Abstract
Labedipinedilol-A is a novel 1, 4-dihydropyridine type calcium antagonist with alpha-receptor blocking activity. This study investigates the effects of labedipinedilol-A on mitogen-induced proliferation of rat vascular smooth muscle cells (VSMCs). Labedipinedilol-A's inhibition on cell proliferation was measured by the tetrazolium salt (XTT) test. Labedipinedilol-A dose-dependently inhibited mitogen-induced DNA synthesis, determined by the incorporation of 5-bromo-2'-deoxyuridine (BrdU). Labedipinedilol-A was also found capable of inhibiting the migration of VSMCs induced by PDGF-BB with an IC50 value of 5.6 microM. In accordance with these findings, labedipinedilol-A revealed blocking of the FBS-inducible progression through G0/G1 to S phase of the cell cycle in synchronized cells. Labedipinedilol-A appeared to cause inhibition of mitogens-induced PKC translocation, suggesting the probable involvement of protein kinase C (PKC) in this cellular response. Labedipinedilol-A reduced both intracellular Ca and the phosphorylation of extracellular signal-regulated protein kinase 1/2 in PDGF-BB-stimulated VSMCs. It also suppressed the levels of proliferative cell nuclear antigen (PCNA) in VSMCs both time- and dose-dependently. These results indicate that labedipinedilol-A may inhibit cell proliferation by attenuating activation of the ERK 1/2 pathway, which is regulated by PKC and Ca, suggesting that it may have great potential in the prevention of progressive atherosclerosis.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anisoles / metabolism
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Anisoles / pharmacology*
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Aorta, Thoracic / pathology
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Bromodeoxyuridine / pharmacology
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Calcium / metabolism
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Cell Culture Techniques
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Cell Movement / drug effects
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Cell Movement / genetics
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Cell Proliferation / drug effects
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China
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DNA / antagonists & inhibitors
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DNA / metabolism
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Dihydropyridines / chemistry
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Dihydropyridines / metabolism
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Dihydropyridines / pharmacology*
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Dose-Response Relationship, Drug
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Drug Evaluation, Preclinical / methods
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Focal Adhesion Kinase 2
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Humans
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Interphase / drug effects
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Isoenzymes / chemistry
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Isoenzymes / metabolism
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MAP Kinase Kinase 2
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Male
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Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors*
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Mitogen-Activated Protein Kinase 1 / drug effects
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Mitogen-Activated Protein Kinase 1 / metabolism
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Muscle, Smooth, Vascular / drug effects
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Muscle, Smooth, Vascular / metabolism
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Muscle, Smooth, Vascular / pathology*
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Phosphorylation / drug effects
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Platelet-Derived Growth Factor / metabolism
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Platelet-Derived Growth Factor / pharmacology
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Proliferating Cell Nuclear Antigen / drug effects
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Proliferating Cell Nuclear Antigen / genetics
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Proliferating Cell Nuclear Antigen / metabolism
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Proline / chemistry
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Protein Kinase C / chemistry
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Protein Kinase C / metabolism*
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Protein-Tyrosine Kinases / chemistry
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Protein-Tyrosine Kinases / metabolism
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Rats
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Rats, Wistar
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Umbilical Veins / drug effects
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Umbilical Veins / metabolism
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Umbilical Veins / pathology
Substances
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Anisoles
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Dihydropyridines
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Isoenzymes
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Platelet-Derived Growth Factor
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Proliferating Cell Nuclear Antigen
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labedipinedilol A
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DNA
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Proline
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Protein-Tyrosine Kinases
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Focal Adhesion Kinase 2
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Ptk2b protein, rat
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Protein Kinase C
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Mitogen-Activated Protein Kinase 1
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MAP Kinase Kinase 2
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Bromodeoxyuridine
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Calcium