title: Endothelin-1 receptors in rat tissues: characterization by bosentan, ambrisentan and CI-1020.
abstract: The present study aimed to characterize comparatively endothelin-1 (ET-1) receptors in rat tissues by radioligand binding assay using [(125)I]ET-1 and to examine receptor binding after oral administration of bosentan. Significant amount of specific [(125)I]ET-1 binding was detected in the lung, heart, kidney, bladder and cerebral cortex of rats. ET-1, bosentan, ambrisentan, and CI-1020 inhibited specific [(125)I]ET-1 binding in these tissues in a concentration-dependent manner. The Hill coefficients of each agent in the rat lung and cerebral cortex and those of bosentan and ET-1 in the heart, kidney and bladder were close to unity, while the Hill coefficients of ambrisentan and CI-1020 in the heart, kidney and bladder were less than one. The nonlinear least squares regression analysis revealed the presence of high- and low-affinity ET-1 receptor sites in these tissues for ambrisentan and CI-1020. Oral administration of bosentan caused a dose-dependent decrease in specific [(125)I]ET-1 binding in the rat lung, kidney and bladder, suggesting significant binding of the tissue ET-1 receptors in vivo. In conclusion, it has been shown that a significant amount of pharmacologically relevant ET-1 receptors may exist in rat tissues and that ET-1 receptor antagonists such as bosentan at pharmacological doses may exert some pharmacological effects by binding these ET-1 receptors.
authors.affiliation: Department of Pharmacokinetics and Pharmacodynamics, School of Pharmaceutical Sciences, University of Shizuoka.
authors.forename: Yoshinari
authors.initials: Y
authors.lastname: Yokoyama
authors.forename: Ayaka
authors.initials: A
authors.lastname: Osano
authors.forename: Hideki
authors.initials: H
authors.lastname: Hayashi
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Itoh
authors.forename: Takashi
authors.initials: T
authors.lastname: Okura
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Deguchi
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Ito
authors.forename: Shizuo
authors.initials: S
authors.lastname: Yamada
mesh_terms: D000818:Animals; D000077300:Bosentan; D002540:Cerebral Cortex / Q000378:metabolism; D004149:Dioxoles / Q000494:pharmacology*; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000378:metabolism; D010666:Phenylpropionates / Q000494:pharmacology*; D011724:Pyridazines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology*; D001743:Urinary Bladder / Q000378:metabolism
chemical_list: D004149:Dioxoles; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; C093321:PD 156707; D010666:Phenylpropionates; D011724:Pyridazines; D044022:Receptor, Endothelin A; D013449:Sulfonamides; C467894:ambrisentan; D000077300:Bosentan