The mechanism of the increasing action of TA-993, a new 1,5-benzothiazepine derivative, on limb blood flow in anesthetized dogs: Selective suppression of sympathetic nerve activity

TA-993, (-)-cis-3-acetoxy-5-(2-(dimethylamino)ethyl)-2,3-di- hydro-8-methyl -2-(4-methylphenyl)-1,5-benzothiazepin-4(5H)-one maleate, a new 1,5-benzoth iazepine derivative with I-cis configuration, has a unique and selective in creasing action on limb blood Row with little influence on arterial pressur e besides an antiplatelet action. We studied the mechanism of increasing ac tion of TA-993 on limb blood flow in anesthetized dogs. In a canine blood-p erfused hindlimb preparation with a donor dog, TA-993 (100 mu g/kg i.v.) di d not increase femoral blood flow when administered to the donor dog, but d id when administered to a recipient dog. TA-993 did not show the increasing action on femoral blood flow in the presence of hexamethonium or phentolam ine, whereas it did in the presence of propranolol or atropine. TA-993 also showed a weak increasing effect on heart rate, which was inhibited by any one of these blockers. TA-993 (300 mu g/kg i.v.) did not alter the phenylep hrine (1-100 ng/kg i.a.)- or the talipexole (3-100 ng/kg i.a.)-induced incr ease in perfusion pressure in an autoperfused hindlimb. These results sugge st that the increasing action of TA-993 on limb blood Row is mediated by th e sympathetic nervous system but that the adrenergic receptors are not like ly to be the central point of action of this new agent. There is a possibil ity that the mechanism of the increasing action on heart rate is different from that of its increasing action on limb blood flow.