title: 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.
abstract: 1. 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. 2. 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. 3. All of the antagonists were tested for their ability to block and reverse endothelin-l-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 microM, 2 microM, 0.01 microM, 0.4 microM and 0.09 microM, 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 ETA 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.
authors.affiliation: Department of Pharmacology, Medical School, Université de Sherbrooke, Québec, Canada.
authors.forename: M C
authors.initials: MC
authors.lastname: Maurice
authors.forename: J P
authors.initials: JP
authors.lastname: Gratton
authors.forename: P
authors.initials: P
authors.lastname: D'Orléans-Juste
mesh_terms: D000818:Animals; D002339:Carotid Arteries / Q000187:drug effects* / Q000502:physiology; D003619:Dansyl Compounds / Q000494:pharmacology; D065128:Endothelin Receptor Antagonists; D005260:Female; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects* / Q000502:physiology; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000494:pharmacology*; D010477:Perfusion; D010880:Piperidines / Q000494:pharmacology*; D011651:Pulmonary Artery / Q000187:drug effects* / Q000502:physiology; D011817:Rabbits; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B
chemical_list: C105143:BQ 238; D003619:Dansyl Compounds; D065128:Endothelin Receptor Antagonists; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; C085754:5-(dimethylamino)-N-(3,4-dimethyl-5-isoxazolyl)-1-naphthalenesulfonamide; C105142:BQ 928