title: Heterogeneity of endothelin-B receptors in rabbit pulmonary resistance arteries.
abstract: We have previously shown that endothelin-B (ETB) receptors mediate contraction in human and rat pulmonary resistance arteries (PRAs). Here we characterize the endothelin (ET) receptors in rabbits PRAs. PRAs (approximately 150 microns i.d.) were studied using wire myography. Vasoconstrictor effects to ET-1, ET-3, and the ETB-selective agonist sarafotoxin S6c (S6c) were studied in the presence and absence of the ETA receptor antagonist FR139317, the ETB-selective antagonist BQ788, and the mixed ETA/ETB antagonist SB209670. The effect of SB209670 was also studied in human PRAs (approximately 250 microns i.d.). Competitive ET-1 binding studies were also carried out on rabbit small pulmonary artery homogenates. The potencies of the agonists were in the following order: S6c > ET-3 = ET-1. Concentration-response curves (CRCs) to ET-1 were biphasic, with a gradual slope up to approximately 1 nM and a steeper component at higher concentrations of ET-1. Neither FR139317 (1 microM) nor BQ788 (1 microM) inhibited responses to ET-1. BQ788 inhibited S6c- and ET-3 induced contractions with pKb values of 6.8 +/- 0.1 and 6.3 +/- 0.2, respectively. SB209670 inhibited responses to ET-1 in the higher concentration component of the CRC and inhibited responses to S6c in a competitive fashion. pKb values for ET-1 and S6c were 6.8 +/- 0.2 and 7.5 +/- 1, respectively. SB209670 (0.1-1 microM) totally abolished responses to ET-1 in human PRAs. The binding assay established two ET binding sites in rabbit PRAs, one low affinity (Ki = 480 pM) and one high affinity (Ki = 64 fM). The study provides evidence for a heterogeneous population of ETB-like receptors in pulmonary resistance arteries, including an atypical ETB receptor sensitive to SB209670.
authors.affiliation: Division of Neuroscience and Biomedical Systems, Institute of Biomedical and Life Sciences, University of Glasgow, Scotland.
authors.forename: M R
authors.initials: MR
authors.lastname: MacLean
authors.forename: J F
authors.initials: JF
authors.lastname: Mackenzie
authors.forename: C C
authors.initials: CC
authors.lastname: Docherty
mesh_terms: D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D011652:Pulmonary Circulation / Q000187:drug effects / Q000502:physiology*; D011817:Rabbits; D051381:Rats; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000819:agonists / Q000502:physiology*; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology
chemical_list: D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D008024:Ligands; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin