Diabetes mellitus aggravates ranolazine-induced ECG changes in rats,Journal of Interventional Cardiac Electrophysiology

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Diabetes mellitus aggravates ranolazine-induced ECG changes in rats
Journal of Interventional Cardiac Electrophysiology ( IF 1.8 ) Pub Date : 2021-06-21 , DOI: 10.1007/s10840-021-01016-9
Habibeh Mashayekhi-Sardoo ₁ , Amir Hooshang Mohammadpour _{2,

3} , Soghra Mehri ₁ , Hossein Kamali _{4,

5} , Amirhossein Sahebkar _{6,

7,

8} , Mohsen Imenshahidi _{1,

3}

Affiliation

Purpose

Diabetes mellitus (DM) is known to affect the pharmacokinetics of drugs. In this study, we evaluated the effect of DM on the liver content of CYP 3A2 enzyme. We also explored the ECG changes after administration of ranolazine in non-DM and DM rats.

Methods

First phase: 24 male Wistar rats were separated into 4 groups. The control group (n = 6) received normal saline and the DM groups (n = 18) were treated with a single dose (55 mg/kg) of streptozocin (STZ; i.p. injection), then were held for 10, 20, and 30 days, respectively. After study duration for each group, the liver CYP 3A2 protein content was determined using western blotting. Second phase: 48 male Wistar rats were classified into two groups of non-DM and DM; and each group was divided into 4 subgroups (n: 6). Experimental groups received oral doses of 20, 40, and 80 mg/kg ranolazine. DM and non-DM control groups received normal saline. Treatment lasted for 28 days, and then the ECG was recorded.

Results

Experimental DM induced by STZ caused a significant decrement in liver CYP3A2 protein content of rats on days 10 and 20 (P < 0.01), and 30 (P < 0.05) compared to the control animals. Significant increases in QT and corrected QT (QTc) intervals (P < 0.01), and bradycardia (P < 0.01) without any significant effect on PR and QRS intervals were observed in DM in comparison with non-DM groups after ranolazine treatment.

Conclusions

In summary, DM induction in animals resulted in CYP 3A2 inhibition and the prolongation of QT and QTc interval as well as bradycardia after ranolazine treatment.

中文翻译：

糖尿病加重雷诺嗪诱导的大鼠心电图变化

目的

众所周知，糖尿病 (DM) 会影响药物的药代动力学。在这项研究中，我们评估了 DM 对肝脏 CYP 3A2 酶含量的影响。我们还探讨了在非 DM 和 DM 大鼠中施用雷诺嗪后的心电图变化。

方法

第一阶段：将24只雄性Wistar大鼠分成4组。对照组 ( n = 6) 接受生理盐水，DM 组 ( n = 18) 接受单剂量 (55 mg/kg) 链脲佐菌素 (STZ; ip injection) 治疗，然后保持 10、20 和分别为 30 天。在每组的研究持续时间后，使用蛋白质印迹测定肝脏 CYP 3A2 蛋白含量。第二阶段：将48只雄性Wistar大鼠分为非DM组和DM组；每组分为4个亚组（n：6）。实验组口服 20、40 和 80 mg/kg 雷诺嗪。DM和非DM对照组接受生理盐水。治疗持续28天，然后记录心电图。

结果

与对照组相比，STZ诱导的实验性DM在第10天和第20天（P < 0.01）和第30天（P < 0.05）导致大鼠肝脏CYP3A2蛋白含量显着下降。在雷诺嗪治疗后，与非 DM 组相比，DM 组的 QT 和校正 QT (QTc) 间期显着增加 ( P < 0.01)，心动过缓 ( P < 0.01) 对 PR 和 QRS 间期没有任何显着影响。