PHARMACOLOGY OF 2 NOVEL MIXED ET(A) ET(B) RECEPTOR ANTAGONISTS, BQ-928 AND BQ-238, IN THE CAROTID AND PULMONARY-ARTERIES AND THE PERFUSED KIDNEY OF THE RABBIT/

1 In the present study, we have pharmacologically characterized two no vel mixed endothelin ET(A)ET(B) receptor antagonists, namely BQ-928 an d 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 antagonist s. 2 In the RbCA, the ET(A) monoreceptor preparation, BQ-238 and BQ-92 8 had apparent affinities (pA(2)) of 7.42+/-10.22 and 7.22+/-0.18, res pectively, BQ-788 being inactive in this preparation. In the ET(B) mon oreceptor preparation, the RbPA (when IRL-1620 was used as an ET(B) re ceptor agonist), the pA(2) for BQ-238 was 7.05+/-0.14 and for BQ-928 w as 8.43+/-0.04. BQ-123 and BMS 182874 were inactive in this preparatio n. Similar to SE 209670, BQ-238 but not BQ-928 had a higher affinity f or the ET(A) than the ET(B) receptor. 3 All of the antagonists were te sted for their ability to block and reverse endothelin-1-induced vasoc onstrictions in the rabbit perfused kidney. In this preparation endoth elin-1-induced increases in vascular resistance have been shown to be mediated solely by ET(A) receptors. All compounds (except BQ-788) bloc ked the presser effects of endothelin within the kidney; the calculate d IC50 values for BQ-123, BMS 182874, SE 209670, BQ-928 and BQ-238 wer e 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 re administered 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-inf used with BQ-788 or BQ-928 (56+/-9 and 41.6+/-15%, respectively, n=8 e ach, P<0.05). 5 Our results suggest that in a system where ET(A) recep tor 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 fo r ET(A) receptors do not induce hyperresponsiveness to endothelin-1. I n contrast, ET(B) selective antagonists or mixed antagonists possessin g 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.