内皮素受体拮抗剂CPU0213对异丙肾上腺素心肌病SERCA2a表达的改善作用

中国临床药理学与治疗学 ›› 2008, Vol. 13 ›› Issue (1): 36-41.

内皮素受体拮抗剂CPU0213对异丙肾上腺素心肌病SERCA2a表达的改善作用

汤晓, 王秋娟, 戴德哉, 戴茵

中国药科大学药理研究室, 南京 210009, 江苏

收稿日期:2007-08-15 修回日期:2007-11-28 出版日期:2008-01-26 发布日期:2020-10-13
通讯作者: 戴德哉,男, 教授, 博士生导师, 研究方向:心血管药理学、离子通道病。Tel:025-83271270 E-mail: dezaidai@vip.sina.com
作者简介:汤晓, 男, 博士研究生, 研究方向:心血管药理学。Tel:025-83271270 　E-mail: sainttxy@gmail.com
基金资助:
国家自然科学基金面上项目(30670706)

Therapic effects of CPU0213, a novel endothelin receptor antagonist, on isopreterenol induced cardiomyopathy

TANG Xiao-yun, WANG Qiu-juan, DAI De-zai, DAI Yin

Research Division of Pharmacology, China Pharmaceutical University, Nanjing 210009, Jiangsu, China

Received:2007-08-15 Revised:2007-11-28 Online:2008-01-26 Published:2020-10-13

摘要/Abstract

摘要： 目的研究异丙肾上腺素心肌病模型心肌细胞肌浆网钙ATP 酶(sarco-endoplasmic reticulumATPase 2a, SERCA2a) 表达的改变, 以及新型内皮素受体拮抗剂CPU0213的治疗作用。方法雄性SD大鼠皮下给予异丙肾上腺素(2 mg·kg^-1·d^-1)10 d, 治疗组动物在第6 到第10 天皮下给予CPU0213 (30 mg·kg^-1·d^-1)。各组动物颈动脉插管记录心功能指标:左心室收缩压(LVSP), 左心室舒张末期压(LVEDP), 和左心室压力变化最大速率(±dp dtmax)。左心室心肌组织SERCA2a 的mRNA 及蛋白表达分别用逆转录聚合酶链反应(RT-PCR) 和蛋白免疫印迹法(Western blotting) 测定。结果异丙肾上腺素引起左心室收缩和舒张功能明显下降, 同时SERCA2a 的mRNA 及蛋白表达均显著下调(P<0.05)。CPU0213 显著提高SERCA2a 表达(P<0.05), 明显改善心功能(P<0.05)。结论 CPU0213 可通过逆转肌浆网钙调控蛋白SERCA2a 的表达下调, 使异丙肾上腺素引起的心功能下降得以恢复。本实验证明SERCA2a是β 受体过度激活引发心衰过程中的重要靶点。内皮素受体介导了β 受体过度激活状态下SERCA2a的表达下调, 是内皮素受体拮抗剂治疗心衰的重要依据之一。

关键词: 异丙肾上腺素, 心肌细胞肌浆网钙ATP酶, 内皮素受体拮抗剂, CPU0213

Abstract: AIM: The present study was focused on the effects of isoproteronol induced cardiomyopathy, and the expression of sarcoplasm reticulum Ca2 + handlingprotein, sarco-endoplasmic reticulum ATPase 2a(SERCA2a). The therapeutic effects of CPU0213, a novel endothelin receptor antagonist were evaluated. METHODS: Male SD rats were administrated isoproterenol (2 mg·kg^-1 ·d^-1,s.c.) for 10 days. A subset of the rats were administrated CPU0213 (30mg·kg^-1 ·d^-1, s. c.) from d 6 to d 10.All the animals were subjected to cannulation through left carotid artery to measure LVSP, LVEDP, and±dp dtmax Expressions of SERCA2a were measured by reverse transcription polymerase chain reaction (RT-PCR) and western blotting assays. RESULTS: Isoproteronol caused a significant decline of SERCA2a expression in both mRNA and protein levels(P<0.05), in conjunction with decreased LVSP,±dp dt max, and elevated LVEDP(P<0.05). And CPU0213 recovered all these alterations partially. CONCLUSION: Blockade of endothelin receptors by CPU0213 is beneficial to isoproterenol caused impairment of cardiac function, in which process endothelin system probably mediates the adverse effects of excessive β-receptor activation.

Key words: isopreterenol, sarco-endoplasmic reticulum ATPase 2a(SERCA2a), endothelin receptor antagonist, CPU0213

中图分类号:

R965.2

汤晓, 王秋娟, 戴德哉, 戴茵. 内皮素受体拮抗剂CPU0213对异丙肾上腺素心肌病SERCA2a表达的改善作用[J]. 中国临床药理学与治疗学, 2008, 13(1): 36-41.

TANG Xiao-yun, WANG Qiu-juan, DAI De-zai, DAI Yin. Therapic effects of CPU0213, a novel endothelin receptor antagonist, on isopreterenol induced cardiomyopathy[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2008, 13(1): 36-41.

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