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Journal of Pharmacology and Experimental Therapeutics

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OtherCARDIOVASCULAR PHARMACOLOGY

TAS-301, an Inhibitor of Smooth Muscle Cell Migration and Proliferation, Inhibits Intimal Thickening after Balloon Injury to Rat Carotid Arteries

Yoshiyuki Muranaka, Yasundo Yamasaki, Yoshihisa Nozawa, Hiroshi Terakawa, Yasutaka Tanahashi, Nobuyuki Oda, Atsushi Satoh, Tetsuji Asao, Hidekazu Miyake and Naosuke Matsuura
Journal of Pharmacology and Experimental Therapeutics June 1998, 285 (3) 1280-1286;
Yoshiyuki Muranaka
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Yasundo Yamasaki
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Yoshihisa Nozawa
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Hiroshi Terakawa
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Yasutaka Tanahashi
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Nobuyuki Oda
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Atsushi Satoh
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Tetsuji Asao
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Hidekazu Miyake
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Naosuke Matsuura
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Abstract

The purpose of this study was to determine the efficacy and the possible mechanism of action of a recently synthesized drug, TAS-301 [3-bis (4-methoxyphenyl)methylene-2-indolinone], on intimal formation in comparison with those of tranilast, the clinical efficacy of which was reported earlier. Rat carotid arteries were injured using a balloon catheter. Neointimal thickening, measured 14 days after injury, was reduced by the oral administration of TAS-301 in a dose-dependent fashion (3–100 mg/kg), and the effect of TAS-301 at a dose of 100 mg/kg was significantly greater than that of tranilast (300 mg/kg). Fewer cells were found on the intima of balloon-injured arteries of TAS-301-treated rats than on arteries of tranilast-treated rats. In anin vitro assay, TAS-301 inhibited the migration of smooth muscle cells (SMCs) stimulated by platelet-derived growth factor-BB, insulin-like growth factor-1 or heparin-binding epidermal growth factor-like growth factor. In addition, TAS-301 and tranilast reduced the proliferation of medial and intimal SMCs at 4 and 8 days, respectively, after the injury. In vitro, TAS-301 inhibited basic fibroblast growth factor-induced proliferation of SMCs dose dependently. These findings indicate that TAS-301 shows a higher inhibitory potency on intimal formation than tranilast due to inhibition of both migration of medial SMCs and proliferation of medial and intimal SMCs. Our results suggest that further evaluation of TAS-301 as an inhibitor of postangioplasty intimal thickening is warranted.

Footnotes

  • Send reprint requests to: Dr. Yasundo Yamasaki, Cardiovascular Science Research Laboratory, Taiho Pharmaceutical Co. Ltd., 1–27 Hanno-City, Saitama 357, Japan. E-mail:yamasaki{at}taiho.co.jp

  • Abbreviations:
    bFGF
    basic fibroblast growth factor
    BrdU
    5-bromo-2′-deoxyuridine
    BSA
    bovine serum albumin
    DMEM
    Dulbecco’s modified Eagle’s medium
    HB-EGF
    heparin-binding epidermal growth factor-like growth factor
    HPF
    high-power fields
    IGF-1
    insulin-like growth factor-1
    LDH
    lactate dehydrogenase
    PBS
    phosphate-buffered saline
    PCNA
    proliferating cell nuclear antigen
    PDGF
    platelet-derived growth factor
    PTCA
    percutaneous transluminal coronary angioplasty
    SMC
    smooth muscle cell
    • Received October 2, 1997.
    • Accepted February 13, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 285, Issue 3
1 Jun 1998
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OtherCARDIOVASCULAR PHARMACOLOGY

TAS-301, an Inhibitor of Smooth Muscle Cell Migration and Proliferation, Inhibits Intimal Thickening after Balloon Injury to Rat Carotid Arteries

Yoshiyuki Muranaka, Yasundo Yamasaki, Yoshihisa Nozawa, Hiroshi Terakawa, Yasutaka Tanahashi, Nobuyuki Oda, Atsushi Satoh, Tetsuji Asao, Hidekazu Miyake and Naosuke Matsuura
Journal of Pharmacology and Experimental Therapeutics June 1, 1998, 285 (3) 1280-1286;

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OtherCARDIOVASCULAR PHARMACOLOGY

TAS-301, an Inhibitor of Smooth Muscle Cell Migration and Proliferation, Inhibits Intimal Thickening after Balloon Injury to Rat Carotid Arteries

Yoshiyuki Muranaka, Yasundo Yamasaki, Yoshihisa Nozawa, Hiroshi Terakawa, Yasutaka Tanahashi, Nobuyuki Oda, Atsushi Satoh, Tetsuji Asao, Hidekazu Miyake and Naosuke Matsuura
Journal of Pharmacology and Experimental Therapeutics June 1, 1998, 285 (3) 1280-1286;
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