| Autor: |
Opgenorth, Terry J., Wessale, Jerry L., Dixon, Douglas B., Adler, Andrew L., Calzadilla, Samuel V., Padley, Robert J., WuWong, Jinshyun R. |
| Zdroj: |
Journal of Cardiovascular Pharmacology; January 2000, Vol. 36 Issue: 5, Number 5 Supplement 1 pS292S296-S292S296, 1p |
| Abstrakt: |
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 endothelin1 irET1 level, and different classes of antagonists seem to affect the plasma ET1 level differently. In this report, we study effects of ETAselective, ETBselective, and nonselective receptor antagonists on the plasma irET1 level in the rat, and also compare available clinical data. The plasma irET1 level was increased by five and tenfold after rats were treated with A192621, an ETBselective antagonist with Kivalues for ETAand ETBat 5600 and 8.8 nM, for 3 days at 30 and 100 mgkgday via food. The plasma irET1 level was increased by 1.8 and 2.4fold when rats were treated with A216546, an antagonist with Kivalues for ETAand ETBat 0.46 and 13 000 nM, at 10 and 50 mgkgday via food for 7 days. As a comparison, the plasma irET1 level was increased by > 24fold when rats were treated with A182086, a nonselective antagonist with Kivalues for ETAand ETBat 0.2 and 1.2 nM, at 100 mgkgday via food for 9 days. In humans, blockade of ETAby ABT627 did not result in an elevation in irET1 until after 7 days of treatment. The results are consistent with the hypothesis that the ETBreceptor is the clearance receptor for ET1. Our data also suggest that the modest effect of ETAantagonists on the plasma irET1 level is probably a result of the upregulation of the ET1 gene via a feedback mechanism. |
| Databáze: |
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