title: Comparative effects of the two endothelin ETA receptor antagonists, BQ-123 and FR139317, on endothelin-1-induced contraction in guinea-pig iliac artery.
abstract: The effects of two recently introduced endothelin ETA receptor antagonists, BQ-123 and FR139317, were investigated and compared in guinea-pig isolated iliac artery. Endothelins and sarafotoxins induced contraction of guinea-pig iliac artery with a pharmacological profile characteristic of the ETA receptor. The rank order of agonist potency was (mean EC50 values, nM): endothelin-1 (11.7) > or = endothelin-2 (14.9) > or = vasoactive intestinal contractor (19.5) > sarafotoxin S6b (49.8) > or = [Ala3,11]endothelin-1 (55.0) > sarafotoxin S6a (> 100) > endothelin-3 (> or = 1000). The C-terminal hexapeptide, endothelin-(16-21), sarafotoxin S6c and sarafotoxin S6d were neither agonists nor antagonists at concentrations up to 10, 3 and 1 microM, respectively. Both FR139317 (1-10 microM) and BQ-123 (0.1-1 microM) surmountably antagonized the effects of endothelin-1. Schild analysis suggested competitive antagonism for FR139317 (Schild slope 1.32 +/- 0.21, pA2 5.82 +/- 0.16, n = 5), but not for BQ-123 (Schild slope 0.28 +/- 0.08, n = 5), which was however more potent (apparent pKB 6.6-7.2) than FR139317. The potency of FR139317 was particularly low with respect to the reported affinity for ETA receptors, suggesting heterogeneity among ETA receptors. Thus, the endothelin receptor present in guinea-pig iliac artery has the following features: (1) rank order of agonist potencies of the ETA type; (2) low potency of FR139317 and (3) non-competitive antagonism by BQ-123.
authors.affiliation: Preclinical Research 386/527, Sandoz Pharma Ltd., Basel, Switzerland.
authors.forename: P
authors.initials: P
authors.lastname: Schoeffter
authors.forename: A
authors.initials: A
authors.lastname: Randriantsoa
authors.forename: B
authors.initials: B
authors.lastname: Jost
authors.forename: K
authors.initials: K
authors.lastname: Bruttel
mesh_terms: D000818:Animals; D001012:Aorta, Abdominal / Q000187:drug effects; D001381:Azepines / Q000494:pharmacology*; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000037:antagonists & inhibitors*; D005263:Femoral Artery / Q000187:drug effects; D006168:Guinea Pigs; D007083:Iliac Artery / Q000187:drug effects; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D010456:Peptides, Cyclic / Q000494:pharmacology*; D044022:Receptor, Endothelin A; D014661:Vasoconstriction / Q000187:drug effects*
chemical_list: D001381:Azepines; D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D007211:Indoles; D010456:Peptides, Cyclic; D044022:Receptor, Endothelin A; C079574:FR 139317; C072247:cyclo(Trp-Asp-Pro-Val-Leu)