Pharmacology of two novel mixed ETA/ETB receptor antagonists, BQ‐928 and 238, in the carotid and pulmonary arteries and the perfused kidney of the rabbit

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Abstract
In the present study, we have pharmacologically characterized two novel mixed endothelin ETA/ETB receptor antagonists, namely BQ‐928 and BQ‐238, in ETA and ETB preparations, the rabbit carotid artery (RbCA) and the rabbit pulmonary artery (RbPA), respectively. These two antagonists were compared to established ETA (BQ‐123 and BMS 182874), ETB (BQ‐788) and mixed ETA/ETB (SB 209670) receptor antagonists. In the RbCA, the ETA monoreceptor preparation, BQ‐238 and BQ‐928 had apparent affinities (pA2) of 7.42±0.22 and 7.22±0.18, respectively, BQ‐788 being inactive in this preparation. In the ETB monoreceptor preparation, the RbPA (when IRL‐1620 was used as an ETB receptor agonist), the pA2 for BQ‐238 was 7.05±0.14 and for BQ‐928 was 8.43±0.04. BQ‐123 and BMS 182874 were inactive in this preparation. Similar to SB 209670, BQ‐238 but not BQ‐928 had a higher affinity for the ETA than the ETB receptor. All of the antagonists were tested for their ability to block and reverse endothelin‐1‐induced vasoconstrictions in the rabbit perfused kidney. In this preparation endothelin‐1‐induced increases in vascular resistance have been shown to be mediated solely by ETA receptors. All compounds (except BQ‐788) blocked the pressor effects of endothelin within the kidney; the calculated IC50 values for BQ‐123, BMS 182874, SB 209670, BQ‐928 and BQ‐238 were 0.4 μm, 2 μm, 0.01 μm, 0.4 μm and 0.09 μm, respectively. In all experiments in the rabbit perfused kidney, endothelin‐1 was readministered for a third time, 60 min following cessation of infusion of the above‐mentioned antagonists. The response to the third infusion of endothelin‐1 following cessation of infusion of BQ‐123, BMS 182874 and SB 209670 was not significantly different from that to the third infusion of endothelin in control conditions. However, the response to endothelin‐1 was significantly higher than control in tissues pre‐infused with BQ‐788 or BQ‐928 (56±9 and 41.6±15%, respectively, n=8 each, PA receptor activation is responsible for vasoconstriction and ETB‐receptor activation for vasodilatation, ETA receptor selective antagonists or mixed ETA/ETB receptor antagonists which possess high affinity for ETA receptors do not induce hyperresponsiveness to endothelin‐1. In contrast, ETB selective antagonists or mixed antagonists possessing a high affinity for ETB receptors (such as BQ‐928) interfere with the ETB‐receptor‐dependent physiological antagonism of endothelin‐1‐induced pressor responses in these same tissues. British Journal of Pharmacology (1997) 120, 319–325; doi:10.1038/sj.bjp.0700895

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