title: Antihypertensive, insulin-sensitising and renoprotective effects of a novel, potent and long-acting angiotensin II type 1 receptor blocker, azilsartan medoxomil, in rat and dog models.
abstract: The pharmacological profile of a novel angiotensin II type 1 receptor blocker, azilsartan medoxomil, was compared with that of the potent angiotensin II receptor blocker olmesartan medoxomil. Azilsartan, the active metabolite of azilsartan medoxomil, inhibited the binding of [(125)I]-Sar(1)-I1e(8)-angiotensin II to angiotensin II type 1 receptors. Azilsartan medoxomil inhibited angiotensin II-induced pressor responses in rats, and its inhibitory effects lasted 24h after oral administration. The inhibitory effects of olmesartan medoxomil disappeared within 24h. ID(50) values were 0.12 and 0.55 mg/kg for azilsartan medoxomil and olmesartan medoxomil, respectively. In conscious spontaneously hypertensive rats (SHRs), oral administration of 0.1-1mg/kg azilsartan medoxomil significantly reduced blood pressure at all doses even 24h after dosing. Oral administration of 0.1-3mg/kg olmesartan medoxomil also reduced blood pressure; however, only the two highest doses significantly reduced blood pressure 24h after dosing. ED(25) values were 0.41 and 1.3mg/kg for azilsartan medoxomil and olmesartan medoxomil, respectively. In renal hypertensive dogs, oral administration of 0.1-1mg/kg azilsartan medoxomil reduced blood pressure more potently and persistently than that of 0.3-3mg/kg olmesartan medoxomil. In a 2-week study in SHRs, azilsartan medoxomil showed more stable antihypertensive effects than olmesartan medoxomil and improved the glucose infusion rate, an indicator of insulin sensitivity, more potently (≥ 10 times) than olmesartan medoxomil. Azilsartan medoxomil also exerted more potent antiproteinuric effects than olmesartan medoxomil in Wistar fatty rats. These results suggest that azilsartan medoxomil is a potent angiotensin II receptor blocker that has an attractive pharmacological profile as an antihypertensive agent.
authors.affiliation: Metabolic Disease Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd., Osaka, Japan. kusumoto_keiji@takeda.co.jp
authors.forename: Keiji
authors.initials: K
authors.lastname: Kusumoto
authors.forename: Hideki
authors.initials: H
authors.lastname: Igata
authors.forename: Mami
authors.initials: M
authors.lastname: Ojima
authors.forename: Ayako
authors.initials: A
authors.lastname: Tsuboi
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Imanishi
authors.forename: Fuminari
authors.initials: F
authors.lastname: Yamaguchi
authors.forename: Hiroki
authors.initials: H
authors.lastname: Sakamoto
authors.forename: Takanobu
authors.initials: T
authors.lastname: Kuroita
authors.forename: Naohiro
authors.initials: N
authors.lastname: Kawaguchi
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Nishigaki
authors.forename: Hideaki
authors.initials: H
authors.lastname: Nagaya
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D001786:Blood Glucose / Q000032:analysis; D001794:Blood Pressure / Q000187:drug effects; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004285:Dogs; D006973:Hypertension / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D006977:Hypertension, Renal / Q000188:drug therapy* / Q000503:physiopathology; D007093:Imidazoles / Q000494:pharmacology*; D007328:Insulin / Q000097:blood / Q000502:physiology; D008297:Male; D000068557:Olmesartan Medoxomil; D010069:Oxadiazoles / Q000494:pharmacology*; D020011:Protective Agents / Q000494:pharmacology*; D011507:Proteinuria / Q000188:drug therapy* / Q000652:urine; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D013777:Tetrazoles / Q000494:pharmacology*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001786:Blood Glucose; D007093:Imidazoles; D007328:Insulin; D010069:Oxadiazoles; D020011:Protective Agents; D013777:Tetrazoles; D000804:Angiotensin II; D000068557:Olmesartan Medoxomil; C557413:azilsartan medoxomil