Nagata S, Takeyama K, Fukuya F, Nagai R, Hosoki K, Nishimura K, Deguchi T, Karasawa T
Department of Pharmacology I, Dainippon Pharmaceutical Co., Ltd., Suita, Osaka, Japan.
Arzneimittelforschung. 1995 Aug;45(8):853-8.
The antihypertensive properties of a new long-acting, angiotensin-I-converting enzyme (ACE) inhibiting agent, (2S,3aS,7aS)-1-(N2-nicotinoyl-L-lysyl-gamma-D-glutamyl) octahydro-1H-indole-2-carboxylic acid (CAS 116662-73-8, DU-1777), were investigated orally in various experimental models of hypertension in comparison to a standard ACE inhibitor, lisinopril. The hypotensive potency of DU-1777 was not as marked as that of lisinopril in renin-dependent hypertensive models, i.e., two-kidney one-clip renal hypertensive rats (2K-1C RHR) (ED-20mmHg: 3.1 versus 1.0 mg/kg) or two-kidney two-clip renal hypertensive dogs (2K-2C RHD) (ED-20 mmHg: 2.5 versus 1.0 mg/kg), though the actions of the two drugs were both long-lasting and dose-related. When spontaneously hypertensive rats (SHR) were used, however, DU-1777 was as active as lisinopril (ED-20 mmHg: 17.9 versus 13.6 mg/kg). The most distinguishing results with DU-1777 were its hypotensive effects in renin-independent hypertensive models. In contrast to lisinopril, the drug produced a sustained and dose-related hypotensive effect in DOCA salt hypertensive rats (DOCA-HR) and one-kidney one-clip renal hypertensive rats (1K-1C RHR). There exists an inconsistency between the long duration of the agent's hypotensive action in all tested hypertensive models and its short duration of ACE inhibiting activity as demonstrated both in vivo and ex vivo. The sustained antihypertensive action of DU-1777 cannot be reasoned solely with respect to ACE inhibition, suggesting some additional mechanisms of action yet to be defined.
一种新型长效血管紧张素转换酶（ACE）抑制剂（2S,3aS,7aS）-1-（N2-烟酰-L-赖氨酰-γ-D-谷氨酰）八氢-1H-吲哚-2-羧酸（CAS 116662-73-8，DU-1777）的降压特性，与标准ACE抑制剂赖诺普利相比，在多种高血压实验模型中进行了口服研究。在肾素依赖性高血压模型中，即两肾一夹肾性高血压大鼠（2K-1C RHR）（降压20mmHg的半数有效剂量：3.1对1.0mg/kg）或两肾两夹肾性高血压犬（2K-2C RHD）（降压20mmHg的半数有效剂量：2.5对1.0mg/kg）中，DU-1777的降压效力不如赖诺普利显著，尽管两种药物的作用都是长效且与剂量相关的。然而，当使用自发性高血压大鼠（SHR）时，DU-1777与赖诺普利的活性相当（降压20mmHg的半数有效剂量：17.9对13.6mg/kg）。DU-1777最显著的结果是其在肾素非依赖性高血压模型中的降压作用。与赖诺普利相反，该药物在去氧皮质酮盐性高血压大鼠（DOCA-HR）和一肾一夹肾性高血压大鼠（1K-1C RHR）中产生了持续且与剂量相关的降压作用。在所有测试的高血压模型中，该药物降压作用的持续时间较长，而其体内和体外ACE抑制活性的持续时间较短，两者之间存在不一致性。DU-1777的持续降压作用不能仅通过ACE抑制来解释，这表明还有一些尚未明确的额外作用机制。
