Action of dihydropyridine calcium antagonists on early growth response gene expression and cell growth in vascular smooth muscle cells.
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.
Ko
Y
Y
Medizinische Universitäts-Poliklinik, Bonn, Germany.
Totzke
G
G
Graack
G H
GH
Heidgen
F J
FJ
Meyer zu Brickwedde
M K
MK
Düsing
R
R
Vetter
H
H
Sachinidis
A
A
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*
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