Opgenorth T J, Wessale J L, Dixon D B, Adler A L, Calzadilla S V, Padley R J, Wu-Wong J R
Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Ilinois 95054, USA.
J Cardiovasc Pharmacol. 2000 Nov;36(5 Suppl 1):S292-6. doi: 10.1097/00005344-200036051-00086.
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-1 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 Ki 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 Ki 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 Ki values for ETA and ETB at 0.2 and 1.2 nM, at 100 mg/kg/day via food for 9 days. In humans, blockade of ETA 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.
内皮素（ET）受体拮抗剂可能对治疗多种医学病症有益。对各种ET受体拮抗剂进行的人体试验表明，这些拮抗剂会提高血浆免疫反应性内皮素-1（irET-1）水平，而且不同类别的拮抗剂似乎对血浆ET-1水平的影响有所不同。在本报告中，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。在用A-192621（一种ETB选择性拮抗剂，其对ETA和ETB的Ki值分别为5600和8.8 nM）以30和100 mg/kg/天的剂量通过食物给药3天的大鼠中，血浆irET-1水平升高了5倍和10倍。在用A-216546（一种拮抗剂，其对ETA和ETB的Ki值分别为0.46和13000 nM）以10和50 mg/kg/天的剂量通过食物给药7天的大鼠中，血浆irET-1水平升高了1.8倍和2.4倍。作为比较，在用A-182086（一种非选择性拮抗剂，其对ETA和ETB的Ki值分别为0.2和1.2 nM）以100 mg/kg/天的剂量通过食物给药9天的大鼠中，血浆irET-1水平升高了超过24倍。在人类中，ABT-627对ETA的阻断直到治疗7天后才导致irET-1升高。这些结果与ETB受体是ET-1的清除受体这一假设一致。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使ET-1基因上调的结果。
