Inhibitory effect of TAS-301, a new synthesized constrictive remodeling regulator, on renarrowing after balloon overstretch injury of porcine coronary artery

The purpose of this study was to determine the efficacy and the possible me chanism of action of a recently synthesized drug, TAS-301 [3-bis(4-methoxyp henyl)methylene-2-indolinone], on stenosis after balloon overstretch injury of porcine arteries. We measured the diameter of vessels by angiography an d conducted histological analysis. The oral administration of TAS-301 kept dilated the angiographic luminal diameter of injured segment 4 weeks after overstretch injury and reduced calculated stenosis ratio in a dose-dependen t manner, significantly reducing it at doses of 30 and 100 mg/kg. Histopath ological analysis showed that TAS-301 significantly reduced the adventitial area at doses of 30 and 100 mg/kg with moderate reduction of the neointima l area, resulting in the larger residual lumen. In an in vitro assay, TAS-3 01 dose dependently inhibited the proliferation of adventitial fibroblasts stimulated by basic fibroblast growth factor or transforming growth factor- beta (1). In addition, the drug reduced adventitial fibroblast-mediated thr ee-dimensional collagen gel contraction. These findings indicate that TAS-3 01, the first compound developed for targeting the constrictive remodeling, showed a high inhibitory potency on coronary artery stenosis of micropigs after injury, mainly due to inhibition of adventitial fibroblast proliferat ion and of the contractile ability of myofibroblasts. Our results suggest t he strong possibility that TAS-301 may be efficacious for prevention of res tenosis after angioplasty and the need to examine the therapeutic usefulnes s of this drug in clinical trials.