title: A new endothelin receptor antagonist, TAK-044, shows long-lasting inhibition of both ETA- and ETB-mediated blood pressure responses in rats.
abstract: The present study describes the pharmacological profile of an endothelin (ET) receptor antagonist, TAK-044, in anesthetized rats. TAK-044 given 10 min before administration of ET-1 (0.3 nmol/kg i.v.) partially inhibited the ET-1-induced pressor response at 0.1 and 1 mg/kg i.v. and almost completely inhibited the response at a dose of 10 mg/kg. The transient depressor response induced by ET-1 was also inhibited by 1 and 10 mg/kg TAK-044. BQ-123 partially inhibited the pressor response at 0.1-10 mg/kg i.v., whereas it did not inhibit the depressor response except at a dose of 10 mg/kg. These inhibitory effects of TAK-044 were longer lasting than those of BQ-123: 3 hr for TAK-044 and 1 hr for BQ-123 at 10 mg/kg. A selective ETB agonist, sarafotoxin S6c (0.3 nmol/kg i.v.), induced both depressor and pressor responses similar to ET-1. The initial depressor response was inhibited by TAK-044 in a dose-dependent manner (0.1-10 mg/kg i.v.) and by BQ-123 at the highest dose, whereas the sustained pressor response was inhibited only by TAK-044 at a dose of 10 mg/kg. Similar differences between TAK-044 and BQ-123 were observed for sarafotoxin S6c-induced renal vasoconstriction: TAK-044 but not BQ-123 inhibited the response at a dose of 3 mg/kg i.v. We conclude that TAK-044 inhibited both ETA- and ETB-mediated blood pressure responses and that these effects were longer lasting than those of BQ-123. In addition, the ETB-mediated vasoconstriction and pressor responses were inhibited by TAK-044 and not by BQ-123.
authors.affiliation: Pharmaceutical Research Laboratories, Takeda Chemical Industries, Ltd., Osaka, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Ikeda
authors.forename: Y
authors.initials: Y
authors.lastname: Awane
authors.forename: K
authors.initials: K
authors.lastname: Kusumoto
authors.forename: M
authors.initials: M
authors.lastname: Wakimasu
authors.forename: T
authors.initials: T
authors.lastname: Watanabe
authors.forename: M
authors.initials: M
authors.lastname: Fujino
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000502:physiology*; D007668:Kidney / Q000098:blood supply; D008297:Male; D010456:Peptides, Cyclic / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014664:Vasodilation / Q000187:drug effects
chemical_list: D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D010456:Peptides, Cyclic; C088196:TAK 044; C072247:cyclo(Trp-Asp-Pro-Val-Leu)