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 vas cular smooth muscle cell (VSMC) growth and proliferation, which may be a crucial step in the pathogenesis of hypertension and atherosclerosi s. Design: The effects of the dihydropyridine calcium antagonists nife dipine, nitrendipine, nisoldipine, nimodipine and isradipine on cell g rowth induced by platelet-derived growth factor (PDGF)-AB and angioten sin II (Ang II), and expression of the transcription factors c-fos and early-growth response gene 1 (egr-1) were investigated. Methods: Prol iferation of VSMC in culture was measured by [H-3]-thymidine incorpora tion into cell DNA and by cell count. Expression of c-fos and egr-1 me ssenger RNA (mRNA) was determined by the Northern blot technique. Resu lts: All of the calcium antagonists blunted the PDGF-induced rise in V SMC DNA synthesis. The inhibitory potency of isradipine on PDGF-stimul ated DNA synthesis was approximately 10-fold that of the other calcium antagonists used, isradipine having a half-maximal inhibitory concent ration (IC50) of (4.2 +/- 0.16) x 10(-7) mol/l. The calcium antagonist s investigated also inhibited Ang II-induced DNA synthesis. Isradipine (10(-6) mol/1) completely abolished the PDGF-induced cell proliferati on. Both PDGF (50 ng/ml) and Ang II (10(-7) mol/l) induced c-fos and e gr-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 dec rease in both Ang II- and PDGF-induced expression of this immediate-ea rly gene. The expression of egr-1 was not affected by pre-incubation w ith 5 x 10(-6) mol/l isradipine. Conclusions: All calcium antagonists investigated in the present study inhibited cell growth. Isradipine wa s more potent in blocking growth factor-induced cell growth than the o ther calcium antagonists studied. The inhibitory effect of the dihydro pyridine calcium antagonists appears to be dependent on the expression of c-fos.