Benidipine, a calcium channel blocker, regulates proliferation and phenotype of vascular smooth muscle cells.
Hyperproliferation of phenotypically modified vascular smooth muscle cells (VSMCs) is one of the major factors in the development of atherosclerosis and restenosis. Previously it was demonstrated that benidipine, a dihydropyridine-calcium channel antagonist, reduced neointimal formation in a rat balloon-injury model. In the present study, we examined the effect of benidipine on the phenotypic modulation and proliferation of VSMCs, using primary cultures of rat VSMCs. In the absence of drug treatment, protein levels of the smooth muscle specific markers, such as smooth muscle myosin heavy chain-1 (SM1), calponin 1, and alpha-actin, decreased during culture. However, treatment of VSMCs with benidipine (3 - 10 micromol/L) for 1 week reversed the effect in a concentration-related manner so that high levels of marker proteins were maintained. The expression of calponin mRNAs was reduced markedly during 1-week culture, and treatment with benidipine (3 micromol/L) significantly inhibited the reduction. Treatment with benidipine for 2 days increased the level of p21 protein and partially reduced p70 S6 kinase 1 (p70S6K1) activity. These data suggest that benidipine may arrest the growth of VSMCs, thereby preventing cell dedifferentiation. These additional properties of benidipine suggest that the drug should provide useful therapy for atherosclerosis and restenosis.
Pharmaceutical Research Center, Kyowa Hakko Kogyo Co., Ltd., Sunto-gun, Shizuoka, Japan. emi.arakawa@kyowa.co.jp
Emi
E
Arakawa
Kazuhide
K
Hasegawa
D000818:Animals; D001012:Aorta, Abdominal / Q000166:cytology; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D015153:Blotting, Western; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D018929:Cell Culture Techniques; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004095:Dihydropyridines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D010641:Phenotype; D016133:Polymerase Chain Reaction; D051381:Rats; D017208:Rats, Wistar; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000032:analysis / Q000378:metabolism
D015415:Biomarkers; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; C061004:benidipine; D038762:Ribosomal Protein S6 Kinases, 70-kDa