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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

2011; Elsevier BV; Volume: 669; Issue: 1-3 Linguagem: Inglês

10.1016/j.ejphar.2011.07.014

1879-0712

Keiji Kusumoto, Hideki Igata, Mami Ojima, Ayako Tsuboi, Mitsuaki Imanishi, Fuminari Yamaguchi, Hiroki Sakamoto, Takanobu Kuroita, Naohiro Kawaguchi, Nobuhiro Nishigaki, Hideaki Nagaya,

Receptor Mechanisms and Signaling

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 [125I]–Sar1–I1e8-angiotensin II to angiotensin II type 1 receptors. Azilsartan medoxomil inhibited angiotensin II-induced pressor responses in rats, and its inhibitory effects lasted 24 h after oral administration. The inhibitory effects of olmesartan medoxomil disappeared within 24 h. ID50 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 0.1–1 mg/kg azilsartan medoxomil significantly reduced blood pressure at all doses even 24 h after dosing. Oral administration of 0.1–3 mg/kg olmesartan medoxomil also reduced blood pressure; however, only the two highest doses significantly reduced blood pressure 24 h after dosing. ED25 values were 0.41 and 1.3 mg/kg for azilsartan medoxomil and olmesartan medoxomil, respectively. In renal hypertensive dogs, oral administration of 0.1–1 mg/kg azilsartan medoxomil reduced blood pressure more potently and persistently than that of 0.3–3 mg/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.