Effects of endothelin receptor antagonists on the plasma immunoreactive endothelin-1 level
Effects of endothelin receptor antagonists on the plasma immunoreactive endothelin-1 level
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DOI：
10.1097/00005344-200036051-00086
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发表时间：
2000-01-01
影响因子：
3
通讯作者：
Wu-Wong, JR
中科院分区：
文献类型：
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作者：
Opgenorth, TJ;Wessale, JL;Wu-Wong, JR
内皮素（ET）受体拮抗剂可有益于治疗几种医学病症。各种ET受体拮抗剂的人体试验表明，这些拮抗剂提高血浆免疫反应性内皮素-1（irET-1）水平，不同类别的拮抗剂似乎影响血浆ET-1水平不同。在这份报告中，我们研究了ETA选择性，ETB选择性和非选择性受体拮抗剂对大鼠血浆irET-1水平的影响，并比较了现有的临床数据。大鼠经食物给予A-192621（一种ETB选择性拮抗剂，ETA和ETB的Ki值分别为5600和8.8 nM）30和100 mg/kg/天3天后，血浆irET-1水平升高5倍和10倍。当大鼠经食物给予A-216546（一种ETA和ETB的k（i）值为0.46和13 000 nM的拮抗剂）10和50 mg/kg/天7天时，血浆irET-1水平分别升高1.8和2.4倍。作为比较，当大鼠以100 mg/kg/天的剂量通过食物给予A-182086（一种非选择性拮抗剂，ETA和ETB的Ki值为0.2和1.2 Mn）9天时，血浆irET-1水平增加> 24倍。在人体中，ABT-627对ET的阻断在治疗7天后才导致irET-1升高。结果与ETB受体是ET-1清除受体的假设一致。我们的数据还表明，ETA拮抗剂对血浆irET-1水平的适度影响可能是通过反馈机制上调ET-1基因的结果。
Endothelin (ET) receptor antagonists may be beneficial for treating several medical conditions. Human trials with various ET receptor antagonists show that these antagonists elevate the plasma immunoreactive endothelin-1 (irET-1) level, and different classes of antagonists seem to affect the plasma ET-I level differently. In this report, we study effects of ETA-selective, ETB-selective, and nonselective receptor antagonists on the plasma irET-1 level in the rat, and also compare available clinical data. The plasma irET-1 level was increased by five- and ten-fold after rats were treated with A-192621, an ETB-selective antagonist with K-i values for ETA and ETB at 5600 and 8.8 nM, for 3 days at 30 and 100 mg/kg/day via food. The plasma irET-1 level was increased by 1.8 and 2.4-fold when rats were treated with A-216546, an antagonist with k(i) values for ETA and ETB at 0.46 and 13 000 nM, at 10 and 50 mg/kg/day via food for 7 days. As a comparison, the plasma irET-1 level was increased by > 24-fold when rats were treated with A-182086, a nonselective antagonist with K-i values for ETA and ETB at 0.2 and 1.2 Mn, at 100 mg/kg/day via food for 9 days. In humans, blockade of ET, by ABT-627 did not result in an elevation in irET-1 until after 7 days of treatment. The results are consistent with the hypothesis that the ETB-receptor is the clearance receptor for ET-1. Our data also suggest that the modest effect of ETA antagonists on the plasma irET-1 level is probably a result of the upregulation of the ET-1 gene via a feedback mechanism.