Minato H, Hosoki K, Hayashi K, Sawayama T, Kadokawa T, Hashimoto M
Department of Pharmacology, Research Laboratories, Dainippon Pharmaceutical Co., Ltd., Osaka, Japan.
Arzneimittelforschung. 1989 Mar;39(3):319-24.
To elucidate the antihypertensive mechanisms of alacepril (DU-1219), the drug itself and its metabolites, desacetylalacepril (DU-1227) and captopril, were examined both in vitro and in vivo for their effects on the sympathetic nerve which innervates the peripheral vessels. 1. In isolated perfused mesenteric preparations from spontaneously hypertensive rats (SHR, DU-1227 (10(-6)-10(-5) mol/l) attenuated dose-dependently the increases in perfusion pressure and in norepinephrine (NE) overflow which were induced by electrical stimulation of periarterial sympathetic nerves (15 Hz). Captopril (10(-6)-10(-5) mol/l) caused a similar attenuation, though to a lesser degree, of the perfusion pressure but did not inhibit the increase in NE overflow. 2. The sympatho-inhibitory effect of DU-1227 in the above experiment was shown to be caused by DU-1227 per se, since no captopril was detected in either the perfusate or tissues perfused with DU-1227. 3. In pithed SHR, alacepril (3 mg/kg) caused as potent an inhibitory effect as captopril (3 mg/kg) on the pressor response to the electrical sympathetic nerve stimulation (3 Hz) at an oral dose about half as that of captopril on the molar basis. The effect of alacepril tended to last longer than that of captopril. However, at higher oral dose levels, the inhibitory effect of alacepril (30 mg/kg) was of the similar extent to that of captopril (30 mg/kg). 4. In pithed SHR which had received bilateral nephrectomy 2 to 8 h previously, alacepril (30 mg/kg p.o.) significantly attenuated the vasopressor response induced by electrical stimulation (1-30 Hz) 1 and 3 h after administration.(ABSTRACT TRUNCATED AT 250 WORDS)
为阐明阿拉普利（DU - 1219）及其代谢产物去乙酰阿拉普利（DU - 1227）和卡托普利的降压机制，在体外和体内研究了它们对支配外周血管的交感神经的作用。1. 在来自自发性高血压大鼠（SHR）的离体灌注肠系膜制备物中，DU - 1227（10⁻⁶ - 10⁻⁵mol/L）剂量依赖性地减弱了由电刺激动脉周围交感神经（15Hz）诱导的灌注压升高和去甲肾上腺素（NE）溢出增加。卡托普利（10⁻⁶ - 10⁻⁵mol/L）对灌注压有类似但程度较小的减弱作用，但不抑制NE溢出增加。2. 在上述实验中，DU - 1227的交感神经抑制作用被证明是由DU - 1227本身引起的，因为在用DU - 1227灌注的灌流液或组织中均未检测到卡托普利。3. 在脊髓横断的SHR中，阿拉普利（3mg/kg）对电刺激交感神经（3Hz）引起的升压反应的抑制作用与卡托普利（3mg/kg）相当，按摩尔基础计算，阿拉普利的口服剂量约为卡托普利的一半。阿拉普利的作用倾向于比卡托普利持续更长时间。然而，在较高口服剂量水平时，阿拉普利（30mg/kg）的抑制作用与卡托普利（30mg/kg）相似。4. 在2至8小时前接受双侧肾切除术的脊髓横断SHR中，阿拉普利（30mg/kg口服）在给药后1小时和3小时显著减弱了由电刺激（1 - 30Hz）诱导的血管升压反应。（摘要截取自250字）
