Effects of endothelin receptor antagonists on the plasma immunoreactive endothelin-1 level

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 (irE T-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 l evel 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-2165 46, an antagonist with k(i) values for ETA and ETB at 0.46 and 13 000 nM, a t 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-62 7 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 th e 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.