咖啡酸类衍生物hit 1对肾血管性高血压大鼠的降压作用研究

Anti-hypertensive Effect of a Caffeic Acid Derivative hit 1 on Renovascular Hypertensive Rats

关键词:  咖啡酸衍生物  血管紧张素II 1型受体  抗高血压

Key words:  caffeic acid derivative  angiotensin II type 1 receptor  anti-hypertensive

摘要:

目的 对血管紧张素II 1型受体(angiotensin II type 1 receptor，AT₁R)的特异性拮抗剂hit 1(咖啡酸类衍生物)进行体内药效学评价。方法 制作双肾双夹高血压大鼠模型，设定假手术组、高血压模型组、缬沙坦组(8.3 mg·kg^-1)和hit 1低、中、高剂量组(5，15，30 mg·kg^-1)，每日8:00灌胃给药1次，持续4周。从大鼠体质量、血压、心率、心重指数以及组织形态学五方面系统评价hit 1的体内药效学。Western blotting分析hit 1对大鼠股动脉AT₁R表达量的影响。结果 大鼠双肾双夹手术后，平均收缩压和舒张压分别达到(153.87±7.03)mmHg和(116.50±8.68)mmHg，提示高血压大鼠造模成功。与模型组相比，hit 1中、高剂量组与缬沙坦组作用相当，能以剂量依赖性的方式显著降低肾性高血压大鼠的血压，且不影响其心率；而hit 1低剂量组血压无显著改善。组织形态学研究证明hit 1能够改善大鼠高血压所致的心肌细胞肥大，降低心重指数；且能够通过显著降低壁腔比的方式改善肾性高血压大鼠股动脉血管壁的顺应性与抵抗力。Western blotting结果表明，hit 1能特异性作用于AT₁R，显著降低其在大鼠股动脉血管中的表达。结论 化合物hit 1在大鼠体内的抗高血压活性显著，具有进一步深入开发的价值。

Abstract:

OBJECTIVE To evaluate the in vivo pharmacodynamic of a specific antagonist of angiotensin II type 1 receptor(AT₁R) named hit 1(caffeic acid derivatives). METHODS The rat’s hypertension model by a two-kidney two clip(2k2c) method was performed. The rats were divided into 6 groups including sham group, model group, valsartan group (8.3 mg·kg^-1), hit 1 low, middle and high dose group(5, 15, 30 mg·kg^-1). These groups were orally administered at 8:00 once a day for 4 weeks. The in vivo pharmacodynamics of hit 1 was evaluated from 5 aspects including body weight, blood pressure, heart rate, cardiac mass index and histomorphology. And the effect of hit 1 on the expression of AT₁R in rat femoral artery was determined by Western blotting. RESULTS The mean systolic and diastolic blood pressure values of the rats after the 2k2c operation were (153.87±7.03)mmHg and (116.50±8.68)mmHg, indicating that the model of renovascular hypertensive rats was established successfully. Compared with the model group, hit 1 medium and high dose groups had the same effect as valsartan group, and could significantly reduce the blood pressure of renovascular hypertensive rats in a dose-dependent manner, without affecting their heart rate. However, the blood pressure of low dose hit 1 group was not significantly improved. Histomorphological studies showed that hit 1 could improve cardiac hypertrophy induced by hypertension in rats and reduce cardiac weight index. Moreover, hit 1 could also enhance the compliance and resistance of the femoral artery wall in renovascular hypertensive rats by significantly reducing the ratio of membrane area to cavity area. The result of Western blotting showed that hit 1 could significantly decrease the expression of AT₁R in rat femoral arteries.CONCLUSION This work provide potential possibilities for further evaluation of hit 1 which have significant antihypertensive activity in rats.