双重中性内肽酶-血管紧张素转换酶抑制与血管紧张素转换酶抑制对人体的药效学作用。

Pharmacodynamic effects of dual neutral endopeptidase-angiotensin-converting enzyme inhibition versus angiotensin-converting enzyme inhibition in humans.

作者信息

Massien C, Azizi M, Guyene T T, Vesterqvist O, Mangold B, Ménard J

机构信息

Broussais Hospital Clinical Investigation Center 9201, INSERM, Paris, France.

出版信息

Clin Pharmacol Ther. 1999 Apr;65(4):448-59. doi: 10.1016/S0009-9236(99)70140-2.

DOI:10.1016/S0009-9236(99)70140-2

PMID:10223783

Abstract

BACKGROUND

There is currently no clear evidence that dual neutral endopeptidase-angiotensin-converting enzyme inhibitors have effects on angiotensin-converting enzyme, renin, or blood pressure that are different from specific angiotensin-converting enzyme inhibitors in humans.

METHODS AND RESULTS

In a double-blind, placebo-controlled crossover study, single oral doses of the dual neutral endopeptidase-angiotensin-converting enzyme inhibitor, 10 mg BMS-186716 and the angiotensin-converting enzyme inhibitor fosinopril (20 mg) were administered to 9 normotensive subjects with induced mild sodium depletion. Values for area under the time curve from 0 to 24 hours [AUC(0-24)] for the plasma angiotensin II/angiotensin I ratio and for angiotensin II were similar for 10 mg BMS-186716 and 20 mg fosinopril. Plasma atrial natriuretic peptide decreased significantly after 20 mg fosinopril (9+/-3 pg/mL; P < .05 versus 10 mg BMS-186716 and placebo) compared with 10 mg BMS-186716 (16+/-5 pg/mL) and placebo (16+/-5 pg/mL). BMS-186716, 10 mg, significantly increased urinary atrial natriuretic peptide from baseline by 2+/-1.3-fold (P < .05 versus placebo and 20 mg fosinopril). AUC(0-24) of plasma active renin did not differ significantly between 10 mg BMS-186716 (3898+/-333 pg x h x mL(-1)) and 20 mg fosinopril (4383+/-302 pg x h x mL(-1); difference not significant). Both drugs decreased blood pressure, but the AUC(0-24) of the changes in mean blood pressure differed significantly from placebo (79+/-84 mm Hg x h) only for 20 mg fosinopril (181+/-6 mm Hg x h; P < .05) but not for 10 mg BMS-186716 (118+/-7 mmHg x h).

CONCLUSIONS

In this model, single oral doses of 10 mg BMS-186716 and 20 mg fosinopril induced similar 24-hour in vivo angiotensin-converting enzyme inhibition. BMS-186716, 10 mg, increased urinary atrial natriuretic peptide and blunted the expected decrease in plasma atrial natriuretic peptide caused by angiotensin-converting enzyme inhibition. BMS-186716, 10 mg, did not inhibit plasma active renin rise compared with 20 mg fosinopril. A single oral dose of 10 mg BMS-186716 had a shorter blood pressure-lowering effect than 20 mg fosinopril.

摘要

背景

目前尚无明确证据表明双重中性内肽酶 - 血管紧张素转换酶抑制剂对血管紧张素转换酶、肾素或血压的作用与人类特定血管紧张素转换酶抑制剂不同。

方法与结果

在一项双盲、安慰剂对照的交叉研究中，对9名轻度钠缺失的正常血压受试者口服单剂量的双重中性内肽酶 - 血管紧张素转换酶抑制剂10 mg BMS - 186716和血管紧张素转换酶抑制剂福辛普利（20 mg）。10 mg BMS - 186716和20 mg福辛普利的血浆血管紧张素II/血管紧张素I比值及血管紧张素II的0至24小时时间曲线下面积值[AUC(0 - 24)]相似。与10 mg BMS - 186716（16±5 pg/mL）和安慰剂（16±5 pg/mL）相比，20 mg福辛普利后血浆心钠素显著降低（9±3 pg/mL；与10 mg BMS - 186716和安慰剂相比，P <.05）。10 mg BMS - 186716使尿心钠素较基线显著增加2±1.3倍（与安慰剂和20 mg福辛普利相比，P <.05）。10 mg BMS - 186716（3898±333 pg·h·mL⁻¹）和20 mg福辛普利（4383±302 pg·h·mL⁻¹）的血浆活性肾素AUC(0 - 24)无显著差异。两种药物均降低血压，但仅20 mg福辛普利的平均血压变化AUC(0 - 24)与安慰剂（79±84 mmHg·h）相比有显著差异（181±6 mmHg·h；P <.05），而10 mg BMS - 186716（118±7 mmHg·h）无显著差异。

结论

在此模型中，口服单剂量10 mg BMS - 186716和20 mg福辛普利在体内诱导相似的24小时血管紧张素转换酶抑制作用。10 mg BMS - 186716增加尿心钠素，并减弱血管紧张素转换酶抑制导致的血浆心钠素预期降低。与20 mg福辛普利相比，10 mg BMS - 186716未抑制血浆活性肾素升高。口服单剂量10 mg BMS - 186716的降压作用比20 mg福辛普利短。