Pharmacology of two novel mixed ET_A/ET_B receptor antagonists, BQ-928 and 238, in the carotid and pulmonary arteries and the perfused kidney of the rabbit

Abstract

1. In the present study, we have pharmacologically characterized two novel mixed endothelin ET_A/ET_B receptor antagonists, namely BQ-928 and BQ-238, in ET_A and ET_B preparations, the rabbit carotid artery (RbCA) and the rabbit pulmonary artery (RbPA), respectively. These two antagonists were compared to established ET_A (BQ-123 and BMS 182874), ET_B (BQ-788) and mixed ET_A/ET_B (SB 209670) receptor antagonists.

2. In the RbCA, the ET_A 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 ET_B monoreceptor preparation, the RbPA (when IRL-1620 was used as an ET_B 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 ET_A than the ET_B receptor.

3. 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 ET_A 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.

4. 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, P<0.05).

5. Our results suggest that in a system where ET_A receptor activation is responsible for vasoconstriction and ET_B-receptor activation for vasodilatation, ET_A receptor selective antagonists or mixed ET_A/ET_B receptor antagonists which possess high affinity for ET_A receptors do not induce hyperresponsiveness to endothelin-1. In contrast, ET_B selective antagonists or mixed antagonists possessing a high affinity for ET_B receptors (such as BQ-928) interfere with the ET_B-receptor-dependent physiological antagonism of endothelin-1-induced pressor responses in these same tissues.

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