Effects of Endothelin Receptor Antagonists on the Plasma Immunoreactive Endothelin-1 Level
| Autor: | Jinshyun R. Wu-Wong, Terry J. Opgenorth, Douglas B. Dixon, Robert J. Padley, Samuel V. Calzadilla, Jerry L. Wessale, Andrew L. Adler |
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| Rok vydání: | 2000 |
| Předmět: |
Endothelin Receptor Antagonists
Male medicine.medical_specialty Pyrrolidines Enzyme-Linked Immunosorbent Assay Peptide hormone Rats Sprague-Dawley Downregulation and upregulation Internal medicine Blood plasma medicine Animals Receptor Pharmacology Endothelin-1 Chemistry Atrasentan Antagonist respiratory system Receptor Endothelin A Receptor Endothelin B Endothelin 1 Rats Endocrinology cardiovascular system Endothelin receptor Cardiology and Cardiovascular Medicine circulatory and respiratory physiology medicine.drug |
| Zdroj: | Journal of Cardiovascular Pharmacology. 36:S292-S296 |
| ISSN: | 0160-2446 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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