Jpn. J. Pharmacol. 84 (3), 252-258 (2000)

TAS-301 Blocks Receptor-Operated Calcium Influx and Inhibits Rat Vascular Smooth Muscle Cell Proliferation Induced by Basic Fibroblast Growth Factor and Platelet-Derived Growth Factor

Eiji Sasaki1, Yoshihisa Nozawa1, Kazuhisa Miyoshi1, Atsuhiro Kanda1, Yasundo Yamasaki2,*,
Hidekazu Miyake2 and Naosuke Matsuura1

1Pharmacology Research Laboratory, Tokushima Research Center, Taiho Pharmaceutical Co., Ltd.,
224-2, Ebisuno, Hiraishi, Kawauchi-cho, Tokushima 771-0194, Japan
2Cardiovascular Science Research Laboratory, Hanno Research Center, Taiho Pharmaceutical Co., Ltd.,
1-27 Misugidai, Hanno City, Saitama 357-8527, Japan
*Corresponding author.╩╩FAX:+81-429-72-0034

Abstract: The purpose of this study was to determine the effect of a recently synthesized drug, TAS-301 [3-bis(4-methoxyphenyl)methylene-2-indolinone], on vascular smooth muscle cell (VSMC) proliferation and the intracellular signal transduction pathways involved in VSMC proliferation. In an in vitro assay, TAS-301 inhibited the proliferation of rat VSMCs stimulated by platelet-derived growth factor (PDGF)-BB, basic fibroblast growth factor, or 2% fetal bovine serum in a concentration-dependent manner. TAS-301 dose-dependently inhibited the PDGF-induced Ca2+ influx; the concentration for the inhibition of Ca2+ influx was nearly identical to that for inhibition of VSMC proliferation. The Ca2+ influx induced by PDGF was also attenuated by NiCl2 but not by nifedipine, suggesting that PDGF-induced Ca2+ influx would be mediated by some non-voltage-dependent mechanisms. Furthermore, TAS-301 inhibited PDGF-induced activation of protein kinase╩C (PKC) and the phorbol 12-myristate 13-acetate-mediated induction of activator protein╩1 (AP-1) in a concentration-dependent manner. These findings indicate that TAS-301 inhibited the proliferation of VSMCs by blocking voltage-independent Ca2+ influx and downstream signals such as the Ca2+/PKC signaling pathway, leading to AP-1 induction.

Keywords: TAS-301, Vascular smooth muscle cell proliferation, Receptor-operated calcium influx,
Signal transduction

Copyrightę The Japanese Pharmacological Society 2000

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