Division of Medical Physiology, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa.
South African Medical Research Council, Biomedical Research and Innovation Platform, Tygerberg, South Africa.
Cardiovasc Drugs Ther. 2019 Feb;33(1):1-11. doi: 10.1007/s10557-018-06847-9.
Cardiotoxicity is a well-known side effect of chloroquine. Several studies have proposed chloroquine as a potential anti-diabetic treatment but do not address this problem. The current study investigated the effect of ex vivo chloroquine treatment on (1) heart function and glucose uptake, (2) mitochondrial function and (3) in vivo treatment on heart function.
Control or obese male Wistar rats were used throughout. Dose responses of increasing chloroquine concentrations versus vehicle on cardiac function were measured using isolated, Langendorff-perfused hearts whilst glucose uptake and cell viability were determined in ventricular cardiomyocytes. Mitochondrial function was assessed with a Clark-type oxygraph (Hansatech) after ex vivo perfusion with 30 μM chloroquine versus vehicle. Animals were treated orally with 5 mg/kg/day chloroquine for 6 weeks.
Acute chloroquine treatment of 10 μM was sufficient to significantly decrease heart function (p < 0.05) whilst 30 μM significantly reduced heart rate (p < 0.05). Chloroquine became toxic to isolated cardiomyocytes at high concentrations (100 μM), and had no effect on cardiomyocyte glucose uptake. Ex vivo treatment did not affect mitochondrial function, but chronic low-dose in vivo chloroquine treatment significantly decreased aortic output and total work in hearts (p < 0.005).
Low and intermediate chloroquine doses administered either chronically or acutely are sufficient to result in myocardial dysfunction.
氯喹是一种众所周知的心脏毒性药物。有几项研究提出氯喹可能是一种潜在的抗糖尿病治疗药物，但并未解决这一问题。本研究旨在探讨氯喹体外处理对（1）心脏功能和葡萄糖摄取、（2）线粒体功能和（3）体内心脏功能的影响。
本研究使用了雄性 Wistar 肥胖大鼠。通过 Langendorff 离体灌流心脏模型，测量了不同浓度氯喹（递增浓度，最高达 100 μM）与载体处理对心脏功能的影响，同时测定了心室肌细胞的葡萄糖摄取和细胞活力。用 Clark 型氧电极（Hansatech）对离体灌流 30 μM 氯喹或载体后的心脏线粒体功能进行评估。动物接受 5mg/kg/天的氯喹口服处理，共 6 周。
10 μM 的急性氯喹处理足以显著降低心脏功能（p<0.05），而 30 μM 则显著降低心率（p<0.05）。高浓度（100 μM）的氯喹对分离的心肌细胞有毒性，且对心肌细胞的葡萄糖摄取无影响。体外处理对线粒体功能无影响，但慢性低剂量体内氯喹处理显著降低了心脏的主动脉输出和总功（p<0.005）。
无论是慢性还是急性给予低剂量或中剂量的氯喹，都足以导致心肌功能障碍。
