Mechanism of increasing action of TA-993, a novel therapeutic agent for peripheral circulatory insufficiency, on limb blood flow

TA-993 (TA), a new 1,5-benzothiazepine derivative, has an unique and selective increasing action on limb blood flow (LBF) besides an antiplatelet aggregating action. We studied the mechanism of its LBF-increasing action in vivo. [Methods] In a canine blood-perfused hindlimb preparation with a donor-dog, the effect of TA (100μg/kg, i.v.) was studied. Moreover, influence of hexamethonium (C6), phentolamine (Ph), propranolol (Pro) or atropine (A) on TA (300μg/kg,i.v.)-induced increase of femoral blood flow (FBF) in anesthetized dogs and the influences of TA (300μg/kg,i.v.) on phenylephrine (Phe)- and talipexole (Tal)induced increase of perfusion pressure in canine constantly autoperfused hindlimbs were studied. Besides, we studied the possibility that TA might induce orthostatic hypotension with 60° head-up-tilt test in anesthetized rats. [Results] In the first experiment, TA did not increase FBF when administered to the donor-dog, but to the recipient. TA did not show the increasing action on FBF in the existence of both C6 and Ph, whereas TAs action was not influenced in the existence of either Pro or A. TA influenced on neither Phe- nor Tal-induced increase of femoral perfusion pressure. In addition, even 10mg/kg, i.d. of TA did not induce orthostatic hypotension, although the minimal effective dose of FBF-increasing action was 30μg/kg, i.d. in anesthetized rats. [Conclusion] These results suggest that TA increases LBF due to either depression of sympathetic vasoconstrictor nerve activity, or inhibition of norepinephrine release from these nerve terminals.