格列吡嗪对正常及糖尿病大鼠心肌线粒体ATP敏感性钾通道的影响

Influence of glipizide on myocardial mitochondrial ATP-sensitive potassium channels in normal and diabetic rats

目的:探讨格列吡嗪(Glip)对正常及糖尿病大鼠心肌线粒体ATP敏感性钾通道(mito KATP)的影响.方法:取分离鉴定的Wister大鼠和2型糖尿病GK大鼠心肌组织线粒体悬浮液,加入到含有K+和KATP通道阻滞剂ATP的待测溶液中,再按如下分组进行药物干预,即空白对照组(Con组)、特异性mitoKATP激活剂二氮嗪组(Dia组)、Dia+Glip组(分别为5,50μmol/LGlip),即刻检测溶液在3min内光散射值的变化,以此作为反映线粒体体积变化的指标.结果:各组线粒体体积均随时间增大,Con组增加速度极慢,Dia组最快,而Dia+Glip组则介于两者之间.不同浓度Glip均能使两种大鼠线粒体体积增加速度减慢(P<0.01),高浓度作用更明显(P<0.01);相同浓度Glip对不同大鼠组的影响程度不同,对糖尿病GK大鼠的影响明显弱于正常大鼠(P<0.01).结论:Glip对正常及糖尿病大鼠心肌mitoKATP均有关闭作用,但对糖尿病大鼠的作用明显较弱.相当于临床治疗中血药浓度峰值的Glip浓度(5μmol/L)虽可干扰正常大鼠心肌mitoKATP的活性,但对糖尿病大鼠心肌mitoKATP无显著影响.

AIM： To study the influence of glipizide on myocardial mitochondrial ATP-sensitive potassium channels （mitOKATP ） in normal and diabetic rats by measuring the changes of mltochondrial volume. METHODS： Myocardial mitochondria of Wister and diabetic Goto-Kakizaki（GK） rats were isolated, identified, and then added into solution containing KCl, Adenosine triphosphate（ATP） and so on. Reagents were added into the solution as follows ： solution （ control group ）, specific mitOKATP activator diazoxide（Dia group）, diazoxide ＋ 5 μmol/L glipizide and diazoxide ＋ 50 μmol/L glipizide. Mitochondrial volume was measured by determining the light-scattering value changes within 3 minutes. RESULTS： In two control groups, mitochondrial volume increased slowly as time went on, the increase was accelerated after addition of diazoxide, it was again depressed significantly by another adding of 5 μmol/L or 50 μmol/L glipizide （ P 〈 0.01 ）, and the influence of 50 μmol/L glipizide was greater than that of 5 μmol/L glipizide（P 〈0.01 ）. The depression caused by identical concentration of glipizide was different between normal and GK rat groups, and it was smaller in GK rat group than in normal rat group（P 〈0.01 ）. CONCLUSION： Glipizide can block myocardial mitoKATP in both normal and diabetic rats, and it is weaker in the latter. Five μmol/L glipizide, the equivalent dosage of peak plasma concentration in clinical therapy, can inhibit the activity of myocardial mitoKATP in normal rats, but can＇t influence it in diabetic rats.