Rousso P, Buclin T, Nussberger J, Décosterd L A, La Roche S D, Brunner-Ferber F, Brunner H R, Biollaz J
Division de Pharmacologie clinique, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
J Hypertens. 1999 Mar;17(3):427-37. doi: 10.1097/00004872-199917030-00017.
To investigate the endocrine and renal effects of the dual inhibitor of angiotensin converting enzyme and neutral endopeptidase, MDL 100,240.
A randomized, placebo-controlled, crossover study was performed in 12 healthy volunteers.
MDL 100,240 was administered intravenously over 20 min at single doses of 6.25 and 25 mg in subjects with a sodium intake of 280 (n = 6) or 80 (n = 6) mmol/day. Measurements were taken of supine and standing blood pressure, plasma angiotensin converting enzyme activity, angiotensin II, atrial natriuretic peptide, urinary atrial natriuretic peptide and cyclic GMP excretion, effective renal plasma flow and the glomerular filtration rate as p-aminohippurate and inulin clearances, electrolytes and segmental tubular function by endogenous lithium clearance.
Supine systolic blood pressure was consistently decreased by MDL 100,240, particularly after the high dose and during the low-salt intake. Diastolic blood pressure and heart rate did not change. Plasma angiotensin converting enzyme activity decreased rapidly and dose-dependently. In both the high- and the low-salt treatment groups, plasma angiotensin II levels fell and renin activity rose accordingly, while plasma atrial natriuretic peptide levels remained unchanged. In contrast, urinary atrial natriuretic peptide excretion increased dose-dependently under both diets, as did urinary cyclic GMP excretion. Effective renal plasma flow and the glomerular filtration rate did not change. The urinary flow rate increased markedly during the first 2 h following administration of either dose of MDL 100,240 (P < 0.001) and, similarly, sodium excretion tended to increase from 0 to 4 h after the dose (P = 0.07). Potassium excretion remained stable. Proximal and distal fractional sodium reabsorption were not significantly altered by the treatment. Uric acid excretion was increased. The safety and clinical tolerance of MDL 100,240 were good.
The increased fall in blood pressure in normal volunteers together with the preservation of renal hemodynamics and the increased urinary volume, atrial natriuretic peptide and cyclic GMP excretion distinguish MDL 100,240 as a double-enzyme inhibitor from inhibitors of the angiotensin converting enzyme alone. The differences appear to be due, at least in part, to increased renal exposure to atrial natriuretic peptide following neutral endopeptidase blockade.
研究血管紧张素转换酶和中性内肽酶双重抑制剂MDL 100,240对内分泌和肾脏的影响。
对12名健康志愿者进行了一项随机、安慰剂对照、交叉研究。
在钠摄入量为280（n = 6）或80（n = 6）mmol/天的受试者中，以6.25和25 mg的单剂量在20分钟内静脉注射MDL 100,240。测量仰卧位和站立位血压、血浆血管紧张素转换酶活性、血管紧张素II、心房利钠肽、尿心房利钠肽和环磷酸鸟苷排泄量、有效肾血浆流量以及以对氨基马尿酸和菊粉清除率表示的肾小球滤过率、电解质和通过内源性锂清除率评估的节段性肾小管功能。
MDL 100,240持续降低仰卧位收缩压，尤其是高剂量和低盐摄入时。舒张压和心率未改变。血浆血管紧张素转换酶活性迅速且呈剂量依赖性降低。在高盐和低盐治疗组中，血浆血管紧张素II水平均下降，肾素活性相应升高，而血浆心房利钠肽水平保持不变。相比之下，两种饮食条件下尿心房利钠肽排泄量均呈剂量依赖性增加，尿环磷酸鸟苷排泄量也是如此。有效肾血浆流量和肾小球滤过率未改变。在给予任一剂量的MDL 100,240后的最初2小时内尿流率显著增加（P < 0.001），同样，给药后0至4小时钠排泄量有增加趋势（P = 0.07）。钾排泄保持稳定。治疗对近端和远端钠分数重吸收无显著改变。尿酸排泄增加。MDL 100,240的安全性和临床耐受性良好。
正常志愿者血压下降幅度增加，同时肾血流动力学得以保留，尿量、心房利钠肽和环磷酸鸟苷排泄量增加，这些特点使MDL 100,240作为一种双重酶抑制剂有别于单纯的血管紧张素转换酶抑制剂。这些差异似乎至少部分归因于中性内肽酶被阻断后肾脏对心房利钠肽的暴露增加。
