Lee B H, Seo H W, Kwon K J, Yoo S E, Shin H S
Screening and Toxicology Research Center, Korea Research Institute of Chemical Technology, Yusong, Taejon.
J Cardiovasc Pharmacol. 1999 Mar;33(3):375-82. doi: 10.1097/00005344-199903000-00005.
The pharmacologic profile of SK-1080, a newly synthesized AT1-receptor antagonist, was evaluated in conscious normotensive rats, conscious renally (RHRs) and spontaneously (SHRs) hypertensive rats, and conscious furosemide-treated beagle dogs. In angiotensin II-challenged normotensive rats, orally administered SK-1080 had no agonistic effect and dose-dependently inhibited the pressor response to angiotensin II with a slightly weaker potency (ID50: 1.12 and 0.47 mg/kg, respectively), but with a more rapid onset of action than losartan (time to Emax, 30 min and 6 h, respectively). In RHRs, orally given SK-1080 produced a dose-dependent and long-lasting (>24 h) antihypertensive effect with a potency similar to that of losartan (ED20, 5.06 and 3.36 mg/kg, respectively). Intravenously administered SK-1080 exerted a very highly potent antihypertensive effect (ED20, 0.06 mg/kg), thus indicating a poor oral bioavailability in rats. On repeated dosing for 21 days in SHRs, SK-1080 significantly reduced blood pressure without inducing tachycardia and tolerance throughout the dosing period. On repeated dosing, the antihypertensive effect gradually increased from days 1 to 7 (Emax on day 7, 15.0 and 19.7% at 10 and 30 mg/kg, respectively) and remained at a significant level on days 14 and 21. In furosemide-treated dogs, orally given SK-1080 produced a dose-dependent and long-lasting (>8 h) antihypertensive effect with a rapid onset of action (time to Emax, 1-1.5 h) and 10-fold greater potency than losartan (ED20, 0.72 and 8.13 mg/kg, respectively). In furosemide-treated dogs, SK-1080 showed a good oral bioavailability, unlike that in RHRs. These results suggest that SK-1080 is a potent, orally active AT1-receptor antagonist useful for the treatment of hypertension.
在清醒的正常血压大鼠、清醒的肾性高血压大鼠（RHRs）、自发性高血压大鼠（SHRs）以及清醒的经速尿处理的比格犬中评估了新合成的AT1受体拮抗剂SK - 1080的药理学特性。在接受血管紧张素II激发的正常血压大鼠中，口服给予的SK - 1080没有激动作用，且剂量依赖性地抑制对血管紧张素II的升压反应，效力略弱（ID50分别为1.12和0.47 mg/kg），但起效比氯沙坦更快（达到Emax的时间分别为30分钟和6小时）。在RHRs中，口服给予SK - 1080产生剂量依赖性且持久（>24小时）的降压作用，效力与氯沙坦相似（ED20分别为5.06和3.36 mg/kg）。静脉注射SK - 1080发挥非常强效的降压作用（ED20为0.06 mg/kg），因此表明其在大鼠中的口服生物利用度较差。在SHRs中重复给药21天，SK - 1080显著降低血压，在整个给药期间未诱发心动过速和耐受性。重复给药时，降压作用从第1天到第7天逐渐增强（第7天Emax，10和30 mg/kg时分别为15.0%和19.7%），并在第14天和第21天保持在显著水平。在经速尿处理的犬中，口服给予SK - 1080产生剂量依赖性且持久（>8小时）的降压作用，起效迅速（达到Emax的时间为1 - 1.5小时），效力比氯沙坦高10倍（ED20分别为0.72和8.13 mg/kg）。与在RHRs中不同，在经速尿处理的犬中SK - 1080显示出良好的口服生物利用度。这些结果表明SK - 1080是一种强效的口服活性AT1受体拮抗剂，可用于治疗高血压。
