Protective Effect of TA-993, a Novel Therapeutic Agent for Peripheral Circulatory Insufficiency, on Skeletal Muscle Fatigue in a Rat Model of Hindlimb Ischemia

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.