Delineation of endothelin receptor subtypes in rat and rabbit aortas.
The receptor subtypes mediating tension responses to endothelin-1 (ET-1) in isolated rat and rabbit aortic preparations were examined with various ET receptor antagonists. In the presence of 3 microM IRL 2500 (an ETB-selective antagonist), SB 209670 (an ETA/ETB antagonist) induced monophasic inhibitions of the ET-1 dose-response curves of both rat (pKB 9.1) and rabbit aortas (pKB 8.9). In the presence of IRL 2500, PD 156707 (an ETA antagonist) also caused a similar monophasic inhibition of the agonist-induced dose-response curve of the rat aorta (pKB 7.7) but produced a biphasic inhibition of the curve obtained with the rabbit aorta. PD 156707, however, produced monophasic inhibitions of the ET-1-induced dose-response curve of rabbit aortas pretreated either with BQ 788 (an ETB-selective antagonist) or desensitized with sarafotoxin S6c (an ETB-selective agonist). The receptor subtypes mediating the contractile responses to ET-1 were further characterized by examining the effects of the antagonists on the binding of [125I]ET-1 to these two tissues. In the presence of 1 nM IRL 2500, SB 209670 displaced [125I]ET-1 binding in both rat and rabbit aortic membrane preparations in a monophasic manner, with similar potencies (IC50 1.2-1.6 nM). Similar results were also ontained with PD 156707 in rat aortic membrane (IC50 0.27 nM). In contrast, the data obtained with PD 156707 using rabbit aortic membrane were best-fitted with a two-site model (site 1, IC50 0.21 nM, 67% of Bmax; site 2, 100 nM and 33%, respectively). Therefore, the constrictor response to ET-1 in the rat aorta is mediated exclusively by the ETA receptor, whereas that in the rabbit aorta is additionally mediated by an ETB receptor subtype that is sensitive to SB 209670 and BQ 788 but insensitive to IRL 2500.
Shetty
S S
SS
Research Department, Ciba-Geigy Corporation, Summit, New Jersey, USA.
DelGrande
D
D
Savage
P
P
Ksander
G M
GM
Jeng
A Y
AY
D000818:Animals; D001013:Aorta, Thoracic / Q000737:chemistry*; D004149:Dioxoles / Q000494:pharmacology; D016232:Endothelins / Q000378:metabolism; D066298:In Vitro Techniques; D007189:Indans / Q000494:pharmacology; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D017466:Receptors, Endothelin / Q000032:analysis* / Q000145:classification
D004149:Dioxoles; D016232:Endothelins; D007189:Indans; D009842:Oligopeptides; C093321:PD 156707; D010880:Piperidines; D017466:Receptors, Endothelin; 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)-; C086539:BQ 788