Cardiovascular and antihypertensive activities of the novel non-sulfhydryl converting enzyme inhibitor 2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S,3S,5S)-2- azabicyclo[3.3.0]octane-3-carboxylic acid (Hoe 498).
Cardiovascular and antihypertensive activities of the novel non-sulfhydryl converting enzyme inhibitor 2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S,3S,5S)-2- azabicyclo[3.3.0]octane-3-carboxylic acid (Hoe 498).
复制标题
新型非巯基转化酶抑制剂2-[N-[(S)-1-乙氧基羰基-3-苯基丙基]-L-丙氨酰]-(1S,3S,5S)-2-氮杂双环[3.3]的心血管和抗高血压活性
DOI：
10.1097/00005344-198600101-00016
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发表时间：
1984
期刊：
影响因子：
--
通讯作者：
J. Kaiser
中科院分区：
文献类型：
--
作者：
B. Schölkens;R. Becker;J. Kaiser
在几种实验制剂中评价了新型口服活性非巯基转换酶（CE）抑制剂2-[N-[（S）-1-乙氧基羰基-3-苯基-丙基]-L-丙氨酰] -（1 S，3S，5S）-2-氮杂双环[3.3.0]辛烷-3-羧酸（Hoe 498）的心血管和抗高血压活性。Hoe 498在麻醉动物中的血流动力学特征表现为全身血压降低，这与总外周和肾血管阻力降低相关。这些作用在钠耗尽后增强。在清醒的正常血压大鼠中，单次经口给予Hoe 498可降低全身血压超过5小时。经口给予Hoe 498预处理可预防麻醉大鼠发生急性肾血管性高血压。在肾血管性高血压（两肾一夹）清醒大鼠中，Hoe 498单次经口给药可诱导持久的降压作用。Hoe 498长期口服治疗自发性高血压大鼠比依那普利更有效地降低动脉血压。Hoe 498的降压阈值剂量为0.01 mg/kg/d，依那普利为1 mg/kg/d。在清醒的高血压犬（双肾，双包）中，Hoe 498以10 mg/kg单次经口给药可降低全身血压超过6小时。在清醒的高血压犬中，Hoe 498以1 mg/kg/d的剂量经口给药5天，使全身血压正常化。这些研究结果表明，在各种实验性高血压模型中，新型口服活性转化酶抑制剂Hoe 498具有显著的心血管和有效的长期抗高血压活性，值得探索可能的治疗益处。
The cardiovascular and antihypertensive activities of the novel orally active non-sulfhydryl converting enzyme (CE) inhibitor 2-[N-[(S)-1-Ethoxycarbonyl-3-phenyl-propyl]-L-alanyl] -(1S,3S,5S)-2-azabicyclo[3.3.0]octane-3-carboxylic acid (Hoe 498) were evaluated in several experimental preparations. The hemodynamic profile of Hoe 498 in anesthetized animals was characterized by a reduction in systemic blood pressure which was associated with a decrease in total peripheral and renal vascular resistance. These effects were enhanced upon sodium depletion. In conscious normotensive rats a single oral administration of Hoe 498 reduced systemic blood pressure for more than 5 h. The development of acute renovascular hypertension in anesthetized rats was prevented by oral pretreatment with Hoe 498. In conscious rats with renovascular hypertension (two-kidney, one clip) single oral doses of Hoe 498 induced a long lasting antihypertensive effect. Chronic oral treatment of spontaneously hypertensive rats with Hoe 498 lowered arterial blood pressure more effectively than enalapril. The threshold antihypertensive dose for Hoe 498 was 0.01 mg/kg/d, for enalapril 1 mg/kg/d. In conscious hypertensive dogs (two-kidney, two wrapped) Hoe 498 at a single oral dose of 10 mg/kg reduced systemic blood pressure for more than 6 h. Oral administration of Hoe 498 in a dose of 1 mg/kg/d for 5 d normalized systemic blood pressure in conscious hypertensive dogs. These findings demonstrate that in various models of experimental hypertension the novel orally active converting enzyme inhibitor Hoe 498 exerts marked cardiovascular and potent prolonged antihypertensive activities, which merit exploration with respect to possible therapeutic benefits.