靶向心肌线粒体ATP 敏感性钾通道苯并噻二嗪类新衍生物的药理学特征

中国临床药理学与治疗学 ›› 2009, Vol. 14 ›› Issue (5): 498-503.

靶向心肌线粒体ATP 敏感性钾通道苯并噻二嗪类新衍生物的药理学特征

曾源^1,2, 邱财荣², 杨永林¹, 潘志远², 金俊华¹, 汪海^1,2,3

¹北京赛德维康医药研究院, 北京100039;
²军事医学科学院毒物药物研究所, 北京100850;
³军事医学科学院卫生学环境医学研究所, 天津300050

收稿日期:2009-03-13 修回日期:2009-05-17 发布日期:2020-11-09
通讯作者: 汪海, 男, 医学博士, 研究员, 博士生导师, 从事药理学和病理生理学研究。Tel:010-66932651 E-mail:Wh9588 @yahoo. com. cn
作者简介:曾源, 邱财荣, 杨永林, 潘志远四位对本文贡献相同。曾源, 女, 医学硕士, 主治医师, 从事心血管药理学与治疗学研究。Tel:010-66931557 E-mail:panzhiyuan2004 @tom. com
基金资助:
军队医药卫生杰出人才项目(06J023)

Pharmacological characteristic of new benzothiadiazine derivatives, targeting the cardiac mitochondrial ATP-sensitive potassium channel

ZENG Yuan^1,2, QIU Cai-rong², YANG Yong-lin¹, PAN Zhi-yuan², JIN Jun-hua¹, WANG Hai^1,2,3

¹Thadweik Academy of Medicine, Beijing 100039, China;
²Institute of Pharmacology and Toxicology, Academy of military Medical Sciences, Beijing 100850, China;
³Institute of Hygiene and Environmental Medicine, Academy of Military Medical Sciences, Tianjin 300050, China

Received:2009-03-13 Revised:2009-05-17 Published:2020-11-09

摘要/Abstract

摘要： 目的:设计合成苯并噻二嗪类新衍生物, 研究其激活心肌线粒体ATP 敏感性钾通道的药理学活性并与二氮嗪进行对比分析。方法:采用氧电极法评价新衍生物对心肌线粒体态3 呼吸(R3)、态4 呼吸(R4)以及呼吸控制率(RCR)等呼吸功能参数的影响。戊巴比妥钠麻醉Wistar 大鼠, 颈总动脉插管, 连接八导生理记录仪记录二氮嗪及新衍生物对大鼠血压的影响。结果: 100 μmol/L 衍生物16 和17 可同时降低心肌线粒体琥珀酸氧化呼吸链中的R3 和R4, 但不影响RCR, 作用与二氮嗪类似;衍生物15 在降低心肌线粒体R3 和R4 的同时可显著提高线粒体RCR。静脉注射10 mg/kg 二氮嗪具有迅速的降压作用, 与对照组对比, 在3 min 时血压下降约为28%, 而20 种衍生物均无降压作用。结论:衍生物15 可激活心肌线粒体ATP 敏感性钾通道, 提高线粒体RCR, 且无降压作用, 其心血管选择性优于二氮嗪。

关键词: 苯并噻二嗪, 二氮嗪, 线粒体ATP 敏感性钾通道, 心肌缺血

Abstract: AIM:Series of new benzothiadiazine derivatives were designed and synthesized, which were considered to be the openers of mitoK_ATP channel. The pharmacological activity of these compounds were researched and compared with the effects of Diazoxide. METHODS:The effects of new benzothiadiazine derivatives on rat myocardial mitochondrial respiratory functions such as R3, R4, RCR were evaluated by oxygen electrode method. After Wistar rats were anesthetized with pentobarbital-Na and catheterized into carotid artery, the effects of these new compounds and Diazoxide on blood pressure were recorded by eight channel electrophysiolograph. RESULTS:The mitochondrial respiratory parameters R3 and R4 were both decreased while oxidizing FAD-dependent substrates (succinate)by the compound 16/17 at the concentration of 100 μmol/L, but RCR were not affected; those effects were similar to Diazoxide. However, the compound 15 could not only decrease R3 and R4, but also increase RCR. The blood pressure was quickly decreased through intravenous injection diazoxide (10 mg/kg)in anesthetized rats.Compared with control group, the blood pressure was decreased by 28% at the time of 3 min after administration. The other 20 new benzothiadiazine derivatives had no effects on blood pressure. CONCLUSION: The compound 15, as a selective opener of mitoK_ATP channel, can improve the mitochondrial respiratory function and has no effect on the blood pressure, and its cardiovascular selectivity is prior to Diazoxide.

Key words: benzothiadiozine, Diazoxide, mitoK_ATP channel, myocardial ischemia

中图分类号:

R965. 2

曾源, 邱财荣, 杨永林, 潘志远, 金俊华, 汪海. 靶向心肌线粒体ATP 敏感性钾通道苯并噻二嗪类新衍生物的药理学特征[J]. 中国临床药理学与治疗学, 2009, 14(5): 498-503.

ZENG Yuan, QIU Cai-rong, YANG Yong-lin, PAN Zhi-yuan, JIN Jun-hua, WANG Hai. Pharmacological characteristic of new benzothiadiazine derivatives, targeting the cardiac mitochondrial ATP-sensitive potassium channel[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2009, 14(5): 498-503.

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