Richards A M, Wittert G, Espiner E A, Yandle T G, Frampton C, Ikram H
Department of Endocrinology, Princess Margaret Hospital, Christchurch, New Zealand.
J Clin Endocrinol Metab. 1991 Jun;72(6):1317-22. doi: 10.1210/jcem-72-6-1317.
Metabolic clearance and the biological effects of exogenous human atrial natriuretic factor (ANF) were assessed in two groups each of eight normal volunteers receiving 2-h iv infusions of ANF (2.5 pmol/kg.min) on the fifth day of dosing with the orally active inhibitor of endopeptidase 24.11, candoxatril (25 mg every 12 h in group 1 and 100 mg every 12 h in group 2), and placebo in balanced randomized, double blind, placebo-controlled, cross-over experiments. Although 4 days of pretreatment with the endopeptidase inhibitor did not affect basal plasma ANF, candoxatril enhanced mean ANF-induced increases in plasma ANF by 27 pmol/L (P = NS) and 42 pmol/L (P less than 0.002) in groups 1 and 2, respectively. Calculated MCRs for ANF were significantly reduced by both doses of candoxatril [group 1, 2.5 +/- 0.4 vs. 4.3 +/- 0.6 L/min (P less than 0.01); group 2, 2.3 +/- 0.4 vs. 5.6 +/- 0.8 L/min (P less than 0.001)]. ANF significantly enhanced urinary sodium excretion above preinfusion values in both study phases in both groups. Candoxatril significantly further augmented natriuresis in group 2 (P less than 0.01), but not group 1. Inulin clearance was minimally enhanced, and para-aminohippuran clearance was slightly decreased by candoxatril in both groups. Neither effect alone was statistically significant, but derived renal filtration fractions were significantly enhanced in both groups [group 1, 15.5 +/- 0.5% vs. 13.9 +/- 0.6% (P less than 0.01); group 2, 19.3 +/- 1.9% vs. 18.0 +/- 2.7% (P less than 0.01)]. Basal and stimulated cGMP concentrations in both plasma and urine were significantly enhanced by candoxatril in the two groups (P less than 0.001 and P less than 0.01, respectively, for combined data). Urinary ANF immunoreactivity was significantly enhanced by candoxatril in both groups (P less than 0.05 and P less than 0.01 in groups 1 and 2, respectively), with a more pronounced effect evident at the higher dose (P less than 0.01). These results show that chronic pretreatment with an endopeptidase inhibitor in normal man causes a dose-related reduction in the metabolic clearance of exogenous ANF, amplifies cGMP, and increases renal filtration and the natriuretic responses to infused ANF.
在一项平衡随机、双盲、安慰剂对照、交叉试验中，两组各8名正常志愿者接受口服活性内肽酶24.11抑制剂坎多沙坦（第1组每12小时25mg，第2组每12小时100mg）和安慰剂治疗，在给药第5天静脉输注心房钠尿肽（ANF，2.5pmol/kg·min）2小时，评估外源性人ANF的代谢清除率及其生物学效应。虽然内肽酶抑制剂预处理4天对基础血浆ANF无影响，但坎多沙坦在第1组和第2组分别使平均ANF诱导的血浆ANF升高增强了27pmol/L（P=无显著性差异）和42pmol/L（P<0.002）。两种剂量的坎多沙坦均显著降低了ANF的计算代谢清除率[第1组，2.5±0.4对4.3±0.6L/min（P<0.01）；第2组，2.3±0.4对5.6±0.8L/min（P<0.001）]。在两个研究阶段，两组中ANF均使尿钠排泄显著高于输注前水平。坎多沙坦在第2组显著进一步增强了利钠作用（P<0.01），但在第1组未增强。两组中坎多沙坦使菊粉清除率略有增强，对氨基马尿酸清除率略有降低。单独的两种效应均无统计学显著性，但两组中推导的肾滤过分数均显著增强[第1组，15.5±0.5%对13.9±0.6%（P<0.01）；第2组，19.3±1.9%对18.0±2.7%（P<0.01）]。两组中坎多沙坦均显著增强了血浆和尿液中基础和刺激后的环磷酸鸟苷（cGMP）浓度（合并数据分别为P<0.001和P<0.01）。两组中坎多沙坦均显著增强了尿ANF免疫反应性（第1组和第2组分别为P<0.05和P<0.01），高剂量时效应更明显（P<0.01）。这些结果表明，在正常人体内，用内肽酶抑制剂进行慢性预处理会导致外源性ANF的代谢清除率呈剂量相关降低，增强cGMP，并增加肾滤过以及对输注ANF的利钠反应。
