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

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 (pA(2)) of 7.42+/-10.22 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 pA(2) 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 SE 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 presser effects of endothelin within the kidney; the calculated IC50 values for BQ-123, BMS 182874, SE 209670, BQ-928 and BQ-238 were 0.4 mu M, 2 mu M, 0.01 mu M, 0.4 mu M and 0.09 mu M, 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, EMS 182874 and SE 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 presser responses in these same tissues.