肾素抑制剂GR70982对清醒狨猴的急性和慢性影响。

Acute and chronic effects of renin inhibitor GR70982 in the conscious marmoset.

作者信息

Gardner C J, Twissell D J, Charlton P A, Cherry P C

机构信息

Glaxo Group Research Ltd., Greenford, Middlesex, U.K.

出版信息

Eur J Pharmacol. 1991 Jan 17;192(3):329-35. doi: 10.1016/0014-2999(91)90221-b.

DOI:10.1016/0014-2999(91)90221-b

PMID:1905233

Abstract

The effects on plasma renin activity (PRA), mean arterial blood pressure (MABP) and heart rate (HR) of GR70982, a low molecular weight inhibitor of human renin, were studied in conscious marmosets. In vitro, GR70982 is a potent and selective inhibitor of human plasma renin (concentration producing 50% inhibition (IC50): human renin = 6.9 x 10(-9) M; porcine pepsin and bovine cathepin D = greater than 10(-3) M). In normotensive marmosets, i.v. GR70982 (0.001-0.1 mg kg-1) produced a dose-related inhibition of PRA. Larger oral doses (0.2, 1 and 5 mg kg-1) were required to achieve similar effects. In renin-dependent hypertensive marmosets, i.v. GR70982 (0.01 and 0.5 mg kg-1) produced dose-related decreases in MABP (-12 and -18 mm Hg) and PRA (-93 and -100%), with only minimal effects on HR. A 7-day continuous i.v. infusion of GR70982 (0.36 mg kg-1 day-1) in sodium-deplete marmosets produced a gradual decrease in MABP (-17 mm Hg at day 7, cf. control), accompanied by an inhibition of PRA (approximately 75%) and minimal HR effects.

摘要

在清醒的狨猴中研究了人肾素低分子量抑制剂GR70982对血浆肾素活性（PRA）、平均动脉血压（MABP）和心率（HR）的影响。在体外，GR70982是一种强效且选择性的人血浆肾素抑制剂（产生50%抑制作用的浓度（IC50）：人肾素=6.9×10⁻⁹ M；猪胃蛋白酶和牛组织蛋白酶D>10⁻³ M）。在血压正常的狨猴中，静脉注射GR70982（0.001 - 0.1 mg kg⁻¹）可产生与剂量相关的PRA抑制作用。需要更大的口服剂量（0.2、1和5 mg kg⁻¹）才能达到类似效果。在肾素依赖性高血压狨猴中，静脉注射GR70982（0.01和0.5 mg kg⁻¹）可使MABP（-12和-18 mmHg）和PRA（-93和-100%）产生与剂量相关的下降，对HR的影响极小。在缺钠的狨猴中连续7天静脉输注GR70982（0.36 mg kg⁻¹天⁻¹）可使MABP逐渐下降（第7天为-17 mmHg，与对照组相比），同时伴有PRA抑制（约75%），对HR的影响极小。