title: Agonist-dependent inhibition by peptide and nonpeptide endothelin receptor antagonists in the rabbit isolated pulmonary artery.
abstract: This study examined the effect of peptide and nonpeptide endothelin (ET) receptor antagonists on the contractile actions of ET-1 and sarafotoxin S6c (STXc) in the rabbit isolated pulmonary artery (RbPA). The peptide antagonists BQ-123, BQ-788, and RES-701 (10 microM) did not inhibit ET-1-induced RbPA contractions. The nonpeptide antagonists PD 156123, Ro 47-0203, and SB 217242 (10 microM) also had no effect on ET-1--induced contractions. In contrast, the nonpeptide antagonists SB 209670 and L-749,239 (10 microM) both caused a shift to the right of the ET-1 concentration-response curve (Kbs of 231 nM and 1.42 microM, respectively) and a two- to three-fold increase in nH (Hill slope), without altering the Rmax (maximal agonist-induced contraction). Contractile responses to STXc were unaffected by BQ-123, RES-701, and PD 156123 (10 microM). SB 209670, SB 217242, L-749,239, Ro 47-0203, and BQ-788 (10 microM) caused a shift to the right of the STXc response curve (Kbs of 16, 353, 202, 1,303 and 1,499 nM, respectively) and an increase in nH and Rmax. SB 209670 and L-749,239 were both approximately 10-fold more potent in antagonizing STXc than ET-1. Assuming, at best, Kbs of 10 microM for SB 217242, Ro 47-0203, and BQ-788 against ET-1, these antagonists were also at least 10-fold more potent in blocking STXc. The effects of various incubation and washout times on the antagonistic properties of SB 209670 (1 microM) against STXc were studied. Washing the antagonist from the tissue bath caused a 100-fold decrease in affinity (Kbs of 23-2,373 nM at 0 and 30 min, respectively) and a return to near control levels of nH (within 30 min). In contrast, the augmented Rmax response did not return to control levels until 6 hr later. As the incubation time was increased, the augmented Rmax was sustained (6 h), but affinity decreased (Kbs of 21 and 793 nM after 5 min and 6 h of incubation), and nH returned to near control values. In conclusion, agonist-dependent inhibition by ETB receptor antagonists is observed in the RbPA. Heterogenous populations of ET receptors, differential binding domains, and/or functionally uncoupled receptors may account for this phenomenon.
authors.affiliation: Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania, 19406-0939, USA.
authors.forename: G R
authors.initials: GR
authors.lastname: Beck
authors.forename: S A
authors.initials: SA
authors.lastname: Douglas
authors.forename: J D
authors.initials: JD
authors.lastname: Elliott
authors.forename: E H
authors.initials: EH
authors.lastname: Ohlstein
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000494:pharmacology; D066298:In Vitro Techniques; D007189:Indans / Q000494:pharmacology; D008297:Male; D011651:Pulmonary Artery / Q000187:drug effects* / Q000502:physiology; D011817:Rabbits; D017466:Receptors, Endothelin / Q000819:agonists; D014661:Vasoconstriction / Q000187:drug effects; D014757:Viper Venoms / Q000494:pharmacology
chemical_list: D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D007189:Indans; D017466:Receptors, Endothelin; D014757:Viper Venoms; C057354:sarafotoxins s6; C087551:1H-Indene-2-carboxylic acid, 1-(1,3-benzodioxol-5-yl)-3-(2- (carboxymethoxy)-4-methoxyphenyl)-2,3-dihydro-5-propoxy-, (1S,2R,3S)-