title: Atypical antagonism observed with BQ-123 in human saphenous vein.
abstract: At present, endothelin (ET) receptor classification remains controversial. We investigated the presence of atypical ETA receptors in human saphenous veins (SV). Human SV was obtained from 24 patients undergoing coronary artery bypass grafting. Vessels were set up in organ baths, stretched to a tension of 6 g, and left to relax before being challenged with 90 mM KCl. After KCl challenge, tissues were incubated with 2.8 microM indomethacin and 100 microM L-NMMA for 30 min followed by 30 min in the presence of antagonist before a concentration-response curve to ET-1 or sarafotoxin 6b (S6b) (10(-10)-10(-7) M) was constructed. In endothelium-intact vessels, incubated with indomethacin and L-NMMA, BQ-123 (1 microM) caused nonparallel shifts, with lower concentrations of ET-1 being antagonized more than higher concentrations. This antagonism with BQ-123 was unaffected by BQ-788 (0.1 microM; n = 6) or by desensitization of ETB receptors with S6c (0.1 microM; n = 8). Blocking the Ca2+ channels with nifedipine (1 microM; n = 5) did not affect the antagonism, nor did denuding the endothelium or leaving the endothelium intact (n = 5). When S6b was used as an agonist, BQ-123 (0.3-3 microM) caused concentration-dependent biphasic shifts, with low concentrations of S6b not being antagonized. In conclusion, the antagonism observed with BQ-123 is not due to the action of ET-1 at ETB receptors, changes in Ca2+ handling, or endothelium. This unusual action of BQ-123 suggests subtypes of the ETA receptor.
authors.affiliation: Department of Cardiothoracic Surgery, Harefield Hospital, Middlesex, England.
authors.forename: M A
authors.initials: MA
authors.lastname: Pate
authors.forename: A H
authors.initials: AH
authors.lastname: Chester
authors.forename: T J
authors.initials: TJ
authors.lastname: Brown
authors.forename: A G
authors.initials: AG
authors.lastname: Roach
authors.forename: M H
authors.initials: MH
authors.lastname: Yacoub
mesh_terms: D000328:Adult; D000368:Aged; D065128:Endothelin Receptor Antagonists; D006801:Humans; D066298:In Vitro Techniques; D008875:Middle Aged; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009842:Oligopeptides / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D012501:Saphenous Vein / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014757:Viper Venoms / Q000494:pharmacology
chemical_list: D065128:Endothelin Receptor Antagonists; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D014662:Vasoconstrictor Agents; D014757:Viper Venoms; C057354:sarafotoxins s6; C086539:BQ 788; C072247:cyclo(Trp-Asp-Pro-Val-Leu)