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 (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.
Opgenorth
T J
TJ
Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Ilinois 95054, USA.
Wessale
J L
JL
Dixon
D B
DB
Adler
A L
AL
Calzadilla
S V
SV
Padley
R J
RJ
Wu-Wong
J R
JR
D000818:Animals; D000077868:Atrasentan; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood* / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D008297:Male; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B
C120508:A 192621; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D011759:Pyrrolidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; C114054:A 216546; D000077868:Atrasentan