title: Pharmacological endothelin receptor interaction does not occur in veins from ET(B) receptor deficient rats.
abstract: Heterodimerization of G-protein coupled receptors can alter receptor pharmacology. ET A and ET B receptors heterodimerize when co-expressed in heterologous expression lines. We hypothesized that ET A and ET B receptors heterodimerize and pharmacologically interact in vena cava from wild-type (WT) but not ET B receptor deficient (sl/sl) rats. Pharmacological endothelin receptor interaction was assessed by comparing ET-1-induced contraction in rings of rat thoracic aorta and thoracic vena cava from male Sprague Dawley rats under control conditions, ET A receptor blockade (atrasentan, 10 nM), ET B receptor blockade (BQ-788, 100 nM) or ET B receptor desensitization (Sarafotoxin 6c, 100 nM) and ET A plus ET B receptor blockade or ET A receptor blockade plus ET B receptor desensitization. In addition, similar pharmacological ET receptor antagonism experiments were performed in rat thoracic aorta and vena cava from WT and sl/sl rats. ET A but not ET B receptor blockade or ET B receptor desensitization inhibited aortic and venous ET-1-induced contraction. In vena cava but not aorta, when ET B receptors were blocked (BQ-788, 100 nM) or desensitized (S6c, 100 nM), atrasentan caused a greater inhibition of ET-1-induced contraction. Vena cava from WT but not sl/sl rats exhibited similar pharmacological ET receptor interaction. Immunocytochemistry was performed on freshly dissociated aortic and venous vascular smooth muscle cells to determine localization of ET A and ET B receptors. ET A and ET B receptors qualitatively co-localized more strongly to the plasma membrane of aortic compared to venous vascular smooth muscle cells. Our data suggest that pharmacological ET A and ET B receptor interaction may be dependent on the presence of functional ET B receptors and independent of receptor location.
authors.affiliation: Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48823, USA. KMThakali@uams.edu
authors.forename: Keshari
authors.initials: K
authors.lastname: Thakali
authors.forename: James J
authors.initials: JJ
authors.lastname: Galligan
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Fink
authors.forename: Cheryl E
authors.initials: CE
authors.lastname: Gariepy
authors.forename: Stephanie W
authors.initials: SW
authors.lastname: Watts
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001013:Aorta, Thoracic / Q000166:cytology / Q000187:drug effects; D015153:Blotting, Western; D003627:Data Interpretation, Statistical; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D044023:Receptor, Endothelin B / Q000187:drug effects* / Q000235:genetics / Q000502:physiology*; D017466:Receptors, Endothelin / Q000187:drug effects*; D014680:Veins / Q000187:drug effects*; D014683:Vena Cava, Superior / Q000187:drug effects / Q000502:physiology
chemical_list: D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin