mol/l isradipine.
  
  
  CONCLUSIONS
  All calcium antagonists investigated in the present study inhibited cell growth. Isradipine was more potent in blocking growth factor-induced cell growth than the other calcium antagonists studied. The inhibitory effect of the dihydropyridine calcium antagonists appears to be dependent on the expression of c-fos.
authors.affiliation: Medizinische Universitäts-Poliklinik, Bonn, Germany.
authors.forename: Y
authors.initials: Y
authors.lastname: Ko
authors.forename: G
authors.initials: G
authors.lastname: Totzke
authors.forename: G H
authors.initials: GH
authors.lastname: Graack
authors.forename: F J
authors.initials: FJ
authors.lastname: Heidgen
authors.forename: M K
authors.initials: MK
authors.lastname: Meyer zu Brickwedde
authors.forename: R
authors.initials: R
authors.lastname: Düsing
authors.forename: H
authors.initials: H
authors.lastname: Vetter
authors.forename: A
authors.initials: A
authors.lastname: Sachinidis
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics*; D051766:Early Growth Response Protein 1; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D017781:Genes, Immediate-Early / Q000187:drug effects*; D016762:Genes, fos / Q000187:drug effects*; D017874:Immediate-Early Proteins; D017275:Isradipine / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D051381:Rats; D011921:Rats, Inbred WKY; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D002121:Calcium Channel Blockers; D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D017874:Immediate-Early Proteins; D010982:Platelet-Derived Growth Factor; D014157:Transcription Factors; D002118:Calcium; D017275:Isradipine