新化合物HYY-002抑制大鼠阵发性房颤作用

doi:10.12092/j.issn.1009-2501.2019.12.005

中国临床药理学与治疗学 ›› 2019, Vol. 24 ›› Issue (12): 1347-1352.doi: 10.12092/j.issn.1009-2501.2019.12.005

新化合物HYY-002抑制大鼠阵发性房颤作用

杨蕾熙，冯凯，凡学婷，尉延春，刘婷婷，汤依群

中国药科大学临床药学教研室，南京 210009，江苏

收稿日期:2019-08-23 修回日期:2019-11-20 出版日期:2019-12-26 发布日期:2020-01-07
通讯作者: 汤依群，女，博士，副教授，硕士生导师，研究方向：心血管药理学。 Tel：025-83271070 E-mail: tyq@cpu.edu.cn
作者简介:杨蕾熙，女，硕士，研究方向：心血管药理学。 Tel：18628227847 E-mail: ylx_qb123@163.com
基金资助:
国家新药创制重大专项（2011ZX09401-021）

Novel compound HYY-002 inhibits paroxysmal atrial fibrillation in rats

YANG Leixi, FENG Kai, FAN Xueting, WEI Yanchun, LIU Tingting, TANG Yiqun

Department of Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, Jiangsu, China

Received:2019-08-23 Revised:2019-11-20 Online:2019-12-26 Published:2020-01-07

摘要/Abstract

摘要：

目的:观察新化合物N-{4-［4-(5-苯基-1H-四唑-1-基)丁氧基］苯基}乙酰胺（HYY-002）抗房颤作用。方法:雄性SD大鼠，随机分为正常组、模型组、胺碘酮，低剂量（2 mg/kg）和高剂量HYY-002（10 mg/kg）组。大鼠尾静脉注射乙酰胆碱合并氯化钙［CaCl2（10 mg/kg）-Ach（66 μg/kg）］10 d制备房颤模型。治疗组从造模第4天开始，每天造模前1 h，分别腹腔注射胺碘酮（30 mg/kg）或灌胃给予低、高剂量HYY-002。Ⅱ导联心电图记录房颤持续时间，测定各组大鼠心房有效不应期（AERP），血浆炎性因子及microRNA-135a(miR-135a)的变化。结果:模型组大鼠房颤时间持续延长，AERP较正常组缩短［（61.83±4.13) vs. (72.70±7.05) ms，P<0.05］，血浆中炎性因子TNF-α、IL-1和IL-6的含量高于正常组。HYY-002 给药剂量10 mg/kg能有效缩短房颤持续时间［（6.42±1.38) vs. (16.32±1.31) s，P<0.01］，缓解房颤引起的AERP缩短［（77.78±3.79) vs. (61.83±4.13) ms，P<0.01］，降低血浆中炎性因子浓度，效果与胺碘酮相当。与正常组相比，模型组血浆miR-135a表达明显降低（P<0.01），HYY-002给药后miR-135a在血浆中含量显著上升（P<0.01）。结论:HYY-002对房颤有显著治疗效果，miR-135a可能参与房颤发生发展过程。

关键词: 心动过缓, 阵发性房颤, 炎症, miR-135a

Abstract:

AIM:To investigate the inhibitory effect of HYY-002 on atrial fibrillation(AF). METHODS:Male SD rats were randomized into 5 groups:normal,model,amiodarone(30 mg/kg,i.p.), low-dose and high-dose HYY-002 group. The rats were administrated Ach-CaCl2 (i.v.) for 10 days to establish rat AF model. From the 4th day, rats in treatment group were treated with amiodarone (30 mg/kg, i.p.) and HYY-002 (2 mg/kg, 10 mg/kg, i.g.) 1 hour before modeling. AF duration and ECG parameters were measured every day. On the 11th day, AERP of every rat were measured and the inflammatory cytokines and miR-135a in plasma were detected. RESULTS:In the model group, AF duration increased persistently and AERP shortened distinctly compared with normal group ［(61.83±4.13) vs. (72.70±7.05) ms, P<0.05］. The expression of TNF-α, IL-1 and IL-6 in plasma of model group were higher than normal group (P<0.05). High dose of HYY-002 (10 mg/kg) shortened AF duration effectively ［(6.42±1.38) vs. (16.32±1.31) s，P<0.01 vs. model group］, relieved the shortening of AERP induced by AF ［(77.78±3.79) vs. (61.83±4.13) ms, P<0.01 vs. model group］ and lowered the inflammatory cytokines level in plasma. Compared with normal group, the expression of miR-135a in plasma of model group was down-regulated obviously (P<0.01). CONCLUSION: HYY-002 has a significant therapeutic effect on AF, and miR-135a might be involved in the development of AF.

Key words: bradycardia, paroxysmal atrial fibrillation, inflammation, miR-135a

中图分类号:

R965.2

杨蕾熙，冯凯，凡学婷，尉延春，刘婷婷，汤依群. 新化合物HYY-002抑制大鼠阵发性房颤作用[J]. 中国临床药理学与治疗学, 2019, 24(12): 1347-1352.

YANG Leixi, FENG Kai, FAN Xueting, WEI Yanchun, LIU Tingting, TANG Yiqun. Novel compound HYY-002 inhibits paroxysmal atrial fibrillation in rats[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2019, 24(12): 1347-1352.

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新化合物HYY-002抑制大鼠阵发性房颤作用

Novel compound HYY-002 inhibits paroxysmal atrial fibrillation in rats

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