Massien C, Azizi M, Guyene T T, Vesterqvist O, Mangold B, Ménard J
Broussais Hospital Clinical Investigation Center 9201, INSERM, Paris, France.
Clin Pharmacol Ther. 1999 Apr;65(4):448-59. doi: 10.1016/S0009-9236(99)70140-2.
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.
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).
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.
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。
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。
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。
