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

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：100μmol／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10mg／kg二氮嗪具有迅速的降压作用，与对照组对比，在3min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。

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

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 elec-trophysiolograph. 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 mi-toK_(ATP) channel, can improve the mitochondrial respiratory function and has no effect on the blood pressure, and its cardiovascular selectivity is prior to Diazoxide.