Takeyama K, Minato H, Ikeno A, Hosoki K, Kadokawa T
Arzneimittelforschung. 1986;36(1):74-7.
To investigate the antihypertensive mechanism of 1-[(S)-3-acetylthio-2-methylpropanoyl]-L-prolyl-L-phenylalanine (alacepril, DU-1219) a novel orally active angiotensin converting enzyme inhibitor, we studied the inhibitory activity of alacepril and DU-1227 (desacetyl-alacepril, a metabolite of alacepril) on the norepinephrine (noradrenaline, NA)-induced vasoconstrictive and pressor response in vitro and in vivo, and compared with that of captopril. Alacepril and captopril (3 X 10(-4) mol/l) attenuated slightly the NA-induced contractile response in isolated rat thoracic aorta and mesenteric artery, however, DU-1227 (3 X 10(-4) mol/l) inhibited more strongly the response in main artery and peripheral vascular bed. Orally given alacepril (18.7 mg/kg) inhibited the NA-induced pressor response in conscious normotensive rats, and the activity was more potent and long-lasting than that of an equimolar dose of captopril (10 mg/kg). After oral administration in hypertensive rats challenged with NA, alacepril (1.87 to 18.7 mg/kg) showed a dose-related antihypertensive effect which was slower in onset and longer lasting than that of equimolar dose of captopril (1.0 to 10.0 mg/kg). Consequently, the reduced sensitivity of the sympathetic nervous system in peripheral vasculature might contribute partly to the antihypertensive mechanism of alacepril.
为研究新型口服活性血管紧张素转换酶抑制剂1-[(S)-3-乙酰硫基-2-甲基丙酰基]-L-脯氨酰-L-苯丙氨酸（阿拉普利，DU-1219）的降压机制，我们研究了阿拉普利和DU-1227（去乙酰阿拉普利，阿拉普利的一种代谢产物）在体外和体内对去甲肾上腺素（NA）诱导的血管收缩和升压反应的抑制活性，并与卡托普利进行了比较。阿拉普利和卡托普利（3×10⁻⁴mol/L）对离体大鼠胸主动脉和肠系膜动脉中NA诱导的收缩反应有轻微减弱作用，然而，DU-1227（3×10⁻⁴mol/L）对主动脉和外周血管床的反应抑制作用更强。口服给予阿拉普利（18.7mg/kg）可抑制清醒正常血压大鼠中NA诱导的升压反应，且该活性比等摩尔剂量的卡托普利（10mg/kg）更强且更持久。在给予NA激发的高血压大鼠口服给药后，阿拉普利（1.87至18.7mg/kg）呈现剂量相关的降压作用，其起效较慢但持续时间比等摩尔剂量的卡托普利（1.0至10.0mg/kg）更长。因此，外周血管系统中交感神经系统敏感性降低可能部分促成了阿拉普利的降压机制。
