Fischli W, Clozel J P, Breu V, Buchmann S, Mathews S, Stadler H, Vieira E, Wostl W
Pharma Division, Preclinical Research, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
Hypertension. 1994 Aug;24(2):163-9. doi: 10.1161/01.hyp.24.2.163.
The present study characterizes the new transition-state renin inhibitor ciprokiren (Ro 44-9375) in squirrel monkeys. Arterial blood pressure was monitored by telemetry in freely moving, chronically instrumented conscious animals. In vitro at pH 7.4, ciprokiren inhibited human renin in buffer and human plasma with an IC50 of 0.07 and 0.65 nmol/L, respectively. It was equipotent against primate plasma renin and also inhibited plasma renin from dog and guinea pig in the nanomolar range (IC50, 29 and 65 nmol/L, respectively). After acute oral administration it reduced arterial blood pressure dose dependently in normotensive sodium-depleted and cyclosporin-induced hypertensive squirrel monkeys, starting with the minimal oral dose of 3 micrograms/kg. Daily oral doses of 1 microgram/kg showed a progressive blood pressure decrease, with a maximal response reached after 1 week. The drug could also be applied transdermally with similar hemodynamic effects without any decrease of plasma renin activity or plasma immunoreactive angiotensin II. Thus, ciprokiren is characterized in squirrel monkeys as a renin inhibitor with high in vivo potency that might act mainly in the tissular compartment.
本研究对松鼠猴体内新型过渡态肾素抑制剂西普罗瑞林（Ro 44-9375）进行了特性研究。通过遥测技术对自由活动、长期植入仪器的清醒动物的动脉血压进行监测。在体外pH 7.4条件下，西普罗瑞林在缓冲液和人血浆中抑制人肾素的IC50分别为0.07和0.65 nmol/L。它对灵长类动物血浆肾素的抑制作用相当，在纳摩尔范围内也能抑制狗和豚鼠的血浆肾素（IC50分别为29和65 nmol/L）。急性口服给药后，在正常血压的缺钠和环孢素诱导的高血压松鼠猴中，从最低口服剂量3微克/千克开始，动脉血压呈剂量依赖性降低。每日口服剂量1微克/千克时，血压逐渐下降，1周后达到最大反应。该药物也可经皮给药，具有相似的血流动力学效应，且血浆肾素活性或血浆免疫反应性血管紧张素II无任何降低。因此，在松鼠猴体内，西普罗瑞林被表征为一种体内效力高的肾素抑制剂，可能主要在组织部位起作用。
