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

Abstract

TA-993 (cis-(-)-2-(4-methylphenyl)-3-acetoxy-2,3-dihydro-5-(2-dimethylaminoethy l)-8-methyl1,5-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.

Effects of Exposure to a 50Hz Electric Field on Plasma Levels of Lactate, Glucose, Free Fatty Acids, Triglycerides and Creatine Phosphokinase Activity in Hind-Limb Ischemic Rats

“…The aim of this study was not to examine the relationship between an EF and blood circulation. The changes in lactate levels after ischemic surgery seen in this study may be an indirect parameter of a process in vascularization [12] and did not suggest any influences by EF exposure. In all treatment groups, plasma glucose levels were not different.…”

“…The results presented here, obtained using the rat ischemia model [12,21,35], enhance our understanding of the relationship between exposure to an EF and energy metabolism under the ischemic condition. Several earlier studies using this model suggested that stimulation with an EMF has an impact on the process of angiogenesis that is related to both cancer and ischemia [37,46,48].…”

“…The results indicate that a severe change, such as the depletion of stored glucose, would not occur even if ischemia or an EF actually had a minor impact on glycolysis. The ischemia-dependent transient plasma lactate increases on day-4 followed by decreases until day-14, suggest two things: 1) the ischemia induced the imbalance of lactate metabolism by hypoxia; and 2) the ischemia is normalized gradually via micro bypass [12]. Obvious EFrelated changes were not shown in plasma lactate levels in the double treatment group compared to those of the ischemia alone group.…”

“…), the abdominal aorta was isolated free from surrounding tissue and the vena cava just above the bifurcation to the iliac arteries and occluded by a thread [12]. Sham-operated rats underwent the same surgery, but the aorta was not occluded.…”

“…However, when mice were exercised on a treadmill, we found no influence of exposure to an EF on plasma lactate levels (unpublished data). The aim of the present study was to reproduce the results of EF influences on energy metabolism parameters using an animal model in which marked changes in plasma lactate levels can be observed [12,21,35]. In order to identify the kind of condition of organisms that an exposure to EF influences on plasma lactate level, experimental ischemic rat model was applied in presence study.…”