title: Nonpeptide endothelin receptor antagonists: IV. Identification of receptors in rabbit colonic mucosa and smooth muscle and correlation with physiological effects.
abstract: Endothelin (ET) has been previously demonstrated to be a potent intestinal secretory stimuli and to elicit intestinal smooth muscle contractions. In rat distal colon, the ETA receptor antagonist cyclo[D-Asp-L-Pro-D-Val-L-Leu-D-Trp] abolishes the changes in ion transport (as measured by short-circuit current) elicited by ET-1. In this study, effects of ET-1, sarafotoxin 6c and "big" ET in the absence and presence of the endothelin receptor antagonists cyclo [D-Asp-L-Pro-D-Val-L-Leu-D-Trp] and (+/-)-3-[2-(carboxymethoxy)-4-methoxyphenyl]-1-[3,4- (methylenedioxy)phenyl]-5-(prop-1-yloxy)indan-2-carboxylic acid on ion transport in rabbit distal colon were assessed through measurement of short-circuit current changes in segments of muscle-stripped mucosa in Ussing chambers. In addition, changes in smooth muscle contraction in response to acetylcholine, ET-1, ET-3 and sarafotoxin 6c in the absence and presence of (+/-)-3-[2-(carboxymethoxy)-4-methoxyphenyl]-1-[3,4- (methylenedioxy)phenyl]-5-(prop-1-yloxy)indan-2-carboxylic acid and of cyclo [D-Asp-L-Pro-D-Val-L-Leu-D-Trp] were measured in mucosa-free preparations oriented along their longitudinal axes. Receptor binding studies with mucosal or smooth muscle homogenates were conducted with [125I]ET-1, with [125I]ET-3 and with [125I]Tyr13Suc-[Glu9,Ala11,15]-endothelin-1(8-21 ) to identify the subtypes of ET receptors present in these preparations. From studies with rabbit colonic mucosa, both binding studies and measurement of short-circuit current confirm that the ETB receptor subtype is the predominant subtype and is responsible for the changes observed in ion transport.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Drug Delivery, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania.
authors.forename: P L
authors.initials: PL
authors.lastname: Smith
authors.forename: C P
authors.initials: CP
authors.lastname: Lee
authors.forename: M
authors.initials: M
authors.lastname: Pullen
authors.forename: E H
authors.initials: EH
authors.lastname: Ohlstein
authors.forename: G
authors.initials: G
authors.lastname: Beck
authors.forename: E P
authors.initials: EP
authors.lastname: Eddy
authors.forename: P
authors.initials: P
authors.lastname: Nambi
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D003106:Colon / Q000187:drug effects / Q000502:physiology*; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000378:metabolism / Q000494:pharmacology*; D005769:Gastrointestinal Motility / Q000187:drug effects; D007413:Intestinal Mucosa / Q000187:drug effects / Q000502:physiology; D017136:Ion Transport / Q000187:drug effects; D008566:Membranes / Q000378:metabolism; D008969:Molecular Sequence Data; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D011817:Rabbits; D011869:Radioligand Assay; D014757:Viper Venoms / Q000494:pharmacology*
chemical_list: D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D014757:Viper Venoms; C057354:sarafotoxins s6