Richards A M, Wittert G A, Espiner E A, Yandle T G, Ikram H, Frampton C
Department of Cardiology, Princess Margaret Hospital, Christchurch, New Zealand.
Circ Res. 1992 Dec;71(6):1501-7. doi: 10.1161/01.res.71.6.1501.
The effects of endopeptidase 24.11 inhibition on angiotensin-induced changes in plasma angiotensin II, aldosterone, and atrial natriuretic factor concentrations and blood pressure were assessed in normal volunteers. Two groups, each consisting of eight normal volunteers, received stepwise infusions of angiotensin II (2, 4, and 8 ng/kg per minute) on day 5 of dose administration with 25 mg every 12 hours (group 1) or 100 mg every 12 hours (group 2) of an oral inhibitor of endopeptidase 24.11 (UK 79300, candoxatril) or placebo in balanced randomized, double-blind, placebo-controlled crossover studies. Both doses of candoxatril significantly enhanced achieved plasma angiotensin II concentrations during infusions (group 1, p < 0.001; group 2, p < 0.01; overall treatment effect for combined data, p < 0.001). This effect was most pronounced at the highest dose of angiotensin II (treatment-time interaction, p < 0.0001 for combined data) and tended to be more marked with the higher dose of candoxatril (treatment-group interaction, p = 0.08). The pressor response to angiotensin II was clearly enhanced by the lower dose of candoxatril; peak systolic and diastolic pressures exceeded placebo values by approximately 10 mm Hg (p < 0.001 and p < 0.05 for systolic and diastolic pressures, respectively). This effect of candoxatril was absent in group 2, which (unlike group 1) had exhibited a modest natriuretic response (sustained cumulative negative sodium balance, -70 +/- 21 mmol; p < 0.01) to the higher dose of inhibitor. Baseline plasma aldosterone concentrations and the incremental aldosterone response to angiotensin II infusions were not significantly altered by low-dose (group 1) candoxatril.(ABSTRACT TRUNCATED AT 250 WORDS)
在正常志愿者中评估了内肽酶24.11抑制对血管紧张素诱导的血浆血管紧张素II、醛固酮和心房利钠因子浓度变化以及血压的影响。在剂量给药的第5天，两组，每组由8名正常志愿者组成，分别接受血管紧张素II（每分钟2、4和8 ng/kg）的逐步输注，同时每12小时口服25 mg（第1组）或100 mg（第2组）的内肽酶24.11口服抑制剂（UK 79300，坎多沙坦酯）或安慰剂，采用平衡随机、双盲、安慰剂对照交叉研究。两种剂量的坎多沙坦酯在输注期间均显著提高了血浆血管紧张素II浓度（第1组，p < 0.001；第2组，p < 0.01；合并数据的总体治疗效果，p < 0.001）。这种效应在血管紧张素II最高剂量时最为明显（合并数据的治疗时间交互作用，p < 0.0001），并且随着坎多沙坦酯剂量的增加而更显著（治疗组交互作用，p = 0.08）。较低剂量的坎多沙坦酯明显增强了对血管紧张素II的升压反应；收缩压和舒张压峰值分别比安慰剂值高出约10 mmHg（收缩压和舒张压分别为p < 0.001和p < 0.05）。第2组未出现坎多沙坦酯的这种效应，该组（与第1组不同）对较高剂量抑制剂表现出适度的利钠反应（持续累积负钠平衡，-70 +/- 21 mmol；p < 0.01）。低剂量（第1组）坎多沙坦酯未显著改变基线血浆醛固酮浓度以及对血管紧张素II输注的醛固酮增量反应。（摘要截短至250字）
