Hisayoshi Doi, Minako Kaburaki, Hirotaka Inoue, Kuniharu Suzumura and
Discovery Research Laboratory, Tanabe Seiyaku Co., Ltd., 2-2-50, Kawagishi, Toda, Saitama 335-8505, Japan
Abstract: TA-993 (cis-(-)-2-(4-methylphenyl)-3-acetoxy-2,3-dihydro-5-(2-dimethylaminoethyl)-8-methyl-1,5-benzothiazepine-4(5H)-one maleate), a new 1,5-benzothiazepine derivative, has a selective increasing action on limb blood flow in addition to an antiplatelet action. In this report we studied the effect of TA-993 on a time dependent decrease in developed tension of electrically-induced contraction of tibialis anterior muscle in a rat model of peripheral circulatory insufficiency induced by occlusion of abdominal aorta. In our preparation, the developed tension decreased by 20-30% in a sham-operated group and 30-40% in an abdominal aorta-occluded group at the end of the experimental period of 60╩min. Intraduodenal administration (i.d.) of TA-993 (10╩mg/kg) to the abdominal aorta-occluded rats ameliorated the decrease in developed tension to the level of the sham-operated group. Moreover, TA-993 at 10╩mg/kg,╩i.d. significantly increased femoral arterial blood flow supplied through collateral circulation and decreased the whole blood viscosity in this model. These results suggest that TA-993 improves dysfunction of skeletal muscle contraction due to peripheral circulating insufficiency through an increase in collateral blood flow and an improvement of red blood cell deformability.
Keywords: TA-993, Intermittent claudication, Skeletal muscle, Blood flow