Schaffer L W, Schorn T W, Winquist R J, Strouse J F, Payne L, Chakravarty P K, de Laszlo S E, tenBroeke J, Veber D F, Greenlee W J
Department of Pharmacology, Merck Sharp & Dohme Research Laboratories, West Point, PA 19486.
J Hypertens. 1990 Mar;8(3):251-9.
In order to investigate the hypotensive mechanisms of action of peptide renin inhibitors, blood pressure responses to five renin inhibitors were compared with those to the angiotensin converting enzyme inhibitor, enalaprilat, in conscious African green and rhesus monkeys. (3S-4S)-4-amino-5-cyclohexyl-3-hydroxy pentanoic acid (ACHPA)-containing renin inhibitory peptide (ACRIP) and enalaprilat both decreased blood pressure in euvolemic and volume-depleted African green monkeys. However, while a maximum dose of enalaprilat reduced blood pressure to 80 +/- 4 and 56 +/- 4 mmHg in the euvolemic and volume-depleted monkeys, respectively, ACRIP lowered pressure to life-threatening levels (less than 40 mmHg) under both conditions. The relative potencies of ACRIP and four other renin inhibitors for inhibiting in vitro plasma renin activity (PRA; IC50) were compared with their potencies in reducing blood pressure by 15 mmHg (ED15 mmHg) and lowering blood pressure more than enalaprilat in volume-depleted rhesus monkeys. All renin inhibitors lowered blood pressure significantly beyond the maximal response to enalaprilat. Despite a significant correlation (r = 0.99, P less than 0.05) between the in vitro PRA inhibitory potency and the in vivo ED15 mmHg, doses which lowered blood pressure beyond the maximal responses to enalaprilat were not significantly correlated (r = 0.53, P greater than 0.05) with the in vitro PRA IC50 values. Furthermore, the profound depressor responses to renin inhibitors in rhesus monkeys were accompanied by increases in the heart rate and decreases in pulse pressure.(ABSTRACT TRUNCATED AT 250 WORDS)
为了研究肽类肾素抑制剂的降压作用机制，在清醒的非洲绿猴和恒河猴中，比较了五种肾素抑制剂与血管紧张素转换酶抑制剂依那普利拉的血压反应。含（3S-4S）-4-氨基-5-环己基-3-羟基戊酸（ACHPA）的肾素抑制肽（ACRIP）和依那普利拉均可降低血容量正常和血容量减少的非洲绿猴的血压。然而，虽然依那普利拉的最大剂量分别将血容量正常和血容量减少的猴子的血压降至80±4 mmHg和56±4 mmHg，但在两种情况下，ACRIP都将血压降至危及生命的水平（低于40 mmHg）。将ACRIP和其他四种肾素抑制剂抑制体外血浆肾素活性（PRA；IC50）的相对效力与其在血容量减少的恒河猴中使血压降低15 mmHg（ED15 mmHg）以及使血压降低幅度超过依那普利拉的效力进行了比较。所有肾素抑制剂降低血压的幅度均明显超过依那普利拉的最大反应。尽管体外PRA抑制效力与体内ED15 mmHg之间存在显著相关性（r = 0.99，P < 0.05），但使血压降低幅度超过依那普利拉最大反应的剂量与体外PRA IC50值之间无显著相关性（r = 0.53，P > 0.05）。此外，恒河猴对肾素抑制剂的深度降压反应伴随着心率增加和脉压降低。（摘要截短至250字）
