不同温度条件对药物作用于钠通道Nav1.5的比较研究  

Comparison Study of Effects Induced by Drugs on Sodium Channel Nav1.5 under Different Temperature Conditions

作　　者：杜春燕 张玉卿 邢红艳 赵琪 张艺哲 汪溪洁 DU Chunyan;ZHANG Yuqing;XING Hongyan;ZHAO Qi;ZHANG Yizhe;WANG Xijie(China State Institute of Pharmaceutical Industry,Shanghai 201203;Shanghai InnoStar Bio-Tech Co.,Ltd.,Shanghai 201203)

机构地区：[1]中国医药工业研究总院,上海201203 [2]上海益诺思生物技术股份有限公司,上海201203

出　　处：《中国医药工业杂志》2023年第11期1614-1623,共10页Chinese Journal of Pharmaceuticals

摘　　要：由于一些离子通道药物作用具有温度敏感性,测试温度可能是其安全性评价的重要影响因素。该研究在不同温度(29、33、35和37℃)条件下比较研究了药物对电压门控钠通道(Nav1.5)的作用。采用全细胞膜片钳技术记录不同温度下,温度敏感性药物(美西律、奎尼丁和雷诺嗪)作用于Nav1.5-人胚肾(HEK)293细胞后钠通道电流(I_(Na))的变化,考察温度对I_(Na)的浓度依赖性和上述药物半数抑制浓度(IC50)的影响。结果显示,美西律、奎尼丁和雷诺嗪在不同温度(29、33、35和37℃)条件下均能浓度依赖性地抑制I_(Na);与29℃相比,上述药物在35℃条件下对I_(Na)的抑制作用更加显著。该研究评价了4种温度条件下3种药物对Nav1.5的影响,有助于提高药物临床前心脏毒性筛选和评价的准确性,为GLP机构开展离子通道药物评价试验提供了参考。Due to the temperature sensitivity of some ion channel drugs,the testing temperature might be an important influencing factor in their safety evaluation.Therefore,this study compared the effects of some drugs on the voltage-gated sodium channel(Nav1.5)under different temperature(29,33,35,and 37℃)]conditions.The whole-cell patch clamp technique was used to record the changes in sodium channel current(I_(Na))after the temperature-sensitive drugs(mexiletine,quinidine,and ranolazine)functioned on Nav1.5-human embryonic kidney(HEK)293 cells at different temperatures.The study investigated the influence of temperature on the concentration-dependence of I_(Na)and the halfmaximal inhibitory concentration(IC50)of the aforementioned drugs.The results showed that mexiletine,quinidine,and ranolazine could inhibit I_(Na)in a concentration-dependent manner at different temperatures(29,33,35,and 37℃).Compared to 29℃,the inhibitory effects of these drugs on I_(Na)was more significant at 35℃.This study evaluated the effects of three drugs on the sodium channel Nav1.5 under four temperature conditions,which was benefit to improve the accuracy of preclinical cardiac toxicity screening and evaluation of drugs,providing a reference for GLP institutions to conduct ion channel drug evaluation tests.

关 键 词：美西律 奎尼丁 雷诺嗪 温度敏感性 全细胞膜片钳 电压门控钠通道(Nav1.5) 人胚肾(HEK)293细胞 

分 类 号：R963[医药卫生—微生物与生化药学]