Vol. 288, Issue 3, 1167-1173, March 1999

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

Minako Kaburaki, Hideo Yabana, Hisayoshi Doi, Koichi Nagata, Hiroshi Narita and Sakae Murata

Discovery Research Laboratory, Tanabe Seiyaku Co., Ltd., Saitama, Japan

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-benzothiazepine derivative with l-cis configuration, has a unique and selective increasing action on limb blood flow with little influence on arterial pressure besides an antiplatelet action. We studied the mechanism of increasing action of TA-993 on limb blood flow in anesthetized dogs. In a canine blood-perfused hindlimb preparation with a donor dog, TA-993 (100 µg/kg i.v.) did not increase femoral blood flow when administered to the donor dog, but did when administered to a recipient dog. TA-993 did not show the increasing action on femoral blood flow in the presence of hexamethonium or phentolamine, 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 µg/kg i.v.) did not alter the phenylephrine (1-100 ng/kg i.a.)- or the talipexole (3-100 ng/kg i.a.)-induced increase in perfusion pressure in an autoperfused hindlimb. These results suggest that the increasing action of TA-993 on limb blood flow is mediated by the sympathetic nervous system but that the adrenergic receptors are not likely to be the central point of action of this new agent. There is a possibility that the mechanism of the increasing action on heart rate is different from that of its increasing action on limb blood flow.