title: 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.
authors.affiliation: Discovery Research Laboratory, Tanabe Seiyaku Co., Ltd., Toda, Saitama, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Doi
authors.forename: M
authors.initials: M
authors.lastname: Kaburaki
authors.forename: H
authors.initials: H
authors.lastname: Inoue
authors.forename: K
authors.initials: K
authors.lastname: Suzumura
authors.forename: H
authors.initials: H
authors.lastname: Narita
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001809:Blood Viscosity / Q000187:drug effects; D004110:Diltiazem / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006339:Heart Rate / Q000187:drug effects; D006614:Hindlimb / Q000098:blood supply*; D007511:Ischemia / Q000188:drug therapy* / Q000503:physiopathology; D018763:Muscle Fatigue / Q000187:drug effects*; D010431:Pentoxifylline / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects
chemical_list: D010975:Platelet Aggregation Inhibitors; C097363:TA 993; D004110:Diltiazem; D010431:Pentoxifylline